WHO Guidelines for the Treatment of Neisseria Gonorrhoeae* Web Annex E Systematic Reviews

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WHO guidelines for the treatment of Neisseria gonorrhoeae* Web annex E Systematic reviews

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WHO guidelines for the treatment of Neisseria gonorrhoeae. Contents: Web annex D: Evidence profiles and evidence-to-decision framework -- Web annex E: Systematic reviews -- Web annex F: Summary of conflicts of interest 1.Neisseria gonorrhoeae - drug therapy. 2.Gonorrhea - drug therapy. 3.Drug Resistance, Microbial. 4.Guideline. I.World Health Organization. ISBN 978 92 4 154969 1 (NLM classification: WC 150)

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*The full guidelines and annexes are available at: www.who.int/reproductivehealth/publications/rtis/gonorrhoea-treatment-guidelines/en/

For more information, please contact: Department of Reproductive Health and Research E-mail: [email protected] www.who.int/reproductivehealth

Contents Recommendation 1 ...... 1 1.1 In adults and adolescents, HIV-positive patients and men who have sex with men (MSM) with uncomplicated genital (cervix, urethra) and anorectal gonococcal infections, should other treatments or ceftriaxone be used to treat gonorrhoea (genital or cervix)? ...... 1 Criteria...... 1 Search ...... 1 For systematic reviews ...... 1 For randomized and non-randomized studies ...... 1 Screening of studies and data extraction ...... 2 Methods of analysis ...... 4 Results ...... 4 PRISMA ...... 5 Characteristics of included studies ...... 6 Effects of interventions ...... 25 Risk of bias ...... 58 References ...... 73 1.2 In pregnant women with uncomplicated genital (cervix, urethra) and anorectal gonococcal infections, what are the effects of ceftriaxone compared to other treatments? ...... 78 Criteria...... 78 Search ...... 78 For systematic reviews ...... 78 For randomized and non-randomized studies ...... 78 Screening of studies and data extraction ...... 79 Methods of analyses ...... 79 Results ...... 80 PRISMA ...... 80 Characteristics of included studies ...... 82 Effects of intervention ...... 82 Risk of bias ...... 88 References ...... 88 Patient values, preferences and acceptability ...... 89 Gonococcal infections ...... 89 Search ...... 89 Result ...... 89 Characteristics of included studies ...... 89 Findings: acceptability ...... 89 Other conditions: syphilis ...... 90 Search ...... 90 Result ...... 90 Characteristics of included studies ...... 90 Findings ...... 91 References ...... 91 Other conditions ...... 91 Findings: Values ...... 91 References ...... 92

Recommendation 2 ...... 93 In adults and adolescents, with gonococcal oropharyngeal infections, should ceftriaxone compared to other treatments be recommended? ...... 93 Criteria...... 93 Search ...... 93 For systematic reviews ...... 93 For randomized and non-randomized studies ...... 93 Screening of studies and data extraction ...... 94 Methods of analyses ...... 94 Results ...... 95 PRISMA ...... 96 Characteristics of included studies ...... 97 Effects of interventions ...... 101 Risk of bias ...... 106 References ...... 110 Recommendation 3 ...... 112 In adults and adolescents with treatment failure of N. gonorrhoeae (genital or oropharyngeal) with any medication, what treatments should be used? ...... 112 Criteria...... 112 Search ...... 112 For systematic reviews ...... 112 For randomized and non-randomized studies ...... 112 Screening of studies and data extraction ...... 113 Methods of analyses ...... 113 Results ...... 114 PRISMA ...... 115 Characteristics of included studies ...... 116 Effects of interventions ...... 119 Risk of bias ...... 119 References ...... 120 Recommendation 4 ...... 123 For treatment of gonococcal ophthalmia neonatorum in neonates, should one treatment versus another be recommended? ...... 123 Criteria...... 123 Search ...... 123 For systematic reviews ...... 123 For randomized and non-randomized studies ...... 123 Screening of studies and data extraction ...... 124 Methods of analyses ...... 124 Results ...... 124 PRISMA ...... 125 Characteristics of included studies ...... 126 Effects of intervention ...... 127 Risk of bias ...... 136 References ...... 136 Recommendation 5 and 6 ...... 138 For prevention of ophthalmia neonatorum in neonates, what are the effects of different interventions? ...... 138 Criteria...... 138 Search ...... 138 3

For systematic reviews ...... 138 For randomized and non-randomized studies ...... 138 Screening of studies and data extraction ...... 139 Methods of analyses ...... 139 Results ...... 139 PRISMA ...... 140 Characteristics of included studies ...... 141 Effects of interventions ...... 144 Risk of bias ...... 164 References ...... 164

Web annex E – Systematic reviews

Recommendation 1

1.1 In adults and adolescents, HIV-positive patients and men who have sex with men (MSM) with uncomplicated genital (cervix, urethra) and anorectal gonococcal infections, should other treatments or ceftriaxone be used to treat gonorrhoea (genital or cervix)?

Criteria Population Intervention Comparator Outcome Adults and Ceftriaxone Single therapy: Critical: Microbiological adolescents, ≥ 250 mg IM × 1 Azithromycin 1–2 g po × 1 cure, STI complications, HIV-positive Cefixime 400 mg po × 1 clinical cure, transmission patients, Cefixime 800 mg po × 1 to partners, compliance, MSM with Cefixime 400 mg po × 2 N. gonorrhoeae uncomplicated Gentamicin 240 mg IM × 1 antimicrobial in vitro genital (cervix, Spectinomycin 2 g IM × 1 resistance, side-effects urethra) and Kanamycin 2 g IM × 1 (including allergy, toxicity) anorectal Quinolones (just in vitro resistance data) gonococcal Ceftriaxone 125 mg IM × 1 Important: HIV infections transmission and Dual therapy versus single therapy: acquisition, quality And multiple combinations of of life Cefixime + doxycycline (or azithromycin) versus cefixime alone

And multiple combinations of Ceftriaxone + doxycycline (or azithromycin) versus ceftriaxone alone

IM: intramuscular; po: by mouth (orally)

For systematic reviews To identify pre-existing synthesized evidence, the Cochrane Library suite of databases (Cochrane Database of Systematic Reviews [CDSR], Health Technology Assessment [HTA] database and the American College of Physicians [ACP] Journal Club) was searched for recent systematic reviews and for protocols for reviews from 2004 to February 2015. Keywords used included gonorrhoea, gonorrhea, gonococcal, ophthalmia neonatorum. The search found 111 citations. Some reviews were used to verify the included studies. Five systematic reviews were found.

WHO guidelines for the treatment of Neisseria gonorrhoeae

We excluded letters, editorial, comments, review articles and guidelines. We did not restrict by language. We also reviewed reference lists of relevant studies, guidelines and systematic reviews.

Search strategy 1 gonorrhea.mp. 2 gonorrhoea.mp. 3 gonococcal.mp. 4 ophthalmia neonatorum.mp. 5 or/1-4 6 ceftriaxone.mp. 7 Azithromycin.mp. 8 cefixime.mp. 9 gentamicin.mp. 10 spectinomycin.mp. 11 kanamycin.mp. 12 quinolone*.mp. 13 doxycycline.mp. 14 erythromycin.mp. 15 silver nitrate.mp. 16 chloramphenicol.mp. 17 tetracycline*.mp. 18 povidone iodine.mp. 19 gemifloxacin.mp. 20 cephalosporin*.mp. 21 macrolide*.mp. 22 or/6-21 23 5 and 22 24 (th or tu).xs. 25 (co or cn or dr or dt or rh or si or th).fs. 26 24 or 25 27 23 and 26 28 limit 27 to (book or book series or editorial or letter or note or “review” or case reports or meta-analysis or news or systematic reviews) [Limit not valid in Ovid MEDLINE®, Ovid MEDLINE® Daily Update, Ovid MEDLINE® In-Process; records were retained] 29 case report/ 30 27 not (28 or 29)

The electronic database search for primary studies found 3295 non-duplicate records. After title and abstract screening, we retrieved 488 articles in full text and excluded 2807 as not relevant. Overall we found 126 studies that provided data for the five questions: 23 randomized and 103 non-randomized studies. The number of studies providing data for each question are listed in the respective sections (see Figure 1 for the PRISMA Study Flow diagram).

Screening of studies and data extraction Two investigators independently screened titles and abstracts for relevant studies. The full texts of potentially relevant studies were retrieved and the full text was screened by two investigators. Screening forms were developed and piloted by at least two investigators. We excluded studies that were published before 1970.

Data were abstracted by one investigator and verified by another. We collected data about the study (date of data collection, type of study design, inclusion and exclusion criteria, country, funding sources), population or patient characteristics (type of population: adult/adolescent, pregnant women, neonates at risk, MSM, HIV-positive, people with treatment failures, age), infection (culture positive, types of infection: genital including cervical, urethral, rectal, anal), coinfection and treatment failure, treatments (number of doses, amount, method of treatment, co-intervention), follow- 2

Web annex E – Systematic reviews

up and outcomes of interest (including measures for cure rate by person and sites of infections, treatment results based on return day of visit, and types of adverse effects). We used a pretested data abstraction form.

Most studies did not provide details about the number of people randomized to each group or the losses to follow-up in each group, or did not include people who did not comply with protocol; we therefore collected data for a per-protocol analysis. The data extraction form was developed and piloted by at least two investigators.

WHO guidelines for the treatment of Neisseria gonorrhoeae

Methods of analysis We present the synthesized results by outcome in the results section. We analysed the data using Review Manager (RevMan) [ Computer Program]. Version 5.3. Copenhagen: The Nordic Cochrane Center, The Cochrane Collaboration, 2014) and when available we have included the forest plots of the statistical analyses. For dichotomous outcomes, we pooled the relative risks (e.g. risk ratios and odds ratios) from randomized studies and pooled relative risks from non-randomized studies with two comparison groups. When a study included only one group, we calculated the risk of an event (or proportion) of an outcome and then pooled the proportions from each study weighted by the generic inverse variance. When results could not be pooled we summarized the results from the individual studies narratively.

When available, we pooled and report data for subgroups by HIV status, drug dosage and type of infection. The heterogeneity of pooled results is reported using the I2 statistic.

Results We found five reviews: Bai et al., 2012; Bignell & Unemo, 2012; Dowell & Kirkcaldy, 2012; Hathorn et al., 2014; and Tapsall, 2002 (see below). The reviews did not cover all of the interventions and populations, but we used the search results from these reviews to confirm the studies to include. From our comprehensive search of electronic databases, we included 108 studies (including foreign language articles): 14 randomized and 94 non-randomized studies (including three non-randomized studies with two or more groups and 91 non-randomized studies with one group).

1. Bai ZG, Bao XJ, Cheng WD, Yang KH, Li YP. Efficacy and safety of ceftriaxone for uncomplicated gonorrhoea: a meta-analysis of randomized controlled trials. Int J STD AIDS. 2012;23(2):126-32. doi:10.1258/ijsa.2009.009198. 2. Bignell C, Unemo M; European STI Guidelines Editorial Board. Azithromycin in the treatment of infection with Neisseria gonorrhoeae. Int J STD AIDS. 2013;24(2):85-92. doi:10.1177/0956462412472837. 3. Dowell D, Kirkcaldy RD. Effectiveness of gentamicin for gonorrhoea treatment: systematic review and meta- analysis. Sex Transm Infect. 2012;88(8):589-94. doi:10.1136/sextrans-2012-050604. 4. Hathorn E, Dhasmana D, Duley L, Ross JD. The effectiveness of gentamicin in the treatment of Neisseria gonorrhoeae: a systematic review. Syst Rev. 2014;3:104. doi:10.1186/2046-4053-3-104. 5. Tapsall J. Current concepts in the management of gonorrhoea. Expert Opin Pharmacother. 2002;3(2):147-57.

Web annex E – Systematic reviews

PRISMA

Figure 1: PRISMA Study Flow diagram

WHO guidelines for the treatment of Neisseria gonorrhoeae

Characteristics of included studies Randomized studies with two or more comparison groups

STUDY YEAR POPULATION N INFECTION AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS (mean and/or range, if not indicated)

Shams 2009, 2009 adult/adolescents 184/200 genital 14–55 Gonorrhoea patients Unclear microbiological Ceftriaxone 250 mg IM × 1, Jeddah, (urethra) or cure spectinomycin 2 g IM × 1 Saudi Arabia anorectal

Tian 2002, 2002 adult/adolescents 217/225 genital (cervix) 18–52 Gonorrhoea patients Not mentioned microbiological Ceftriaxone 250 mg IM × 1, China cure, clinical spectinomycin 2 g IM × 1 cure

Cheng 2001, 2001 adult/adolescents 93/94 genital (cervix) 18–56 Gonorrhoea patients Unclear microbiological Ceftriaxone 250 mg IM × 1, China cure, clinical spectinomycin 2 g IM × 1 (in Chinese) cure, side-effect

Handsfield 1994, 1994 adult/adolescents 541/549 genital (cervix) not mentioned Men and women with Pregnant and nursing women microbiological Ceftriaxone 250 mg IM × 1, USA uncomplicated gonorrhoea cure, side-effect azithromycin 2 g po × 1

Rompalo 1994, 1994 adult/adolescents 38/107 genital (cervix) 15–60 Patients who had Gram-stained If they had a history of allergy to any microbiological Spectinomycin 2 g IM × 1, USA urethral, rectal or endocervical of the drug regimens administered, cure, side-effect ceftriaxone 250 mg IM × 1 smears showing Gram-negative were pregnant or nursing, had co-existing diplococci within syphilis, myasthenia gravis, or complicated polymorphonuclear cells were gonococcal infections eligible for enrolment. (i.e. disseminated gonorrhoea, pelvic Also, women with a history of inflammatory disease, or septic arthritis), recent exposure to a sexual partner received antibiotic therapy within 48 hours with gonorrhoea. before clinic presentation, active kidney disease, had bleeding disorders, or active liver disease. Participants were excluded from treatment analysis if cultures obtained at enrolment were negative for N. gonorrhoeae, if patients failed to keep appointment for follow-up or took any other antibiotic between the time of enrolment and follow-up evaluation.

Web annex E – Systematic reviews

Randomized studies with two or more comparison groups

STUDY YEAR POPULATION N INFECTION AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS (mean and/or range, if not indicated)

Mroczkowski 1993 adult/adolescents 11/16 genital 23.6 (18–36) Patients with uncomplicated Patients under 18 years of age, pregnant or microbiological Ceftriaxone 250 mg IM × 1, 1993, USA (urethra) gonorrhoea breastfeeding women, patients with active cure, clinical spectinomycin 2 g IM × 1 liver or kidney disease, myasthenia gravis, cure, side- bleeding disorders or known allergy to effects spectinomycin or beta-lactam antibiotic. None of the study patients had been treated with trospectomycin or other antibiotics within 72 hours prior to enrolment

Portilla 1992, 1992 adult/adolescents genital (cervix) 23.3 (18–44) Patients with clinical evidence of An allergy to penicillin or cephalosporins, microbiological Ceftriaxone 250 mg IM × 1, USA uncomplicated gonorrhoea. Initial chronic bowel disorders, more than one cure, side- cefixime 400 mg po × 1, screening included examination of bacterial infection, evidence of chancroid, effects 800 mg po × 1 (or cefixime those who had recent sexual syphilis or AIDS, severe systematic disease 400 mg po × 2) contact with a person who had such as congestive heart failure or hepatic documented gonorrhoea. If Gram- or renal failure, negative, intracellular diplococci or those who were pregnant consistent with N. gonorrhoeae were positive, the patients were enrolled in the study.

Plourde 1992, 1992 adult/adolescents 181/184 genital (cervix) 18–65 Men were enrolled if a Gram stain Patients with complicated gonococcal microbiological Cefixime 400 mg po × 1, Kenya of their urethral discharge showed infection such as pelvic inflammatory cure, side- ceftriaxone 250 mg IM × 1 intracellular Gram-negative disease, hypersensitivity to penicillins effects diplococci. Women were enrolled if or cephalosporins, any other STDs or a culture of their cervical discharge pregnancy was positive for N. gonorrhoeae.

Handsfield 1991, 1991 adult/adolescents 4/4 genital 27.2 Patients with Gram-stained urethral Patients who had symptoms or signs microbiological Cefixime 400 mg po × 1, USA (urethra) or or endocervical smears showing of pelvic inflammatory disease or other cure, side- cefixime 800 mg po × 1 anorectal Gram-negative diplococci within complications of gonorrhoea, gave effects (or cefixime 400 mg po × 2) polymorphonuclear leukocytes or, a history of allergy to beta-lactam in women, a history of sexual antibiotics or spectinomycin, had received exposure to a man with urethral antimicrobial therapy in the preceding gonorrhoea 7 days, or were pregnant or nursing

WHO guidelines for the treatment of Neisseria gonorrhoeae

Randomized studies with two or more comparison groups

STUDY YEAR POPULATION N INFECTION AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS (mean and/or range, if not indicated)

Judson 1985, 1985 adults/adolescents 41/41 genital (cervix) > 19 Patients who had positive smears Patients with histories of allergy microbiological Ceftriaxone 250 mg IM × 1, Denver, USA and MSM for anogenital gonorrhoea and/or to beta-lactam antibiotics or who cure, side- spectinomycin 2 g IM × 1 a documented exposure to had antimicrobial therapy within the effects gonorrhoea were considered preceding 2 weeks, or complications of gonorrhoea, or any serious illness were excluded

Panikabutra 1985 adults/adolescents 190/190 genital (cervix) not mentioned Women with uncomplicated Not mentioned microbiological Spectinomycin 2 g IM × 1, 1985, Thailand gonorrhoea cure, side- ceftriaxone 250 mg IM × 1 effects

Collier 1984, 1984 adults/adolescents 13/18 genital (cervix) 22.6 ± 4.3 The presence of intracellular Gram- Patients who had symptoms or signs microbiological Ceftriaxone 250 mg IM × 1, USA negative diplococci on a Gram- of pelvic inflammatory disease or other cure, clinical spectinomycin 2 g IM × 1 stained endocervical smear, complications of gonorrhoea, gave cure, side- untreated gonorrhoea documented a history of allergy to beta-lactam effects by earlier isolation of antibiotics or spectinomycin, had received N. gonorrhoeae, or a history of antimicrobial therapy in the preceding recent sexual intercourse with a 7 days, or were pregnant or nursing. man with urethral gonorrhoea Patients from whom N. gonorrhoea was not isolated at entry visit were excluded from the analysis, but they were retained for toxicity analysis

Handsfield 1983, 1983 adult/adolescents 4/10 genital (cervix) 27.6 Men aged ≥ 16 years with Patients with complicated gonorrhoea, had microbiological Ceftriaxone125 mg IM × 1, USA uncomplicated gonorrhoea other antibiotics for preceding 2 weeks, cure, side- ceftriaxone 250 mg IM × 1, urethritis or anorectal infections allergic to B-lactam antibiotics effects spectinomycin 2 g IM × 1

Handsfield 1981, 1981 adult/adolescents 4/4 genital (cervix) 26.9 ± 7.7 years Men aged ≥ 16 years who attended Patients with histories of allergy to beta- microbiological Ceftriaxone 125 mg IM × 1, USA (16–57) a sexually transmitted disease clinic lactam antibiotics, with complications cure, clinical ceftriaxone 250 mg IM × 1, and who had presumptive of gonorrhoea, or who had received cure, side- 500 mg IM × 1 gonococcal urethritis (urethral antimicrobial therapy within the preceding effects smear showing intracellular Gram- 2 weeks negative diplococci) or anorectal infection (positive Gram-stained smear or history of receptive rectal intercourse with a man with documented gonococcal urethritis)

Non-randomized studies with two comparison groups

Web annex E – Systematic reviews

Randomized studies with two or more comparison groups

STUDY YEAR POPULATION N INFECTION AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS (mean and/or range, if not indicated)

Schumacher 2013 adult/adolescents 394/485 genital (cervix) Diagnosed as having uncomplicated Not mentioned microbiological Ceftriaxone + azithromycin, 2013, USA N. gonorrhoeae infection cure ceftriaxone + doxycycline

Deguchi 2003, 2003 adult/adolescents genital (cervix) Patients had symptoms and signs Not mentioned microbiological Cefixime 200 mg po × 2, Japan of acute urethritis. No patient had cure, side- cefixime 400 mg po × 1 received antibiotic treatment effects before admission to the clinic.

Rajan 1982, 1982 adult/adolescents genital (cervix) Only those treated patients whose Patients with reinfections were excluded microbiological Ceftriaxone 250 mg IM × 1, Singapore infections were confirmed by from the study cure, side- kanamycin 2 g IM × 1 culture effects

Non-randomized study with one group

Takahashi 2014, 2014 adult/adolescents 30/33 genital (cervix) 20 or more Heterosexual male patients with Unclear microbiological Azithromycin 2 g po × 1 Japan both gonococcal urethritis (GU) and cure, clinical non-gonococcal urethritis (NGU) cure who were ≥ 20 years old. Diagnosis of GU was based on both symptoms: urethral pain and pus discharge

Kojima 2008, 2008 adult/adolescents 203/210 genital (cervix) 32.3 (17–73) Male patients with uncomplicated Not mentioned microbiological Spectinomycin 2 g IM × 1 Japan gonococcal urethritis cure, clinical cure, side- effects

Muratani 2008, 2008 adult/adolescents 25/25 oropharyngeal 28.1 Outpatients with uncomplicated Not mentioned Microbiological Ceftriaxone 250 mg IM × 1 Japan gonorrhoea either symptomatic cure or asymptomatic, as well as sexual contacts of individuals with known gonorrhoea

WHO guidelines for the treatment of Neisseria gonorrhoeae

Randomized studies with two or more comparison groups

STUDY YEAR POPULATION N INFECTION AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS (mean and/or range, if not indicated)

Khaki 2007, 2007 adult/adolescents 22 genital 18–54 Males with urethritis, females Antibiotic therapy within the preceding microbiological Azithromycin 2 g po × 1 India (urethra) or with endocervicitis 4 weeks, known hypersensitivity to cure, clinical anorectal macrolide antibiotic, serious cardiac, renal cure, side- or hepatic disease, clinical evidence of effects disseminated gonococcal infection, other complications of gonorrhoeae or untreated syphilis and any condition that might affect gastro-intestinal absorption of antibiotics (e.g. peptic ulcer disease, gastrectomy).

Khrianin 2006, 2006 adults/adolescents 119/119 genital (cervix) 18–45 Gonorrhoea patients Allergic to antibiotic, diagnosis something microbiological Ceftriaxone 250 mg IM × 1 Russia else, e.g. syphilis cure, clinical cure

Habib 2004, 2004 adulst/adolescents 168/170 genital (cervix) 25.8 (14–56) Men and women were treated Patients with negative culture results for microbiological Azithromycin 1 g po × 1 United Kingdom for N. gonorrhoeae on the basis N. gonorrhoeae who were initially treated cure of a Gram-stained smear showing were excluded from the study polymorphonuclear leukocytes with intracellular Gram-negative diplococci in the initial visit or with culture-proven N. gonorrhoeae thereafter, or if there was a history of recent unprotected sexual intercourse with a partner infected with gonorrhoea regardless of Gram staining and before culture confirmation.

Rustomjee 2002, 2002 adults/adolescents 55/56 genital Not mentioned First visit, non-pregnant, female, Not mentioned microbiological Azithromycin 1 g po × 1 South Africa (urethra) or clinic attendees if they had a cure, clinical anorectal mucopurulent cervical discharge cure, with a diagnosis of non-gonococcal compliance, cervicitis (NGC), based on a routine side-effects vaginal wet mount and cervical Gram stain

Aplasca 2001, 2001 adults/adolescents 25/26 genital (cervix) 22.3 ± 4.2 Women with positive results for < 16 years, pregnant, signs suggestive microbiological Cefixime 400 mg po × 1 Philippines N. gonorrhoeae by endocervical of pelvic inflammatory diseases cure, side- Gram staining or culture effects

Web annex E – Systematic reviews

Randomized studies with two or more comparison groups

STUDY YEAR POPULATION N INFECTION AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS (mean and/or range, if not indicated)

Jin Hong 2001, 2001 adults/adolescents 77/77 genital (cervix) not mentioned Gonorrhoea patients Unclear microbiological Ceftriaxone 250 mg IM × 1 China cure, clinical cure, side- effects

Swanston 2001, 2001 adults/adolescents 121/127 genital (cervix) 14–83 History of genital discharge Patients had antibiotics within the last 7 microbiological Azithromycin 1 g po × 1 Trinidad to 10 days, with complicated gonorrhoea or cure, clinical chlamydial infection, pregnant, lactating cure, side- effects

Ling 2000, China 2000 adults/adolescents 153/178 genital (cervix) 18–55 Gonorrhoea patients Not mentioned microbiological Azithromycin 1 g po × 1 cure, clinical cure, side- effects

Shi 2000, China 2000 adults/adolescents 28/30 genital (cervix) 25 (19–47) Gonorrhoea patients Unclear microbiological Spectinomycin 2 g IM × 1 cure, clinical cure, side- effects

Zhou, 2000, 2000 adults/adolescents 35/36 genital (cervix) 18–52 Gonorrhoea patient Allergic, pregnant, breastfeeding, cardinal, microbiological Spectinomycin 2 g IM × 1 China (in renal and liver complications cure, clinical Chinese) cure, side- effects

Gruber 1997, 1997 adults/adolescents genital (cervix) 24.5 Gonorrhoea patient Allergic, pregnant, breastfeeding, cardinal, microbiological Azithromycin 1 g po × 1 Croatia renal and liver complications cure, clinical cure, side- effects

WHO guidelines for the treatment of Neisseria gonorrhoeae

Randomized studies with two or more comparison groups

STUDY YEAR POPULATION N INFECTION AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS (mean and/or range, if not indicated)

Hook 1997, USA 1997 adults/adolescents genital (cervix) 27 All participants were required to If they have a history of allergy to quinolone microbiological Cefixime 400 mg po × 1 have a Gram stain of a urethral or cephalosporin antibiotics; cure, side- specimen showing Gram-negative had received antibiotics or any other effects diplococci within investigational drug within 2 weeks before polymorphonuclear leukocytes enrolment; had complicating infection or or a recent culture positive disease that would compromise treatment for N. gonorrhoeae evaluation; received concomitant antimicrobial medication other than topical or antifungal agents; received chronic treatment with warfarin, diflunisal, fluconazole or theophylline; had taken antacids or sucralfate within 4 hours of dosing; or had a known Chlamydia trachomatis infection

Mroczkowski 1997 adults/adolescents 124/125 genital (cervix) 15–54 Women aged 16 years or older If they had concomitant infection(s), such as microbiological Cefixime 400 mg po × 1 1997, USA were eligible for enrolment if they complicated gonococcal infection, or cure, side-effects had a Gram-stained endocervical disease that would compromise treatment smear showing Gram-negative evaluation; were pregnant or nursing; were diplococci within known to have hypersensitivity to polymorphonuclear leukocytes, quinolone or cephalosporin antibiotics; had a recent untreated culture positive received antibiotics or any investigational for N. gonorrhoeae, or sexual drug within 2 weeks of enrolment; needed exposure to men with urethral concurrent antimicrobial medication other gonorrhoea within the 2 weeks than topical or antifungal agents; had prior to enrolment received chronic treatment with warfarin, diflunisal, fluconazole or theophylline; or had taken antacids or sucralfate within 4 hours of dosing. Patients with recent positive cultures for C. trachomatis were also excluded

Web annex E – Systematic reviews

Randomized studies with two or more comparison groups

STUDY YEAR POPULATION N INFECTION AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS (mean and/or range, if not indicated)

Gruber 1995, 1995 adults/adolescents 49 genital (cervix) 24.5 Adults (>18 years) with clinical signs Patients were excluded if they had received microbiological Azithromycin 1 g po × 1 Croatia of gonorrhoea (urethral or cervical antibiotic pretreatment within 2 weeks cure, clinical discharge, but some of the women before enrollment, if they were allergic to cure, side- were asymptomatic partners macrolides or quinolones, if they had other effects of men with gonorrhea). Presence concomitant sexually transmitted infections of intracellular Gram-negative (except chlamydial infection), if they had diplococci in the Gram-stained pharyngeal or rectal gonorrhea, if a female urethral or endocervical smear was pregnant, if they were unlikely to and/or positive culture for return for follow-up, were known alcohol or Neisseria gonorrhoeae drug abusers, or had gastrointestinal diseases that might affect absorption of the drugs.

Mogabgab 1994 1994 adults/adolescents 48/48 genital (cervix) 23.9 Aged > 18 years with laboratory Pregnant and lactating women, complicated microbiological Ceftriaxone 250 mg IM × 1 cost data diagnosis of uncomplicated gonorrhoea patients, allergic to penicillin or cure, clinical available, USA gonorrhoea cephalosporin and received any antibiotic cure, side- therapy within last 2 weeks effects

Steingrimsson 1995 adults/adolescents 55 genital 24.7 (17–58) The patients showed signs or Women of child bearing potential, patients microbiological Azithromycin 1 g po × 1 1994, Iceland (urethra) symptoms of STD or were contacts who had received antibiotics or other cure, side- of patients with STD experimental drugs within 2 weeks prior effects to visit, and patients with serious renal, cardiac or hepatic disease

Covino 1993, 1993 adults/adolescents 3/3 genital (cervix) > 18 Male patients with urethral Pregnant and lactating women, complicated microbiological Ceftriaxone 250 mg IM × 1 USA gonorrhoea, female participants gonorrhoea patients, allergic to penicillin or cure with positive culture. Recent sexual cephalosporin and received any antibiotic contact with person with recently therapy within last 2 weeks documented gonorrhoea.

WHO guidelines for the treatment of Neisseria gonorrhoeae

Randomized studies with two or more comparison groups

STUDY YEAR POPULATION N INFECTION AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS (mean and/or range, if not indicated)

Hook 1993, USA 1993 adults/adolescents 6/6 genital (cervix) 18–50 Women aged 18 to 50 years were They were pregnant or nursing, had been microbiological Ceftriaxone 250 mg IM × 1 eligible for enrolment if they gave a previously enrolled in the study, gave a cure, side- history of sexual exposure to a man history of allergy to carboxyquinolone or effects with urethral gonorrhoea, if they cephalosporin antibiotics, had signs or had a Gram-stained endocervical symptoms of complicated gonococcal smear showing Gram-negative infection (pelvic inflammatory disease), had diplococci within a chronic or acute intercurrent illness which polymorphonuclear leukocytes, would compromise treatment evaluation, or if they had a history of an had evidence of other acute STDs requiring untreated culture positive for treatment at the time of initial evaluation, N. gonorrhoeae or had received systemic antimicrobial therapy with an agent known to be active against N. gonorrhoeae during the 2 weeks prior to study enrolment

McCormack 1993 adults/adolescents 113/115 genital (cervix) 24.4 Male patients with urethral Pregnant and lactating women, complicated microbiological Ceftriaxone 250 mg IM × 1 1993, USA gonorrhoea, female participants gonorrhoea patients, allergic to penicillin or cure, side- with positive culture. Recent sexual cephalosporin and received any antibiotic effects contact with person with recently therapy within past 2 weeks documented gonorrhoea

Odugbemi 1993, 1993 adults/adolescents 114/123 genital (cervix) 16–52 Outpatients over 14 years old, Pregnant or lactating women, patients who microbiological Azithromycin 1 g po × 1 Nigeria diagnosed as STI by clinical signs gave a history of sensitivity to penicillin, and cure, clinical and laboratory tests had not been patients who had received other cure, side- on any antibiotic 2 weeks before antimicrobial therapy during the preceding effects being enrolled in this study week. Patients who were included in the study whose cultures did not contain gonococci were not included

Smith 1993, USA 1993 adults/adolescents 24/24 genital 26.5 (18–58) Men and women ≥ 18 years’. Men Patients with complicated gonococcal microbiological Ceftriaxone 250 mg IM × 1 (urethra) or were enrolled if a Gram stain of infection such as pelvic inflammatory cure, side- anorectal their urethral discharge showed disease, hypersensitivity to penicillins effects intracellular Gram-negative or cephalosporins, any other STDs or diplococci. Women were enrolled if pregnancy a culture of their cervical discharge was positive for N. gonorrhoea

Web annex E – Systematic reviews

Randomized studies with two or more comparison groups

STUDY YEAR POPULATION N INFECTION AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS (mean and/or range, if not indicated)

Tupasi 1993 and 1993 adults/adolescents 52/2 genital (cervix) 13–30 Patients with culture-positive Not mentioned microbiological Spectinomycin 2 g IM × 1 1984 had the gonorrhoea cure, side- same data, effects the Philippines

Verdon 1993, 1993 adults/adolescents 93/98 genital (cervix) > 16 All patients were examined with Unclear microbiological Cefixime 200 mg po × 1 USA a proctoscope and specimens cure, side-effect were taken for microscopy and culture. The diagnosis was confirmed by the finding of Gram- negative intracellular diplococci on the smear and by the isolation and identification of N. gonorrhoeae

Waugh 1993, 1993 adults/adolescents 89/93 genital (cervix) 16–60 Male and female patients between Patients were excluded from the study if microbiological Azithromycin 1 g po × 1 United Kingdom 16 and 60 years of age with a they had received antibiotics, or any other cure, clinical diagnosis of gonorrhoea investigational drug, within 2 weeks before effect, side- the study (except where treatment failure effects was documented). Other exclusion criteria were terminal illness or any other condition which might preclude the patient from completing the study, known hypersensitivity to macrolides, concurrent treatment with ergotamine or carbamazepine, chronic diarrhoea, or any gastrointestinal condition which might affect absorption of azithromycin. Patients with clinical and serological evidence of primary or secondary syphilis were also excluded from the study.

Baddour 1992, 1992 adults/adolescents 35/35 genital (cervix) 23.3 (18–47) Patients were18 years of age If they were pregnant, other complications, microbiological Ceftriaxone 250 mg IM × 1 Tennessee, USA or older had antibiotics in previous weeks cure, side- effects

Dunnett/ 1992 adults/adolescents 71/73 genital (cervix) > 18 Male patients with urethral Pregnant and lactating women, complicated microbiological Cefixime 400 mg po × 1 Dunnel 1992, gonorrhoea, female participants gonorrhoea patients, allergic to penicillin cure, side- USA with positive culture. Recent sexual or cephalosporin and received any effects contact with person with recently antibiotic therapy within past 2 weeks documented gonorrhoea

WHO guidelines for the treatment of Neisseria gonorrhoeae

Randomized studies with two or more comparison groups

STUDY YEAR POPULATION N INFECTION AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS (mean and/or range, if not indicated)

Goldstein 1991, 1991 adults/adolescents genital (cervix) 20–40 Documented urethritis, not allergic Allergic to penicillin and/or cephalosporin microbiological Ceftriaxone 250 mg IM × 1 USA to penicillin and/or cephalosporin antibiotics cure, side- antibiotics effects

Bryan 1990, 1990 adults/adolescents 164/165 genital (cervix) 27.5 Adult males between 18 and A history of antimicrobial treatment within microbiological Ceftriaxone 250 mg IM × 1 Zambia including HIV 50 years of age who presented 14 days, a history of allergy to beta-lactam cure, side- patients with urethral discharge containing antibiotics or quinolones, evidence of extra- effects intracellular Gram-negative urethral gonococcal disease or genital ulcer diplococci (as determined by disease, or clinical evidence of microscopic exam) immunodeficiency

Lassus 1990, 1990 adults/adolescents 40 genital (cervix) 44.9 Patients were enrolled on the basis Not mentioned microbiological Azithromycin 1 g po × 1 Finland of clinical diagnosis alone, although cure, side- every attempt was made to isolate effects causative pathogens from swabs or pus

Covino 1990, 1990 adults/adolescents 41/42 genital (cervix) > 18 Heterosexual men or women at Pregnant or nursing women; patients microbiological Ceftriaxone 250 mg IM × 1 USA least 18 years old. Males had a with a history of allergic reaction to cure, side- urethral Gram stain showing gram- carboxyquinolones, nalidixic acid, effects negative intracellular diplococci. ceftriaxone, or cephalosporins; and patients Females had a known positive who had received systemic antimicrobial culture, a cervical Gram stain therapy within the previous 24 h were showing gram-negative intracellular excluded. diplococci, or recent exposure to a man with documented gonorrhea.

Freedman 1990, 1990 adults/adolescents 51/51 genital (cervix not mentioned If pharynx and rectum are culture Not mentioned microbiological Ceftriaxone 250 mg IM × 1 USA positive for gonococcus (by the cure patient’s history)

Megran 1990, 1990 adults/adolescents 97/98 genital (cervix) > 18 Males aged 18 years and older Patients receiving antimicrobial therapy microbiological Cefixime 800 mg po × 1 Canada MSM with positive cultures for in the preceding 2 weeks were excluded cure, side- N. gonorrhoeae from any site or from the study, as were persons with effects with Gram-negative intracellular a history of hypersensitivity to penicillins diplococci from endo-urethral or cephalosporins and those with serious or rectal swabs underlying disorders

Web annex E – Systematic reviews

Randomized studies with two or more comparison groups

STUDY YEAR POPULATION N INFECTION AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS (mean and/or range, if not indicated)

Steingrimsson 1990 adults/adolescents 41/43 genital 24.7 (17–58) The patients showed signs or Women of child-bearing potential, patients microbiological Azithromycin 1 g po × 1 1990, Iceland (urethra) symptoms of STD or were contacts who had received antibiotics or other cure, side- of patients with STD experimental drugs within 2 weeks prior effects to visit, and patients with serious renal, cardiac or hepatic disease

Wojtowicz 1990, 1990 adults/adolescents 59/59 genital (cervix) not mentioned All comers Not mentioned microbiological Spectinomycin 2 g IM × 1 Polish cure

Backhaus 1990 adults/adolescents 14/14 genital (cervix) 39.4 Male Kidney failure, beta-lactam microbiological Cefixime 400 mg po × 1 1990, intolerance, severe illness, cure, side- Germany alcohol/drug abuse, other venereal effects disease, antibiotic use < 3 days prior

Christophersen 1989 adults/adolescents 40/40 genital (cervix) > 18 A diagnosis of genitourinary or They had received antibiotics in the microbiological Ceftriaxone 250 mg IM × 1 1989, rectal gonorrhoea was made by previous 7 days, if they had known cure, side- Netherlands microscopy of a methylene blue- or suspected hypersensitivity to effects stained smear at the initial visit cephalosporins, penicillins, or lidocaine and test positives were included or if they had known renal or hepatic insufficiency

Korting 1989 1989 adults/adolescents 64/65 genital (cervix) > 18 Gonorrhoea patients As above and mental disability microbiological Ceftriaxone 250 mg IM × 1 Germany cure, side- effects

Kouri 1989, 1989 adults/adolescents 205/210 genital (cervix) 26 (18–53) If they had signs or symptoms of Pregnant or if they had a history of allergy microbiological Spectinomycin 2 g IM × 1 Puerto Rico, genital infection and Gram-negative to penicillin or spectinomycin, evidence of cure, side- Latin America intracellular diplococci on smear of coexistent syphilis, or had received effects the discharge or were contact cases antibiotics within the previous 2 weeks from a culture-positive patient

WHO guidelines for the treatment of Neisseria gonorrhoeae

Randomized studies with two or more comparison groups

STUDY YEAR POPULATION N INFECTION AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS (mean and/or range, if not indicated)

Pabst 1989, USA 1989 adults/adolescents 14/15 genital (cervix) 23 Women aged 16 years or older Allergy to penicillin or quinolone antibiotics; microbiological Ceftriaxone 250 mg IM × 1 were eligible for enrolment if they complicated gonococcal infection; known cure, side- had a Gram-stained endocervical untreated syphilis; or received antimicrobial effects smear showing Gram-negative therapy effective against N. gonorrhoeae in diplococci within the 14 days preceeding initial evaluation. polymorphonuclear leukocytes, a Patients excluded from analysis cultures recent untreated culture positive negative, if patients failed to keep for N. gonorrhoeae, or sexual appointed follow-up visits 7 to 10 days exposure to men with urethral following enrollment, or if patients took gonorrhoea within the 2 weeks therapy effective against N. gonorrhoeae prior to enrolment between the time of enrollment and follow- up evaluation.

Pandhi 1989, 1989 adults/adolescents 54/55 all 21–40 and Patients with acute gonococcal Not mentioned microbiological Gentamicin 240 mg IM × 1 India infections/total 11–20 urethritis cure, side- effects

Calderon 1988, 1988 adults/adolescents 40/40 genital (cervix) 25 ± 8.3 (16–47) Gonorrhoea patients Had history of sensitivity to quinolones, microbiological Ceftriaxone 250 mg IM × 1 Mexico azaquinolones or cephalosporins, had cure, clinical received antibiotics in the previous 2 weeks, cure, side- or failed to follow up test effects

Panikabutra 1988 adults/adolescents 241/243 genital (cervix) 25 (15–58) Men and non-pregnant women Patients with complicated gonococcal microbiological Spectinomycin 2 g IM × 1 1988, Bangkok aged 16–58 years who had culture infections, known hypersensitivity to cure, side- and Singapore positive symptomatic or quinolones, known impaired kidney effects symptomless uncomplicated function (creatinine clearance less than gonorrhoea of the urethra, 30 ml/min), known decreased liver cervix or rectum function, blood disorders or coexistent syphilis, or those who had received concomitant treatment with any other antibacterial drugs, coumarin derivatives, phenytoin or methotrexate

Yoon 1988, 1988 adults/adolescents 164/251 genital (cervix) > 18 Gonorrhoea patients, and those Unclear microbiological Kanamycin 2 g IM × 1, Korea who had contact with gonorrhoea cure gentamicin 240 mg IM × 1 patients

Handsfield 1987, 1987 adults/adolescents 109/110 genital (cervix) not mentioned Gonorrhoea patients Not mentioned microbiological Ceftriaxone 250 mg IM × 1 USA cure, side- effects

Web annex E – Systematic reviews

Randomized studies with two or more comparison groups

STUDY YEAR POPULATION N INFECTION AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS (mean and/or range, if not indicated)

Monayar 1987, 1987 adults/adolescents 59/61 genital (cervix) 15–47 Men with uncomplicated Not mentioned microbiological Spectinomycin 2 g IM × 1 Argentina gonorrhoea cure

Lassau 1987, 1987 adults/adolescents genital (cervix) 31.5 Male with uncomplicated The patients had received antibiotics at microbiological Spectinomycin 2 g IM × 1 France gonococcal urethritis least 2 weeks prior to treatment cure

Davidson 1986, 1986 adults/adolescents 41/45 genital (cervix) not indicated Positive culture Not mentioned microbiological Spectinomycin 2 g IM × 1 USA cure

Dixon 1986, 1986 adults/adolescents 141/141 genital (cervix) not clear Men had to have uncomplicated Patients in whom the initial cultures for microbiological Ceftriaxone 250 mg IM × 1, United Kingdom urethral or rectal gonorrhoea N. gonorrhoeae were negative were cure 500 mg IM × 1 diagnosed by the presence of subsequently excluded from the trial. Gram-negative intracellular Patients were excluded if they had received diplococci (GNICD) in smears. antibiotics in the previous 10 days or if they Women were included if GNICD had undiagnosed genital ulcers or known were seen on urethral, cervical or renal or hepatic disease. Pregnant women rectal smears or if N. gonorrhoeae and those not using adequate was cultured from urethral, cervical contraception (such as the contraceptive or rectal swabs pill, an intrauterine device, or sterilization) and any woman with evidence of salpingitis on clinical examination

Hook 1986, USA 1986 adults/adolescents genital (cervix) > 18 Men > 18 years of age who had With complicated gonococcal infection, microbiological Spectinomycin 2 g IM × 1 either a smear of urethral or rectal with a history of allergy to spectinomycin cure, side- exudate showing Gram-negative or beta-lactam antibiotics, or who had effects intracellular diplococci or culture taken antimicrobial therapy active against isolation of N. gonorrhoeae N. gonorrhoeae within 2 weeks of enrolment

Stapinski 1986, 1986 adults/adolescents 936/946 genital (cervix) all comers with Not mentioned Not mentioned microbiological Spectinomycin 2 g IM × 1 Polish gonorrhoea cure

Hira 1985, 1985 adults/adolescents 678/347 genital Not mentioned Uncomplicated acute urethritis Men with a previous history of urethral microbiological Kanamycin 2 g IM × 1, Zambia (urethra) and those with Gram-negative discharge or recurrent urethritis were cure, side- gentamicin 240entamic× 1 intracellular diplococci in smears excluded, as were those who had recently effects of their urethral discharge were received antibiotics. Although treatment enrolled in the study was started on the basis of Gram-stain results, culture specimens were taken before treatment from all patients, and those with negative results

WHO guidelines for the treatment of Neisseria gonorrhoeae

Randomized studies with two or more comparison groups

STUDY YEAR POPULATION N INFECTION AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS (mean and/or range, if not indicated)

Kim 1984, Korea 1984 adults/adolescents 44/44 genital (cervix) 25.6 (18–42) × Gonorrhoea patients Excluded patients with other complications microbiological Spectinomycin 2 g IM × 1 cure, side- effects

Meheus 1984, 1984 adults/adolescents 197/210 genital (cervix) 23.9 Men with signs and symptoms Allergic to the drugs under study, had microbiological Spectinomycin 2 g IM × 1 Central African of urethritis received antimicrobial treatment within cure, side- Republic the preceding 2 weeks, and had effects complication of gonococcal infection

Tupasi 1984, 1984 adults/adolescents 52/52 genital (cervix) 13–30 Patients with culture-positive Not mentioned microbiological Spectinomycin 2 g IM × 1 Philippines gonorrhoea. cure, side- effects

Judson 1983, 1983 adults/adolescents genital (cervix) > 18 Women 18 years of age or older Women with histories of allergy to P-lactam microbiological Ceftriaxone 250 mg IM × 1 USA with proven (culture-positive) or antibiotics, antimicrobial therapy within the cure, side- suspected (history of exposure to a preceding 2 weeks, complications of effects man with documented gonococcal gonorrhoea, or any recent serious illness urethritis) uncomplicated were excluded gonorrhoea

Panikabutra 1983 adults/adolescents 91/92 genital (cervix) Not mentioned Uncomplicated gonorrhoea Not mentioned microbiological Spectinomycin 2 g IM × 1 1983, Thailand cure, side- effects

Reggiani 1983, 1983 adults/adolescents genital (cervix) Not reported/no Gonorrhoea patients Not mentioned microbiological Spectinomycin 4 g IM × 1 Italy age restriction cure, side- effects

Tupasi 1983, The 1983 adults/adolescents 52/52 genital (cervix) 21 (13–30) Culture-positive patients Unclear microbiological Spectinomycin 2 g IM × 1 Philippines cure, side- effects

Web annex E – Systematic reviews

Randomized studies with two or more comparison groups

STUDY YEAR POPULATION N INFECTION AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS (mean and/or range, if not indicated)

Zajdowicz 1983, 1983 adults/adolescents 61/61 genital (cervix) not mentioned Recent sexual exposure, signs or Had a history of a severe immediate microbiological Ceftriaxone 250 mg IM × 1 USA symptoms of urethritis, and the reaction to penicillin or any type of allergic cure, clinical presence of polymorphonuclear reaction to any of the cephalosporins; cure, side- neutrophils and intracellular hypersensitivity to lignocaine or effects Gram-negative diplococci in a probenecid; evidence of coexisting syphilis Gram-stained smear of urethral or gonococcal infection other than exudate uncomplicated urethritis; or any disease which might require additional antibiotic treatment

Ratnam 1982, 1982 adults/adolescents 115/116 genital (cervix) > 18 Men > 18 years of age who had With complicated gonococcal infection, microbiological Spectinomycin 2 g IM × 1 Zambia either a smear of urethral or rectal with a history of allergy to spectinomycin or cure, side- exudate showing Gram-negative beta-lactam antibiotics, or who had taken effects intracellular diplococci or culture antimicrobial therapy active against N. isolation of N. gonorrhoeae gonorrhoeae within 2 weeks of enrolment

Fluker 1980, 1980 adults/adolescents 53/56 genital (cervix) 30.3 (18–67) All patients were examined with Not mentioned microbiological Spectinomycin 2 g IM × 1 United Kingdom a proctoscope and specimens were cure taken for microscopy and culture. The diagnosis was confirmed by the finding of Gram-negative intracellular diplococci on the smear and by the isolation and identification of N. gonorrhoeae

Sands 1980, USA 1980 adults/adolescents 25/5 genital (cervix) > 18 Only those cases in which a follow- Not mentioned microbiological Spectinomycin 2 g IM × 1 up rectal culture was done 3– cure 14 days after completion of therapy were included. Only those follow- up culture-positive patients with physician histories specifically excluding reinfection were included among the treatment failures

Rajan 1979, 1979 adults/adolescents genital (cervix) not clear Patients with complicated Not mentioned microbiological Kanamycin 2 g IM × 1, Singapore gonococcal infections cure, side- effects

Falman 1978 1978 adults/adolescents genital (cervix) 28.9 Culture-positive patients from anal Not mentioned microbiological Spectinomycin 4 g IM × 1 USA sample cure

WHO guidelines for the treatment of Neisseria gonorrhoeae

Randomized studies with two or more comparison groups

STUDY YEAR POPULATION N INFECTION AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS (mean and/or range, if not indicated)

Karney 1977, 1977 adults/adolescents 2050/2145 urethral or not mentioned All members of the study Not mentioned microbiological Spectinomycin 4 g IM × 1 USA anorectal population had uncomplicated cure, side- gonococcal cervicitis effects

McCann 1977, 1977 adults/adolescents 236/242 total 15–57 Patient with uncomplicated Unclear microbiological Spectinomycin 2 g IM × 1, Belfast gonorrhoea cure, side- spectinomycin 4 g IM × 1 effects

Porter 1977, 1977 adults/adolescents 74/75 genital (cervix) not clear Patients with acute gonococcal Not mentioned microbiological Spectinomycin 2 g IM × 1 urethritis cure, side- effects

Jaffe 1976, USA 1976 adults/adolescents genital (cervix) not clear Patients with suspected of urethral With gonococcal complications, has history side-effects Spectinomycin 2 g IM × 1 and/or anorectal gonorrhoea had of allergy with any of the medicines, either a smear of urethral or rectal pregnant women exudate showing Gram-negative intracellular diplococci or culture isolation of N. gonorrhoeae

Niunikova 1976, 1976 adults/adolescents 98/98 genital (cervix) 18–52 Gonorrhoea patients Not mentioned microbiological Kanamycin 2 g IM × 1 Russia cure, clinical cure, side- effects

Dashevskii 1975, 1975 adults/adolescents 59/62 genital (cervix) 18–40 Gonorrhoea patients Not mentioned microbiological Kanamycin 2 g IM × 1 Russia cure, side- effects

Finger 1975, 1975 adults/adolescents genital (cervix) 21.5 Culture-positive patients from Not mentioned microbiological Spectinomycin 2 g IM × 1, 4 g USA anal sample cure IM × 1

Turanova 1975, 1975 adults/adolescents 67/68 genital (cervix) 19–45 Gonorrhoea patients Not mentioned microbiological Kanamycin 2 g IM × 1 Russia cure, clinical cure

Bowie 1974, 1974 adults/adolescents 44/48 genital (cervix) > 18 Patients with gonorrhoea, had Unclear microbiological Gentamicin 240 mg IM × 1 Canada contact with gonorrhoea patients cure, side- effects

Web annex E – Systematic reviews

Randomized studies with two or more comparison groups

STUDY YEAR POPULATION N INFECTION AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS (mean and/or range, if not indicated)

Brown 1974, 1974 adults/adolescents 146/152 genital (cervix) not clear Adult male patients with acute Not mentioned microbiological Spectinomycin 2 g IM × 1 Canada uncomplicated gonorrhoeal cure, side- urethritis effects

Duancic 1974, 1974 adults/adolescents 107/260 genital (cervix) not mentioned Women who were suspected on Pregnant women, patients who gave a microbiological Spectinomycin, 2 g IM × 1, USA clinical or epidemiological grounds history of sensitivity to penicillin, and cure, side- spectinomycin 4 g IM × 1 of having uncomplicated patients who had received other effects gonococcal infection and who gave antimicrobial therapy during the preceding written informed consent were week. Patients who were included in the randomized study whose cultures did not contain gonococci were not included in the analysis of the data.

Judson 1974, 1974 adults/adolescents 224/242 genital (cervix) adolescents and Born at 37 weeks or more, Not mentioned microbiological Spectinomycin 4 g IM × 1 USA adults healthy neonates without ocular cure, side- malformations whose mothers effects were treated with neither systemic nor local antibiotics 1 week before delivery

Kousa 1974, 1974 adults/adolescents 245/263 genital (cervix) not clear Gonorrhoea patients Not mentioned microbiological Spectinomycin 2 g IM × 1 Finland cure, side- effects

Willcox 1974, 1974 adults/adolescents 76/83 genital (cervix) Male patients with acute Unclear microbiological Spectinomycin 2 g IM × 1 United Kingdom uncomplicated urethral gonorrhoea cure, side- effects

Meyer-Rohn 1974 adults/adolescents 87/100 genital (cervix) 24.5 Men and women with unknown Not mentioned microbiological Spectinomycin 2 g IM × 1 1974, duration of gonorrhoea infection cure, clinical Germany cure, side- effects

Reeves 1974, 1974 adults/adolescents 67/78 genital (cervix) 26.5 (16–60) Patients with acute uncomplicated Not mentioned microbiological Gentamicin 240 mg IM × 1 United gonococcal urethritis attending the cure Kingdom Bristol venereal diseases clinic

Same study as Morrison and Reeves 1973 23

WHO guidelines for the treatment of Neisseria gonorrhoeae

Randomized studies with two or more comparison groups

STUDY YEAR POPULATION N INFECTION AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS (mean and/or range, if not indicated)

Hantschke 1973, 1973 adults/adolescents 58/62 genital (cervix) not mentioned Gonorrhoea patients Not mentioned microbiological Ceftriaxone 250 mg IM × 1 Germany cure, side- effects

Morrison 1973, 1973 adults/adolescents 67/78 genital (cervix) 26.5 (16–60) Patients with acute uncomplicated Not mentioned microbiological Gentamicin 240 mg IM × 1 United Kingdom gonococcal urethritis attending the cure Bristol venereal diseases clinic

Stratigos 1973, 1973 adults/adolescents genital 17–48 Male with gonorrhoea Not mentioned microbiological Spectinomycin 2 g IM × 1 Greece (urethra) cure, clinical cure, side- effects

Tuza 1973, 1973 adults/adolescents 109/113 genital (cervix) 25.1 (17–52) Male patients with urethral Not mentioned microbiological Spectinomycin 2 g IM × 1 Sydney gonorrhoea cure, clinical cure, side- effects

Duncan 1972, 1972 adults/adolescents genital (cervix) Patients proven to have gonococcal Not mentioned microbiological Spectinomycin 2 g IM × 1, 4 g USA infection by culture on Thayer– cure, side- IM × 1 Martin selective medium were effects selected for the study

Holder 1972, 1972 adults/adolescents 15 MSM genital (cervix) not mentioned Homosexual patients were Not mentioned microbiological Spectinomycin 2 g IM × 1 USA examined and specimens were cure, clinical cultured for diagnosis of cure gonorrhoea

Pedersen 1972, 1972 adults/adolescents 104/106 genital (cervix) not clear Men with acute urethritis were Not mentioned microbiological Spectinomycin 2 g IM × 1 USA initially selected for treatment if cure, side- direct smears of urethral exudate effects showed Gram-negative diplococci. Women with uncomplicated endocervical or anorectal infection were accepted for treatment if N. gonorrhoeae was isolated from these sites. IM: intramuscular; po: by mouth (orally)

Web annex E – Systematic reviews

Effects of interventions

Other treatments vs ceftriaxone 250 mg IM × 1 Azithromycin 1–2 g po × 1 by person (number of people) Microbiological cure Azithromycin 1-2 gm po x 1 Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 2.1.1 Microbiological cure RCTs by person on 1st visit after 7 days: all infections Handsfield 1994 370 374 171 175 1.01 [0.99, 1.04] + + + – + – + + + ?

2.1.2 Microbiological cure RCTs by person on 1st visit after 7 days: cervix or urethra Handsfield 1994 370 374 171 175 1.01 [0.99, 1.04] + + + – + – + + + ?

2.1.3 Microbiological cure RCTs by person on 2nd visit after 14 days: Only rectum Handsfield 1994 26 27 17 17 0.97 [0.87, 1.10] + + + – + – + + + ?

2.1.4 Microbiological cure RCTs by person on 2nd visit after 14 days: all infections Handsfield 1994 213 213 80 81 1.02 [0.99, 1.05] + + + – + – + + + ?

0.5 0.7 1 1.5 2 Favours [Ceftriaxone] Favours [Azithromycin]

Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants ( clincal cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators (Clinical cure and a/e) (G) Blinding of the data analyst (H) Incomplete outcome data (attrition bias): (I) Selective reporting (reporting bias) (J) Other bias

Cefixime 400 mg po × 1 by person (number of people) Microbiological cure Cefixime 400 mg po x 1 Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 2.2.1 Microbiological cure RCTs by person Handsfield 1991 89 93 92 94 23.6% 0.98 [0.93, 1.03] + + + – + – + + + ? Plourde 1992 118 121 63 63 46.3% 0.98 [0.94, 1.02] + + + – + – + + + ? Portilla 1992 65 66 47 47 30.1% 0.99 [0.94, 1.03] + + + – + – + + + ? Subtotal (95% CI) 280 204 100.0% 0.98 [0.96, 1.01] Total events 272 202 Heterogeneity: Tau² = 0.00; Chi² = 0.12, df = 2 (P = 0.94); I² = 0% Test for overall effect: Z = 1.45 (P = 0.15)

2.2.2 Microbiological cure RCTs by person: cervix+rectum-only women Handsfield 1991 33 35 28 29 100.0% 0.98 [0.88, 1.09] + + + – + – + + + ? Subtotal (95% CI) 35 29 100.0% 0.98 [0.88, 1.09] Total events 33 28 Heterogeneity: Not applicable Test for overall effect: Z = 0.44 (P = 0.66)

2.2.3 Microbiological cure RCTs by person: urethra only - only men Handsfield 1991 56 58 65 65 100.0% 0.96 [0.91, 1.02] + + + – + – + + + ? Subtotal (95% CI) 58 65 100.0% 0.96 [0.91, 1.02] Total events 56 65 Heterogeneity: Not applicable Test for overall effect: Z = 1.21 (P = 0.23)

0.5 0.7 1 1.5 2 Favours [Ceftriaxone] Favours [Cefixime 400mg]

WHO guidelines for the treatment of Neisseria gonorrhoeae

Cefixime 400 mg po × 1 by infections (number of infection sites) Microbiological cure Cefixime 400 mg po x 1 ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 2.3.1 Microbiological cure RCTs by infections: all inections Portilla 1992 91 92 71 71 0.99 [0.96, 1.02] + + + – + – + + + ?

2.3.2 Microbiological cure RCTs by infections: Only cervix Portilla 1992 44 44 31 31 1.00 [0.95, 1.05] + + + – + – + + + ?

2.3.3 Microbiological cure RCTs by infections: Only urethra Portilla 1992 45 46 37 37 0.98 [0.92, 1.05] + + + – + – + + + ?

2.3.4 Microbiological cure RCTs by infections: Only rectum Portilla 1992 2 2 3 3 1.00 [0.53, 1.87] + + + – + – + + + ?

0.5 0.7 1 1.5 2 Favours [Ceftriaxone] Favours [Cefixime 400mg]

Cefixime 800 mg po × 1 (or cefixime 400 mg po × 2) by person (number of people) Microbiological cure Cefixime 800 mg po x 1 (or Cefixime 400 mg po X 2) ceftriaxone 250mg IM x1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 2.4.1 Microbiological cure RCTs by person: all infections in women and men Handsfield 1991 86 88 92 94 1.00 [0.96, 1.04] + + + – + – + + + ?

2.4.2 Microbiological cure RCTs by person:urethra only - only men Handsfield 1991 63 63 65 65 1.00 [0.97, 1.03] + + + – + – + + + ?

2.4.3 Microbiological cure RCTs by person: cervix+rectum-only women Handsfield 1991 24 25 28 29 0.99 [0.89, 1.10] + + + – + – + + + ?

2.4.4 Microbiological cure RCTs by person Portilla 1992 40 42 47 47 0.95 [0.88, 1.03] + + + – + – + + + ?

0.5 0.7 1 1.5 2 Favours [Ceftriaxone] Favours [Cefixime 800mg]

Web annex E – Systematic reviews

Cefixime 800 mg po × 1 (or cefixime 400 mg po × 2) by infections (number of infection sites) Microbiological cure Cefixime 800 mg po x 1 (or Cefixime 400 mg po X 2) ceftriaxone 250mg IM x1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 2.5.1 Microbiological cure RCTs by infections: all infections Portilla 1992 52 54 71 71 0.96 [0.90, 1.02] + + + – + – + + + ?

2.5.2 Microbiological cure RCTs by infections: Only cervix Portilla 1992 19 19 31 31 1.00 [0.92, 1.09] + + + – + – + + + ?

2.5.3 Microbiological cure RCTs by infections: Only urethra Portilla 1992 32 34 37 37 0.94 [0.85, 1.04] + + + – + – + + + ?

2.5.4 Microbiological cure RCTs by infections: Only rectum Portilla 1992 1 1 3 3 1.00 [0.41, 2.42] + + + – + – + + + ?

0.5 0.7 1 1.5 2 Favours [Ceftriaxone] Favours [Cefixime 800mg]

Ceftriazone vs gentamicin No studies were found for treatment comparison between ceftriazone and gentamicin

Spectinomycin 2 g IM × 1 by person (number of people) Microbiological cure

WHO guidelines for the treatment of Neisseria gonorrhoeae

Spectinomycin 2 gm IM x 1 Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 2.6.2 Microbiological cure RCTs by person: all infections Cheng 2001 45 46 48 48 8.3% 0.98 [0.92, 1.04] + + + – + – + + + ? Collier 1984 (1) 22 23 54 55 3.3% 0.97 [0.89, 1.07] + + + + + – + + + ? Mroczkowski 1993 73 74 38 40 5.1% 1.04 [0.96, 1.12] + + + – + – + + + ? Panikabutra 1985 93 93 97 97 67.7% 1.00 [0.98, 1.02] + ? + – + – + + + ? Shams 2009 94 100 90 100 4.4% 1.04 [0.96, 1.13] + ? + + + + + + + ? Tian 2002 104 110 113 115 11.2% 0.96 [0.91, 1.01] + ? + + + + + + + ? Subtotal (95% CI) 446 455 100.0% 1.00 [0.98, 1.01] Total events 431 440 Heterogeneity: Tau² = 0.00; Chi² = 5.02, df = 5 (P = 0.41); I² = 0% Test for overall effect: Z = 0.37 (P = 0.71)

2.6.3 Microbiological cure RCTs by person: all infections to penicilin negative N. gonorrhoea (PNNG) Handsfield 1983 56 58 28 28 100.0% 0.97 [0.91, 1.05] + + + – + – + + + ? Subtotal (95% CI) 58 28 100.0% 0.97 [0.91, 1.05] Total events 56 28 Heterogeneity: Not applicable Test for overall effect: Z = 0.70 (P = 0.48)

2.6.4 Microbiological cure RCTs by person: ucervix + urethra (women and men) Rompalo 1994 64 68 35 35 100.0% 0.95 [0.88, 1.02] + + + – + – + + + ? Subtotal (95% CI) 68 35 100.0% 0.95 [0.88, 1.02] Total events 64 35 Heterogeneity: Not applicable Test for overall effect: Z = 1.43 (P = 0.15)

2.6.5 Microbiological cure RCTs by person: cervix only women Rompalo 1994 28 28 13 13 100.0% 1.00 [0.89, 1.12] + + + – + – + + + ? Subtotal (95% CI) 28 13 100.0% 1.00 [0.89, 1.12] Total events 28 13 Heterogeneity: Not applicable Test for overall effect: Z = 0.00 (P = 1.00)

2.6.6 Microbiological cure RCTs by person: urethra only men Rompalo 1994 36 40 22 22 100.0% 0.91 [0.80, 1.03] + + + – + – + + + ? Subtotal (95% CI) 40 22 100.0% 0.91 [0.80, 1.03] Total events 36 22 Heterogeneity: Not applicable Test for overall effect: Z = 1.50 (P = 0.13)

0.5 0.7 1 1.5 2 Favours [Ceftriaxone] Favours [Spectinomycin]

Footnotes Risk of bias legend (1) Ceftriaxone dose is 125mg IM (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants ( clincal cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators (Clinical cure and a/e) (G) Blinding of the data analyst (H) Incomplete outcome data (attrition bias): (I) Selective reporting (reporting bias) (J) Other bias

Web annex E – Systematic reviews

Spectinomycin 2 g IM × 1 by infections (number of infection sites) Microbiological cure

Spectinomycin 2 gm IM x 1 Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 2.7.1 Microbiological cure RCTs by infections: all infections Judson 1985 9 9 52 52 1.00 [0.87, 1.16] + + + + + + + + + ?

2.7.2 Microbiological cure RCTs by infections: only cervix Collier 1984 (1) 20 21 52 53 0.97 [0.88, 1.08] + + + + + – + + + ?

2.7.3 Microbiological cure RCTs by infections: only rectum Collier 1984 (2) 12 12 23 23 1.00 [0.88, 1.13] + + + + + – + + + ? Handsfield 1983 21 22 6 6 1.01 [0.80, 1.27] + + + – + – + + + ?

2.7.4 Microbiological cure RCTs by infections: only urethra Handsfield 1983 50 52 27 27 0.97 [0.90, 1.05] + + + – + – + + + ?

2.7.5 Microbiological cure RCTs by infections: all sites of infection with 2 coinfections site Rompalo 1994 74 82 39 39 0.91 [0.84, 0.99] + + + – + – + + + ?

2.7.6 Microbiological cure RCTs by infections: cerrvix + urethral + rectum Rompalo 1994 66 70 37 37 0.95 [0.88, 1.02] + + + – + – + + + ?

0.5 0.7 1 1.5 2 Favours [Ceftriaxone] Favours [Spectinomycin]

Footnotes Risk of bias legend (1) Ceftriaxone dose is 125mg IM (A) Random sequence generation (selection bias) (2) Ceftriaxone dose is 125mg IM (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants ( clincal cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators (Clinical cure and a/e) (G) Blinding of the data analyst (H) Incomplete outcome data (attrition bias): (I) Selective reporting (reporting bias) (J) Other bias

Kanamycin 2 g by person (number of people) Microbiological cure Kanamycin 2 gm Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI 30.6.1 Microbiological cure non-RCTs by person Rajan 1982 (1) 168 183 54 54 0.92 [0.88, 0.97]

30.6.2 Microbiological cure non-RCTs by person in Penicilin producing N. gonorrhoea (PPNG) Rajan 1982 (2) 47 47 19 19 1.00 [0.93, 1.08]

0.5 0.7 1 1.5 2 Favours [Ceftriaxone] Favours [Kanamycin]

Footnotes (1) ceftriaxone dose is 125mg IM (2) ceftriaxone dose is 125mg IM

Ceftriaxone 125 mg IM × 1 by person (number of people) Microbiological cure

Ceftriaxone 125 mg IM x 1 Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 2.9.1 Microbiological cure RCTs by person: all infections Handsfield 1981 (1) 15 15 16 16 1.00 [0.89, 1.13] + + + + + + + + + ? Handsfield 1981 15 15 16 16 1.00 [0.89, 1.13] + + + + + + + + + ?

2.9.2 Microbiological cure RCTs by person: all infections with penicilin negative N. gonorrhoea (PNNG) Handsfield 1983 31 31 28 28 1.00 [0.94, 1.07] + + + – + – + + + ?

0.5 0.7 1 1.5 2 Favours [Ceftriaxonel] Favours [Ceftriaxone ]

Footnotes Risk of bias legend (1) Ceftriaxone dose 500mg (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants ( clincal cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators (Clinical cure and a/e) (G) Blinding of the data analyst (H) Incomplete outcome data (attrition bias): (I) Selective reporting (reporting bias) (J) Other bias

WHO guidelines for the treatment of Neisseria gonorrhoeae

Ceftriaxone 125 mg IM × 1 by infections (number of infections) Microbiological cure

Ceftriaxone 125 mg IM x 1 Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 2.10.1 Microbiological cure RCTs by infections: only rectum Handsfield 1981 3 3 5 5 22.1% 1.00 [0.64, 1.56] Handsfield 1983 8 8 6 6 64.2% 1.00 [0.77, 1.30] Handsfield 1981 (1) 2 2 5 5 13.7% 1.00 [0.57, 1.75] Subtotal (95% CI) 13 16 100.0% 1.00 [0.81, 1.23] Total events 13 16 Heterogeneity: Tau² = 0.00; Chi² = 0.00, df = 2 (P = 1.00); I² = 0% Test for overall effect: Z = 0.00 (P = 1.00)

2.10.2 Microbiological cure RCTs by infections: only urethra Handsfield 1981 (2) 14 14 14 14 18.5% 1.00 [0.88, 1.14] Handsfield 1981 14 14 14 14 18.5% 1.00 [0.88, 1.14] Handsfield 1983 26 26 27 27 63.0% 1.00 [0.93, 1.07] Subtotal (95% CI) 54 55 100.0% 1.00 [0.94, 1.06] Total events 54 55 Heterogeneity: Tau² = 0.00; Chi² = 0.00, df = 2 (P = 1.00); I² = 0% Test for overall effect: Z = 0.00 (P = 1.00)

0.5 0.7 1 1.5 2 Favours [Ceftriaxonel] Favours [Ceftriaxone ]

Footnotes (1) Ceftriaxone dose 500mg (2) Ceftriaxone dose 500mg

Clinical cure

No studies were found comparing these treatments for clinical cure.

Ceftriaxone 250 mg IM × 1 vs azithromycin 1–2 g po × 1 Ceftriaxone 250 mg IM × 1 vs cefixime 400 mg po × 1 Ceftriaxone 250 mg IM × 1 vs cefixime 800 mg po × 1 (or cefixime 400 mg po × 2) Ceftriazone 250 mg IM × 1 vs gentamicin

Spectinomycin 2 g IM × 1 by person (number of people) Clinical cure

Spectinomycin 2 gm IM x 1 Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 31.5.1 Clinical cure RCTs by person Cheng 2001 40 46 42 48 1.9% 0.99 [0.85, 1.16] + + + – + – + + + ? Mroczkowski 1993 72 74 40 40 15.8% 0.98 [0.93, 1.03] + + + – + – + + + ? Tian 2002 83 83 81 81 82.3% 1.00 [0.98, 1.02] + ? + + + + + + + ? Subtotal (95% CI) 203 169 100.0% 1.00 [0.98, 1.02] Total events 195 163 Heterogeneity: Tau² = 0.00; Chi² = 0.67, df = 2 (P = 0.71); I² = 0% Test for overall effect: Z = 0.32 (P = 0.75)

Total (95% CI) 203 169 100.0% 1.00 [0.98, 1.02] Total events 195 163 Heterogeneity: Tau² = 0.00; Chi² = 0.67, df = 2 (P = 0.71); I² = 0% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 0.32 (P = 0.75) Favours [Ceftriaxonel] Favours [Spectinomycin] Test for subgroup differences: Not applicable Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants ( clincal cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators (Clinical cure and a/e) (G) Blinding of the data analyst (H) Incomplete outcome data (attrition bias): (I) Selective reporting (reporting bias) (J) Other bias

Web annex E – Systematic reviews

Spectinomycin 2 g IM × 1 by infections (number of infections) Clinical cure

Spectinomycin 2 gm IM x 1 Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 31.6.1 Clinical cure RCT by infections: only rectal Tian 2002 4 5 7 8 0.91 [0.55, 1.52] + ? + + + + + + + ?

0.5 0.7 1 1.5 2 Favours [Ceftriaxonel] Favours [Spectinomycin]

Ceftriaxone vs kanamycin 2 g No studies were found comparing the above treatments for clinical cure.

Ceftriaxone 125 mg IM × 1 by person (number of people) Clinical cure

Ceftriaxone 125 mg IM x 1 Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 31.7.1 Clinical cure RCTs by person Handsfield 1981 15 15 16 16 1.00 [0.89, 1.13] + + + + + + + + + ?

0.5 0.7 1 1.5 2 Favours [Ceftriaxone 250] Favours [Ceftriaxone 125]

STI complications Transmission to partners Compliance Gonorrhoea antimicrobial in vitro resistance HIV transmission and acquisition No comparative studies reported on these outcomes.

WHO guidelines for the treatment of Neisseria gonorrhoeae

Azithromycin 1–2 g po × 1 Side-effects

Azithromycin 1-2 gm po x 1 Ceftriaxone 250mg IM X1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 33.1.1 Side effects: dizziness Handsfield 1994 6 431 0 212 6.41 [0.36, 113.25] + + + – + – + + + ?

33.1.2 Side effects: Pain at infection site Handsfield 1994 0 431 7 212 0.03 [0.00, 0.57] + + + – + – + + + ?

33.1.3 Side effects: gastrointestinal- nasea, vomiting, dispepsya and abdominnal pain and diarrhoea Handsfield 1994 152 431 5 212 14.95 [6.23, 35.89] + + + – + – + + + ?

0.1 0.2 0.5 1 2 5 10 Favours [Azithromycin] Favours [Ceftriaxone]

Cefixime 400 mg po × 1 Side-effects

Cefixime 400 mg po x 1 Ceftriaxone 250mg IM X1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 33.2.1 Side effects:gastrointestinal-mild diarrhoea, loose stools or flatulence Handsfield 1991 9 107 4 104 68.7% 2.19 [0.69, 6.88] + + + – + – + + + ? Portilla 1992 10 56 1 47 31.3% 8.39 [1.11, 63.19] + + + – + – + + + ? Subtotal (95% CI) 163 151 100.0% 3.33 [0.95, 11.72] Total events 19 5 Heterogeneity: Tau² = 0.26; Chi² = 1.37, df = 1 (P = 0.24); I² = 27% Test for overall effect: Z = 1.87 (P = 0.06)

33.2.2 Side effects: mild nausea or epigastric pain or Headache Handsfield 1991 11 107 15 104 79.9% 0.71 [0.34, 1.48] + + + – + – + + + ? Plourde 1992 0 121 2 63 20.1% 0.10 [0.01, 2.15] + + + – + – + + + ? Subtotal (95% CI) 228 167 100.0% 0.49 [0.11, 2.21] Total events 11 17 Heterogeneity: Tau² = 0.61; Chi² = 1.49, df = 1 (P = 0.22); I² = 33% Test for overall effect: Z = 0.93 (P = 0.35)

33.2.3 Side effects: Fever Plourde 1992 1 121 1 63 100.0% 0.52 [0.03, 8.19] + + + – + – + + + ? Subtotal (95% CI) 121 63 100.0% 0.52 [0.03, 8.19] Total events 1 1 Heterogeneity: Not applicable Test for overall effect: Z = 0.46 (P = 0.64)

33.2.4 Side effects: candidal vaginitis Plourde 1992 1 121 1 63 100.0% 0.52 [0.03, 8.19] + + + – + – + + + ? Subtotal (95% CI) 121 63 100.0% 0.52 [0.03, 8.19] Total events 1 1 Heterogeneity: Not applicable Test for overall effect: Z = 0.46 (P = 0.64)

33.2.5 Side effects: pruritis Plourde 1992 0 121 2 63 100.0% 0.10 [0.01, 2.15] + + + – + – + + + ? Subtotal (95% CI) 121 63 100.0% 0.10 [0.01, 2.15] Total events 0 2 Heterogeneity: Not applicable Test for overall effect: Z = 1.46 (P = 0.14)

0.01 0.1 1 10 100 Favours [Cefixime400mg] Favours [Ceftriaxone]

Web annex E – Systematic reviews

Cefixime 800 mg po × 1 (or cefixime 400 mg po × 2) Side-effects Cefixime 800 mg po x 1 (or Cefixime 400 mg po X 2) Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 33.3.1 Side effects: gastrointestinal - mild diarrhoea, loose stools or flatulence Handsfield 1991 16 91 4 104 81.5% 4.57 [1.59, 13.18] Portilla 1992 3 39 1 47 18.5% 3.62 [0.39, 33.39] Subtotal (95% CI) 130 151 100.0% 4.38 [1.68, 11.39] Total events 19 5 Heterogeneity: Tau² = 0.00; Chi² = 0.03, df = 1 (P = 0.85); I² = 0% Test for overall effect: Z = 3.03 (P = 0.002)

33.3.2 Side effects: mild nausea or epigastric pain Handsfield 1991 18 91 15 104 100.0% 1.37 [0.73, 2.56] Subtotal (95% CI) 91 104 100.0% 1.37 [0.73, 2.56] Total events 18 15 Heterogeneity: Not applicable Test for overall effect: Z = 0.99 (P = 0.32)

0.1 0.2 0.5 1 2 5 10 Favours [Cifixime 800mg] Favours [Ceftriaxone]

Ceftriaxone 250 mg IM × 1 vs gentamicin No studies were found on side-effects for this treatment comparison

Spectinomycin 2 g IM × 1 Side-effects

Spectinomycin 2 gm IM x 1 Ceftriaxone 250mg IM X1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 33.5.1 Side effects: general side effects Cheng 2001 0 46 0 48 Not estimable + + + – + – + + + ? Handsfield 1983 0 58 0 28 Not estimable + + + – + – + + + ? Judson 1985 0 23 1 84 1.18 [0.05, 28.06] + + + + + + + + + ? Panikabutra 1985 0 93 0 97 Not estimable + ? + – + – + + + ?

33.5.2 Side effects: mild to moderate pain or tenderness at injection sites Mroczkowski 1993 5 74 4 40 0.68 [0.19, 2.38] + + + – + – + + + ? Rompalo 1994 23 40 10 22 1.26 [0.74, 2.15] + + + – + – + + + ?

33.5.3 Side effects:generalized pruritic maculo-papular rash with slight oedema of the skin of both hands & maculopapulau skin rash and periorbital edema Mroczkowski 1993 1 74 0 40 1.64 [0.07, 39.35] + + + – + – + + + ? Rompalo 1994 1 40 0 22 1.68 [0.07, 39.65] + + + – + – + + + ?

33.5.4 Side effects:pelvic adnexal tenderness with mild pelvic inflammatory disease Collier 1984 1 24 0 55 6.72 [0.28, 159.30] + + + + + – + + + ?

33.5.5 Side effects: Complication: Occurrence of PGU - post gonococcal urethritis Handsfield 1983 9 47 4 22 1.05 [0.36, 3.05] + + + – + – + + + ?

0.1 0.2 0.5 1 2 5 10 Favours [Spectinomycin] Favours [Ceftriaxone]

WHO guidelines for the treatment of Neisseria gonorrhoeae

Kanamycin 2 g Side-effects Kanamycin 2 gm IM x 1 Ceftriaxone 250mg IM X1 Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI 33.6.1 Side effects: general side effects Rajan 1982 (1) 0 183 0 54 Not estimable

33.6.2 Side effects: Occurance of post gonococcal urethritis (PGU) Rajan 1982 (2) 10 183 3 54 0.98 [0.28, 3.45]

0.1 0.2 0.5 1 2 5 10 Favours [Kanamycin] Favours [Ceftriaxone]

Footnotes (1) ceftriaxone dose is 125mg IM (2) ceftriaxone dose is 125mg IM

Ceftriaxone 125 mg IM × 1 Side-effects Ceftriaxone 125 mg IM x 1 Ceftriaxone 250mg IM X1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 33.7.1 Side effects: general side effects Handsfield 1981 0 15 0 16 Not estimable + + + + + + + + + ? Handsfield 1983 0 31 0 28 Not estimable + + + – + – + + + ?

33.7.2 Side effects: Complication: Occurrence of PGU - post gonococcal urethritis Handsfield 1983 7 22 4 22 1.75 [0.60, 5.14] + + + – + – + + + ?

0.1 0.2 0.5 1 2 5 10 Favours [Ceftriaxone 125] Favours [Ceftriaxone 250]

Quality of life No comparative study reported on this outcome.

Non-randomized studies with one group

Comparison of azithromycin 1 g and 2 g Azithromycin 1 g po × 1: microbiological cure by person (1-arm studies)

event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 35.2.1 Azithromycin 1gm po x 1 by person : Microbiological cure by person (1 arm studies) Gruber 1995 0.96 0.04804813 24 25 2.0% 0.96 [0.87, 1.05] Gruber 1997 0.96 0.031522 48 50 4.6% 0.96 [0.90, 1.02] Habib 2004 0.9882353 0.009858 168 170 47.3% 0.99 [0.97, 1.01] Lassus 1990 1 0.04110462 20 20 2.7% 1.00 [0.92, 1.08] Ling 2000 0.8595506 0.026056 153 178 6.8% 0.86 [0.81, 0.91] Odugbemi 1993 0.95 0.02083932 114 120 10.6% 0.95 [0.91, 0.99] Rustomjee 2002 0.9677419 0.039854 30 31 2.9% 0.97 [0.89, 1.05] Steingrimsson 1990 0.91666667 0.086485 11 12 0.6% 0.92 [0.75, 1.09] Steingrimsson 1994 0.96428571 0.04356975 27 28 2.4% 0.96 [0.88, 1.05] Swanston 2001 0.95275591 0.01974889 125 127 11.8% 0.95 [0.91, 0.99] Waugh 1993 0.95505618 0.02355048 85 89 8.3% 0.96 [0.91, 1.00] Subtotal (95% CI) 805 850 100.0% 0.97 [0.95, 0.98] Heterogeneity: Chi² = 24.09, df = 10 (P = 0.007); I² = 58% Test for overall effect: Z = 142.39 (P < 0.00001)

Total (95% CI) 805 850 100.0% 0.97 [0.95, 0.98] Heterogeneity: Chi² = 24.09, df = 10 (P = 0.007); I² = 58% -2 -1 0 1 2 Test for overall effect: Z = 142.39 (P < 0.00001) Favours [experimental] Favours [control] Test for subgroup differences: Not applicable 34

Web annex E – Systematic reviews

Azithromycin 2 g po × 1: microbiological cure by person (1-arm studies)

event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 35.3.1 Azithromycin 2 gm po x 1 by person: Microbiological cure by person (1 arm studies) Handsfield 1994 0.98930481 0.00586905 370 374 96.5% 0.99 [0.98, 1.00] Khaki 2007 1 0.037923 22 22 2.3% 1.00 [0.93, 1.07] Takahashi 2014 0.9090909 0.052124 30 33 1.2% 0.91 [0.81, 1.01] Subtotal (95% CI) 422 429 100.0% 0.99 [0.98, 1.00] Heterogeneity: Chi² = 2.43, df = 2 (P = 0.30); I² = 18% Test for overall effect: Z = 171.50 (P < 0.00001)

Total (95% CI) 422 429 100.0% 0.99 [0.98, 1.00] Heterogeneity: Chi² = 2.43, df = 2 (P = 0.30); I² = 18% -2 -1 0 1 2 Test for overall effect: Z = 171.50 (P < 0.00001) Favours [experimental] Favours [control] Test for subgroup differences: Not applicable

Azithromycin 1–2 g po × 1 Microbiological cure by number of people

event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Random, 95% CI IV, Random, 95% CI 35.1.1 Non-randomised with 1 group : Microbiological cure by person at 7th day visit Gruber 1997 0.96 0.031522 48 50 7.9% 0.96 [0.90, 1.02] Habib 2004 0.9882353 0.009858 168 170 15.4% 0.99 [0.97, 1.01] Handsfield 1994 0.98930481 0.00586905 370 374 16.5% 0.99 [0.98, 1.00] Khaki 2007 1 0.037923 22 22 6.3% 1.00 [0.93, 1.07] Ling 2000 0.8595506 0.026056 153 178 9.5% 0.86 [0.81, 0.91] Odugbemi 1993 0.92682927 0.02404492 114 123 10.2% 0.93 [0.88, 0.97] Rustomjee 2002 0.9677419 0.039854 30 31 5.9% 0.97 [0.89, 1.05] Steingrimsson 1990 0.91666667 0.086485 11 12 1.7% 0.92 [0.75, 1.09] Swanston 2001 0.95275591 0.01974889 121 127 11.7% 0.95 [0.91, 0.99] Takahashi 2014 0.9090909 0.052124 30 33 4.0% 0.91 [0.81, 1.01] Waugh 1993 0.95698925 0.02259599 89 93 10.7% 0.96 [0.91, 1.00] Subtotal (95% CI) 1156 1213 100.0% 0.96 [0.93, 0.98] Heterogeneity: Tau² = 0.00; Chi² = 35.45, df = 10 (P = 0.0001); I² = 72% Test for overall effect: Z = 79.67 (P < 0.00001)

35.1.2 Non-randomised with 1 group : Microbiological cure by person at 14th day visit Gruber 1997 0.96 0.031522 48 50 19.6% 0.96 [0.90, 1.02] Handsfield 1994 1 0.00451943 213 213 80.4% 1.00 [0.99, 1.01] Subtotal (95% CI) 261 263 100.0% 0.99 [0.96, 1.02] Heterogeneity: Tau² = 0.00; Chi² = 1.58, df = 1 (P = 0.21); I² = 37% Test for overall effect: Z = 62.50 (P < 0.00001)

35.1.3 Non-randomised with 1 group : Microbiological cure by person with penicilin producing N. gonorrhoeae (PPNG) Odugbemi 1993 0.9122807 0.0269464 104 114 100.0% 0.91 [0.86, 0.97] Subtotal (95% CI) 104 114 100.0% 0.91 [0.86, 0.97] Heterogeneity: Not applicable Test for overall effect: Z = 33.86 (P < 0.00001)

-2 -1 0 1 2 Favours [experimental] Favours [control]

Azithromycin 1–2 g po × 1 Microbiological cure by number of infection sites

event total proportion proportion Study or Subgroup proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 36.2.1 Non-randomised with 1 group : Microbiological cure by infections: only urethral Waugh 1993 0.95698925 0.02259599 78 82 0.96 [0.91, 1.00]

36.2.2 Non-randomised with 1 group : Microbiological cure by infections: only rectum Handsfield 1994 0.96296296 0.04496698 26 27 0.96 [0.87, 1.05]

-2 -1 0 1 2 Favours [experimental] Favours [control]

WHO guidelines for the treatment of Neisseria gonorrhoeae

Ceftriaxone ≥ 250 mg IM × 1 Microbiological cure by number of people

event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 35.3.1 Non-randomised with 1 group : Microbiological cure by person Baddour 1992 0.9896907 0.013848 96 97 4.8% 0.99 [0.96, 1.02] Calderon 1988 1 0.022353 40 40 1.9% 1.00 [0.96, 1.04] Christophersen 1989 0.9934211 0.008969 151 152 11.5% 0.99 [0.98, 1.01] Covino 1990 0.9761905 0.030357 41 42 1.0% 0.98 [0.92, 1.04] Dixon 1986 1 0.013454 69 69 5.1% 1.00 [0.97, 1.03] Dixon 1986 (1) 1 0.02342167 38 38 1.7% 1.00 [0.95, 1.05] Goldstein 1991 1 0.009623 98 98 10.0% 1.00 [0.98, 1.02] Handsfield 1981 (2) 1 0.05201257 15 15 0.3% 1.00 [0.90, 1.10] Handsfield 1981 1 0.04939118 16 16 0.4% 1.00 [0.90, 1.10] Hook 1993 0.9885057 0.015368 86 87 3.9% 0.99 [0.96, 1.02] Jin 2001 1 0.012122 77 77 6.3% 1.00 [0.98, 1.02] Judson 1983 1 0.03651 23 23 0.7% 1.00 [0.93, 1.07] Khrianin 2006 1 0.007978 119 119 14.6% 1.00 [0.98, 1.02] Korting 1989 1 0.025231 35 35 1.5% 1.00 [0.95, 1.05] McCormack 1993 0.9910314 0.007562 221 223 16.2% 0.99 [0.98, 1.01] Mogabgab 1994 1 0.011551 81 81 6.9% 1.00 [0.98, 1.02] Muratani 2008 1 0.018904 48 48 2.6% 1.00 [0.96, 1.04] Pabst 1989 0.97333333 0.02162579 73 75 2.0% 0.97 [0.93, 1.02] Tian 2002 0.9826087 0.01439263 113 115 4.5% 0.98 [0.95, 1.01] Zajdowicz 1983 1 0.015114 61 61 4.1% 1.00 [0.97, 1.03] Subtotal (95% CI) 1501 1511 100.0% 1.00 [0.99, 1.00] Heterogeneity: Chi² = 4.26, df = 19 (P = 1.00); I² = 0% Test for overall effect: Z = 326.86 (P < 0.00001)

35.3.2 Non-randomised with 1 group : Microbiological cure by person between 3 to 5 day visit Bryan 1990 0.9878049 0.01626 81 82 24.7% 0.99 [0.96, 1.02] Cheng 2001 1 0.01890374 48 48 18.3% 1.00 [0.96, 1.04] Handsfield 1983 1 0.03077735 28 28 6.9% 1.00 [0.94, 1.06] Handsfield 1994 0.97714286 0.01233815 171 175 43.0% 0.98 [0.95, 1.00] Shams 2009 0.9 0.03039254 90 100 7.1% 0.90 [0.84, 0.96] Subtotal (95% CI) 418 433 100.0% 0.98 [0.96, 1.00] Heterogeneity: Chi² = 8.75, df = 4 (P = 0.07); I² = 54% Test for overall effect: Z = 121.18 (P < 0.00001)

35.3.3 Non-randomised with 1 group : Microbiological cure by person between 7 to 10 day visit Bryan 1990 1 0.016943 54 54 12.1% 1.00 [0.97, 1.03] Handsfield 1991 0.9787234 0.01745853 92 94 11.4% 0.98 [0.94, 1.01] Handsfield 1994 0.98765432 0.01645098 80 81 12.8% 0.99 [0.96, 1.02] Mroczkowski 1993 0.95 0.03857687 38 40 2.3% 0.95 [0.87, 1.03] Panikabutra 1985 1 0.00971821 97 97 36.7% 1.00 [0.98, 1.02] Plourde 1992 1 0.01466153 63 63 16.1% 1.00 [0.97, 1.03] Rompalo 1994 1 0.02006486 45 45 8.6% 1.00 [0.96, 1.04] Subtotal (95% CI) 469 474 100.0% 0.99 [0.98, 1.01] Heterogeneity: Chi² = 2.96, df = 6 (P = 0.81); I² = 0% Test for overall effect: Z = 168.99 (P < 0.00001)

35.3.4 Non-randomised with 1 group : Microbiological cure by person with penicilin producing N. gonorrhoeae (PPNG) Zajdowicz 1983 1 0.02459741 36 36 100.0% 1.00 [0.95, 1.05] Subtotal (95% CI) 36 36 100.0% 1.00 [0.95, 1.05] Heterogeneity: Not applicable Test for overall effect: Z = 40.65 (P < 0.00001)

-2 -1 0 1 2 Favours [ceftriaxone] Favours [control]

Footnotes (1) Dose 500mg (2) Dose 500mg

Web annex E – Systematic reviews

Ceftriaxone ≥ 250 mg IM × 1 Microbiological cure by number of infection sites event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 35.4.1 Non-randomised with 1 group : Microbiological cure by infections: all infections Covino 1990 0.97916667 0.0268642 47 48 2.4% 0.98 [0.93, 1.03] Dixon 1986 (1) 1 0.01754964 52 52 5.5% 1.00 [0.97, 1.03] Dixon 1986 1 0.010556 89 89 15.3% 1.00 [0.98, 1.02] Hook 1993 0.99047619 0.01283276 104 105 10.3% 0.99 [0.97, 1.02] McCormack 1993 0.9923664 0.006455 260 262 40.8% 0.99 [0.98, 1.01] Mogabgab 1994 1 0.008841 107 107 21.7% 1.00 [0.98, 1.02] Pabst 1989 0.97468354 0.02059115 77 79 4.0% 0.97 [0.93, 1.02] Subtotal (95% CI) 736 742 100.0% 0.99 [0.99, 1.00] Heterogeneity: Chi² = 2.22, df = 6 (P = 0.90); I² = 0% Test for overall effect: Z = 241.19 (P < 0.00001)

35.4.2 Non-randomised with 1 group : Microbiological cure by infections: only rectum Baddour 1992 1 0.090393 7 7 5.2% 1.00 [0.82, 1.18] Covino 1993 1 0.11083967 5 5 3.5% 1.00 [0.78, 1.22] Handsfield 1983 1 0.0995773 6 6 4.3% 1.00 [0.80, 1.20] Handsfield 1994 1 0.04702134 17 17 19.4% 1.00 [0.91, 1.09] Hook 1993 1 0.03944996 21 21 27.5% 1.00 [0.92, 1.08] Mogabgab 1994 1 0.14324135 3 3 2.1% 1.00 [0.72, 1.28] Pabst 1989 1 0.11083967 5 5 3.5% 1.00 [0.78, 1.22] Smith 1993 1 0.035199 24 24 34.5% 1.00 [0.93, 1.07] Subtotal (95% CI) 88 88 100.0% 1.00 [0.96, 1.04] Heterogeneity: Chi² = 0.00, df = 7 (P = 1.00); I² = 0% Test for overall effect: Z = 48.34 (P < 0.00001)

35.4.3 Non-randomised with 1 group : Microbiological cure by infections: only urethra Baddour 1992 0.9897959 0.013712 97 98 8.1% 0.99 [0.96, 1.02] Handsfield 1983 1 0.03177526 27 27 1.5% 1.00 [0.94, 1.06] Judson 1983 1 0.06186244 12 12 0.4% 1.00 [0.88, 1.12] McCormack 1993 1 0.00743316 128 128 27.4% 1.00 [0.99, 1.01] Mogabgab 1994 1 0.01637657 56 56 5.6% 1.00 [0.97, 1.03] Pabst 1989 0.98305085 0.02218398 58 59 3.1% 0.98 [0.94, 1.03] Smith 1993 1 0.005302 181 181 53.9% 1.00 [0.99, 1.01] Subtotal (95% CI) 559 561 100.0% 1.00 [0.99, 1.01] Heterogeneity: Chi² = 1.02, df = 6 (P = 0.98); I² = 0% Test for overall effect: Z = 256.57 (P < 0.00001)

35.4.4 Non-randomised with 1 group : Microbiological cure by infections: only genital -cervix Baddour 1992 1 0.025231 35 35 5.3% 1.00 [0.95, 1.05] Covino 1993 0.9666667 0.04102 29 30 2.0% 0.97 [0.89, 1.05] Hook 1993 0.98809524 0.01589093 83 84 13.3% 0.99 [0.96, 1.02] Judson 1983 1 0.03792335 22 22 2.3% 1.00 [0.93, 1.07] McCormack 1993 0.9826087 0.01439263 113 115 16.2% 0.98 [0.95, 1.01] Mogabgab 1994 1 0.01890374 48 48 9.4% 1.00 [0.96, 1.04] Pabst 1989 0.97468354 0.02059115 14 15 7.9% 0.97 [0.93, 1.02] Smith 1993 1 0.008762 108 108 43.7% 1.00 [0.98, 1.02] Subtotal (95% CI) 452 457 100.0% 0.99 [0.98, 1.00] Heterogeneity: Chi² = 2.71, df = 7 (P = 0.91); I² = 0% Test for overall effect: Z = 171.50 (P < 0.00001)

35.4.5 Non-randomised with 1 group : Microbiological cure by infections: only anal Covino 1990 0.83333333 0.13608593 5 6 21.3% 0.83 [0.57, 1.10] Judson 1983 1 0.07080106 10 10 78.7% 1.00 [0.86, 1.14] Subtotal (95% CI) 15 16 100.0% 0.96 [0.84, 1.09] Heterogeneity: Chi² = 1.18, df = 1 (P = 0.28); I² = 15% Test for overall effect: Z = 15.36 (P < 0.00001)

-2 -1 0 1 2 Favours [ceftriaxone] Favours [control]

Footnotes (1) Dose 500mg

WHO guidelines for the treatment of Neisseria gonorrhoeae

Comparison of cefixime 400 mg po × 1 and cefixime 800 mg po × 1 (or cefixime 400 mg po × 2) Cefixime 400 mg po × 1 Microbiological cure by person (1-arm studies)

event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 35.22.1 Cefixime 400 mg po x 1 : Microbiological cure by person (1 arm studies) Aplasca 2001 0.9615385 0.046457 25 26 3.0% 0.96 [0.87, 1.05] Backhaus 1990 0.9285714 0.077033 13 14 1.1% 0.93 [0.78, 1.08] Handsfield 1991 0.95698925 0.02259599 89 93 12.6% 0.96 [0.91, 1.00] Hook 1997 0.9666667 0.015646 145 150 26.2% 0.97 [0.94, 1.00] Mroczkowski 1997 0.9465649 0.020426 124 131 15.4% 0.95 [0.91, 0.99] Plourde 1992 0.97520661 0.0157904 118 121 25.7% 0.98 [0.94, 1.01] Portilla 1992 0.98484848 0.01996978 65 66 16.1% 0.98 [0.95, 1.02] Subtotal (95% CI) 579 601 100.0% 0.97 [0.95, 0.98] Heterogeneity: Chi² = 2.53, df = 6 (P = 0.87); I² = 0% Test for overall effect: Z = 120.73 (P < 0.00001)

Total (95% CI) 579 601 100.0% 0.97 [0.95, 0.98] Heterogeneity: Chi² = 2.53, df = 6 (P = 0.87); I² = 0% -2 -1 0 1 2 Test for overall effect: Z = 120.73 (P < 0.00001) Favours [cefixim] Favours [control] Test for subgroup differences: Not applicable

Cefixime 800 mg po × 1 (or cefixime 400 mg po × 2) all provided as single dose Microbiological cure by person (1-arm studies)

event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 35.23.1 Cefixime 800 mg po x 1 (or Cefixime 400 mg po X 2): Microbiological cure by person (1 arm studies) Dunnett 1992 0.9726027 0.022183 71 73 35.9% 0.97 [0.93, 1.02] Handsfield 1991 0.97727273 0.01858984 86 88 51.1% 0.98 [0.94, 1.01] Portilla 1992 0.95238095 0.03692452 40 42 13.0% 0.95 [0.88, 1.02] Subtotal (95% CI) 197 203 100.0% 0.97 [0.95, 1.00] Heterogeneity: Chi² = 0.36, df = 2 (P = 0.83); I² = 0% Test for overall effect: Z = 73.15 (P < 0.00001)

Total (95% CI) 197 203 100.0% 0.97 [0.95, 1.00] Heterogeneity: Chi² = 0.36, df = 2 (P = 0.83); I² = 0% -2 -1 0 1 2 Test for overall effect: Z = 73.15 (P < 0.00001) Favours [cefixim] Favours [control] Test for subgroup differences: Not applicable

Cefixime 400 mg po × 1 Microbiological cure by number of people

event total proportion proportion Study or Subgroup proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 35.5.1 Non-randomised with 1 group : Microbiological cure by person Aplasca 2001 0.9615385 0.046457 25 26 0.96 [0.87, 1.05] Hook 1997 0.9666667 0.015646 145 150 0.97 [0.94, 1.00] Mroczkowski 1997 0.9465649 0.020426 124 131 0.95 [0.91, 0.99] Verdon 1993 (1) 0.9489796 0.023454 93 98 0.95 [0.90, 0.99]

35.5.2 Non-randomised with 1 group : Microbiological cure by person after 3 days of visit Backhaus 1990 1 0.054928 14 14 1.00 [0.89, 1.11] Handsfield 1991 0.95698925 0.02259599 89 93 0.96 [0.91, 1.00] Plourde 1992 0.97520661 0.0157904 118 121 0.98 [0.94, 1.01] Portilla 1992 0.98484848 0.01996978 65 66 0.98 [0.95, 1.02]

35.5.3 Non-randomised with 1 group : Microbiological cure by person after 13 days of visit Backhaus 1990 0.9285714 0.077033 13 14 0.93 [0.78, 1.08]

-2 -1 0 1 2 Favours [cefixim] Favours [control]

Footnotes (1) Cefixime dose is 200mg oral

Web annex E – Systematic reviews

Cefixime 200 mg po × 1 or 200 mg po × 2 Microbiological cure by number of people

event total proportion proportion Study or Subgroup proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 35.24.1 Cefixime 200 mg po x 1 : Microbiological cure by person (1 arm studies) Verdon 1993 0.9489796 0.023454 93 98 0.95 [0.90, 0.99]

35.24.2 Cefixime 200 mg po x 2 : Microbiological cure by person (1 arm studies) Deguchi 2003 0.88235294 0.0394176 60 68 0.88 [0.81, 0.96]

-2 -1 0 1 2 Favours [cefixim] Favours [control]

Cefixime 400 mg po × 1 Microbiological cure by number of infection sites

event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 35.8.1 Non-randomised with 1 group : Microbiological cure by infections: all infections Hook 1997 0.9673203 0.015351 148 153 20.8% 0.97 [0.94, 1.00] Mroczkowski 1997 0.9877301 0.01027 161 163 46.5% 0.99 [0.97, 1.01] Portilla 1992 0.98913044 0.01456837 91 92 23.1% 0.99 [0.96, 1.02] Verdon 1993 (1) 0.9509804 0.022587 97 102 9.6% 0.95 [0.91, 1.00] Subtotal (95% CI) 497 510 100.0% 0.98 [0.97, 0.99] Heterogeneity: Chi² = 3.29, df = 3 (P = 0.35); I² = 9% Test for overall effect: Z = 140.00 (P < 0.00001)

35.8.2 Non-randomised with 1 group : Microbiological cure by infections: only rectum Hook 1997 1 0.14324135 3 3 4.9% 1.00 [0.72, 1.28] Mroczkowski 1997 0.97368421 0.03323758 37 38 91.5% 0.97 [0.91, 1.04] Portilla 1992 1 0.16776226 2 2 3.6% 1.00 [0.67, 1.33] Subtotal (95% CI) 42 43 100.0% 0.98 [0.91, 1.04] Heterogeneity: Chi² = 0.05, df = 2 (P = 0.97); I² = 0% Test for overall effect: Z = 30.70 (P < 0.00001)

35.8.3 Non-randomised with 1 group : Microbiological cure by infections: only cervix Mroczkowski 1997 0.992 0.01084497 124 125 78.1% 0.99 [0.97, 1.01] Portilla 1992 1 0.02048426 44 44 21.9% 1.00 [0.96, 1.04] Subtotal (95% CI) 168 169 100.0% 0.99 [0.97, 1.01] Heterogeneity: Chi² = 0.12, df = 1 (P = 0.73); I² = 0% Test for overall effect: Z = 103.68 (P < 0.00001)

35.8.4 Non-randomised with 1 group : Microbiological cure by infections: only urethra Portilla 1992 0.97826087 0.02793566 45 46 100.0% 0.98 [0.92, 1.03] Subtotal (95% CI) 45 46 100.0% 0.98 [0.92, 1.03] Heterogeneity: Not applicable Test for overall effect: Z = 35.02 (P < 0.00001)

-2 -1 0 1 2 Favours [cefixim] Favours [control]

Footnotes (1) cefixime dose is 200mg oral

WHO guidelines for the treatment of Neisseria gonorrhoeae

Cefixime 800 mg po × 1 (or cefixime 400 mg po × 2) Microbiological cure by number of people

event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 35.9.1 Non-randomised with 1 group : Microbiological cure by person Dunnett 1992 0.9726027 0.022183 71 73 35.9% 0.97 [0.93, 1.02] Handsfield 1991 0.97727273 0.01858984 86 88 51.1% 0.98 [0.94, 1.01] Portilla 1992 0.95238095 0.03692452 40 42 13.0% 0.95 [0.88, 1.02] Subtotal (95% CI) 197 203 100.0% 0.97 [0.95, 1.00] Heterogeneity: Chi² = 0.36, df = 2 (P = 0.83); I² = 0% Test for overall effect: Z = 73.15 (P < 0.00001)

Cefixime 800 mg po × 1 (or cefixime 400 mg po × 2) – all single doses Microbiological cure by number of infection sites

event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 35.8.1 Non-randomised with 1 group : Microbiological cure by infections Megran 1990 (1) 0.9897959 0.013712 97 98 82.1% 0.99 [0.96, 1.02] Portilla 1992 0.96296296 0.02937192 52 54 17.9% 0.96 [0.91, 1.02] Subtotal (95% CI) 149 152 100.0% 0.98 [0.96, 1.01] Heterogeneity: Chi² = 0.69, df = 1 (P = 0.41); I² = 0% Test for overall effect: Z = 79.28 (P < 0.00001)

-2 -1 0 1 2 Favours [cefixim] Favours [control]

Footnotes (1) dose 200mg 4 capcules X1

Gentamicin 240 mg IM × 1: all single doses Microbiological cure by number of people (1-arm studies)

event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 35.25.1 Gentamicin 240 mg IM : Microbiological cure by person (1 arm studies) Bowie 1974 0.9166667 0.041493 44 48 3.8% 0.92 [0.84, 1.00] Daly 1997 0.95 0.03857687 38 40 4.4% 0.95 [0.87, 1.03] Hantschke 1973 0.9354839 0.032935 58 62 6.1% 0.94 [0.87, 1.00] Hira 1985 0.9818182 0.009877 216 220 67.9% 0.98 [0.96, 1.00] Lule 1994 0.91764706 0.03058633 78 85 7.1% 0.92 [0.86, 0.98] Morrison 1973 0.85 0.056152 34 40 2.1% 0.85 [0.74, 0.96] Pandhi 1989 0.9272727 0.036724 51 55 4.9% 0.93 [0.86, 1.00] Yoon 1988 0.624 0.042715 78 125 3.6% 0.62 [0.54, 0.71] Subtotal (95% CI) 597 675 100.0% 0.95 [0.94, 0.97] Heterogeneity: Chi² = 74.07, df = 7 (P < 0.00001); I² = 91% Test for overall effect: Z = 117.00 (P < 0.00001)

Total (95% CI) 597 675 100.0% 0.95 [0.94, 0.97] Heterogeneity: Chi² = 74.07, df = 7 (P < 0.00001); I² = 91% -2 -1 0 1 2 Test for overall effect: Z = 117.00 (P < 0.00001) Favours [gentamycin] Favours [control] Test for subgroup differences: Not applicable

Web annex E – Systematic reviews

Gentamicin 240 mg IM × 1 Microbiological cure by number of people

event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 35.11.1 Non-randomised with 1 group : Microbiological cure by person after 3 to 5 days visits Bowie 1974 0.9166667 0.041493 44 48 3.3% 0.92 [0.84, 1.00] Daly 1997 0.95 0.03857687 38 40 3.8% 0.95 [0.87, 1.03] Hantschke 1973 0.9354839 0.032935 58 62 5.3% 0.94 [0.87, 1.00] Hira 1985 0.984252 0.008583 250 254 77.5% 0.98 [0.97, 1.00] Morrison 1973 0.85 0.056152 34 40 1.8% 0.85 [0.74, 0.96] Pandhi 1989 0.9454545 0.033115 52 55 5.2% 0.95 [0.88, 1.01] Yoon 1988 0.624 0.042715 78 125 3.1% 0.62 [0.54, 0.71] Subtotal (95% CI) 554 624 100.0% 0.96 [0.95, 0.98] Heterogeneity: Chi² = 75.50, df = 6 (P < 0.00001); I² = 92% Test for overall effect: Z = 127.41 (P < 0.00001)

35.11.2 Non-randomised with 1 group : Microbiological cure by person after 10 to 14 days visit Hira 1985 0.9818182 0.009877 216 220 85.0% 0.98 [0.96, 1.00] Lule 1994 0.91764706 0.03058633 78 85 8.9% 0.92 [0.86, 0.98] Pandhi 1989 0.9272727 0.036724 51 55 6.1% 0.93 [0.86, 1.00] Subtotal (95% CI) 345 360 100.0% 0.97 [0.95, 0.99] Heterogeneity: Chi² = 5.62, df = 2 (P = 0.06); I² = 64% Test for overall effect: Z = 106.83 (P < 0.00001)

-2 -1 0 1 2 Favours [gentamycin] Favours [control] Test for subgroup differences: Chi² = 0.77, df = 1 (P = 0.38), I² = 0%

WHO guidelines for the treatment of Neisseria gonorrhoeae

Spectinomycin 2 g IM × 1 Microbiological cure by number of people

event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 35.12.1 Non-randomised with 1 group : Microbiological cure by person for dose 2g Brown 1974 0.9605263 0.016639 146 152 2.2% 0.96 [0.93, 0.99] Cheng 2001 0.97826087 0.02793566 45 46 0.8% 0.98 [0.92, 1.03] Davidson 1986 0.9111111 0.043936 41 45 0.3% 0.91 [0.82, 1.00] Duancic 1974 0.9047619 0.032596 76 84 0.6% 0.90 [0.84, 0.97] Duncan 1972 0.9308176 0.020551 148 159 1.5% 0.93 [0.89, 0.97] Finger 1975 1 0.01067055 88 88 5.4% 1.00 [0.98, 1.02] Handsfield 1983 0.96551724 0.02749641 56 58 0.8% 0.97 [0.91, 1.02] Holder 1972 0.86666667 0.0871083 13 15 0.1% 0.87 [0.70, 1.04] Hook 1986 0.99 0.013449 99 100 3.4% 0.99 [0.96, 1.02] Judson 1974 0.85483871 0.04467934 53 62 0.3% 0.85 [0.77, 0.94] Karney 1977 0.9446023 0.008686 665 704 8.2% 0.94 [0.93, 0.96] Kim 1984 1 0.020484 44 44 1.5% 1.00 [0.96, 1.04] Kojima 2008 0.9666667 0.012999 203 210 3.7% 0.97 [0.94, 0.99] Kousa 1974 0.9315589 0.015779 245 263 2.5% 0.93 [0.90, 0.96] McCann 1977 0.9637681 0.016949 133 138 2.2% 0.96 [0.93, 1.00] Meheus 1984 0.9380952 0.016961 197 210 2.2% 0.94 [0.90, 0.97] Meyer-Rohn 1974 (1) 0.87 0.03373324 87 100 0.5% 0.87 [0.80, 0.94] Meyer-Rohn 1974 (2) 1 0.009437 100 100 6.9% 1.00 [0.98, 1.02] Monayar 1987 0.9672131 0.02624 59 61 0.9% 0.97 [0.92, 1.02] Panikabutra 1988 0.99176955 0.00695098 241 243 12.8% 0.99 [0.98, 1.01] Ratnam 1982 0.9913793 0.011658 115 116 4.6% 0.99 [0.97, 1.01] Sands 1980 1 0.033979 25 25 0.5% 1.00 [0.93, 1.07] Shams 2009 0.94 0.0247408 94 100 1.0% 0.94 [0.89, 0.99] Shi 2000 0.93333333 0.04968407 28 30 0.3% 0.93 [0.84, 1.03] Stapinski 1986 0.9866221 0.004944 590 598 25.3% 0.99 [0.98, 1.00] Stratigos 1973 0.9846154 0.020259 64 65 1.5% 0.98 [0.94, 1.02] Tian 2002 0.94545454 0.02262342 104 110 1.2% 0.95 [0.90, 0.99] Tupasi 1983 1 0.01755 52 52 2.0% 1.00 [0.97, 1.03] Tupasi 1984 1 0.01755 52 52 2.0% 1.00 [0.97, 1.03] Tuza 1973 0.9646018 0.018788 109 113 1.8% 0.96 [0.93, 1.00] Willcox 1974 0.92771084 0.02941832 77 83 0.7% 0.93 [0.87, 0.99] Wojtowicz 1990 1 0.018202 50 50 1.9% 1.00 [0.96, 1.04] Zhou 2000 0.9722222 0.034893 35 36 0.5% 0.97 [0.90, 1.04] Subtotal (95% CI) 4134 4312 100.0% 0.98 [0.97, 0.98] Heterogeneity: Chi² = 97.76, df = 32 (P < 0.00001); I² = 67% Test for overall effect: Z = 393.05 (P < 0.00001)

35.12.2 Non-randomised with 1 group : Microbiological cure by person for dose 2g Patient with non-PPNG (penicillinase-producing N. gonorrhoeae starins) Lassau 1987 0.9259259 0.030087 75 81 100.0% 0.93 [0.87, 0.98] Subtotal (95% CI) 75 81 100.0% 0.93 [0.87, 0.98] Heterogeneity: Not applicable Test for overall effect: Z = 30.77 (P < 0.00001)

35.12.3 Non-randomised with 1 group : Microbiological cure by person for dose 2g Patient with PPNG (penicillinase-producing N. gonorrhoeae starins Lassau 1987 0.9285714 0.029095 78 84 13.3% 0.93 [0.87, 0.99] Panikabutra 1988 1 0.01141638 82 82 86.7% 1.00 [0.98, 1.02] Subtotal (95% CI) 160 166 100.0% 0.99 [0.97, 1.01] Heterogeneity: Chi² = 5.22, df = 1 (P = 0.02); I² = 81% Test for overall effect: Z = 93.20 (P < 0.00001)

35.12.4 Non-randomised with 1 group : Microbiological cure by person for dose 2g measured between 7 to 14 days of treatment Finger 1975 1 0.0122743 76 76 31.4% 1.00 [0.98, 1.02] Mroczkowski 1993 0.98648649 0.01792498 73 74 14.7% 0.99 [0.95, 1.02] Pedersen 1972 0.9811321 0.015564 104 106 19.5% 0.98 [0.95, 1.01] Porter 1977 0.9866667 0.017698 74 75 15.1% 0.99 [0.95, 1.02] Ratnam 1982 0.9711538 0.018251 101 104 14.2% 0.97 [0.94, 1.01] Rompalo 1994 0.94117647 0.03025727 64 68 5.2% 0.94 [0.88, 1.00] Subtotal (95% CI) 492 503 100.0% 0.99 [0.97, 1.00] Heterogeneity: Chi² = 4.24, df = 5 (P = 0.51); I² = 0% Test for overall effect: Z = 143.33 (P < 0.00001)

35.12.5 Non-randomised with 1 group : Microbiological cure by person for dose 2g measured between 30 to 60 days of treatment Finger 1975 0.85185185 0.04820764 46 54 4.5% 0.85 [0.76, 0.95] Pedersen 1972 0.952381 0.018309 140 147 31.3% 0.95 [0.92, 0.99] Porter 1977 1 0.015114 61 61 45.9% 1.00 [0.97, 1.03] Willcox 1974 1 0.02399514 37 37 18.2% 1.00 [0.95, 1.05] Subtotal (95% CI) 284 299 100.0% 0.98 [0.96, 1.00] Heterogeneity: Chi² = 11.76, df = 3 (P = 0.008); I² = 74% Test for overall effect: Z = 95.50 (P < 0.00001)

-2 -1 0 1 2 Favours [spectinomycin] Favours [control]

Footnotes (1) Dose for Men 2g and women 4 g; infection of unkown duration (2) Dose for Men 2g and women 4 g; infection <6days prior

Web annex E – Systematic reviews

Spectinomycin 2 g IM × 1 Microbiological cure by number of infection sites

event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 35.14.1 Non-randomised with 1 group : Microbiological cure by infections: only rectal Collier 1984 1 0.06186244 12 12 12.9% 1.00 [0.88, 1.12] Handsfield 1983 0.95454546 0.05354992 21 22 17.2% 0.95 [0.85, 1.06] Hook 1986 1 0.02660036 33 33 69.8% 1.00 [0.95, 1.05] Subtotal (95% CI) 66 67 100.0% 0.99 [0.95, 1.04] Heterogeneity: Chi² = 0.60, df = 2 (P = 0.74); I² = 0% Test for overall effect: Z = 44.63 (P < 0.00001)

35.14.2 Non-randomised with 1 group : Microbiological cure by infections: only urethra Handsfield 1983 0.96153846 0.03040888 50 52 23.5% 0.96 [0.90, 1.02] Hook 1986 0.98734177 0.01684679 78 79 76.5% 0.99 [0.95, 1.02] Subtotal (95% CI) 128 131 100.0% 0.98 [0.95, 1.01] Heterogeneity: Chi² = 0.55, df = 1 (P = 0.46); I² = 0% Test for overall effect: Z = 66.59 (P < 0.00001)

35.14.3 Non-randomised with 1 group : Microbiological cure by infections: cervix Collier 1984 0.95238095 0.05567408 20 21 21.9% 0.95 [0.84, 1.06] Rompalo 1994 0.94285714 0.02945869 66 70 78.1% 0.94 [0.89, 1.00] Subtotal (95% CI) 86 91 100.0% 0.94 [0.89, 1.00] Heterogeneity: Chi² = 0.02, df = 1 (P = 0.88); I² = 0% Test for overall effect: Z = 36.29 (P < 0.00001)

35.14.4 Non-randomised with 1 group : Microbiological cure by infections: all infections Rompalo 1994 0.90243902 0.03331782 74 82 100.0% 0.90 [0.84, 0.97] Subtotal (95% CI) 74 82 100.0% 0.90 [0.84, 0.97] Heterogeneity: Not applicable Test for overall effect: Z = 27.09 (P < 0.00001)

-2 -1 0 1 2 Favours [spectinomycin] Favours [control]

Spectinomycin 4 g IM × 1 Microbiological cure by number of people

event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 35.13.7 Non-randomised with 1 group : Microbiological cure by person for dose 4g after 1 to 5 days visit Finger 1975 0.96666667 0.01774088 116 120 100.0% 0.97 [0.93, 1.00] Subtotal (95% CI) 116 120 100.0% 0.97 [0.93, 1.00] Heterogeneity: Not applicable Test for overall effect: Z = 54.49 (P < 0.00001)

35.13.8 Non-randomised with 1 group : Microbiological cure by person for dose 4g after 6 to 10 days visit Duancic 1974 0.9347826 0.03892924 43 46 1.2% 0.93 [0.86, 1.01] Duncan 1972 0.94339623 0.01887873 150 159 5.2% 0.94 [0.91, 0.98] Felman 1978 0.928 0.023685 116 125 3.3% 0.93 [0.88, 0.97] Finger 1975 0.97826087 0.01782003 90 92 5.9% 0.98 [0.94, 1.01] Karney 1977 0.9611381 0.005123 1385 1441 71.1% 0.96 [0.95, 0.97] Reggiani 1983 (1) 0.8993808 0.011862 581 646 13.3% 0.90 [0.88, 0.92] Subtotal (95% CI) 2365 2509 100.0% 0.95 [0.94, 0.96] Heterogeneity: Chi² = 26.45, df = 5 (P < 0.0001); I² = 81% Test for overall effect: Z = 220.33 (P < 0.00001)

35.13.9 Non-randomised with 1 group : Microbiological cure by person for dose 4g after 15 to 30 days visits Finger 1975 0.97058824 0.03672149 33 34 20.3% 0.97 [0.90, 1.04] Judson 1974 0.85483871 0.04467934 53 62 13.7% 0.85 [0.77, 0.94] McCann 1977 0.96153846 0.02032968 100 104 66.1% 0.96 [0.92, 1.00] Subtotal (95% CI) 186 200 100.0% 0.95 [0.92, 0.98] Heterogeneity: Chi² = 5.17, df = 2 (P = 0.08); I² = 61% Test for overall effect: Z = 57.42 (P < 0.00001)

-2 -1 0 1 2 Favours [spectinomycin] Favours [control]

Footnotes (1) Male 4g and Female 8g

WHO guidelines for the treatment of Neisseria gonorrhoeae

Kanamycin 2 g IM × 1 Microbiological cure by number of people

event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 35.17.1 Non-randomised with 1 group : Microbiological cure by person measured within 1 week Hira 1985 0.9569892 0.022596 89 93 11.3% 0.96 [0.91, 1.00] Rajan 1979 0.9795322 0.008084 335 342 88.7% 0.98 [0.96, 1.00] Subtotal (95% CI) 424 435 100.0% 0.98 [0.96, 0.99] Heterogeneity: Chi² = 0.88, df = 1 (P = 0.35); I² = 0% Test for overall effect: Z = 128.35 (P < 0.00001)

35.17.2 Non-randomised with 1 group : Microbiological cure by person measured within 2 weeks Dashevskii 1975 0.9714286 0.035784 34 35 4.7% 0.97 [0.90, 1.04] Hira 1985 0.9550562 0.02355 85 89 10.8% 0.96 [0.91, 1.00] Niunikova 1975 1 0.009623 98 98 64.9% 1.00 [0.98, 1.02] Turanova 1975 0.9852941 0.019416 67 68 15.9% 0.99 [0.95, 1.02] Yoon 1988 0.6825397 0.040944 86 126 3.6% 0.68 [0.60, 0.76] Subtotal (95% CI) 370 416 100.0% 0.98 [0.96, 1.00] Heterogeneity: Chi² = 58.35, df = 4 (P < 0.00001); I² = 93% Test for overall effect: Z = 126.39 (P < 0.00001)

-2 -1 0 1 2 Favours [kanamycin] Favours [control]

Kanamycin 2 g IM × 1 (all studies together) Microbiological cure by number of people

event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 35.21.2 Kanamycin 2g : Microbiological cure by person (1 arm studies) Dashevskii 1975 0.9714286 0.035784 34 35 2.3% 0.97 [0.90, 1.04] Hira 1985 0.9550562 0.02355 85 89 5.3% 0.96 [0.91, 1.00] Niunikova 1975 1 0.009623 98 98 31.5% 1.00 [0.98, 1.02] Rajan 1979 0.9795322 0.008084 335 342 44.6% 0.98 [0.96, 1.00] Rajan 1982 0.91803279 0.02054192 168 183 6.9% 0.92 [0.88, 0.96] Turanova 1975 0.9852941 0.019416 67 68 7.7% 0.99 [0.95, 1.02] Yoon 1988 0.6825397 0.040944 86 126 1.7% 0.68 [0.60, 0.76] Subtotal (95% CI) 873 941 100.0% 0.98 [0.96, 0.99] Heterogeneity: Chi² = 66.77, df = 6 (P < 0.00001); I² = 91% Test for overall effect: Z = 180.68 (P < 0.00001)

Total (95% CI) 873 941 100.0% 0.98 [0.96, 0.99] Heterogeneity: Chi² = 66.77, df = 6 (P < 0.00001); I² = 91% -2 -1 0 1 2 Test for overall effect: Z = 180.68 (P < 0.00001) Favours [kanamycin] Favours [control] Test for subgroup differences: Not applicable

Ceftriaxone 125 mg IM × 1 Microbiological cure by number of people

event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 35.15.1 Non-randomised with 1 group : Microbiological cure by person Collier 1984 0.98181818 0.02368452 54 55 10.6% 0.98 [0.94, 1.03] Freedman 1990 1 0.014236 65 65 29.3% 1.00 [0.97, 1.03] Handsfield 1981 1 0.05201257 15 15 2.2% 1.00 [0.90, 1.10] Handsfield 1983 1 0.0281273 31 31 7.5% 1.00 [0.94, 1.06] Handsfield 1987 0.987013 0.010853 152 154 50.4% 0.99 [0.97, 1.01] Subtotal (95% CI) 317 320 100.0% 0.99 [0.98, 1.01] Heterogeneity: Chi² = 0.81, df = 4 (P = 0.94); I² = 0% Test for overall effect: Z = 128.67 (P < 0.00001)

Total (95% CI) 317 320 100.0% 0.99 [0.98, 1.01] Heterogeneity: Chi² = 0.81, df = 4 (P = 0.94); I² = 0% -2 -1 0 1 2 Test for overall effect: Z = 128.67 (P < 0.00001) Favours [ceftriaxonel] Favours [control] Test for subgroup differences: Not applicable

Web annex E – Systematic reviews

Ceftriaxone 125 mg IM × 1 Microbiological cure by number of infection sites

event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 35.16.1 Non-randomised with 1 group : Microbiological cure by infections: cervical/urethral Handsfield 1981 1 0.05492781 14 14 4.2% 1.00 [0.89, 1.11] Handsfield 1983 1 0.03284006 26 26 11.7% 1.00 [0.94, 1.06] Handsfield 1987 0.99090909 0.01227049 109 110 84.1% 0.99 [0.97, 1.01] Subtotal (95% CI) 149 150 100.0% 0.99 [0.97, 1.01] Heterogeneity: Chi² = 0.09, df = 2 (P = 0.96); I² = 0% Test for overall effect: Z = 88.20 (P < 0.00001)

35.16.2 Non-randomised with 1 group : Microbiological cure by infections: only rectum Collier 1984 1 0.03651049 23 23 28.1% 1.00 [0.93, 1.07] Freedman 1990 1 0.20241243 1 1 0.9% 1.00 [0.60, 1.40] Handsfield 1981 1 0.11083967 5 5 3.1% 1.00 [0.78, 1.22] Handsfield 1983 1 0.08275909 8 8 5.5% 1.00 [0.84, 1.16] Handsfield 1987 0.98113208 0.02451354 52 53 62.4% 0.98 [0.93, 1.03] Subtotal (95% CI) 89 90 100.0% 0.99 [0.95, 1.03] Heterogeneity: Chi² = 0.22, df = 4 (P = 0.99); I² = 0% Test for overall effect: Z = 51.03 (P < 0.00001)

35.16.3 Non-randomised with 1 group : Microbiological cure by infections: only cervix Collier 1984 0.98113208 0.02451354 52 53 34.7% 0.98 [0.93, 1.03] Freedman 1990 1 0.01786965 51 51 65.3% 1.00 [0.96, 1.04] Subtotal (95% CI) 103 104 100.0% 0.99 [0.97, 1.02] Heterogeneity: Chi² = 0.39, df = 1 (P = 0.53); I² = 0% Test for overall effect: Z = 68.80 (P < 0.00001)

-2 -1 0 1 2 Favours [ceftriaxonel] Favours [control]

Cefixime + doxycycline or azithromycin Microbiological cure by number of people No study found

Ceftriaxone + doxycycline Microbiological cure by number of people

event total proportion proportion Study or Subgroup proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 35.18.1 Non-randomised with 1 group : Microbiological cure by person for dx within 30 days treatment results Schumacher 2013 0.8976974 0.005499 2729 3040 0.90 [0.89, 0.91]

35.18.2 Non-randomised with 1 group : Microbiological cure by person for dx within 90 days treatment results Schumacher 2013 0.7893175 0.022151 266 337 0.79 [0.75, 0.83]

-2 -1 0 1 2 Favours [ceftr+DoxyorAz] Favours [control]

WHO guidelines for the treatment of Neisseria gonorrhoeae

Ceftriaxone + azithromycin Microbiological cure by number of people

event total proportion proportion Study or Subgroup proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 36.18.1 Non-randomised with 1 group : Microbiological cure by person for within 30 days treatment results Schumacher 2013 0.9082569 0.007679 1287 1417 0.91 [0.89, 0.92]

36.18.2 Non-randomised with 1 group : Microbiological cure by person for within 90 days treatment results Schumacher 2013 0.8648649 0.028141 128 148 0.86 [0.81, 0.92]

-2 -1 0 1 2 Favours [ceftr+DoxyorAz] Favours [control]

STI complications (1-arm studies) No studies were found on this outcome.

Ceftriaxone 250 mg IM Clinical cure by number of people proportion proportion Study or Subgroup proportion SE Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 36.1.1 Non-randomised with 1 group : Clinical cure by person Calderon 1988 0.75 0.066345 0.7% 0.75 [0.62, 0.88] Cheng 2001 0.875 0.0480708 1.3% 0.88 [0.78, 0.97] Handsfield 1981 1 0.04939118 1.2% 1.00 [0.90, 1.10] Jin 2001 0.974026 0.021096 6.7% 0.97 [0.93, 1.02] Khrianin 2006 1 0.007978 46.8% 1.00 [0.98, 1.02] Mogabgab 1994 0.8369565 0.038357 2.0% 0.84 [0.76, 0.91] Mroczkowski 1993 1 0.0223532 6.0% 1.00 [0.96, 1.04] Tian 2002 1 0.01155094 22.3% 1.00 [0.98, 1.02] Zajdowicz 1983 1 0.015114 13.0% 1.00 [0.97, 1.03] Subtotal (95% CI) 100.0% 0.99 [0.98, 1.00] Heterogeneity: Chi² = 38.21, df = 8 (P < 0.00001); I² = 79% Test for overall effect: Z = 181.72 (P < 0.00001)

-2 -1 0 1 2 Favours [ceftriaxone] Favours [control] Test for subgroup differences: Not applicable

Ceftriaxone 250 mg IM Clinical cure by number of infection sites

event total proportion proportion Study or Subgroup proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 37.2.1 Non-randomised with 1 group : Clinical cure by infections: only rectal Tian 2002 0.875 0.11440763 7 8 0.88 [0.65, 1.10]

-2 -1 0 1 2 Favours [ceftriaxone] Favours [control]

Web annex E – Systematic reviews

Azithromycin 1–2 g po Clinical cure by number of people

event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 36.4.1 Non-randomised with 1 group : Clinical cure by person visit at 7th day Gruber 1997 0.96 0.031522 48 50 31.7% 0.96 [0.90, 1.02] Khaki 2007 1 0.037923 22 22 21.9% 1.00 [0.93, 1.07] Ling 2000 0.8595506 0.026056 153 178 46.4% 0.86 [0.81, 0.91] Subtotal (95% CI) 223 250 100.0% 0.92 [0.89, 0.96] Heterogeneity: Chi² = 11.43, df = 2 (P = 0.003); I² = 82% Test for overall effect: Z = 51.96 (P < 0.00001)

36.4.2 Non-randomised with 1 group : Clinical cure by person visit at 14th day Gruber 1997 0.96 0.031522 48 50 4.2% 0.96 [0.90, 1.02] Odugbemi 1993 1 0.00772617 123 123 70.1% 1.00 [0.98, 1.02] Rustomjee 2002 0.9677419 0.039854 30 31 2.6% 0.97 [0.89, 1.05] Swanston 2001 0.9470199 0.018869 143 151 11.8% 0.95 [0.91, 0.98] Takahashi 2014 0.8484848 0.061913 28 33 1.1% 0.85 [0.73, 0.97] Waugh 1993 0.96774194 0.02029717 90 93 10.2% 0.97 [0.93, 1.01] Subtotal (95% CI) 462 481 100.0% 0.99 [0.97, 1.00] Heterogeneity: Chi² = 14.18, df = 5 (P = 0.01); I² = 65% Test for overall effect: Z = 152.43 (P < 0.00001)

-2 -1 0 1 2 Favours [Azithromycin] Favours [control]

WHO guidelines for the treatment of Neisseria gonorrhoeae

Azithromycin 1–2 g po Clinical cure by number of infection sites

event total proportion proportion Study or Subgroup proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 37.3.1 Non-randomised with 1 group : Clinical cure by infections: only rectum Waugh 1993 1 0.1249745 4 4 1.00 [0.76, 1.24]

37.3.2 Non-randomised with 1 group : Clinical cure by infections: cervix Waugh 1993 1 0.07631448 9 9 1.00 [0.85, 1.15]

-2 -1 0 1 2 Favours [Azithromycin] Favours [control]

Cefixime 400 mg po × 1; cefixime 800 mg po × 1 or 400 mg po × 2; gentamicin 240 mg IM × 1 Clinical cure No studies were found on clinical cure for the above treatments

Spectinomycin 2 g IM ×1 Clinical cure by number of people

proportion proportion Study or Subgroup proportion SE Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 36.7.1 Non-randomised with 1 group : Clinical cure by person Cheng 2001 0.86956522 0.04986831 1.9% 0.87 [0.77, 0.97] Kojima 2008 0.9666667 0.012999 27.9% 0.97 [0.94, 0.99] Meyer-Rohn 1974 0.87 0.033733 4.1% 0.87 [0.80, 0.94] Mroczkowski 1993 0.97297297 0.0219009 9.8% 0.97 [0.93, 1.02] Shi 2000 1 0.041105 2.8% 1.00 [0.92, 1.08] Stratigos 1973 0.9846154 0.020259 11.5% 0.98 [0.94, 1.02] Tian 2002 1 0.01128491 37.0% 1.00 [0.98, 1.02] Tuza 1973 0.5752212 0.045747 2.3% 0.58 [0.49, 0.66] Zhou 2000 0.9444444 0.042367 2.6% 0.94 [0.86, 1.03] Subtotal (95% CI) 100.0% 0.97 [0.95, 0.98] Heterogeneity: Chi² = 95.74, df = 8 (P < 0.00001); I² = 92% Test for overall effect: Z = 140.85 (P < 0.00001)

-2 -1 0 1 2 Favours [spectinomycin] Favours [control] Test for subgroup differences: Not applicable

Spectinomycin 2 g IM × 1 Clinical cure by number of infection sites

event total proportion proportion Study or Subgroup proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 37.8.1 Non-randomised with 1 group : Clinical cure by infections: only rectal Tian 2002 0.8 0.15006341 4 5 0.80 [0.51, 1.09]

-2 -1 0 1 2 Favours [spectinomycin] Favours [control]

Web annex E – Systematic reviews

Kanamycin 2 g (1-arm studies) Clinical cure by number of people

event total proportion proportion Study or Subgroup proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 37.8.1 Non-randomised with 1 group : Clinical cure by person Niunikova 1975 0.8571429 0.03535 84 98 0.86 [0.79, 0.93] Turanova 1975 0.8676471 0.04122 59 68 0.87 [0.79, 0.95]

-2 -1 0 1 2 Favours [proportion] Favours [control]

Ceftriaxone 125 mg IM × 1 Clinical cure by number of people

proportion proportion Study or Subgroup proportion SE IV, Fixed, 95% CI IV, Fixed, 95% CI 36.10.1 Non-randomised with 1 group : Clinical cure by person Handsfield 1981 1 0.05201568 1.00 [0.90, 1.10]

-100 -50 0 50 100 Favours [experimental] Favours [control]

Ceftriaxone 125 mg IM × 1 Clinical cure No studies were found on this treatment

Transmission to partners (1-arm studies) Gonorrhoea antimicrobial in vitro resistance (1-arm studies) No study found for the above outcomes of any of the treatments of interest

Azithromycin 1–2 g po × 1 Compliance

event total proportion proportion Study or Subgroup proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 38.2.1 Non-randomised with 1 group : Compliance Rustomjee 2002 1 0.028127 31 31 1.00 [0.94, 1.06]

-2 -1 0 1 2 Favours [Azithromycin] Favours [control]

WHO guidelines for the treatment of Neisseria gonorrhoeae

Ceftriaxone 250 mg IM × 1 Side-effects including allergy, toxicity

event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 38.1.1 Non-randomised with 1 group: Side effects: general side effects Bryan 1990 0 0.016943 0 54 5.0% 0.00 [-0.03, 0.03] Calderon 1988 0 0.022353 0 40 2.9% 0.00 [-0.04, 0.04] Cheng 2001 0 0.01890374 0 48 4.0% 0.00 [-0.04, 0.04] Christophersen 1989 0.0666667 0.020855 10 150 3.3% 0.07 [0.03, 0.11] Covino 1993 0 0.028958 0 30 1.7% 0.00 [-0.06, 0.06] Dixon 1986 0.11827957 0.03371343 11 93 1.3% 0.12 [0.05, 0.18] Goldstein 1991 0 0.009623 0 98 15.4% 0.00 [-0.02, 0.02] Handsfield 1981 0 0.04939118 0 16 0.6% 0.00 [-0.10, 0.10] Handsfield 1983 0 0.03077735 0 28 1.5% 0.00 [-0.06, 0.06] Jin 2001 0.038961 0.024251 3 77 2.4% 0.04 [-0.01, 0.09] Judson 1983 0 0.03651 0 23 1.1% 0.00 [-0.07, 0.07] Judson 1985 0.01190476 0.01589093 1 84 5.7% 0.01 [-0.02, 0.04] McCormack 1993 0.103139 0.020483 23 223 3.4% 0.10 [0.06, 0.14] Muratani 2008 0 0.015847 0 58 5.7% 0.00 [-0.03, 0.03] Pabst 1989 0 0.01243 0 75 9.2% 0.00 [-0.02, 0.02] Panikabutra 1985 0 0.00971821 0 97 15.1% 0.00 [-0.02, 0.02] Rajan 1982 0 0.01694282 0 54 5.0% 0.00 [-0.03, 0.03] Smith 1993 0.0526316 0.011624 20 380 10.6% 0.05 [0.03, 0.08] Zajdowicz 1983 0 0.015114 0 61 6.3% 0.00 [-0.03, 0.03] Subtotal (95% CI) 68 1689 100.0% 0.01 [0.01, 0.02] Heterogeneity: Chi² = 57.07, df = 18 (P < 0.00001); I² = 68% Test for overall effect: Z = 3.80 (P = 0.0001)

38.1.2 Non-randomised with 1 group: Side effects: diarrhea, nausea, Gastrointestinal disturbance/pain, other pain Baddour 1992 0.0309278 0.019502 3 97 9.6% 0.03 [-0.01, 0.07] Covino 1990 0.047619 0.036925 2 42 2.7% 0.05 [-0.02, 0.12] Handsfield 1991 0.03846154 0.02032968 4 104 8.8% 0.04 [-0.00, 0.08] Handsfield 1994 0.02358491 0.01119859 5 212 29.0% 0.02 [0.00, 0.05] Hook 1993 0.059322 0.022544 7 118 7.2% 0.06 [0.02, 0.10] McCormack 1993 0.05381166 0.01546994 12 223 15.2% 0.05 [0.02, 0.08] Mogabgab 1994 0.0108696 0.014568 1 92 17.1% 0.01 [-0.02, 0.04] Plourde 1992 0.03174603 0.02546364 2 63 5.6% 0.03 [-0.02, 0.08] Portilla 1992 0.0212766 0.02738946 1 47 4.8% 0.02 [-0.03, 0.07] Subtotal (95% CI) 37 998 100.0% 0.03 [0.02, 0.04] Heterogeneity: Chi² = 6.56, df = 8 (P = 0.59); I² = 0% Test for overall effect: Z = 5.23 (P < 0.00001)

38.1.3 Non-randomised with 1 group: Side effects: rash, pruritus Baddour 1992 0.0103093 0.013848 1 97 35.8% 0.01 [-0.02, 0.04] Hook 1993 0.059322 0.022544 7 118 13.5% 0.06 [0.02, 0.10] Mogabgab 1994 0.0108696 0.014568 1 92 32.4% 0.01 [-0.02, 0.04] Mroczkowski 1993 0.1 0.04870966 4 40 2.9% 0.10 [0.00, 0.20] Plourde 1992 0.03174603 0.02546364 2 63 10.6% 0.03 [-0.02, 0.08] Rompalo 1994 0 0.03792335 0 22 4.8% 0.00 [-0.07, 0.07] Subtotal (95% CI) 15 432 100.0% 0.02 [0.01, 0.04] Heterogeneity: Chi² = 7.08, df = 5 (P = 0.21); I² = 29% Test for overall effect: Z = 2.59 (P = 0.010)

38.1.4 Non-randomised with 1 group: Side effects: pain at site of infection Handsfield 1994 0.03301887 0.01288054 7 212 33.9% 0.03 [0.01, 0.06] Hook 1993 0.0169492 0.01404 2 118 28.6% 0.02 [-0.01, 0.04] Korting 1989 0.1142857 0.054634 4 35 1.9% 0.11 [0.01, 0.22] McCormack 1993 0.05381166 0.01546994 12 223 23.5% 0.05 [0.02, 0.08] Mogabgab 1994 0.0543478 0.024886 5 92 9.1% 0.05 [0.01, 0.10] Mroczkowski 1993 0.1 0.04870966 4 40 2.4% 0.10 [0.00, 0.20] Rompalo 1994 0.45454546 0.09801151 10 22 0.6% 0.45 [0.26, 0.65] Subtotal (95% CI) 44 742 100.0% 0.04 [0.03, 0.06] Heterogeneity: Chi² = 25.36, df = 6 (P = 0.0003); I² = 76% Test for overall effect: Z = 5.44 (P < 0.00001)

38.1.5 Non-randomised with 1 group: Side effects: Postgonococcal urethritis PGU Dixon 1986 0.24637681 0.05094704 17 69 27.0% 0.25 [0.15, 0.35] Handsfield 1983 0.18181818 0.079618 4 22 11.1% 0.18 [0.03, 0.34] Rajan 1982 0.05555556 0.03367388 3 54 61.9% 0.06 [-0.01, 0.12] Subtotal (95% CI) 24 145 100.0% 0.12 [0.07, 0.17] Heterogeneity: Chi² = 10.42, df = 2 (P = 0.005); I² = 81% Test for overall effect: Z = 4.57 (P < 0.00001)

38.1.6 Non-randomised with 1 group: Side effects: Dizziness, headache, somnolence, fever Handsfield 1991a 0.14423077 0.03444332 15 104 1.3% 0.14 [0.08, 0.21] Handsfield 1994 0 0.00454037 0 212 72.5% 0.00 [-0.01, 0.01] McCormack 1993 0.01793722 0.00974702 4 223 15.7% 0.02 [-0.00, 0.04] Mogabgab 1994 0.0108696 0.014568 1 92 7.0% 0.01 [-0.02, 0.04] Plourde 1992 0.01587302 0.0208622 1 63 3.4% 0.02 [-0.03, 0.06] Subtotal (95% CI) 21 694 100.0% 0.01 [-0.00, 0.01] Heterogeneity: Chi² = 19.69, df = 4 (P = 0.0006); I² = 80% Test for overall effect: Z = 1.54 (P = 0.12)

38.1.7 Non-randomised with 1 group: side effects: urinary tract infection, candidal vaginitis Mogabgab 1994 0.0108696 0.014568 1 92 67.2% 0.01 [-0.02, 0.04] Plourde 1992 0.01587302 0.0208622 1 63 32.8% 0.02 [-0.03, 0.06] Subtotal (95% CI) 2 155 100.0% 0.01 [-0.01, 0.04] Heterogeneity: Chi² = 0.04, df = 1 (P = 0.84); I² = 0% Test for overall effect: Z = 1.05 (P = 0.29)

-2 -1 0 1 2 Favours [ceftriaxone] Favours [control]

Web annex E – Systematic reviews

Azithromycin 1–2 g IM × 1 Side-effects including allergy, toxicity

event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 38.2.1 Non-randomised with 1 group: Side effects: general side effects Ling 2000 0.0674157 0.01917 12 178 12.0% 0.07 [0.03, 0.10] Rustomjee 2002 0.0322581 0.039854 1 31 2.8% 0.03 [-0.05, 0.11] Steingrimsson 1990 0.0847458 0.0261 10 118 6.5% 0.08 [0.03, 0.14] Swanston 2001 0 0.00749 0 127 78.7% 0.00 [-0.01, 0.01] Subtotal (95% CI) 23 454 100.0% 0.01 [0.00, 0.03] Heterogeneity: Chi² = 18.81, df = 3 (P = 0.0003); I² = 84% Test for overall effect: Z = 2.18 (P = 0.03)

38.2.2 Non-randomised with 1 group: Side effects:moderate angioedema Waugh 1993 0.0084746 0.011467 1 118 100.0% 0.01 [-0.01, 0.03] Subtotal (95% CI) 1 118 100.0% 0.01 [-0.01, 0.03] Heterogeneity: Not applicable Test for overall effect: Z = 0.74 (P = 0.46)

38.2.3 Non-randomised with 1 group: Side effects: diarrhoea, gastrointestinal problems Gruber 1997 0.02 0.025872 1 50 24.6% 0.02 [-0.03, 0.07] Khaki 2007 0.0909091 0.060505 2 22 4.5% 0.09 [-0.03, 0.21] Odugbemi 1993 0.0491803 0.016512 9 183 60.5% 0.05 [0.02, 0.08] Takahashi 2014 0.2666667 0.039909 32 120 10.4% 0.27 [0.19, 0.34] Subtotal (95% CI) 44 375 100.0% 0.07 [0.04, 0.09] Heterogeneity: Chi² = 29.65, df = 3 (P < 0.00001); I² = 90% Test for overall effect: Z = 5.17 (P < 0.00001)

38.2.4 Non-randomised with 1 group: Side effects: abdominal pain Gruber 1997 0.02 0.025872 1 50 84.5% 0.02 [-0.03, 0.07] Khaki 2007 0.0909091 0.060505 1 22 15.5% 0.09 [-0.03, 0.21] Subtotal (95% CI) 2 72 100.0% 0.03 [-0.02, 0.08] Heterogeneity: Chi² = 1.16, df = 1 (P = 0.28); I² = 14% Test for overall effect: Z = 1.30 (P = 0.19)

38.2.5 Non-randomised with 1 group: Side effects: nausea, vomit Gruber 1997 0.04 0.031522 2 50 9.6% 0.04 [-0.02, 0.10] Handsfield 1994 0.35266821 0.02292258 152 431 18.1% 0.35 [0.31, 0.40] Waugh 1993 0.0084746 0.011467 1 118 72.3% 0.01 [-0.01, 0.03] Subtotal (95% CI) 155 599 100.0% 0.07 [0.05, 0.09] Heterogeneity: Chi² = 181.61, df = 2 (P < 0.00001); I² = 99% Test for overall effect: Z = 7.57 (P < 0.00001)

-2 -1 0 1 2 Favours [Azithromycin] Favours [control]

WHO guidelines for the treatment of Neisseria gonorrhoeae

Cefixime 400 mg po × 1 Side-effects including allergy, toxicity Favours [cefixime] total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 38.3.1 Non-randomised with 1 group: Side effects: general side effects Backhaus 1990 0 0.054928 0 14 100.0% 0.00 [-0.11, 0.11] Subtotal (95% CI) 0 14 100.0% 0.00 [-0.11, 0.11] Heterogeneity: Not applicable Test for overall effect: Z = 0.00 (P = 1.00)

38.3.2 Non-randomised with 1 group: Side effects: nausea, vomit Hook 1997 0.02 0.012838 3 150 27.0% 0.02 [-0.01, 0.05] Mroczkowski 1997 0.010582 0.00889 2 189 56.3% 0.01 [-0.01, 0.03] Verdon 1993 (1) 0.019802 0.016301 2 101 16.7% 0.02 [-0.01, 0.05] Subtotal (95% CI) 7 440 100.0% 0.01 [0.00, 0.03] Heterogeneity: Chi² = 0.48, df = 2 (P = 0.79); I² = 0% Test for overall effect: Z = 2.20 (P = 0.03)

38.3.3 Non-randomised with 1 group: Side effects: headache Handsfield 1991 0.10280374 0.02968948 11 107 21.7% 0.10 [0.04, 0.16] Hook 1997 0.0333333 0.015646 5 150 78.3% 0.03 [0.00, 0.06] Subtotal (95% CI) 16 257 100.0% 0.05 [0.02, 0.08] Heterogeneity: Chi² = 4.29, df = 1 (P = 0.04); I² = 77% Test for overall effect: Z = 3.50 (P = 0.0005)

38.3.4 Non-randomised with 1 group: Side effects: viginitis Mroczkowski 1997 0.037037 0.014391 7 189 100.0% 0.04 [0.01, 0.07] Subtotal (95% CI) 7 189 100.0% 0.04 [0.01, 0.07] Heterogeneity: Not applicable Test for overall effect: Z = 2.57 (P = 0.01)

38.3.5 Non-randomised with 1 group: Side effects: leukorrhea Mroczkowski 1997 0.026455 0.012519 5 189 100.0% 0.03 [0.00, 0.05] Subtotal (95% CI) 5 189 100.0% 0.03 [0.00, 0.05] Heterogeneity: Not applicable Test for overall effect: Z = 2.11 (P = 0.03)

38.3.6 Non-randomised with 1 group: Side effects: diarrhea Handsfield 1991 0.08411215 0.02736977 9 107 5.8% 0.08 [0.03, 0.14] Mroczkowski 1997 0.005291 0.007251 1 189 82.6% 0.01 [-0.01, 0.02] Portilla 1992 0.17857143 0.05061653 10 56 1.7% 0.18 [0.08, 0.28] Verdon 1993 (2) 0.039604 0.020901 4 101 9.9% 0.04 [-0.00, 0.08] Subtotal (95% CI) 24 453 100.0% 0.02 [0.00, 0.03] Heterogeneity: Chi² = 19.96, df = 3 (P = 0.0002); I² = 85% Test for overall effect: Z = 2.46 (P = 0.01)

38.3.7 Non-randomised with 1 group: Side effects: pruritis,rash Mroczkowski 1997 0.010582 0.00889 2 189 69.2% 0.01 [-0.01, 0.03] Verdon 1993 (3) 0.009901 0.013321 1 101 30.8% 0.01 [-0.02, 0.04] Subtotal (95% CI) 3 290 100.0% 0.01 [-0.00, 0.02] Heterogeneity: Chi² = 0.00, df = 1 (P = 0.97); I² = 0% Test for overall effect: Z = 1.40 (P = 0.16)

-2 -1 0 1 2 Favours [cefixime] Favours [control]

Footnotes (1) dose 200mg (2) dose 200mg (3) dose 200mg

Cefixime 800 mg po or 400 mg × 2 Side-effects including allergy, toxicity

event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 38.4.1 Non-randomised with 1 group: Side effects: Headache, dizziness Megran 1990 0.1717172 0.03771 7 99 100.0% 0.17 [0.10, 0.25] Subtotal (95% CI) 7 99 100.0% 0.17 [0.10, 0.25] Heterogeneity: Not applicable Test for overall effect: Z = 4.55 (P < 0.00001)

38.4.2 Non-randomised with 1 group: Side effects: nausea,gastric upset Dunnett 1992 0.0410959 0.025492 3 73 54.5% 0.04 [-0.01, 0.09] Handsfield 1991 0.1978022 0.04137718 18 91 20.7% 0.20 [0.12, 0.28] Megran 1990 0.1717172 0.03771 7 99 24.9% 0.17 [0.10, 0.25] Subtotal (95% CI) 28 263 100.0% 0.11 [0.07, 0.14] Heterogeneity: Chi² = 14.44, df = 2 (P = 0.0007); I² = 86% Test for overall effect: Z = 5.63 (P < 0.00001)

38.4.3 Non-randomised with 1 group: Side effects: rash Megran 1990 0.010101 0.013579 1 99 100.0% 0.01 [-0.02, 0.04] Subtotal (95% CI) 1 99 100.0% 0.01 [-0.02, 0.04] Heterogeneity: Not applicable Test for overall effect: Z = 0.74 (P = 0.46)

38.4.4 Non-randomised with 1 group: Side effects: lower gastrointestinal symptoms (diarrhea: one or more loose stools), flatulence, cramping, Handsfield 1991 0.17582418 0.03965853 16 91 25.0% 0.18 [0.10, 0.25] Megran 1990 0.0707071 0.026568 17 99 55.7% 0.07 [0.02, 0.12] Portilla 1992 0.07692308 0.04507827 3 39 19.3% 0.08 [-0.01, 0.17] Subtotal (95% CI) 36 229 100.0% 0.10 [0.06, 0.14] Heterogeneity: Chi² = 5.12, df = 2 (P = 0.08); I² = 61% Test for overall effect: Z = 4.95 (P < 0.00001)

-2 -1 0 1 2 Favours [cefixime] Favours [control]

Web annex E – Systematic reviews

Gentamicin 240 mg IM × 1 Side-effects including allergy, toxicity

event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 38.5.1 Non-randomised with 1 group: Side effects: general side effects Bowie 1974 0 0.018904 0 48 4.4% 0.00 [-0.04, 0.04] Hantschke 1973 (1) 0 0.014884 0 62 7.2% 0.00 [-0.03, 0.03] Hira 1985 0 0.004378 0 220 82.7% 0.00 [-0.01, 0.01] Pandhi 1989 0 0.016655 0 55 5.7% 0.00 [-0.03, 0.03] Subtotal (95% CI) 0 385 100.0% 0.00 [-0.01, 0.01] Heterogeneity: Chi² = 0.00, df = 3 (P = 1.00); I² = 0% Test for overall effect: Z = 0.00 (P = 1.00)

38.5.2 Non-randomised with 1 group: Side effects: postgonococcal urethritis (PGU) complication Hira 1985 0.09090909 0.01954588 20 220 100.0% 0.09 [0.05, 0.13] Subtotal (95% CI) 20 220 100.0% 0.09 [0.05, 0.13] Heterogeneity: Not applicable Test for overall effect: Z = 4.65 (P < 0.00001)

-2 -1 0 1 2 Favours [gentamycin] Favours [control]

Footnotes (1) dose of injection was 5 mg/kg body wt

WHO guidelines for the treatment of Neisseria gonorrhoeae

Spectinomycin 2 g IM × 1 Side-effects including allergy, toxicity event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 38.6.1 Non-randomised with 1 group: Side effects: with 2gm dose: general side effects Brown 1974 0 0.006288 0 152 2.5% 0.00 [-0.01, 0.01] Duncan 1972 0 0.006018 0 159 2.8% 0.00 [-0.01, 0.01] Hook 1986 0 0.009437 0 100 1.1% 0.00 [-0.02, 0.02] Jaffe 1976 0.0061043 0.00191 11 1802 27.4% 0.01 [0.00, 0.01] Judson 1974 0.9047619 0.032596 0 128 0.1% 0.90 [0.84, 0.97] Karney 1977 0.0127841 0.004433 9 704 5.1% 0.01 [0.00, 0.02] Kousa 1974 0 0.003673 0 263 7.4% 0.00 [-0.01, 0.01] McCann 1977 0 0.006909 0 138 2.1% 0.00 [-0.01, 0.01] Meheus 1984 0.0285714 0.012185 6 210 0.7% 0.03 [0.00, 0.05] Pedersen 1972 0 0.006497 0 147 2.4% 0.00 [-0.01, 0.01] Porter 1977 0.0133333 0.017698 1 75 0.3% 0.01 [-0.02, 0.05] Ratnam 1982 0 0.009087 0 104 1.2% 0.00 [-0.02, 0.02] Reggiani 1983 0 0.001508 0 646 44.0% 0.00 [-0.00, 0.00] Shi 2000 0 0.041105 0 20 0.1% 0.00 [-0.08, 0.08] Stratigos 1973 0 0.014236 0 65 0.5% 0.00 [-0.03, 0.03] Tuza 1973 0 0.008387 0 113 1.4% 0.00 [-0.02, 0.02] Willcox 1974 0 0.011285 0 83 0.8% 0.00 [-0.02, 0.02] Zhou 2000 0 0.024597 0 36 0.2% 0.00 [-0.05, 0.05] Subtotal (95% CI) 27 4945 100.0% 0.00 [0.00, 0.01] Heterogeneity: Chi² = 783.41, df = 17 (P < 0.00001); I² = 98% Test for overall effect: Z = 3.41 (P = 0.0006)

38.6.2 Non-randomised with 1 group: Side effects: with 2gm dose: Chills Duancic 1974 0.00666667 0.00908571 1 150 100.0% 0.01 [-0.01, 0.02] Subtotal (95% CI) 1 150 100.0% 0.01 [-0.01, 0.02] Heterogeneity: Not applicable Test for overall effect: Z = 0.73 (P = 0.46)

38.6.3 Non-randomised with 1 group: Side effects: with 2gm dose: Fever, headache Duancic 1974 0.0133333 0.011134 2 150 83.0% 0.01 [-0.01, 0.04] Tupasi 1983 0.0576923 0.03485 3 52 8.5% 0.06 [-0.01, 0.13] Tupasi 1984 0.0576923 0.03485 3 52 8.5% 0.06 [-0.01, 0.13] Subtotal (95% CI) 8 254 100.0% 0.02 [0.00, 0.04] Heterogeneity: Chi² = 2.69, df = 2 (P = 0.26); I² = 26% Test for overall effect: Z = 2.06 (P = 0.04)

38.6.4 Non-randomised with 1 group: Side effects: with 2gm dose: syncope, pruritis, rash, urticaria Jaffe 1976 0.0044393 0.001654 8 1802 100.0% 0.00 [0.00, 0.01] Subtotal (95% CI) 8 1802 100.0% 0.00 [0.00, 0.01] Heterogeneity: Not applicable Test for overall effect: Z = 2.68 (P = 0.007)

38.6.5 Non-randomised with 1 group: Side effects: with 2gm dose: local reation/pain with unknown duration of infection/<6days prior Meyer-Rohn 1974 0.03 0.018946 3 100 59.6% 0.03 [-0.01, 0.07] Meyer-Rohn 1974 0.05 0.023012 5 100 40.4% 0.05 [0.00, 0.10] Subtotal (95% CI) 8 200 100.0% 0.04 [0.01, 0.07] Heterogeneity: Chi² = 0.45, df = 1 (P = 0.50); I² = 0% Test for overall effect: Z = 2.60 (P = 0.009)

38.6.6 Non-randomised with 1 group: Side effects: with 2gm dose: diarrhea Meyer-Rohn 1974 0.02 0.016457 2 100 40.0% 0.02 [-0.01, 0.05] Meyer-Rohn 1974 0.01 0.013449 1 100 60.0% 0.01 [-0.02, 0.04] Subtotal (95% CI) 3 200 100.0% 0.01 [-0.01, 0.03] Heterogeneity: Chi² = 0.22, df = 1 (P = 0.64); I² = 0% Test for overall effect: Z = 1.34 (P = 0.18)

38.6.8 Non-randomised with 1 group: Side effects: with 2gm dose: exanthem with unknown duration of infection Meyer-Rohn 1974 0.01 0.013449 1 100 100.0% 0.01 [-0.02, 0.04] Subtotal (95% CI) 1 100 100.0% 0.01 [-0.02, 0.04] Heterogeneity: Not applicable Test for overall effect: Z = 0.74 (P = 0.46)

38.6.9 Non-randomised with 1 group: Side effects: with 2gm dose: Giddiness Panikabutra 1988 0.00411523 0.00566628 1 243 100.0% 0.00 [-0.01, 0.02] Subtotal (95% CI) 1 243 100.0% 0.00 [-0.01, 0.02] Heterogeneity: Not applicable Test for overall effect: Z = 0.73 (P = 0.47)

38.6.10 Non-randomised with 1 group: Side effects: with 2gm dose: numbness,dizziness, Panikabutra 1988 0.00411523 0.00566628 1 243 90.6% 0.00 [-0.01, 0.02] Tupasi 1983 0.0192308 0.02495 1 52 4.7% 0.02 [-0.03, 0.07] Tupasi 1984 0.0192308 0.02495 1 52 4.7% 0.02 [-0.03, 0.07] Subtotal (95% CI) 3 347 100.0% 0.01 [-0.01, 0.02] Heterogeneity: Chi² = 0.67, df = 2 (P = 0.72); I² = 0% Test for overall effect: Z = 1.02 (P = 0.31)

38.6.11 Non-randomised with 1 group: Side effects: with 2gm dose: pain at injection site Mroczkowski 1993 0.06756757 0.03046179 5 74 20.3% 0.07 [0.01, 0.13] Panikabutra 1988 0.0617284 0.01570818 15 243 76.3% 0.06 [0.03, 0.09] Rompalo 1994 0.575 0.07473477 23 40 3.4% 0.57 [0.43, 0.72] Subtotal (95% CI) 43 357 100.0% 0.08 [0.05, 0.11] Heterogeneity: Chi² = 45.39, df = 2 (P < 0.00001); I² = 96% Test for overall effect: Z = 5.85 (P < 0.00001)

38.6.12 Non-randomised with 1 group: Side effects: with 2gm dose: complication- Postgonococcal urethris (PGU) Handsfield 1983 0.19148936 0.05645016 9 47 8.2% 0.19 [0.08, 0.30] Porter 1977 0.17567568 0.0438982 13 74 13.5% 0.18 [0.09, 0.26] Ratnam 1982 0.02884615 0.01825096 3 104 78.3% 0.03 [-0.01, 0.06] Subtotal (95% CI) 25 225 100.0% 0.06 [0.03, 0.09] Heterogeneity: Chi² = 15.27, df = 2 (P = 0.0005); I² = 87% Test for overall effect: Z = 3.84 (P = 0.0001)

38.6.13 Non-randomised with 1 group: Side effects: with 2gm dose: malaise Tupasi 1983 0.0192308 0.02495 1 52 50.0% 0.02 [-0.03, 0.07] Tupasi 1984 0.0192308 0.02495 1 52 50.0% 0.02 [-0.03, 0.07] Subtotal (95% CI) 2 104 100.0% 0.02 [-0.02, 0.05] Heterogeneity: Chi² = 0.00, df = 1 (P = 1.00); I² = 0% Test for overall effect: Z = 1.09 (P = 0.28)

-2 -1 0 1 2 Favours [spectinomycin] Favours [control] 54

Web annex E – Systematic reviews

Spectinomycin 4 g IM × 1 Side-effects including allergy, toxicity event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 38.7.1 Non-randomised with 1 group: Side effects: with 4gm dose: general side effects Duncan 1972 0 0.00601812 0 159 16.1% 0.00 [-0.01, 0.01] Finger 1975 0 0.004626 0 208 27.3% 0.00 [-0.01, 0.01] Karney 1977 0.0166551 0.00343 24 1441 49.6% 0.02 [0.01, 0.02] McCann 1977 0 0.009087 0 104 7.1% 0.00 [-0.02, 0.02] Subtotal (95% CI) 24 1912 100.0% 0.01 [0.00, 0.01] Heterogeneity: Chi² = 11.89, df = 3 (P = 0.008); I² = 75% Test for overall effect: Z = 3.42 (P = 0.0006)

38.7.2 Non-randomised with 1 group: Side effects: with 4gm dose: Chills Duancic 1974 0.04666667 0.01795952 7 150 100.0% 0.05 [0.01, 0.08] Subtotal (95% CI) 7 150 100.0% 0.05 [0.01, 0.08] Heterogeneity: Not applicable Test for overall effect: Z = 2.60 (P = 0.009)

38.7.3 Non-randomised with 1 group: Side effects: with 4gm dose: Fever Duancic 1974 0.03333333 0.01564608 5 150 100.0% 0.03 [0.00, 0.06] Subtotal (95% CI) 5 150 100.0% 0.03 [0.00, 0.06] Heterogeneity: Not applicable Test for overall effect: Z = 2.13 (P = 0.03)

38.7.4 Non-randomised with 1 group: Side effects: with 4gm dose: Pain at site of injection Finger 1975 0.0240385 0.011408 5 208 100.0% 0.02 [0.00, 0.05] Subtotal (95% CI) 5 208 100.0% 0.02 [0.00, 0.05] Heterogeneity: Not applicable Test for overall effect: Z = 2.11 (P = 0.04)

-2 -1 0 1 2 Favours [spectinomycin] Favours [control]

Kanamycin 2 g Side-effects including allergy, toxicity

event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 38.8.1 Non-randomised with 1 group: Side effects: general side effects Dashevskii 1975 0 0.025231 0 35 1.1% 0.00 [-0.05, 0.05] Hira 1985 0 0.010556 0 89 6.2% 0.00 [-0.02, 0.02] Niunikova 1975 0 0.009623 0 98 7.4% 0.00 [-0.02, 0.02] Rajan 1979 0 0.002834 0 342 85.4% 0.00 [-0.01, 0.01] Subtotal (95% CI) 0 564 100.0% 0.00 [-0.01, 0.01] Heterogeneity: Chi² = 0.00, df = 3 (P = 1.00); I² = 0% Test for overall effect: Z = 0.00 (P = 1.00)

38.8.2 Non-randomised with 1 group: Side effects: postgonococcal urethritis (PGU) complica Hira 1985 0.09859155 0.03602731 7 71 100.0% 0.10 [0.03, 0.17] Subtotal (95% CI) 7 71 100.0% 0.10 [0.03, 0.17] Heterogeneity: Not applicable Test for overall effect: Z = 2.74 (P = 0.006)

-2 -1 0 1 2 Favours [Kanamycin] Favours [control]

Ceftriaxone 125 mg IM × 1 Side-effects including allergy, toxicity

event total proportion proportion Study or Subgroup proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 39.9.1 Non-randomised with 1 group: Side effects: general side effects Handsfield 1987 0 0.006209 0 154 0.00 [-0.01, 0.01]

-2 -1 0 1 2 Favours [ceftriaxone] Favours [control]

HIV transmission and acquisition (1-arm studies) Quality of life (1-arm studies) No studies were found for these outcomes. 55

WHO guidelines for the treatment of Neisseria gonorrhoeae

For men who have sex with men (MSM)

Spectinomycin versus ceftriaxone Microbiological cure by number of people among MSM

spectinomycin 2g ceftriaxone 125mg Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 39.1.1 Microbiological cure RCTs spectinomycin 2g by person amomg MSM Judson 1985 (1) 9 9 52 52 1.00 [0.87, 1.16] + + + + + + + + + ?

0.1 0.2 0.5 1 2 5 10 Favours [Ceftriaxonel] Favours [Spectinomycin]

Footnotes Risk of bias legend (1) Ceftriaxone dose 125 mg (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants ( clincal cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators (Clinical cure and a/e) (G) Blinding of the data analyst (H) Incomplete outcome data (attrition bias): (I) Selective reporting (reporting bias) (J) Other bias

Spectinomycin 2 g IM × 1 Microbiological cure by number of people among MSM event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 41.6.1 Non-randomised with 1 group : Microbiological cure by person among MSM Fluker 1980 0.9464286 0.032574 53 56 87.7% 0.95 [0.88, 1.01] Holder 1972 0.86666667 0.0871083 13 15 12.3% 0.87 [0.70, 1.04] Subtotal (95% CI) 66 71 100.0% 0.94 [0.88, 1.00] Heterogeneity: Chi² = 0.74, df = 1 (P = 0.39); I² = 0% Test for overall effect: Z = 30.70 (P < 0.00001)

-2 -1 0 1 2 Favours [spectinomycin] Favours [control] Test for subgroup differences: Not applicable

Spectinomycin 2 g IM × 1 Microbiological cure by number of infection sites among MSM event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 41.7.1 Non-randomised with 1 group : Microbiological cure by infection among MSM: only urethra Holder 1972 1 0.20241243 1 1 100.0% 1.00 [0.60, 1.40] Subtotal (95% CI) 1 1 100.0% 1.00 [0.60, 1.40] Heterogeneity: Not applicable Test for overall effect: Z = 4.94 (P < 0.00001)

41.7.2 Non-randomised with 1 group : Microbiological cure by infection among MSM: only rectal Holder 1972 0.8 0.15006341 4 5 20.5% 0.80 [0.51, 1.09] Judson 1985 1 0.07631448 9 9 79.5% 1.00 [0.85, 1.15] Subtotal (95% CI) 13 14 100.0% 0.96 [0.83, 1.09] Heterogeneity: Chi² = 1.41, df = 1 (P = 0.23); I² = 29% Test for overall effect: Z = 14.10 (P < 0.00001)

41.7.3 Non-randomised with 1 group : Microbiological cure by infection among MSM: only urehtral + rectum Holder 1972 0.88888889 0.1058969 8 9 100.0% 0.89 [0.68, 1.10] Subtotal (95% CI) 8 9 100.0% 0.89 [0.68, 1.10] Heterogeneity: Not applicable Test for overall effect: Z = 8.39 (P < 0.00001)

-2 -1 0 1 2 Favours [spectinomycin] Favours [control]

Web annex E – Systematic reviews

Ceftriaxone 125 mg IM × 1 Microbiological cure by number of people among MSM

event total proportion proportion Study or Subgroup proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 42.10.1 Non-randomised with 1 group : Microbiological cure by person among MSM Handsfield 1987 0.971831 0.02277 69 71 0.97 [0.93, 1.02]

-2 -1 0 1 2 Favours [ceftriaxonel] Favours [control]

Cefixime 800 mg po × 1 Microbiological cure by sites of infection among MSM

event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 41.10.1 Non-randomised with 1 group : Microbiological cure by person among MSM Megran 1990 0.98979592 0.01371241 97 98 100.0% 0.99 [0.96, 1.02] Subtotal (95% CI) 97 98 100.0% 0.99 [0.96, 1.02] Heterogeneity: Not applicable Test for overall effect: Z = 72.18 (P < 0.00001)

-2 -1 0 1 2 Favours [ceftriaxonel] Favours [control]

WHO guidelines for the treatment of Neisseria gonorrhoeae

Risk of bias Randomized studies: see forest plots Non-randomized studies (LOW: low risk of bias; MOD: moderate risk of bias; HIGH: high risk of bias; NI: no information) STUDY INFORMATION INFECTION OUTCOME INTERVENTIONS Risk of bias for non-RCTs

First author

(last name Year Infection Outcome Enter specific outcomes Treatment only) interventions Confounding Selection of participants Measurement of Intended interventions Missing data Measurement of outcomes Reporting Overall

genital (urethra) Khaki 2007 Microbiological cure Azithromycin MOD LOW LOW LOW LOW LOW LOW LOW or anorectal genital (urethra) Khaki 2007 Side-effects (including allergy) Mild diarrhoea (8%) Azithromycin MOD LOW LOW LOW LOW MOD LOW MOD or anorectal genital (urethra) Mild abdominal Khaki 2007 Side-effects (including allergy) Azithromycin MOD LOW LOW LOW LOW MOD LOW MOD or anorectal pain (1.6%) genital (urethra) Rustomjee 2002 Microbiological cure Azithromycin MOD LOW LOW MOD LOW LOW LOW LOW or anorectal genital (urethra) Rustomjee 2002 Compliance Azithromycin MOD LOW LOW MOD LOW LOW LOW LOW or anorectal genital (urethra) Rustomjee 2002 Clinical cure Azithromycin MOD LOW LOW MOD LOW LOW LOW LOW or anorectal genital (urethra) Rustomjee 2002 Side-effects (including allergy) Mild diarrhoea Azithromycin MOD LOW LOW MOD LOW MOD LOW MOD or anorectal Goldstein 1991 genital (cervix) Microbiological cure Ceftriaxone LOW LOW LOW NI LOW LOW LOW LOW Goldstein 1991 all infections/total Side-effects (including allergy) Ceftriaxone LOW LOW LOW NI LOW LOW LOW LOW genital (urethra) McCann 1977 Microbiological cure Spectinomycin MOD LOW LOW NI LOW LOW LOW MOD or anorectal genital (urethra) McCann 1977 Side-effects (including allergy) Spectinomycin MOD LOW LOW NI LOW MOD LOW MOD or anorectal Steingrimsson 1990 genital (urethra) Microbiological cure LOW LOW LOW LOW LOW LOW LOW LOW Steingrimsso 1990 genital (urethra) Side-effects (including allergy) Diarrhoea, nausea LOW LOW LOW LOW LOW LOW LOW LOW Steingrimsso 1990 genital (urethra) Microbiological cure LOW LOW LOW LOW LOW LOW LOW LOW 58

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STUDY INFORMATION INFECTION OUTCOME INTERVENTIONS Risk of bias for non-RCTs

First author

Judson 1974 genital (cervix) Microbiological cure Culture MOD LOW LOW NI LOW LOW LOW LOW Judson 1974 genital (cervix) Side-effects (including allergy) Not clear MOD LOW LOW NI LOW MOD LOW MOD genital (urethra) Karney 1977 Microbiological cure Spectinomycin MOD LOW LOW NI LOW LOW LOW LOW or anorectal Moderately severe pain at the injection site. Less common were transient genital (urethra) Karney 1977 Side-effects (including allergy) skin rash, pruritus, Spectinomycin MOD LOW LOW NI LOW MOD LOW MOD or anorectal abdominal cramps, nausea or vomiting and dizziness. genital (urethra) Smith 1993 Microbiological cure Ceftriaxone MOD LOW LOW LOW LOW LOW LOW LOW or anorectal Smith 1993 genital (cervix) Side-effects (including allergy) Ceftriaxone MOD LOW LOW NI LOW MOD LOW MOD Korting 1989 genital (cervix) Microbiological cure Ceftriaxone MOD LOW LOW NI LOW LOW LOW LOW Korting 1989 genital (cervix) Side-effects (including allergy) Pain at injection site Ceftriaxone MOD LOW LOW NI LOW MOD LOW MOD Kousa 1974 genital (cervix) Microbiological cure Spectinomycin MOD LOW LOW LOW LOW LOW LOW MOD Kousa 1974 genital (cervix) Side-effects (including allergy) Spectinomycin MOD LOW LOW LOW LOW MOD LOW MOD Aplasca 2001 genital (cervix) Microbiological cure Cefixime LOW LOW LOW NI LOW LOW LOW LOW Baddour 1992 genital (cervix) Microbiological cure By person Ceftriaxone MOD LOW LOW LOW LOW LOW LOW MOD Baddour 1992 genital (cervix) Microbiological cure By site of infection Ceftriaxone MOD LOW LOW LOW LOW LOW LOW MOD Baddour 1992 genital (cervix) Side-effects (including allergy) Diarrhoea Ceftriaxone MOD LOW LOW LOW LOW LOW LOW MOD Baddour 1992 genital (cervix) Side-effects (including allergy) Rash Ceftriaxone MOD LOW LOW LOW LOW LOW LOW MOD Baddour 1992 oropharyngeal Microbiological cure By person Ceftriaxone MOD LOW LOW LOW LOW LOW LOW MOD Bowie 1974 genital (cervix) Microbiological cure Gentamicin MOD LOW LOW LOW LOW LOW LOW MOD

WHO guidelines for the treatment of Neisseria gonorrhoeae

STUDY INFORMATION INFECTION OUTCOME INTERVENTIONS Risk of bias for non-RCTs

First author

Bowie 1974 genital (cervix) Side-effects (including allergy) Gentamicin MOD LOW LOW LOW LOW MOD LOW MOD Deguchi 2003 genital (cervix) Microbiological cure Cefixime MOD MOD LOW LOW LOW LOW LOW MOD Deguchi 2003 genital (cervix) Side-effects (including allergy) Cefixime MOD MOD LOW LOW LOW MOD LOW MOD Duancic 1974 genital (cervix) Microbiological cure Spectinomycin MOD LOW LOW NI LOW LOW LOW MOD Duancic 1974 genital (cervix) Side-effects (including allergy) Fever Spectinomycin MOD LOW LOW NI LOW MOD LOW MOD Duancic 1974 genital (cervix) Side-effects (including allergy) Chills Spectinomycin MOD LOW LOW NI LOW MOD LOW MOD Duncan 1972 genital (cervix) Microbiological cure Spectinomycin MOD LOW LOW LOW LOW LOW LOW MOD Duncan 1972 genital (cervix) Side-effects (including allergy) Spectinomycin MOD LOW LOW LOW LOW MOD LOW MOD Rajan 1982 genital (cervix) Microbiological cure Ceftriaxone MOD LOW LOW LOW LOW LOW LOW MOD Rajan 1982 genital (cervix) Side-effects (including allergy) Ceftriaxone MOD LOW LOW LOW LOW MOD LOW MOD genital (urethra) Karney 1977 Microbiological cure Spectinomycin MOD LOW LOW LOW LOW LOW LOW LOW or anorectal Mostly severe pain at the injection site. Less common were transient genital (urethra) Karney 1977 Side-effects (including allergy) skin rash, pruritus, Spectinomycin MOD LOW LOW LOW LOW MOD LOW MOD or anorectal abdominal cramps, nausea or vomiting and dizziness. Monayar 1987 genital (cervix) Microbiological cure Spectinomycin MOD LOW LOW LOW LOW LOW LOW MOD Morrison 1973 genital (cervix) Microbiological cure Gentamicin MOD LOW LOW LOW LOW LOW LOW MOD Odugbemi 1993 genital (cervix) Microbiological cure Azithromycin MOD LOW LOW LOW LOW LOW LOW MOD Odugbemi 1993 genital (cervix) Clinical cure Azithromycin MOD LOW LOW LOW LOW LOW LOW MOD Odugbemi 1993 genital (cervix) Side-effects (including allergy) Gastrointestinal- Azithromycin MOD LOW LOW LOW LOW MOD LOW MOD

Web annex E – Systematic reviews

STUDY INFORMATION INFECTION OUTCOME INTERVENTIONS Risk of bias for non-RCTs

First author

Pedersen 1972 genital (cervix) Microbiological cure Spectinomycin MOD LOW LOW LOW LOW LOW LOW MOD Pedersen genital (cervix) Microbiological cure Spectinomycin MOD LOW LOW LOW LOW LOW LOW MOD Pedersen genital (cervix) Side-effects (including allergy) Spectinomycin MOD LOW LOW LOW LOW MOD LOW MOD Schumacher 2013 genital (cervix) Microbiological cure Ceftazidime MOD LOW LOW LOW LOW LOW LOW MOD Schumacher 2013 genital (cervix) Microbiological cure CeftAzi MOD LOW LOW LOW LOW LOW LOW MOD Schumacher 2013 genital (cervix) Microbiological cure CeftAzi MOD LOW LOW LOW LOW LOW LOW MOD Schumacher 2013 genital (cervix) Microbiological cure CeftAzi MOD LOW LOW LOW LOW LOW LOW MOD Schumacher 2013 genital (cervix) Microbiological cure CeftAzi MOD LOW LOW LOW LOW LOW LOW MOD Schumacher 2013 genital (cervix) Microbiological cure CeftAzi MOD LOW LOW LOW LOW LOW LOW MOD Tupasi 1993 genital (cervix) Microbiological cure Spectinomycin MOD LOW LOW LOW LOW LOW LOW MOD Tupasi 1984 genital (cervix) Side-effects (including allergy) Spectinomycin MOD LOW LOW LOW LOW MOD LOW MOD Tupasi 1984 genital (cervix) Side-effects (including allergy) Spectinomycin MOD LOW LOW LOW LOW MOD LOW MOD Tupasi 1984 genital (cervix) Side-effects (including allergy) Spectinomycin MOD LOW LOW LOW LOW MOD LOW MOD Zajdowicz 1983 genital (cervix) Microbiological cure Ceftriaxone LOW LOW LOW LOW LOW LOW LOW LOW Zajdowicz 1983 genital (cervix) Clinical cure Ceftriaxone LOW LOW LOW LOW LOW LOW LOW LOW Zajdowicz 1983 genital (cervix) Side-effects (including allergy) Ceftriaxone LOW LOW LOW LOW LOW MOD LOW MOD Calderon 1988 genital (cervix) Microbiological cure Ceftriaxone LOW LOW LOW LOW LOW LOW LOW LOW Calderon 1988 genital (cervix) Clinical cure Ceftriaxone LOW LOW LOW LOW LOW LOW LOW LOW Calderon 1988 genital (cervix) Side-effects (including allergy) Ceftriaxone LOW LOW LOW LOW LOW MOD LOW MOD Tuza 1973 genital (cervix) Microbiological cure Spectinomycin MOD LOW LOW LOW LOW LOW LOW MOD Tuza 1973 genital (cervix) Side-effects (including allergy) Spectinomycin MOD LOW LOW LOW LOW MOD LOW MOD

WHO guidelines for the treatment of Neisseria gonorrhoeae

STUDY INFORMATION INFECTION OUTCOME INTERVENTIONS Risk of bias for non-RCTs

First author

Tuza 1973 genital (cervix) Clinical cure Spectinomycin MOD LOW LOW LOW LOW LOW LOW MOD Swanston 2001 genital (cervix) Microbiological cure Azithromycin MOD LOW LOW LOW LOW LOW LOW MOD Swanston 2001 genital (cervix) Clinical cure Azithromycin MOD LOW LOW LOW LOW LOW LOW MOD Swanston 2001 genital (cervix) Side-effects (including allergy) Azithromycin MOD LOW LOW LOW LOW MOD LOW MOD Brown 1974 genital (cervix) Microbiological cure Spectinomycin MOD LOW LOW LOW LOW LOW LOW MOD Brown 1974 genital (cervix) Side-effects (including allergy) Spectinomycin MOD LOW LOW LOW LOW MOD LOW MOD Bryan 1990 genital (cervix) Microbiological cure Ceftriaxone LOW LOW LOW LOW LOW LOW LOW LOW Bryan 1990 genital (cervix) Microbiological cure Ceftriaxone LOW LOW LOW LOW LOW LOW LOW LOW Bryan 1990 genital (cervix) Side-effects (including allergy) Ceftriaxone LOW LOW LOW LOW LOW LOW LOW LOW Christophersen 1989 genital (cervix) Microbiological cure Ceftriaxone LOW LOW LOW LOW LOW LOW LOW LOW Minor gastrointestinal Christophersen 1989 genital (cervix) Side-effects (including allergy) complaints (loose stools Ceftriaxone LOW LOW LOW LOW LOW MOD MOD MOD or diarrhoea) Covino 1993 genital (cervix) Microbiological cure Ceftriaxone LOW LOW LOW LOW LOW LOW LOW LOW Covino 1993 oropharyngeal Microbiological cure Ceftriaxone LOW LOW LOW LOW LOW LOW LOW LOW Covino 1993 genital (cervix) Side-effects (including allergy) Ceftriaxone LOW LOW LOW LOW LOW MOD MOD MOD Covino 1990 genital (cervix) Microbiological cure By person Ceftriaxone LOW LOW LOW LOW LOW LOW LOW LOW Covino 1990 genital (cervix) Microbiological cure By site of infection Ceftriaxone LOW LOW LOW LOW LOW LOW LOW LOW Davidson 1986 genital (cervix) Microbiological cure Spectinomycin MOD LOW LOW LOW LOW LOW LOW MOD Dixon 1986 genital (cervix) Microbiological cure By person Ceftriaxone LOW LOW LOW LOW LOW LOW LOW LOW Dixon 1986 genital (cervix) Microbiological cure By site of infection Ceftriaxone LOW LOW LOW LOW LOW LOW LOW LOW Dixon 1986 genital (cervix) Side-effects (including allergy) Ceftriaxone LOW LOW LOW LOW LOW LOW LOW LOW

Web annex E – Systematic reviews

STUDY INFORMATION INFECTION OUTCOME INTERVENTIONS Risk of bias for non-RCTs

First author

Dunnett/ 1992 genital (cervix) Microbiological cure Cefixime MOD LOW LOW LOW LOW LOW LOW MOD Dunnel Dunnett/ 1992 genital (cervix) Side-effects (including allergy) Nausea Cefixime MOD LOW LOW LOW LOW MOD LOW MOD Dunnel Fluker 1980 genital (cervix) Microbiological cure Spectinomycin MOD LOW LOW LOW LOW LOW LOW MOD Freedman 1990 genital (cervix) Microbiological cure Ceftriaxone MOD LOW LOW MOD MOD LOW LOW MOD Gruber 1997 genital (cervix) Microbiological cure Azithromycin LOW LOW LOW LOW LOW LOW LOW LOW Gruber 1997 genital (cervix) Microbiological cure Azithromycin LOW LOW LOW LOW LOW LOW LOW LOW Gruber 1997 genital (cervix) Clinical cure Azithromycin LOW LOW LOW LOW LOW LOW LOW LOW Gruber 1997 genital (cervix) Clinical cure Azithromycin LOW LOW LOW LOW LOW LOW LOW LOW Gruber 1997 genital (cervix) Side-effects (including allergy) Nausea Azithromycin LOW LOW LOW LOW LOW LOW MOD MOD Gruber 1997 genital (cervix) Side-effects (including allergy) Diarrhoea Azithromycin LOW LOW LOW LOW LOW LOW MOD MOD Gruber 1997 genital (cervix) Side-effects (including allergy) Abdominal pain Azithromycin LOW LOW LOW LOW LOW LOW MOD MOD Habib 2004 genital (cervix) Microbiological cure Azithromycin MOD MOD LOW MOD MOD MOD LOW MOD Handsfield 1987 genital (cervix) Microbiological cure By person Ceftriaxone MOD MOD LOW MOD MOD MOD LOW MOD Handsfield 1987 genital (cervix) Microbiological cure By site of infection Ceftriaxone MOD MOD LOW MOD MOD MOD LOW MOD Handsfield 1987 genital (cervix) Microbiological cure By person Ceftriaxone MOD MOD LOW MOD MOD MOD LOW MOD Handsfield 1987 genital (cervix) Side-effects (including allergy) Ceftriaxone MOD MOD LOW MOD MOD MOD MOD MOD Hantschke 1973 genital (cervix) Microbiological cure Gentamicin MOD LOW LOW LOW LOW LOW LOW MOD Hantschke 1973 genital (cervix) Side-effects (including allergy) Gentamicin MOD LOW LOW LOW LOW LOW LOW MOD Holder 1972 genital (cervix) Microbiological cure Spectinomycin MOD LOW LOW MOD MOD LOW LOW MOD Holder 1972 genital (cervix) Clinical cure Spectinomycin MOD LOW LOW MOD MOD MOD LOW MOD Hook 1997 genital (cervix) Microbiological cure By person Cefixime LOW LOW LOW LOW LOW LOW LOW LOW

WHO guidelines for the treatment of Neisseria gonorrhoeae

STUDY INFORMATION INFECTION OUTCOME INTERVENTIONS Risk of bias for non-RCTs

First author

Hook 1997 genital (cervix) Microbiological cure By site of infection Cefixime LOW LOW LOW LOW LOW LOW LOW LOW Hook 1997 all infections/total Side-effects (including allergy) Headache Cefixime LOW LOW LOW LOW LOW MOD MOD MOD Hook 1997 all infections/total Side-effects (including allergy) Nausea Cefixime LOW LOW LOW LOW LOW MOD MOD MOD Hook 1993 genital (cervix) Microbiological cure By person Ceftriaxone LOW LOW LOW LOW LOW LOW LOW LOW Hook 1993 oropharyngeal Microbiological cure By site of infection Ceftriaxone LOW LOW LOW LOW LOW LOW LOW LOW Hook 1993 all infections/total Microbiological cure Ceftriaxone LOW LOW LOW LOW LOW LOW LOW LOW By site of infection irritability, nausea, Hook 1993 all infections/total Side-effects (including allergy) diarrhoea, abdominal Ceftriaxone LOW LOW LOW LOW LOW LOW LOW LOW discomfort, vaginitis and vaginal pruritus Pain in the site of Hook 1993 all infections/total Side-effects (including allergy) Ceftriaxone LOW LOW LOW LOW LOW LOW LOW LOW injection Hook 1986 genital (cervix) Microbiological cure Spectinomycin LOW LOW LOW LOW LOW LOW LOW LOW Hook 1986 genital (cervix) Microbiological cure Spectinomycin LOW LOW LOW LOW LOW LOW LOW LOW Jaffe 1976 genital (cervix) Side-effects (including allergy) Spectinomycin MOD MOD MOD LOW MOD LOW MOD MOD Syncope, pruritus, Jaffe 1976 genital (cervix) Side-effects (including allergy) Spectinomycin MOD MOD MOD LOW MOD LOW MOD MOD rash, urticaria Judson 1983 genital (cervix) Microbiological cure Ceftriaxone LOW LOW LOW LOW LOW LOW LOW LOW Judson 1983 genital (cervix) Side-effects (including allergy) Ceftriaxone LOW LOW LOW LOW LOW LOW LOW LOW Kim 1984 genital (cervix) Microbiological cure Spectinomycin LOW LOW LOW LOW LOW LOW LOW LOW Kojima 2008 genital (cervix) Microbiological cure Spectinomycin MOD LOW LOW LOW LOW LOW LOW MOD Kojima 2008 genital (cervix) Clinical cure Spectinomycin MOD LOW LOW LOW LOW LOW LOW MOD Kojima 2008 genital (cervix) Side-effects (including allergy) Spectinomycin MOD LOW LOW LOW LOW MOD MOD MOD Kouri 1989 genital (cervix) Microbiological cure Spectinomycin LOW LOW LOW LOW LOW LOW LOW LOW 64

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STUDY INFORMATION INFECTION OUTCOME INTERVENTIONS Risk of bias for non-RCTs

First author

Kouri 1989 genital (cervix) Side-effects (including allergy) Spectinomycin LOW LOW LOW LOW LOW MOD MOD MOD McCormack 1993 genital (cervix) Microbiological cure By person Ceftriaxone LOW LOW LOW LOW LOW LOW LOW LOW McCormack 1993 genital (cervix) Microbiological cure By site of infection Ceftriaxone LOW LOW LOW LOW LOW LOW LOW LOW McCormack 1993 all infections/total Side-effects (including allergy) Ceftriaxone LOW LOW LOW LOW LOW LOW LOW LOW Megran 1990 genital (cervix) Microbiological cure By infection site Cefixime LOW LOW LOW LOW LOW LOW LOW LOW Lower gastrointestinal symptoms (diarrhoea: Megran 1990 genital (cervix) Side-effects (including allergy) one or more loose Cefixime LOW LOW LOW LOW LOW MOD MOD MOD stools), flatulence, cramping Megran 1990 genital (cervix) Side-effects (including allergy) Headache, dizziness Cefixime LOW LOW LOW LOW LOW MOD MOD MOD Megran 1990 genital (cervix) Side-effects (including allergy) Rash Cefixime LOW LOW LOW LOW LOW MOD MOD MOD Meheus 1984 genital (cervix) Microbiological cure Spectinomycin MOD MOD LOW LOW LOW LOW LOW MOD Meheus 1984 genital (cervix) Side-effects (including allergy) Spectinomycin MOD MOD LOW LOW LOW MOD MOD MOD Mogabgab 1994 genital (cervix) Microbiological cure By person Ceftriaxone MOD LOW LOW LOW LOW LOW LOW MOD Mogabgab 1994 genital (cervix) Microbiological cure By site of infection Ceftriaxone MOD LOW LOW LOW LOW LOW LOW MOD Mogabgab 1994 genital (cervix) Clinical cure Ceftriaxone MOD LOW LOW LOW LOW LOW LOW MOD Pain at injection site or Mogabgab 1994 genital (cervix) Side-effects (including allergy) Ceftriaxone MOD LOW LOW LOW LOW MOD MOD MOD local reaction One each of gastrointestinal pain, unspecified pain, Mogabgab 1994 genital (cervix) Side-effects (including allergy) Ceftriaxone MOD LOW LOW LOW LOW MOD MOD MOD headache, pruritus, urinary tract infection (mostly severe) Mroczkowski 1997 genital (cervix) Microbiological cure By person Cefixime LOW LOW LOW LOW LOW LOW LOW LOW Mroczkowski 1997 genital (cervix) Microbiological cure By site of infection Cefixime LOW LOW LOW LOW LOW LOW LOW LOW 65

WHO guidelines for the treatment of Neisseria gonorrhoeae

STUDY INFORMATION INFECTION OUTCOME INTERVENTIONS Risk of bias for non-RCTs

First author

Mroczkowski 1997 all infections/total Side-effects (including allergy) Vaginitis Cefixime LOW LOW LOW LOW LOW MOD MOD MOD Mroczkowski 1997 all infections/total Side-effects (including allergy) Nausea Cefixime LOW LOW LOW LOW LOW MOD MOD MOD Mroczkowski 1997 all infections/total Side-effects (including allergy) Vomiting Cefixime LOW LOW LOW LOW LOW MOD MOD MOD Mroczkowski 1997 all infections/total Side-effects (including allergy) Leukorrhoea Cefixime LOW LOW LOW LOW LOW MOD MOD MOD Mroczkowski 1997 all infections/total Side-effects (including allergy) Pruritus Cefixime LOW LOW LOW LOW LOW MOD MOD MOD Mroczkowski 1997 all infections/total Side-effects (including allergy) Diarrhoea Cefixime LOW LOW LOW LOW LOW MOD MOD MOD Muratani 2008 genital (cervix) Microbiological cure Ceftriaxone MOD LOW LOW LOW LOW LOW MOD MOD Muratani 2008 all infections/total Side-effects (including allergy) Ceftriaxone MOD LOW LOW LOW LOW MOD MOD MOD Pabst 1989 genital (cervix) Microbiological cure By person Ceftriaxone LOW LOW LOW LOW LOW LOW LOW MOD Pabst 1989 genital (cervix) Microbiological cure By site of infection Ceftriaxone LOW LOW LOW LOW LOW LOW LOW MOD Pabst 1989 all infections/total Side-effects (including allergy) Ceftriaxone LOW LOW LOW LOW LOW MOD MOD MOD Pabst 1989 genital (cervix) Microbiological cure Ceftriaxone Pandhi 1989 all infections/total Microbiological cure Gentamicin MOD LOW LOW LOW LOW LOW LOW MOD Pandhi 1989 all infections/total Microbiological cure Culture Gentamicin MOD LOW LOW LOW LOW LOW LOW MOD Pandhi 1989 all infections/total Microbiological cure Culture Gentamicin MOD LOW LOW LOW LOW LOW LOW MOD May be reported by Pandhi 1989 all infections/total Side-effects (including allergy) Gentamicin MOD LOW LOW LOW LOW MOD MOD MOD patients Panikabutra 1983 genital (cervix) Microbiological cure Spectinomycin MOD LOW LOW LOW LOW LOW LOW MOD Panikabutra 1983 genital (cervix) Side-effects (including allergy) Reported by patients Spectinomycin MOD LOW LOW LOW LOW MOD MOD MOD Panikabutra 1988 genital (cervix) Microbiological cure Spectinomycin LOW LOW LOW LOW LOW LOW LOW LOW Panikabutra 1988 genital (cervix) Microbiological cure Spectinomycin LOW LOW LOW LOW LOW LOW LOW LOW Panikabutra 1988 genital (cervix) Side-effects (including allergy) Pain at injection site Spectinomycin LOW LOW LOW LOW LOW MOD MOD MOD Panikabutra 1988 genital (cervix) Side-effects (including allergy) Numbness Spectinomycin LOW LOW LOW LOW LOW MOD MOD MOD Panikabutra 1988 genital (cervix) Side-effects (including allergy) Giddiness Spectinomycin LOW LOW LOW LOW LOW MOD MOD MOD 66

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STUDY INFORMATION INFECTION OUTCOME INTERVENTIONS Risk of bias for non-RCTs

First author

Porter 1977 genital (cervix) Microbiological cure Spectinomycin MOD LOW LOW LOW LOW LOW LOW MOD Porter 1977 genital (cervix) Microbiological cure Spectinomycin MOD LOW LOW LOW LOW LOW LOW MOD Porter 1977 genital (cervix) Side-effects (including allergy) Pain at injection site Spectinomycin MOD LOW LOW LOW LOW MOD MOD MOD Rajan 1979 genital (cervix) Microbiological cure Kanamycin MOD LOW LOW LOW LOW LOW LOW MOD Rajan 1979 genital (cervix) Side-effects (including allergy) Kanamycin MOD LOW LOW LOW LOW MOD MOD MOD Ratnam 1982 genital (cervix) Microbiological cure Spectinomycin MOD LOW LOW LOW LOW LOW LOW MOD Ratnam 1982 genital (cervix) Microbiological cure Spectinomycin MOD LOW LOW LOW LOW LOW LOW MOD Ratnam 1982 genital (cervix) Side-effects (including allergy) Spectinomycin MOD LOW LOW LOW LOW MOD MOD MOD Sands (a) 1980 genital (cervix) Microbiological cure Spectinomycin MOD LOW MOD MOD MOD LOW MOD Critical Stratigos 1973 all infections/total Microbiological cure Spectinomycin MOD LOW LOW LOW LOW LOW LOW MOD Stratigos 1973 all infections/total Clinical cure Spectinomycin MOD LOW LOW LOW LOW LOW LOW MOD Stratigos 1973 all infections/total Side-effects (including allergy) Spectinomycin MOD LOW LOW LOW LOW LOW LOW MOD Takahashi 2014 genital (cervix) Microbiological cure Azithromycin LOW LOW LOW LOW LOW LOW LOW MOD Takahashi 2014 genital (cervix) Clinical cure Azithromycin LOW LOW LOW LOW LOW LOW LOW MOD Takahashi 2014 genital (cervix) Side-effects (including allergy) Temporary diarrhoea Azithromycin LOW LOW LOW LOW LOW MOD MOD MOD Tupasi 1983 genital (cervix) Microbiological cure Spectinomycin MOD LOW LOW LOW LOW LOW LOW MOD Tupasi 1983 genital (cervix) Side-effects (including allergy) Headache Spectinomycin MOD LOW LOW LOW LOW MOD MOD MOD Tupasi 1983 genital (cervix) Side-effects (including allergy) Dizziness Spectinomycin MOD LOW LOW LOW LOW MOD MOD MOD Tupasi 1983 genital (cervix) Side-effects (including allergy) Malaise Spectinomycin MOD LOW LOW LOW LOW MOD MOD MOD Verdon 1993 genital (cervix) Microbiological cure By person Cefixime LOW LOW LOW LOW LOW LOW LOW LOW Verdon 1993 genital (cervix) Microbiological cure By site of infection Cefixime LOW LOW LOW LOW LOW LOW LOW LOW Transient nausea without Verdon 1993 all infections/total Side-effects (including allergy) Cefixime LOW LOW LOW LOW LOW MOD MOD MOD vomiting 67

WHO guidelines for the treatment of Neisseria gonorrhoeae

STUDY INFORMATION INFECTION OUTCOME INTERVENTIONS Risk of bias for non-RCTs

First author

Verdon 1993 all infections/total Side-effects (including allergy) Mild diarrhoea Cefixime LOW LOW LOW LOW LOW MOD MOD MOD Verdon 1993 all infections/total Side-effects (including allergy) Transient rash Cefixime LOW LOW LOW LOW LOW MOD MOD MOD Waugh 1993 genital (cervix) Microbiological cure By site of infection Azithromycin LOW MOD LOW LOW LOW LOW LOW MOD Waugh 1993 all infections/total Clinical cure By site of infection Azithromycin LOW MOD LOW LOW LOW LOW LOW MOD Waugh 1993 genital (cervix) Side-effects (including allergy) Moderate angioedema Azithromycin LOW MOD LOW LOW LOW MOD MOD MOD Waugh 1993 genital (cervix) Side-effects (including allergy) Vomited all the capsules Azithromycin LOW MOD LOW LOW LOW MOD MOD MOD Willcox 1974 genital (cervix) Microbiological cure Spectinomycin LOW MOD LOW LOW LOW LOW LOW MOD Willcox 1974 genital (cervix) Side-effects (including allergy) Spectinomycin LOW MOD LOW LOW LOW MOD MOD MOD Hira 1985 treatment failure Microbiological cure Gentamicin LOW LOW LOW NI LOW LOW LOW MOD Hira 1985 treatment failure Microbiological cure Gentamicin LOW LOW LOW NI LOW LOW LOW MOD Hira 1985 Side-effects (including allergy) Gentamicin LOW LOW LOW NI LOW LOW LOW MOD Hira 1985 Side-effects (including allergy) Serum creatinine Gentamicin LOW LOW LOW NI LOW LOW LOW MOD Felman 1978 genital (cervix) Microbiological cure Spectinomycin MOD LOW LOW NI LOW LOW LOW MOD genital (urethra) Finger 1975 Microbiological cure Spectinomycin MOD LOW LOW NI LOW LOW LOW MOD or anorectal genital (urethra) Finger 1975 Microbiological cure Spectinomycin MOD LOW LOW NI LOW LOW LOW MOD or anorectal genital (urethra) Finger 1975 Microbiological cure Spectinomycin MOD LOW LOW NI LOW LOW LOW MOD or anorectal genital (urethra) Finger 1975 Side-effects (including allergy) Spectinomycin MOD LOW LOW NI LOW LOW LOW MOD or anorectal genital (urethra) Pain at site of injection Finger 1975 Side-effects (including allergy) Spectinomycin MOD LOW LOW NI LOW LOW LOW MOD or anorectal for 1–2 days Foreign language articles Yoon (Korean) 1988 genital (cervix) Microbiological cure Kanamycin 68

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STUDY INFORMATION INFECTION OUTCOME INTERVENTIONS Risk of bias for non-RCTs

First author

Ling (Chinese) 2000 genital (cervix) Microbiological cure Azithromycin Ling (Chinese) 2000 genital (cervix) Clinical cure Azithromycin Ling (Chinese) 2000 genital (cervix) Side-effects (including allergy) Stomach pain/abdominal Azithromycin Shi (Chinese) 2000 genital (cervix) Microbiological cure Spectinomycin Shi (Chinese) 2000 genital (cervix) Clinical cure Spectinomycin Shi (Chinese) 2000 genital (cervix) Side-effects (including allergy) Spectinomycin Jin Hong 2001 genital (cervix) Microbiological cure Ceftriaxone (Chinese) Jin Hong 2001 genital (cervix) Clinical cure Ceftriaxone (Chinese) Jin Hong Headache, nausea, 2001 genital (cervix) Side-effects (including allergy) Ceftriaxone (Chinese) abdominal pain Zhou (Chinese) 2000 genital (cervix) Microbiological cure Spectinomycin Zhou (Chinese) 2000 genital (cervix) Clinical cure Spectinomycin Zhou (Chinese) 2000 genital (cervix) Side-effects (including allergy) Spectinomycin Niunikova 1975 genital (cervix) Microbiological cure Kanamycin (Russian) Niunikova 1975 genital (cervix) Clinical cure Kanamycin (Russian) Niunikova 1975 genital (cervix) Side-effects (including allergy) Kanamycin (Russian) Khrianin 2006 genital (cervix) Microbiological cure Ceftriaxone (Russian) Khrianin 2006 genital (cervix) Clinical cure Ceftriaxone (Russian)

WHO guidelines for the treatment of Neisseria gonorrhoeae

STUDY INFORMATION INFECTION OUTCOME INTERVENTIONS Risk of bias for non-RCTs

First author

Turanova 1975 genital (cervix) Microbiological cure Kanamycin (Russian) Turanova 1975 genital (cervix) Clinical cure Kanamycin (Russian) Dashevskii 1975 genital (cervix) Microbiological cure Kanamycin (Russian) Dashevskii 1975 genital (cervix) Side-effects (including allergy) Kanamycin (Russian) Wojtowicz 1990 genital (cervix) Microbiological cure Spectinomycin (Polish) Stapinski 1986 genital (cervix) Microbiological cure Spectinomycin (Polish) Reggiani 1983 genital (cervix) Microbiological cure Spectinomycin (Italian) Reggiani 1983 genital (cervix) Side-effects (including allergy) Spectinomycin (Italian) Backhaus 1990 all infections/total Microbiological cure Cefixime (German) Backhaus 1990 all infections/total Microbiological cure Cefixime (German) Backhaus 1990 all infections/total Side-effects (including allergy) Cefixime (German) German Meyer-Rohn 1974 all infections/total Microbiological cure Spectinomycin (German) Meyer-Rohn 1974 all infections/total Clinical cure Spectinomycin (German) Meyer-Rohn 1974 all infections/total Side-effects (including allergy) Diarrhoea Spectinomycin (German)

Web annex E – Systematic reviews

STUDY INFORMATION INFECTION OUTCOME INTERVENTIONS Risk of bias for non-RCTs

First author

Meyer-Rohn 1974 all infections/total Side-effects (including allergy) Exanthem Spectinomycin (German) Meyer-Rohn 1974 all infections/total Side-effects (including allergy) Local reaction/pain Spectinomycin (German) Meyer-Rohn 1974 all infections/total Side-effects (including allergy) Diarrhoea Spectinomycin (German) Meyer-Rohn 1974 all infections/total Side-effects (including allergy) Local reaction/pain Spectinomycin (German) Lassau 1987 genital (cervix) Microbiological cure Patients with PPNG Spectinomycin (French) Lassau 1987 genital (cervix) Microbiological cure Patients with non-PPNG Spectinomycin (French) 1 arm from randomized studies with 2 or more comparison groups 1994, By person Ceftriaxone, Handsfield genital (cervix) Microbiological cure MOD LOW LOW NI LOW LOW LOW MOD USA spectinomycin 1994, By person Ceftriaxone, Handsfield genital (cervix) Microbiological cure MOD LOW LOW NI LOW LOW LOW MOD USA spectinomycin 1994, Ceftriaxone, Handsfield genital (cervix) Side-effect MOD LOW LOW NI LOW MOD LOW MOD USA spectinomycin 1981, Handsfield Ceftriaxone MOD LOW LOW NI LOW MOD LOW MOD USA 1991, Ceftriaxone, Handsfield MOD LOW LOW NI LOW MOD LOW MOD USA cefixime 1983, Ceftriaxone, Handsfield MOD LOW LOW NI LOW MOD LOW MOD USA spectinomycin 2001 Ceftriaxone, Cheng genital (cervix) Microbiological cure By person MOD LOW LOW NI LOW LOW LOW MOD China spectinomycin 2001 Ceftriaxone, Cheng genital (cervix) Clinical cure MOD LOW LOW NI LOW LOW LOW MOD China spectinomycin 71

WHO guidelines for the treatment of Neisseria gonorrhoeae

STUDY INFORMATION INFECTION OUTCOME INTERVENTIONS Risk of bias for non-RCTs

First author

2001 Ceftriaxone, Cheng genital (cervix) Side-effect MOD LOW LOW NI LOW MOD LOW MOD China spectinomycin 1992, Ceftriaxone, Portilla genital (cervix) Microbiological cure MOD LOW LOW NI LOW LOW LOW MOD USA cefixime

2009, Ceftriaxone, Shams Saudi genital (cervix) Microbiological cure MOD LOW LOW NI LOW LOW LOW MOD Arabia spectinomycin 1984, Ceftriaxone, Collier genital (cervix) Microbiological cure MOD LOW LOW NI LOW LOW LOW MOD USA spectinomycin 1985, Ceftriaxone, Judson genital (cervix) Microbiological cure MOD LOW LOW NI LOW LOW LOW MOD USA spectinomycin 1993, Ceftriaxone, Mroczkowski genital (cervix) Microbiological cure MOD LOW LOW NI LOW LOW LOW MOD USA spectinomycin

1985, Ceftriaxone, Panikabutra Thaila genital (cervix) Microbiological cure MOD LOW LOW NI LOW LOW LOW MOD nd spectinomycin 1992, Ceftriaxone, Plourde genital (cervix) Microbiological cure MOD LOW LOW NI LOW LOW LOW MOD Kenya cefixime 1994, Ceftriaxone, Rompalo genital (cervix) Microbiological cure MOD LOW LOW NI LOW LOW LOW MOD USA spectinomycin 2002, Tian China 1 arm from non-randomized studies with 2 or more comparison groups Ceftriaxone, Rajan 1982, genital (cervix) Microbiological cure MOD LOW LOW NI LOW LOW LOW MOD Singapore kanamycin

Web annex E – Systematic reviews

References 1. Aplasca De Los Reyes MR, Pato-Mesola V, Klausner JD, Manalastas R, Wi T, Tuazon CU, et al. A randomized trial of ciprofloxacin versus cefixime for treatment of gonorrhea after rapid emergence of gonococcal ciprofloxacin resistance in The Philippines. Clin Infect Dis. 2001;32(9):1313-8. 2. Backhaus A, Tinzl J. [Cefixime therapy in patients with proven gonorrhea]. Infection. 1990;18 Suppl 3:S145-6. 3. Baddour LM, Busby L, Shapiro E, Cox KB, Glassco S, Johnson JK. Evaluation of treatment with single-dose ampicillin/sulbactam with probenecid or ceftriaxone in patients with uncomplicated gonorrhea. Sex Transm Dis. 1992;19(6):341-5. 4. Bowie W, Ronald AR, Krywulak W, Cates CY, Boutros P. Gentamicin in the treatment of gonorrhoea in females. Br J Vener Dis. 1974;50(3):208-11. 5. Brown J, Tabert O, Hanna JD, Rentiers PL. Treatment of gonorrheal urethritis with spectinomycin hydrochloride. Can Med Assoc J. 1974;110(2):173 passim. 6. Bryan JP, Hira SK, Brady W, Luo N, Mwale C, Mpoko G, et al. Oral ciprofloxacin versus ceftriaxone for the treatment of urethritis from resistant Neisseria gonorrhoeae in Zambia. Antimicrob Agents Chemother. 1990;34(5):819-22. 7. Calderon E, Conde-Glez C, Echaniz G, Arredondo JL, Olvera J, Hirata C, et al. Results of treatment of uncomplicated urogenital gonorrhoea with enoxacin compared with ceftriaxone. Int J Clin Pharmacol Res. 1988;8(4):247-51. 8. Cheng Wh, Xie LH, Huang SJ, Lu HK. A randomised controlled trial of ceftriaxone sodium versus spectinomycin hydrochloride in the treatment of simple gonorrhoea. J Clin Dermatol. 2001;30(3):186. 9. Christophersen J, Bollerup AC, From E, Ronne-Rasmussen JO, Quitzau K. Treating genitourinary and pharyngeal gonorrhoea with single dose ceftriaxone. Genitourin Med. 1989;65(1):14-7. 10. Collier AC, Judson FN, Murphy VL, Leach LA, Root CJ, Handsfield HH. Comparative study of ceftriaxone and spectinomycin in the treatment of uncomplicated gonorrhea in women. Am J Medicine. 1984;77(4C):68-72. 11. Covino JM, Cummings M, Smith B, Benes S, Draft K, McCormack WM. Comparison of ofloxacin and ceftriaxone in the treatment of uncomplicated gonorrhea caused by penicillinase-producing and non-penicillinase- producing strains. Antimicrob Agents Chemother. 1990;34(1):148-9. 12. Covino JM, Smith BL, Cummings MC, Benes S, Draft K, McCormack WM. Comparison of enoxacin and ceftriaxone in the treatment of uncomplicated gonorrhea. Sex Transm Dis. 1993;20(4):227-9. 13. Daly CC, Hoffman I, Hobbs M, Maida M, Zimba D, Davis R, et al. Development of an antimicrobial susceptibility surveillance system for Neisseria gonorrhoeae in Malawi: comparison of methods. J Clin Microbiol. 1997;35(11):2985-8. 14. Dashevskii NV. [Results of the use of kanamycin for treatment of newly-contracted uncomplicated gonorrhea in men]. Vestn Dermatol Venerol. 1975(7):82-5. 15. Davidson AJ, Judson FN. Anorectal gonorrhea in women. Is it more difficult to cure? Sex Transm Dis. 1986;13(2):97-101. 16. Deguchi T, Yasuda M, Yokoi S, Ishida K, Ito M, Ishihara S, et al. Treatment of uncomplicated gonococcal urethritis by double-dosing of 200 mg cefixime at a 6-h interval. J Infect Chemother. 2003;9(1):35-9. 17. Dixon CA, Bittiner JB, Shahidullah M, Slack RC, Sulaiman MZ. Randomised observer blind comparative trial of ceftriaxone and penicillin in treating uncomplicated gonorrhoea in men and women. Genitourin Med. 1986;62(2):78-81. 18. Duancic A, Fiumara NJ, Alpert S, Lee YH, Tarr PI, Rosner B, et al. Comparison of spectinomycin hydrochloride and aqueous procaine penicillin G in the treatment of uncomplicated gonorrhea. Antimicrob Agents Chemother. 1974;6(4):512-5. 19. Duncan WC, Holder WR, Roberts DP, Knox JM. Treatment of gonorrhea with spectinomycin hydrochloride: comparison with standard penicillin schedules. Antimicrob Agents Chemother. 1972;1(3):210-4. 20. Dunnett DM, Moyer MA. Cefixime in the treatment of uncomplicated gonorrhea. Sex Transm Dis. 1992;19(2):92-3. 21. Fluker JL, Deherogoda P, Platt DJ, Gerken A. Rectal gonorrhoea in male homosexuals. Presentation and therapy. Br J Vener Dis. 1980;56(6):397-9. 22. Freedman LD. Reduced dosage of ceftriaxone for uncomplicated gonorrhea in women. J Family Practice. 1990;31(2):201-2. 73

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23. Felman YM, William DC, Corsaro MC. Spectinomycin in the treatment of anal gonorrhea: a retrospective study. Sex Transm Dis. 1978;5(4):158-9. 24. Finger AH. Spectinomycin in the treatment of gonorrhoea in females and males. Br J Vener Dis. 1975;51(1):38-40. 25. Goldstein AM, Clark JH, Wickler MA. Comparison of single-dose ceftizoxime or ceftriaxone in the treatment of uncomplicated urethral gonorrhea. Sex Transm Dis. 1991;18(3):180-2. 26. Gruber F, Brajac I, Jonjic A, Grubisic-Greblo H, Lenkovic M, Stasic A. Comparative trial of azithromycin and ciprofloxacin in the treatment of gonorrhea. J Chemother. 1997;9(4):263-6. 27. Gruber F, Grubisic-Greblo H, Jonjic A, Markusic J. Treatment of gonococcal and chlamydial urethritis with azitromycin or doxycycline. Chronica Dermatologica. 1995;5(2):213-8. 28. Habib AR, Fernando R. Efficacy of azithromycin 1 g single dose in the management of uncomplicated gonorrhoea. Int J STD AIDS. 2004;15(4):240-2. 29. Handsfield HH, Dalu ZA, Martin DH, Douglas JM, Jr., McCarty JM, Schlossberg D. Multicenter trial of single-dose azithromycin vs. ceftriaxone in the treatment of uncomplicated gonorrhea. Azithromycin Gonorrhea Study Group. Sex Transm Dis. 1994;21(2):107-11. 30. Handsfield HH, Hook IEW. Ceftriaxone for treatment of uncomplicated gonorrhea: routine use of a single 125-mg dose in a sexually transmitted disease clinic. Sex Transm Dis. 1987;14(4):227-30. 31. Handsfield HH, McCormack WM, Hook IEW, Douglas Jr JM, Covino JM, Verdon MS, et al. A comparison of single- dose cefixime with ceftriaxone as treatment for uncomplicated gonorrhea. N Engl J Med. 1991;325(19):1337-41. 32. Handsfield HH, Murphy VL. Comparative study of ceftriaxone and spectinomycin for treatment of uncomplicated gonorrhoea in men. Lancet. 1983;2(8341):67-70 33. Handsfield HH, Murphy VL, Holmes KK. Dose-ranging study of ceftriaxone for uncomplicated gonorrhea in men. Antimicrob Agents Chemother. 1981;20(6):839-40. 34. Hantschke D, Strauss P, Linzenmeier G, Gahlen D, Heller W. Treatment of gonorrhoea with single injections of gentamicin. Br J Vener Dis. 1973;49(1):62-4. 35. Hira SK, Attili VR, Kamanga J, Mkandawire O, Patel JS, Patel MI. Efficacy of gentamicin and kanamycin in the treatment of uncomplicated gonococcal urethritis in Zambia. Sex Transm Dis. 1985;12(1):52-4. 36. Holder WR, Roberts DP, Duncan WC, Knox JM. Preliminary report on spectinomycin HCl in the treatment of gonorrhoea in homosexual men. Br J Vener Dis. 1972;48(4):274-6. 37. Hook EW, 3rd, Jones RB, Martin DH, Bolan GA, Mroczkowski TF, Neumann TM, et al. Comparison of ciprofloxacin and ceftriaxone as single-dose therapy for uncomplicated gonorrhea in women. Antimicrob Agents Chemother. 1993;37(8):1670-3. 38. Hook EW, 3rd, Judson FN, Verdon MS, Ehret JM, Handsfield HH. Comparative study of cefoperazone and spectinomycin for treatment of uncomplicated gonorrhea in men. Antimicrob Agents Chemother. 1986;30(4):619-21. 39. Hook EW, 3rd, McCormack WM, Martin D, Jones RB, Bean K, Maroli AN. Comparison of single-dose oral grepafloxacin with cefixime for treatment of uncomplicated gonorrhea in men. The STD Study Group. Antimicrob Agents Chemother. 1997;41(8):1843-5. 40. Jaffe HW, Reynolds GH, Wiesner PJ. National gonorrhea therapy monitoring study: adverse drug reactions. J Am Vener Dis Assoc. 1976;3(1):29-31. 41. Jin Z, Deng LH, Zhang H, Lu T, Xie M, Hu YL, et al. [Treatment of simple gonorrhoea with ceftriaxone]. J Clin Dermatol. 2001;25(3):187-8 (in Chinese). 42. Judson FN, Allaman J, Dans PE. Treatment of gonorrhea. Comparison of penicillin g procaine, doxycycline, spectinomycin, and ampicillin. JAMA. 1974;230(5):705-8. 43. Judson FN, Ehret JM, Handsfield HH. Comparative study of ceftriaxone and spectinomycin for treatment of pharyngeal and anorectal gonorrhea. JAMA. 1985;253(10):1417-9. 44. Judson FN, Ehret JM, Root CJ. Comparative study of ceftriaxone and aqueous procaine penicillin g in the treatment of uncomplicated gonorrhea in women. Antimicrob Agents Chemother. 1983;23(2):218-20. 45. Karney WW, Pedersen AH, Nelson M, Adams H, Pfeifer RT, Holmes KK. Spectinomycin versus tetracycline for the treatment of gonorrhea. N Engl J Med. 1977;296(16):889-94. 46. Khaki P, Bhalla P, Sharma A, Kumar V. Correlation between in vitro susceptibility and treatment outcome with azithromycin in gonorrhoea: a prospective study. Indian J Med Microbiol. 2007;25(4):354-7. 47. Khrianin AA, Reshetnikov OV, Anpilogova AD. [Rocefin (ceftriaxone) in therapy of uncomplicated gonorrhea

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in males]. Antibiot Khimioter. 2006;51(8):35-7. 48. Kim JH. Comparison of thiamphenicol and spectinomycin in the treatment of uncomplicated gonorrhea in men. Sex Transm Dis. 1984;11(4 Suppl):386-90. 49. Kojima M, Masuda K, Yada Y, Hayase Y, Muratani T, Matsumoto T. Single-dose treatment of male patients with gonococcal urethritis using 2g spectinomycin: microbiological and clinical evaluations. Int J Antimicrob Agents. 2008;32(1):50-4. 50. Korting HC, Abeck D. One-shot treatment of uncomplicated gonorrhoea with third-generation cephalosporins with differing serum half-life. Results of a controlled trial with ceftriaxone and cefotaxime. Chemotherapy. 1989;35(6):441-8. 51. Kouri YH, Gonzalez L, Perez M, Menar R, Gadea CR, Kraiselburd E, et al. Effect of penicillin and spectinomycin given for urethritis and cervicitis with Neisseria gonorrhoeae: high prevalence of penicillin-resistant isolates. Genitourin Med. 1989;65(5):342-6. 52. Kousa M, Lassus A, Jarvelainen R, Renkonen OV. Spectinomycin hydrochloride in the treatment of uncomplicated gonorrhoea in males and females. Br J Vener Dis. 1974;50(4):291-3. 53. Lassus A. Comparative studies of azithromycin in skin and soft-tissue infections and sexually transmitted infections by Neisseria and Chlamydia species. J Antimicrob Chemother. 1990;25 Suppl A:115-21. 54. Ling G, Jun-Qing P, Ping W. Clinical efficacy of azithromycin on gonorrhoeal urethritis and gonorrhoeal vaginitis: a report on 178 cases. Chinese J Antibiotics. 2000;25(5):397-8 (in Chinese). 55. Lule G, Behets FM, Hoffman IF, Dallabetta G, Hamilton HA, Moeng S, et al. STD/HIV control in Malawi and the search for affordable and effective urethritis therapy: a first field evaluation. Genitourin Med. 1994;70(6):384-8. 56. McCann JS, Horner T, Shepherd I, Quin N, Dougan H. Spectinomycin hydrochloride (Trobicin) in the treatment of gonorrhoea. Ir Med J. 1977;70(3):86-8. 57. McCormack WM, Mogabgab WJ, Jones RB, Hook EW 3rd, Wendel GD, Jr., Handsfield HH. Multicenter, comparative study of cefotaxime and ceftriaxone for treatment of uncomplicated gonorrhea. Sex Transm Dis. 1993;20(5):269-73. 58. McMillan A, Young H. The treatment of pharyngeal gonorrhoea with a single oral dose of cefixime. Int J STD AIDS. 2007;18(4):253-4. 59. Megran DW, Lefebvre K, Willetts V, Bowie WR. Single-dose oral cefixime versus amoxicillin plus probenecid for the treatment of uncomplicated gonorrhea in men. Antimicrob Agents Chemother. 1990;34(2):355-7. 60. Meheus A, Widy-Wirski R, D’Costa J, Van Dyck E, Delgadillo R, Piot P. Treatment of gonorrhoea in males in the Central African Republic with spectinomycin and procaine penicillin. Bull World Health Organ. 1984;62(1):89-94. 61. Meyer-Rohn J. [Minute treatment of gonorrhea with spectinomycin]. Z Hautkr. 1974;49(15):667-70. (German) 62. Mogabgab WJ, Lutz FB. Randomized study of cefotaxime versus ceftriaxone for uncomplicated gonorrhea. South Med J. 1994;87(4):461-4. 63. Monayar HK, Ledesma A, Nobile V, Viarengo JA. Epidemiology and treatment of uncomplicated gonorrhoea caused by non-PPNG strains in Cordoba, Argentina: auxotypes, susceptibility profiles, and plasmid analyses of urethral isolates from men. Genitourin Med. 1987;63(4):246-9. 64. Morrison GD, Reeves DS. Gentamicin in the treatment of gonococcal urethritis. A microbiological, pharmacological, and clinical study. Br J Vener Dis. 1973;49(6):513-6. 65. Mroczkowski TF, Hook IEW, Jones RB, McCormack WM, Martin DH. Grepafloxacin versus cefixime as single-dose therapy for uncomplicated gonorrhea in women. Inf Dis Obstet Gynecol. 1997;5(6):370-5. 66. Mroczkowski TF, Millikan LE, Martin DH, Leonik KJ. Treatment of gonococcal infections with a single 250 mg intramuscular injection of trospectomycin sulphate vs ceftriaxone sodium. Drugs Exp Clin Res. 1993;19(1):41-6. 67. Muratani T, Inatomi H, Ando Y, Kawai S, Akasaka S, Matsumoto T. Single dose 1 g ceftriaxone for urogenital and pharyngeal infection caused by Neisseria gonorrhoeae. Int J Urol. 2008;15(9):837-42. 68. Niunikova OI, Potapnev FV, Skuratovich AA, Nikolaeva IV, Danilova TN. [Treatment of gonorrheal urethritis in men using kanamycin and vibramycin]. Antibiotiki. 1975;20(4):373-7. 69. Odugbemi T, Oyewole F, Isichei CS, Onwukeme KE, Adeyemi-Doro FA. Single oral dose of azithromycin for therapy of susceptible sexually transmitted diseases: a multicenter open evaluation. West Afr J Med. 1993;12(3):136-40. 70. Pabst KM, Siegel NA, Smith S, Black JR, Handsfield HH, Hook EW, 3rd. Multicenter, comparative study of enoxacin and ceftriaxone for treatment of uncomplicated gonorrhea. Sex Transm Dis. 1989;16(3):148-51.

WHO guidelines for the treatment of Neisseria gonorrhoeae

71. Pandhi RK, Jayant D, Gupta A, Vaswani N, Sharma SD. Efficacy of gentamicin in gonococcal urethritis. Indian J Sex Transm Dis. 1989;10(2):48-50. 72. Panikabutra K, Ariyarit C, Chitwarakorn A, Saensanoh C. Cefaclor and cefamandole as alternatives to spectinomycin in the treatment of men with uncomplicated gonorrhoea. Br J Vener Dis. 1983;59(5):298-301. 73. Panikabutra K, Ariyarit C, Chitwarakorn A, Saensanoh C, Wongba C. Randomised comparative study of ceftriaxone and spectinomycin in gonorrhoea. Genitourin Med. 1985;61(2):106-8. 74. Panikabutra K LCTHBBP. Single dose oral norfloxacin or intramuscular spectinomycin to treat gonorrhoea (PPNG and non-PPNG infections): analysis of efficacy and patient preference. Genitourin Med. 1988;64(4):235-40. 75. Pedersen AH, Wiesner PJ, Holmes KK, Johnson CJ, Turck M. Spectinomycin and penicillin g in the treatment of gonorrhea. A comparative evaluation. JAMA. 1972;220(2):205-8. 76. Plourde PJ, Tyndall M, Agoki E, Ombette J, Slaney LA, D’Costa LJ, et al. Single-dose cefixime versus single-dose ceftriaxone in the treatment of antimicrobial-resistant Neisseria gonorrhoeae infection. J Infect Dis. 1992;166(4):919-22. 77. Porter IA, Rutherford HW. Treatment of uncomplicated gonorrhoea with spectinomycin hydrochloride (Trobicin). Br J Vener Dis. 1977;53(2):115-7. 78. Portilla I, Lutz B, Montalvo M, Mogabgab WJ. Oral cefixime versus intramuscular ceftriaxone in patients with uncomplicated gonococcal infections. Sex Transm Dis. 1992;19(2):94-8. 79. Rajan VS, Pang R, Tan NJ, Sng EH. Kanamycin in the treatment of penicillinase-producing gonococcai infections. Asian J Infect Dis. 1979;3(1):37-9. 80. Rajan VS, Sng EH, Thirumoorthy T, Goh CL. Ceftriaxone in the treatment of ordinary and penicillinase-producing strains of Neisseria gonorrhoeae. Br J Vener Dis. 1982;58(5):314-6. 81. Ratnam AV, Patel MI, Hira SK, Mulenga RC. Penicillin and spectinomycin in treatment of gonococcal urethritis. Sex Transm Dis. 1982;9(3):135-7. 82. Reggiani M, Cremonesi G. [5 years’ experience with spectinomycin in treating gonorrhea]. Minerva Med. 1983;74(14-15):815-7. 83. Rompalo AM, Colletta L, Caine VA, Linnemeier P, Neumann T, Hook EW, 3rd, et al. Efficacy of 250 mg trospectomycin sulfate i.m. vs. 250 mg ceftriaxone i.m. for treatment of uncomplicated gonorrhea. Sex Transm Dis. 1994;21(4):213-6. 84. Rustomjee R, Kharsany AB, Connolly CA, Karim SS. A randomized controlled trial of azithromycin versus doxycycline/ciprofloxacin for the syndromic management of sexually transmitted infections in a resource-poor setting. J Antimicrob Chemother. 2002;49(5):875-8. 85. Sands M. Treatment of anorectal gonorrhea infections in men. JAMA. 1980;243(11):1143-4. 86. Schumacher CM, Ghanem KG. Retreatment rates for uncomplicated gonorrhea infection: Comparing ceftriaxone and azithromycin versus ceftriaxone and doxycycline. Sex Transm Dis. 2013;40(7):539-45. 87. Shams ur R, Khan A, Amanullah, Akhter K. Clinical efficacy of the various drugs used in the treatment of gonorrhoeae. J Ayub Med Coll Abbottabad. 2009;21(4):28-30. 88. Shi D. Clinical efficacy of sparfloxacin compared with spectinomycin in the treatment of gonorrhea. [Chinese]. Chinese J Antibiotics. 2000;25(3): S2-S3. 89. Smith BL, Mogabgab WJ, Dalu ZA, Jones RB, Douglas JM, Jr., Handsfield HH, et al. Multicenter trial of fleroxacin versus ceftriaxone in the treatment of uncomplicated gonorrhea. Am J Med. 1993;94(3A):81S-4S. 90. Stratigos JD, Marsellou-Kinti O, Kassimatis V, Daikos GK. Treatment of gonorrhoea with spectinomycin hydrochloride. Br J Vener Dis. 1973;49(1):60-1. 91. Stapinski A, Gede K. [Further observations with regard to the treatment of gonorrhea with spectinomycin]. Przegl Dermatol. 1986;73(2):131-6. 92. Steingrimsson O, Olafsson JH, Thorarinsson H, Ryan RW, Johnson RB, Tilton RC. Azithromycin in the treatment of sexually transmitted disease. J Antimicrob Chemother. 1990;25(Suppl A):109-14. 93. Steingrimsson O, Olafsson JH, Thorarinsson H, Ryan RW, Johnson RB, Tilton RC. Single dose azithromycin treatment of gonorrhea and infections caused by C. trachomatis and U. urealyticum in men. Sex Transm Dis. 1994;21(1):43-6. 94. Swanston WH, Prabhakar P, Barrow L, Mahabir BS, Furlonge C. Single dose (direct observed) azithromycin therapy for Neisseria gonorrhoeae and Chlamydia trachomatis in STD clinic attenders with genital discharge in Trinidad and Tobago. West Indian Med J. 2001;50(3):198-202

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95. Takahashi S, Kiyota H, Ito S, Iwasawa A, Hiyama Y, Uehara T, et al. Clinical efficacy of a single two gram dose of azithromycin extended release for male patients with urethritis. Antibiotics. 2014;3(2):109-20. 96. Tian HQ, Dong LY. Ceftriaxone in treating one hundred and fifteen patients with gonorrhea. Chinese Journal of New Drugs and Clinical Remedies. 2002;21(8):487-8. 97. Tupasi TE, Crisologo LB, Torres CA, Calubiran OV, de Jesus I. Cefuroxime, thiamphenicol, spectinomycin, and penicillin g in uncomplicated infections due to penicillinase-producing strains of Neisseria gonorrhoeae. Br J Vener Dis. 1983;59(3):172-5. 98. Tupasi TE, Vizconde LC, Torres CA, Calubiran OV. Thiamphenicol in the treatment of gonococcal infections: a comparative trial with penicillin and spectinomycin. Sex Transm Dis. 1984;11(4 Suppl):382-5. 99. Tupasi T, Crisologo LB, Torres CA, Calubiran OV. Comparison of spectinomycin, cefuroxime, thiamphenicol and penicillin g in the treatment of gonococcal infections in women. Br J Vener Dis. 1983;59(1):72. 100. Turanova EN, Mirkhodzhaeva IR, Nikitina LV, Iatsukha MV, Afanas’ev BA. Clinical-laboratory study of the effectiveness of kanamycin in the treatment of gonorrhea in women. Vestn Dermatol Venerol. 1975(6):75-8 (in Russian). 101. Tuza F, Hatos G. Treatment of male urethral gonorrhoea with spectinomycin hydrochloride (Trobicin). Med J Aust. 1973;2(24):1090-1. 102. Verdon MS, Douglas Jr JM, Wiggins SD, Handsfield HH. Treatment of uncomplicated gonorrhea with single doses of 200 mg cefixime. Sex Transm Dis. 1993;20(5):290-3. 103. Waugh MA. Open study of the safety and efficacy of a single oral dose of azithromycin for the treatment of uncomplicated gonorrhoea in men and women. J Antimicrob Chemother. 1993;31 Suppl E:193-8. 104. Willcox RR. Spectinomycin in the treatment of gonorrhoea in males. Br J Vener Dis. 1974;50(4):294-7. 105. Wojtowicz U, Napiorkowska T, Stapinski A, Przedpelska G. [Incidence and the results of treatment of beta- lactamase-positive gonorrhea with spectinomycin (trobicin)]. Przegl Dermatol. 1990;77(3):193-6. (Polish) 106. Yoon JY, Kim YT, Kim JH. Treatment of uncomplicated male gonococcal urethritis. Kanamycin vs. gentamicin. Korean J Dermatology. 1988;26(2):184-8 (in Korean). 107. Zajdowicz TR, Sanches PL, Berg SW, Kerbs SB, Newquist RL, Harrison WO. Comparison of ceftriaxone with cefoxitin in the treatment of penicillin-resistant gonococcal urethritis. Br J Vener Dis. 1983;59(3):176-8. 108. Zhou YS, Tao R, Wang EP, Jiang SC. [Clinical observation of etimicin sulfate and spectinomycin in treatment of gonorrhoea]. Chinese J Antibiotics. 2000;25(S1):42-5 (in Chinese).

WHO guidelines for the treatment of Neisseria gonorrhoeae

1.2 In pregnant women with uncomplicated genital (cervix, urethra) and anorectal gonococcal infections, what are the effects of ceftriaxone compared to other treatments?

Criteria Population Intervention Comparator Outcome Pregnant Ceftriaxone Single therapy: Critical: Microbiological cure, women with ≥ 250 mg IM × 1 Cefixime 800 mg po × 1 fetal/neonatal outcomes uncomplicated Cefixime 400 mg po × 2 (toxicity, teratogenicity, fetal genital (cervix, Azithromycin 1–2 g po × 1 loss, purulent conjunctivitis, urethra) and Cefixime 400 mg po × 1 polyarthritis, STI transmission, anorectal premature rupture of gonococcal Dual therapy versus single membranes, small for gestational infections therapy: age babies, chorioamionitis), compliance, maternal outcomes Cefixime + azithomycin versus including postpartum Cefixime alone endometritis, STI complications,

gonorrhoea antimicrobial in vitro Ceftriaxone + azithomycin versus resistance, side-effects (including Ceftriaxone alone allergy, toxicity), clinical cure, transmission to partners

Important: HIV transmission and acquisition, quality of life

For systematic reviews To identify pre-existing synthesized evidence, the Cochrane Library suite of databases (CDSR, HTA database and the ACP Journal Club) was searched for recent systematic reviews and for protocols for reviews from 2004 to February 2015. Keywords used included gonorrhoea, gonorrhea, gonococcal, ophthalmia neonatorum. The search found 111 citations. One review was used to verify our included studies. One systematic review was found.

For randomized and non-randomized studies We used one search of the databases to find articles for all five questions. We searched all databases up to March 2015: MEDLINE (from 1946), Embase (from 1980) and CENTRAL (Cochrane Central Register of Controlled Trials) and LILACS from inception. The search strategy included keywords and text words for gonorrhoeae and medications. We excluded letters, editorial, comments, review articles and guidelines. We did not restrict by language. We also reviewed reference lists of relevant studies, guidelines and systematic reviews.

Search strategy 1 gonorrhea.mp. 2 gonorrhoea.mp. 3 gonococcal.mp. 4 ophthalmia neonatorum.mp. 5 or/1-4 6 ceftriaxone.mp. 7 Azithromycin.mp. 8 cefixime.mp. 9 gentamicin.mp.

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10 spectinomycin.mp. 11 kanamycin.mp. 12 quinolone*.mp. 13 doxycycline.mp. 14 erythromycin.mp. 15 silver nitrate.mp. 16 chloramphenicol.mp. 17 tetracycline*.mp. 18 povidone iodine.mp. 19 gemifloxacin.mp. 20 cephalosporin*.mp. 21 macrolide*.mp. 22 or/6-21 23 5 and 22 24 (th or tu).xs. 25 (co or cn or dr or dt or rh or si or th).fs. 26 24 or 25 27 23 and 26 28 limit 27 to (book or book series or editorial or letter or note or “review” or case reports or meta-analysis or news or systematic reviews) [Limit not valid in Ovid MEDLINE(R), Ovid MEDLINE(R) Daily Update, Ovid MEDLINE(R) In-Process; records were retained] 29 case report/ 30 27 not (28 or 29)

Data were abstracted by one investigator and verified by another. We collected data about the study (date of data collection, type of study design, inclusion and exclusion criteria, country, funding sources), population or patient characteristics (type of population – adult/adolescent, pregnant women, neonates at risk, MSM, HIV-positive, people with treatment failures, age), infection (culture positive, types of infection – genital including cervix, urethral, oropharyngeal, neonatal ophthalmia, coinfection), treatments (number of doses, amount, method of treatment, co-intervention), follow-up and outcomes of interest (including measures for cure rate by person and sites of infections, treatment results based on return day of visit, and types of adverse effects). We used a pretested data abstraction form.

Most studies did not provide details about the number of people randomized to each group, the losses to follow-up in each group, or did not include people who did not comply with protocol, we therefore collected data for a per-protocol analysis. The data extraction form was developed and piloted by at least two investigators.

WHO guidelines for the treatment of Neisseria gonorrhoeae

non-randomized studies with two comparison groups. When a study included only one group, we calculated the risk of an event (or proportion) of an outcome and then pooled the proportions from each study weighted by the generic inverse variance. When results could not be pooled we summarized the results from the individual studies narratively. When available, we pooled and report data for subgroups by HIV status, drug dosage and type of infection. The heterogeneity of pooled results is reported using the I2 statistic.

Results We found a systematic review by Brocklehurst (2002) (see below) and used related studies (Ramus, 2001; Cavance, 1993) to confirm the data. From the comprehensive search of electronic databases, we included three studies: two randomized and one non-randomized studies.

1. Brocklehurst P. Antibiotics for gonorrhoea in pregnancy (Review) 2002. Cochrane Database Syst Rev. 2002;(2):CD000098.

PRISMA

Figure 2: PRISMA Study Flow diagram

Web annex E – Systematic reviews

WHO guidelines for the treatment of Neisseria gonorrhoeae

Characteristics of included studies

STUDY N AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS Randomized studies with 2 or more comparison groups

Cavenee 168 19.7; Patients with positive culture Negative pretreatment culture, microbiological Ceftriaxone 1993, USA gestational and pregnant women Patients with penicillin allergy and cure, fatal 250 mg IM age who did not return for follow up after neonatal × 1, 22.2 weeks 14 days, had unprotected coitus outcome, spectinomycin reinfection, 2 g IM × 1 side-effect Ramus 95/161 19.1; All untreated women Not clear microbiological Cefixime 2001, USA gestational cure, fatal 400 mg po×1, age neonatal ceftriaxone 21 weeks outcome 125 mg IM × 1 Non-randomized studies with 2 comparison groups Miller 102 14–37 Pregnant women with Not mentioned microbiological Cefixime 1996, USA a positive gonorrhoeal cure, fatal 400 mg po × 1 screen neonatal, side-effect

Effects of intervention

Other treatments vs ceftriaxone 250 mg IM × 1 Cefixime 400 mg po × 1 by person (number of people) Microbiological cure (genital – cervix, urethra, rectum)

Cefixime 400 mg po x 1 Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J K L 1.2.1 Microbiological cure RCTs by person: all infections Ramus 2001 (1) 50 52 41 43 1.01 [0.93, 1.10] + + + + + + + + + + + ?

0.5 0.7 1 1.5 2 Favours ceftriaxone Favours cefixime

Footnotes Risk of bias legend (1) Ceftriaxone dose is 125mg IM (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) blinding of participants (clinical cure and adverse events) (E) Blinding of Investigators (micro cure) (F) Blinding of Investigators (clinical cure & a/e) ( ) Blinding of outcome assessor (micro cure) G (H) Blinding of Outcome assessor (a/e, sub outcomes) (I) Blinding of data analyst (J) Incomplete outcome data (attrition bias) (K) Selective reporting (reporting bias) (L) Other bias

Footnotes (1) Ceftriaxone dose is 125mg IM (2) Ceftriaxone dose is 125mg IM

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Cefixime 400 mg po × 1 by infections (number of infection sites) Microbiological cure (genital – cervix, urethra, rectum)

Cefixime 400 mg po x 1 Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J K L 2.2.1 Microbiological cure RCTs by infections: anogenital- cervix and/or anal Ramus 2001 (1) 50 52 40 42 1.01 [0.93, 1.10] + + + + + + + + + + + ?

2.2.2 Microbiological cure RCTs by infections: only cervix Ramus 2001 (2) 44 46 38 40 1.01 [0.92, 1.11] + + + + + + + + + + + ?

2.2.3 Microbiological cure RCTs by infections: only anal Ramus 2001 (3) 16 16 23 23 1.00 [0.90, 1.11] + + + + + + + + + + + ?

0.5 0.7 1 1.5 2 Favours ceftriaxone Favours cefixime

Footnotes Risk of bias legend (1) ceftriaxone dose is 125mg IM (A) Random sequence generation (selection bias) (2) ceftriaxone dose is 125mg IM (B) Allocation concealment (selection bias) (3) ceftriaxone dose is 125mg IM (C) Blinding of participants (micro cure) (D) blinding of participants (clinical cure and adverse events) (E) Blinding of Investigators (micro cure) (F) Blinding of Investigators (clinical cure & a/e) (G) Blinding of outcome assessor (micro cure) (H) Blinding of Outcome assessor (a/e, sub outcomes) (I) Blinding of data analyst (J) Incomplete outcome data (attrition bias) (K) Selective reporting (reporting bias) (L) Other bias

Cefixime 400 mg po × 1 Microbiological cure (oropharyngeal)

Cefixime 400 mg po x 1 Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J K L 8.2.1 Microbiological cure RCTs by person: (oropharyngeal) Ramus 2001 6 6 5 5 1.00 [0.73, 1.37] + + + + + + + + + + + ?

0.5 0.7 1 1.5 2 Favours [Ceftriaxone] Favours [Cefixime 400mgl]

Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) blinding of participants (clinical cure and adverse events) (E) Blinding of Investigators (micro cure) (F) Blinding of Investigators (clinical cure & a/e) (G) Blinding of outcome assessor (micro cure) (H) Blinding of Outcome assessor (a/e, sub outcomes) (I) Blinding of data analyst (J) Incomplete outcome data (attrition bias) (K) Selective reporting (reporting bias) (L) Other bias

Other treatments vs ceftriaxone 250 mg IM × 1 Cefixime 400 mg po × 1 Minor anomalies

Cefixime 400 mg po X 1 Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J K L Ramus 2001 7 62 10 60 0.68 [0.28, 1.66] + + + + + + + + + + + ?

0.5 0.7 1 1.5 2 Favours cefixime Favours ceftriaxone

WHO guidelines for the treatment of Neisseria gonorrhoeae

Cefixime 400 mg po × 1 Fatal neonatal outcomes

Cefixime 400 mg po x 1 Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J K L 3.2.1 Fatal neonatal outcomes:Cleft palate Ramus 2001 (1) 1 62 0 60 2.90 [0.12, 69.93] + + + + + + + + + + + ?

3.2.2 Fatal neonatal outcomes: Nevus Ramus 2001 2 62 3 60 0.65 [0.11, 3.73] + + + + + + + + + + + ?

3.2.3 Fatal neonatal outcomes: Clinodactyly Ramus 2001 0 62 1 60 0.32 [0.01, 7.77] + + + + + + + + + + + ?

3.2.4 Fatal neonatal outcomes: hyper bilirubinemia Ramus 2001 0 62 5 60 0.09 [0.00, 1.56] + + + + + + + + + + + ?

3.2.5 Fatal neonatal outcomes: super numerary nipple Ramus 2001 0 62 2 60 0.19 [0.01, 3.95] + + + + + + + + + + + ?

3.2.6 Fatal neonatal outcomes: hemanginoma Ramus 2001 0 62 2 60 0.19 [0.01, 3.95] + + + + + + + + + + + ?

3.2.7 Fatal neonatal outcomes: malformation Ramus 2001 7 62 10 60 0.68 [0.28, 1.66] + + + + + + + + + + + ?

3.2.8 Fatal neonatal outcomes: skin tag Ramus 2001 1 62 0 60 2.90 [0.12, 69.93] + + + + + + + + + + + ?

3.2.9 Fatal neonatal outcomes: hyper bilirubinemia Ramus 2001 0 62 5 60 0.09 [0.00, 1.56] + + + + + + + + + + + ?

3.2.10 Fatal neonatal outcomes: cafe aulait spots Ramus 2001 0 62 3 60 0.14 [0.01, 2.62] + + + + + + + + + + + ?

3.2.11 Fatal neonatal outcomes: absent right pectoral muscle Ramus 2001 1 62 0 60 2.90 [0.12, 69.93] + + + + + + + + + + + ?

3.2.12 Fatal neonatal outcomes: poly dactyly Ramus 2001 1 62 0 60 2.90 [0.12, 69.93] + + + + + + + + + + + ?

3.2.13 Fatal neonatal outcomes: pre eauricular pit Ramus 2001 1 62 0 60 2.90 [0.12, 69.93] + + + + + + + + + + + ?

0.01 0.1 1 10 100 Favours cefixime Favours ceftriaxone

Footnotes Risk of bias legend (1) ceftriaxone dose is 125mg IM (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) blinding of participants (clinical cure and adverse events) (E) Blinding of Investigators (micro cure) (F) Blinding of Investigators (clinical cure & a/e) (G) Blinding of outcome assessor (micro cure) (H) Blinding of Outcome assessor (a/e, sub outcomes) (I) Blinding of data analyst (J) Incomplete outcome data (attrition bias) (K) Selective reporting (reporting bias) (L) Other bias

Side-effects Ramus 2001 reported no maternal side-effects in either group. The group receiving IM ceftriaxone complained of discomfort at injection site.

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Spectinomycin 2 g IM × 1 by person (number of people) Microbiological cure (genital – cervix, urethra, rectum) Spectinomycin 2 gm IM x 1 Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J K L 1.5.1 Microbiological cure RCTs by person: all infections Cavenee 1993 80 84 80 84 1.00 [0.93, 1.07] + + + + + + + + + + + ?

1.5.2 Microbiological cure RCTs by person in penicillin producing N. gonorroheae (PPNG) Cavenee 1993 6 6 7 7 1.00 [0.76, 1.31] + + + + + + + + + + + ?

0.5 0.7 1 1.5 2 Favours [Ceftriaxone] Favours [Spectinomycin]

Spectinomycin 2 g IM × 1 by infections (number of infection sites) Microbiological cure (genital – cervix, urethra, rectum)

Spectinomycin 2 gm IM x 1 Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J K L 2.5.1 Microbiological cure RCTs by infections: only rectum Cavenee 1993 19 19 21 22 1.04 [0.92, 1.19] + + + + + + + + + + + ?

2.5.2 Microbiological cure RCTs by infections: cervix or rectum Cavenee 1993 81 84 79 83 1.01 [0.95, 1.08] + + + + + + + + + + + ?

2.5.3 Microbiological cure RCTs by infections: only cervix Cavenee 1993 78 81 78 82 1.01 [0.95, 1.08] + + + + + + + + + + + ?

0.5 0.7 1 1.5 2 Favours [Ceftriaxone] Favours [Spectinomycin]

Ri k f bi l d

Spectinomycin 2 g IM × 1

Microbiological cure (oropharyngeal)

Spectinomycin 2 gm IM x 1 Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J K L

8.5.1 Microbiological cure RCTs by person: (oropharyngeal) Cavenee 1993 5 6 6 6 0.85 [0.55, 1.31] + + + + + + + + + + + ?

0.5 0.7 1 1.5 2 Favours [Ceftriaxone] Favours [Cefixime]

WHO guidelines for the treatment of Neisseria gonorrhoeae

Other treatments vs ceftriaxone 250 mg IM × 1 Spectinomycin 2 g IM × 1 Fatal neonatal outcomes

Spectinomycin 2 gm IM x 1 Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J K L 3.5.1 Fatal neonatal outcomes : Minor congenital malformation Cavenee 1993 9 69 12 75 0.82 [0.37, 1.81] + + + + + + + + + + + ?

3.5.2 Fatal neonatal outcomes : Major congenital malformation Cavenee 1993 1 69 0 75 3.26 [0.13, 78.65] + + + + + + + + + + + ?

0.1 0.2 0.5 1 2 5 10 Favours [Spectinomycin] Favours [Ceftriaxone]

Spectinomycin 2 g IM × 1 Side-effects (including allergy, toxicity)

Spectinomycin 2 gm IM x 1 Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J K L 9.5.1 Side effects: General side effects Cavenee 1993 0 84 0 84 Not estimable + + + + + + + + + + + ?

0.5 0.7 1 1.5 2 Favours [Spectinomycin] Favours [Ceftriaxone]

Compliance, maternal outcomes including postpartum endometritis, STI complications, gonorrhoea antimicrobial in vitro resistance, clinical cure, transmission to partners, HIV transmission and acquisition, and quality of life

No comparative studies reported on these outcomes.

Cefixime 400 mg po × 1 Microbiological cure by person (number of people)

event total proportion proportion Study or Subgroup proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 13.2.1 Microbiological cure (genital- cervix,ure, rec) with 1 group Miller 1997 0.9518072 0.025143 79 83 0.95 [0.90, 1.00]

-2 -1 0 1 2 Favours [cefixime] Favours [control]

Web annex E – Systematic reviews

Cefixime 400 mg po × 1 Fatal neonatal outcomes

event total proportion proportion Study or Subgroup proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 14.2.1 Fatal neonatal outcomes: small for dates babies, pre-term delivery (before <37weeks) Miller 1997 0.13513514 0.03982249 10 74 0.14 [0.06, 0.21]

14.2.2 Fatal neonatal outcomes: fetal loss Miller 1997 0.00980392 0.01319554 1 102 0.01 [-0.02, 0.04]

-2 -1 0 1 2

Cefixime 400 mg po ×1 Side-effects including allergy, toxicity

event total proportion proportion Study or Subgroup proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 16.2.1 studies Side effects with 1 group: vomitting, diarrhea Miller 1997 0.0294118 0.018592 3 102 0.03 [-0.01, 0.07]

-2 -1 0 1 2 Favours [cefixime] Favours [control]

There were no studies which evaluated the effects with azithromycin and also other treatments such as cefixime 800 mg po (orally) × 1 (or cefixime 400 mg po × 2), azithromycin 1–2 g po × 1, cefixime + azithomycin versus cefixime alone, ceftriaxone + azithomycin versus ceftriaxone alone for treatment of pregnant women.

WHO guidelines for the treatment of Neisseria gonorrhoeae

Risk of bias

Randomized studies: see forest plots Non-randomized studies (LOW: low risk of bias; MOD: moderate risk of bias; HIGH: high risk of bias; NI: no information)

STUDY INFORMATION OUTCOME INTERVENTION Risk of bias for non-RCTs First author (last Year Outcome Enter Treatment name only) specific of outcome

(for the

fetal

outcome or type of side-effect) Confounding Selection of participants Measurement interventions Intended interventions Missing data Measurement of outcomes Reporting Overall Microbiological Cefixime MOD LOW LOW LOW LOW LOW LOW MOD Miller 1997 cure Side-effects nausea, Cefixime MOD LOW LOW LOW LOW LOW LOW MOD (including vomiting, allergy diarrhoea, abdominal pain, skin Miller 1997 rash Fetal neonatal Cefixime MOD LOW LOW LOW LOW LOW LOW MOD Miller 1997 outcome fetal loss Fetal neonatal small for Cefixime MOD LOW LOW LOW LOW LOW LOW MOD outcome gestational age babies, pre-term delivery (before Miller 1997 < 37 weeks) Microbiological Cefixime MOD LOW LOW LOW LOW LOW LOW MOD Miller 1997 cure

References

1. Cavenee MR, Farris JR, Spalding TR, Barnes DL, Castaneda YS, Wendel GD, Jr. Treatment of gonorrhea in pregnancy. Obstet Gynecol. 1993;81(1):33-8. 2. Miller Jr JM. Open study of the safety and efficacy of a single oral dose of cefixime for the treatment of gonorrhea in pregnancy. Inf Dis Obstet Gynecol. 1997;5(3):259-61. 3. Ramus RM, Sheffield JS, Mayfield JA, Wendel GD, Jr. A randomized trial that compared oral cefixime and intramuscular ceftriaxone for the treatment of gonorrhea in pregnancy. Am J Obstet Gynecol. 2001;185(3):629-32.

Web annex E – Systematic reviews

Patient values, preferences and acceptability

Gonococcal infections

Search We searched for reviews and studies specific to gonorrhoea treatment acceptability, values and preferences. For systematic reviews we searched the Turning Research to Practice TRIP database (January 2011 to January 2015) and the Cochrane Databases for Systematic Reviews (CDSR), Economic Evaluation Database (EED), Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA) database (up to January 2014). The search strategy included keywords and text words for gonorrhoea. We did not restrict by language. We used one search of the databases to find articles for all five questions. We searched MEDLINE, Embase (up to 26 February 2015) CENTRAL (up to March 2015) and LILACS (up to 19 April 2015). The search strategy included keywords and text words for gonorrhoea and the above-mentioned drugs. We excluded editorials, case reports, news, book chapters, meta-analyses and systematic reviews. We did not restrict by language. We also reviewed reference lists of relevant studies, guidelines and systematic reviews.

Result The electronic database search for primary studies found 3295 non-duplicate records. After title and abstract screening, we retrieved 488 articles in full text and excluded 2807 as not relevant. We found only four studies applicable to gonorrhoea. We also added two systematic reviews.

Characteristics of included studies

Study (author and year) Country Number of Treatments participants Rustomjee 2002 South Africa 31 Azithromycin 1 g orally × 1

Anschuetz 2004 USA 3279 Cefixime 400 mg plus either 1 g azithromycin or doxycycline 7 days twice daily or 2 g azithromycin Habib 2004 United 301 Azithromycin 1 g stat dose and different regimens Kingdom

Findings: acceptability

Rustomjee 2002 All 31 participants complied with the treatment (azithromycin 1 g) that was provided at one session orally for urethral or anorectal gonorrhoea. Anschuetz 2004 From July through December 2012, 3551 gonococcal cases were reported to the Philadelphia Department of Public Health. The purpose of this evaluation was to assess provider compliance to recently modified gonococcal treatment recommendations and to identify gaps in provider performance.

Of the 3279 treated patients, 2845 (87%) were given recommended treatment. One hundred fifty-six gonococcal cases (5%) received an alternative treatment of either dual therapy with cefixime 400 mg plus either 1 g azithromycin or doxycycline 7 days twice daily or 2 g azithromycin. Two hundred and fifty gonorrhoea cases (8%) received cephalosporin-based therapy (i.e. ceftriaxone/cefixime only) that did not meet treatment guidelines, and 28 (1%) received fluoroquinolone-based therapy that did not meet treatment guidelines.

WHO guidelines for the treatment of Neisseria gonorrhoeae

Use of cefixime was reported most often in facilities where use of injectable medications is problematic, such as high schools and juvenile detention facilities (50% among high schools/juvenile detention vs 5% overall).

In conclusion, 87% of cases received first-line recommended therapy for gonococcal infections, 5% received an acceptable alternative regimen, and 8% received a regimen not currently in the treatment guidelines.

Habib 2004 Three hundred and one patients were treated for gonorrhoea between January 2000 and June 2001; 226/301 (75.1%) were treated with azithromycin 1 g stat dose while the rest were treated with different regimens.

Nearly a quarter of the cohort (26.1%) failed to attend for test-of-cure after their initial treatment, nearly one-third of males (31.2%) and one fifth (21.6%) of females.

“This also highlights the need for an initial, reliable and single-dose curative treatment for gonorrhoea.”

Other conditions: syphilis

Search We searched for reviews and studies specific to syphilis treatment acceptability. For systematic reviews we searched the TRIP database (January 2011 to January 2015) and the Cochrane Library suite of databases (CDSR, EED, DARE, HTA up to January 2014). The search strategy included keywords and text words for syphilis. We did not restrict by language. We used one search of the databases to find articles for all five questions. We searched MEDLINE, Embase (up to 26 February 2015) CENTRAL (up to March 2015) and LILACS (up to 19 April 2015). The search strategy included keywords and text words for syphilis and the above-mentioned drugs. We excluded editorials, case reports, news, book chapters, meta-analyses and systematic reviews. We did not restrict by language. We also reviewed reference lists of relevant studies, guidelines and systematic reviews.

Result The electronic database search for primary studies found 2799 non-duplicate records for all PICO questions. After title and abstract screening, for syphilis, we retrieved 229 articles in full text and included four studies specific to syphilis treatment acceptability

Characteristics of included studies Study No. Country Treatments – No. of participants participants Chauhan 31 men United Benzathine penicillin 2 injections of benzathine penicillin 1 week apart – 28 men (70%) 2006 Kingdom Benzathine penicillin weekly injections for 3 weeks co-infected with HIV – 3 (7.5%) Doxycycline – 2 Crowe 1997 210 Procane penicillin United – 90 (high regimen: 1.8 g daily + oral probenecid 500 mg every 6 hours for 17 days) Kingdom – 57 (low regimen: 0.6 g daily for 10–17 days) – 21 mixed regimen: 0.5 g to 2.4 g Doxycycline or amoxicillin – 42 Kingston 72 Procane penicillin IM – 56 2004 United Doxycycline – 15 Kingdom Amoxicillin – 1 Tayal 2009 80 Benzathine penicillin 2.4 MU, 2 doses (1 week apart) IM – 75 United Doxycycline 100 mg twice daily 2 weeks – 4 Kingdom Amoxicillin 500 mg 2-week course plus probenecid 500 mg four times daily – 1

Web annex E – Systematic reviews

Findings

Chauhan et al. (2006) mentioned procaine penicillin g is the recommended first line of treatment in the United Kingdom. However, this entails daily injections and all patients rejected this option. He also found that the overall percentage of patients who finished syphilis treatment was 90% and only 10% of the patients refused injections, underlining the fact that compliance may be better with weekly injections rather than daily injections.

Kingston and Higgins (2004) and Crowe et al. (1997) have suggested excellent compliance to procaine penicillin g (86% and 88%, respectively). Crowe et al. (1997) in their study found 22% of the patients initially declined to have the daily injections and were then commenced on doxycycline. The reasons for declining therapy were refusal to have injections (25 cases), inability to attend daily (6 cases), penicillin allergy (10 cases) and bleeding disorder (1 case).

Tayal et al. (2009) showed all patients were offered two injections of benzathine penicillin (2.4 MU intramuscularly) 1 week apart and the treatment rate of the population was 100%.

References 1. Chauhan M, Serisha B, Sankar KN, Pattman RS, Schmid ML. Audit of the use of benzathine penicillin, post- treatment syphilis serology and partner notification of patients with early infectious syphilis. Int J STD AIDS. 2006;17(3):200-2. 2. Crowe G, Theodore C, Forster GE, Goh BT. Acceptability and compliance with daily injections of procaine penicillin in the outpatient treatment of syphilis-treponemal infection. Sex Transm Dis. 1997;24(3):127-30. 3. Kingston MA, Higgins SP. Audit of the management of early syphilis at North Manchester General Hospital. Int J STD AIDS. 2004;15(5):352-4. 4. Tayal S, Ahmed MS, Hanif U. Audit of early syphilis: Teesside experience 2005–2007. Int J STD AIDS. 2009;20(9):647-9.

Other conditions A systematic review of the literature for treatment utilization in STIs reported (Nagarkar 2015) that utilization ranged from 16% to 55% in the community-based studies, and was higher (approximately 70%) in research trials. Treatment may not be acceptable to patients due to the resources and availability of services, social factors and distance from a clinic. Non-utilization was also due to ignorance, illiteracy and lack of awareness. Women reported a lack of female doctors, being afraid of results, judgement of doctors, stigma, shyness and embarrassment. Cost of care and lack of faith in clinical care were also factors.

An overview of reviews of medication adherence in any condition reported (Ryan 2014) that adherence may be improved with simpler drug regimens.

Findings: Values Dixon-Woods (2001) reported semi-structured interviews with 37 women screened for chlamydia. They found that making the decision to seek help, women act on a range of specific prompts, including lay ideas about the significance of symptoms, their own behaviour, their partner’s symptoms or behaviour, contact tracing and health promotion. Women’s priority to access service is mediated by psychosocial factors such as embarrassment.

WHO guidelines for the treatment of Neisseria gonorrhoeae

References

Systematic reviews 1. Nagarkar A, Mhaskar P. A systematic review on the prevalence and utilization of health care services for reproductive tract infections/sexually transmitted infections: evidence from India. Indian J Sex Transm Dis. 2015;36(1):18-25. doi:10.4103/0253-7184.156690. 2. Ryan R, Santesso N, Lowe D, Hill S, Grimshaw J, Prictor M, et al. Interventions to improve safe and effective medicines use by consumers: an overview of systematic reviews. Cochrane Database Syst Rev. 2014;4:CD007768.

Included studies 1. Anschuetz G, Asbel L, Salmon ME, Johnson CC. Use of first-line treatment for Neisseria gonorrhoeae after treatment guideline changes. Sex Transm Dis. 2014;41(1):64-6. 2. Habib AR, Fernando R. Efficacy of azithromycin 1 g single dose in the management of uncomplicated gonorrhoea. Int J STD AIDS. 2004;15(4):240-2. 3. Rustomjee R, Kharsany AB, Connolly CA, Karim SS. A randomized controlled trial of azithromycin versus doxycycline/ciprofloxacin for the syndromic management of sexually transmitted infections in a resource-poor setting. J Antimicrob Chemother. 2002;49(5):875-8. 4. Dixon-Woods M, Stokes T, Young B, Phelps K, Windridge K, Shukla R. Choosing and using services for sexual health: a qualitative study of women’s views. Sex Transm Infect. 2001;77(5):335-9.

Web annex E – Systematic reviews

Recommendation 2

In adults and adolescents, with gonococcal oropharyngeal infections, should ceftriaxone compared to other treatments be recommended?

Criteria Population Intervention Comparator Outcome Adults and Ceftriaxone > or = Single therapy: Critical: Microbiological adolescents 250 mg IM × 1 Ceftriaxone 125 mg IM × 1 cure, clinical cure, with Cefixime 400 mg po × 1 gonorrhoea antimicrobial in gonococcal vitro resistance, compliance Cefixime 800 mg po × 1 oropharyngeal × infections Cefixime 400 mg po 2 Important: STI Gentamicin 240 mg IM × 1 complications, side-effects Azithromycin 2 g po × 1 (including allergy, toxicity), quality of life, transmission Dual therapy: to partners Azithromycin 1 g po × 1 PLUS one of the following: Ceftriaxone 500 mg IM × 1 Ceftriaxone 250 mg IM × 1 Ceftriaxone 125 mg IM × 1 Cefixime 400 mg po × 1 Cefixime 800 mg po × 1; Cefixime 400 mg po × 2 Gentamicin 240 mg IM × 1 IM: intramuscular; po: by mouth (orally)

For systematic reviews To identify pre-existing synthesized evidence, the Cochrane Library suite of databases (CDSR, HTA and ACP Journal Club) was searched for recent systematic reviews and for protocols for reviews from 2004 to February 2015. Keywords used included gonorrhoea, gonorrhea, gonococcal, ophthalmia neonatorum. The search found 111 citations. Some reviews were used to verify the included studies. One systematic review was found.

Search strategy 1 gonorrhea.mp. 2 gonorrhoea.mp. 3 gonococcal.mp. 4 ophthalmia neonatorum.mp. 5 or/1-4 6 ceftriaxone.mp. 93

WHO guidelines for the treatment of Neisseria gonorrhoeae

7 Azithromycin.mp. 8 cefixime.mp. 9 gentamicin.mp. 10 spectinomycin.mp. 11 kanamycin.mp. 12 quinolone*.mp. 13 doxycycline.mp. 14 erythromycin.mp. 15 silver nitrate.mp. 16 chloramphenicol.mp. 17 tetracycline*.mp. 18 povidone iodine.mp. 19 gemifloxacin.mp. 20 cephalosporin*.mp. 21 macrolide*.mp. 22 or/6-21 23 5 and 22 24 (th or tu).xs. 25 (co or cn or dr or dt or rh or si or th).fs. 26 24 or 25 27 23 and 26 28 limit 27 to (book or book series or editorial or letter or note or “review” or case reports or meta-analysis or news or systematic reviews) [Limit not valid in Ovid MEDLINE®, Ovid MEDLINE® Daily Update, Ovid MEDLINE® In-Process; records were retained] 29 case report/ 30 27 not (28 or 29)

Data were abstracted by one investigator and verified by another. We collected data about the study (date of data collection, type of study design, inclusion and exclusion criteria, country, funding sources), population or patient characteristics (type of population – adult/adolescent, pregnant women, neonates at risk, MSM, HIV-positive, people with treatment failures, age), infection (culture positive, types of infection – genital including cervix, urethral, oropharyngeal, coinfection), treatments (number of doses, amount, method of treatment, co-intervention), follow-up and outcomes of interest (including measures for cure rate by person and sites of infections, treatment results based on return day of visit, and types of adverse effects). We used a pre-tested data abstraction form.

Most studies did not provide details about the number of people randomized to each group, the losses to follow-up in each group, or did not include people who did not comply with protocol, we therefore collected data for a per- protocol analysis. The data extraction form was developed and piloted by at least two investigators.

Methods of analyses

Web annex E – Systematic reviews

We present the synthesized results by outcome in the results section. We analysed the data using RevMan 5.3 (RevMan, Computer Program, Copenhagen: The Nordic Cochrane Center, The Cochrane Collaboration, 2014) and when available we have included the forest plots of the statistical analyses. For dichotomous outcomes, we pooled the relative risks (e.g. risk ratios and odds ratios) from randomized studies and pooled relative risks from non-randomized studies with two comparison groups. When a study included only one group, we calculated the risk of an event (or proportion) of an outcome and then pooled the proportions from each study weighted by the generic inverse variance. When results could not be pooled we summarized the results from the individual studies narratively.

When available, we pooled and report data for subgroups by HIV status, drug dosage and type of infection. The heterogeneity of pooled results is reported using the I2 statistic.

Results

We found one review by Bignell, 2012 (see below). This review did not cover all of the interventions and populations, but we used the search results from these reviews to confirm the studies to include. From the comprehensive search of electronic databases, we included 28 studies: 8 randomized and 20 non-randomized studies (including 2 non- randomized studies with two or more groups and 18 non-randomized studies with one group).

Most studies mentioned both genital and pharyngeal infections together. However, we included data only for people who had oropharyngeal infections (at least 90% had to have oropharyngeal infections). Side-effects were not reported for people with pharyngeal infections separately.

1. Bignell C, Unemo M; European STI Guidelines Editorial Board. Azithromycin in the treatment of infection with Neisseria gonorrhoeae. Int J STD AIDS. 2013;24(2):85-92. doi:10.1177/0956462412472837.

WHO guidelines for the treatment of Neisseria gonorrhoeae

PRISMA

Figure 3: PRISMA Study Flow diagram

Web annex E – Systematic reviews

Characteristics of included studies

STUDY N AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS Randomized studies with 2 or more comparison groups Handsfield 74 27.6 ≥ 16 years male with uncomplicated Patients with complicated microbiological cure, Ceftriaxone 1983, USA gonorrhoea urethritis or anorectal gonorrhoea, had other antibiotics for side-effects 250 mg IM × 1, infections preceding 2 weeks, allergic to beta- spectinomycin 2 g lactam antibiotics. IM × 1 Collier 1984, 79/94 22.6 ± 4.3 As above As above microbiological cure Ceftriaxone USA 250 mg IM × 1, spectinomycin 2 g IM × 1 Handsfield 46/52 26.9 + As above As above microbiological cure Ceftriaxone 1981, USA 7.7 years 250 mg IM × 1, ceftriaxone 500 mg IM × 1 Handsfield 548/724 Men and women with uncomplicated Pregnant and nursing women microbiological cure Ceftriaxone 1994, USA gonorrhoea. 250 mg IM × 1, azithromycin 1 g po × 1 Handsfield 275/333 27.2 Had Gram-stained urethral or Patients who had symptoms or signs microbiological cure, Cefixime 400 mg 1991, USA endocervical smears showing of pelvic inflammatory disease or side-effects po × 1, cefixime Gram-negative diplococci within other complications of gonorrhoea, 800 mg po × 1 polymorphonuclear leukocytes or, in gave a history of allergy to beta- (or cefixime women, a history of sexual exposure lactam antibiotics or spectinomycin, to a man with urethral gonorrhoea had received antimicrobial therapy 400 mg po × 2) in the preceding 7 days, or were pregnant or nursing Judson 1985, 208 > 19 Had positive smears for anogenital Patients with histories of allergy to microbiological cure Ceftriaxone Denver, USA gonorrhoea and/or a documented beta-lactam antibiotics or who had 250 mg IM × 1, exposure to gonorrhoea antimicrobial therapy within the spectinomycin 2 g preceding 2 weeks, or complications IM × 1 of gonorrhoea, or any serious illness were excluded Rompalo 1994, 103/142 15–60 Patients who had Gram-stained If they had a history of allergy to any microbiological cure Spectinomycin 2 g USA urethral, rectal or endocervical of the drug regimens administered, IM × 1, smears showing Gram-negative were pregnant or nursing, had co- ceftriaxone diplococci within polymorphonuclear existing syphilis, myasthenia gravis, 250 mg IM × 1 cells were eligible for enrolment. or complicated gonococcal infections Also, women with a history of recent (i.e. disseminated gonorrhoea, pelvic exposure to a sexual partner with inflammatory disease, or septic gonorrhoea. arthritis), received antibiotic therapy within 48 hours before clinic presentation, active kidney disease, had bleeding disorders, or active liver disease. Participants were excluded from treatment analysis if cultures obtained at enrolment were negative for N. gonorrhoeae, if patients failed to keep appointment for follow-up or took any other antibiotic between the time of enrolment and follow-up evaluation. Tian 2002, 225 18–52 Gonorrhoea patient Not mentioned microbiological cure, Ceftriaxone China clinical cure 250 mg IM × 1, spectinomycin 2 g IM × 1 Non-randomized studies with 2 comparison groups

WHO guidelines for the treatment of Neisseria gonorrhoeae

STUDY N AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS Barbee 2013, 1275/1440 32 All patients who tested positive for Not mentioned microbiological cure Azithromycin 1 g USA pharyngeal gonorrhoea po × 1, ceftriaxone 250 mg IM × 1, cefixime 400 mg po × 1 McMillan 53 All patients with gonorrhoea Not mentioned microbiological cure, Cefixime, 2007, United side-effects cefixime + Kingdom azithromycin

Non-randomized study with one group Ota 2009, 169/178 Not mentioned Not mentioned microbiological cure Cefixime 400 mg Canada po × 1 Portilla 1992, Total: 225; 23.3 (18– Patients with clinical evidence of An allergy to penicillin or microbiological cure, Ceftriaxone USA positive 44) uncomplicated gonorrhoea. Initial cephalosporins, chronic bowel side-effects 250 mg IM × 1 culture: screening included examination of disorders, more than one bacterial 187 those who had recent sexual contact infection, evidence of chancroid, with a person who had documented syphilis or AIDS, severe systematic gonorrhoea. If Gram-negative, disease such as congestive heart intracellular diplococci consistent failure or hepatic or renal failure, with N. gonorrhoeae were positive, or those who were pregnant. the patients were enrolled in the study. Christophersen 18 > 18 A diagnosis of genitourinary or They had received antibiotics in the microbiological cure, Ceftriaxone 1989, rectal gonorrhoea was made by previous 7 days, if they had known side-effects 250 mg IM × 1 microscopy of a methylene blue- or suspected hypersensitivity stained smear at the initial visit to cephalosporins, penicillins, and test positives were included or lidocaine or if they had known renal or hepatic insufficiency Covino 1993, 30 Male patients with urethral Pregnant and lactating women, microbiological cure Ceftriaxone USA gonorrhoea, female participants with complicated gonorrhoea patients, 250 mg IM × 1 positive culture. Recent sexual allergic to penicillin or cephalosporin contact with person with recently and received any antibiotic therapy documented gonorrhoea. within last 2 weeks Covino 1990, > 18 Heterosexual men or women at least Pregnant or nursing women; patients microbiological cure Ceftriaxone USA 18 years old. Males had a urethral with a history of allergic reaction to 250 mg IM × 1 Gram stain showing gram-negative carboxyquinolones, nalidixic acid, intracellular diplococci. Females had ceftriaxone, or cephalosporins; and a known positive culture, a cervical patients who had received systemic Gram stain showing gram-negative antimicrobial therapy within the intracellular diplococci, or recent previous 24 h were excluded. exposure to a man with documented gonorrhea. Fiumara 1979, 28.1 Patients diagnosed clinical signs and Not mentioned microbiological cure Spectinomycin 2 g laboratory tests IM × 1 Freedman If pharynx and rectum were culture- Not mentioned microbiological cure Ceftriaxone 1990, positive for gonococcus by the 125 mg IM × 1 patient’s history. Handsfield 154/359 Gonorrhoea patients Not mentioned microbiological cure Ceftriaxone 1987, USA 125 mg IM × 1

Web annex E – Systematic reviews

STUDY N AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS Hook 1997, 150 27 All participants were required to have If they have a history of allergy to microbiological cure Cefixime 400 mg USA a Gram stain of a urethral specimen quinolone or cephalosporin po × 1 showing Gram-negative diplococci antibiotics; had received antibiotics within polymorphonuclear leukocytes or any other investigational drug or a recent culture positive for within 2 weeks before enrolment; had N. gonorrhoeae complicating infection or disease that would compromise treatment evaluation; received concomitant antimicrobial medication other than topical or antifungal agents; received chronic treatment with warfarin, diflunisal, fluconazole or theophylline; had taken antacids or sucralfate within 4 hours of dosing; or had a known Chlamydia trachomatis infection Hook 1993, 87/128 Women aged 18 to 50 years were They were pregnant or nursing, had microbiological cure Ceftriaxone USA eligible for enrolment if they gave a been previously enrolled in the study, 250 mg IM × 1 history of sexual exposure to a man gave a history of allergy to with urethral gonorrhoea, if they had carboxyquinolone or cephalosporin a Gram-stained endocervical smear antibiotics, had signs or symptoms showing Gram-negative diplococci of complicated gonococcal infection within polymorphonuclear (pelvic inflammatory disease), had a leukocytes, or if they had a history of chronic or acute intercurrent illness an untreated culture positive for which would compromise treatment N. gonorrhoeae evaluation, had evidence of other acute STDs requiring treatment at the time of initial evaluation, or had received systemic antimicrobial therapy with an agent known to be active against N. gonorrhoeae during the 2 weeks prior to study enrolment McCormack 24.4 Male patients with urethral Pregnant and lactating women, microbiological cure Ceftriaxone 1993, gonorrhoea, female participants with complicated gonorrhoea patients, 250 mg IM × 1 positive culture. Recent sexual allergic to penicillin or cephalosporin contact with person with recently and received any antibiotic therapy documented gonorrhoea within past 2 weeks Megran 1990, 99/146 > 18 Males aged 18 years and older with Patients receiving antimicrobial microbiological cure Cefixime 800 mg Canada positive cultures for N. gonorrhoeae therapy in the preceding 2 weeks po × 1 (or from any site or with Gram-negative were excluded from the study, as Cefixime 400 mg intracellular diplococci from endo- were persons with a history of po × 2) urethral or rectal swabs hypersensitivity to penicillins or cephalosporins and those with serious underlying disorders Mroczkowski 15–54 Women aged 16 years or older were Women of childbearing age were microbiological cure Cefixime 400 mg 1997, USA eligible for enrolment if they had a required to use a recognized po × 1 Gram-stained endocervical smear contraceptive method during the showing Gram-negative diplococci study period if they had concomitant within polymorphonuclear infection(s), such as complicated leukocytes, a recent untreated gonococcal infection, or disease that culture positive for N. gonorrhoeae, would compromise treatment or sexual exposure to men with evaluation; were pregnant or nursing; urethral gonorrhoea within the were known to have hypersensitivity 2 weeks prior to enrolment. to quinolone or cephalosporin antibiotics; had received antibiotics or any investigational drug within 2 weeks of enrolment; needed concurrent antimicrobial medication other than topical or antifungal agents; had received chronic treatment with warfarin, diflunisal, fluconazole or theophylline; or had taken antacids or sucralfate within 4 hours of dosing. Patients with recent positive cultures for C. trachomatis were also excluded.

WHO guidelines for the treatment of Neisseria gonorrhoeae

STUDY N AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS Muratani,2008, Outpatients with uncomplicated Not mentioned microbiological cure Ceftriaxone Japan gonorrhoea either symptomatic or 250 mg IM × 1 asymptomatic, as well as sexual contacts of individuals with known gonorrhoea Pabst 1989, 75 23 Women aged 16 years or older were Allergy to penicillin or quinolone microbiological cure Ceftriaxone USA eligible for enrolment if they had a antibiotics; complicated gonococcal 250 mg IM × 1 Gram-stained endocervical smear infection; known untreated syphilis; showing Gram-negative diplococci or received antimicrobial therapy within polymorphonuclear effective against N. gonorrhoeae in leukocytes, a recent untreated the 14 days preceeding initial culture positive for N. gonorrhoeae, evaluation. Patients excluded from or sexual exposure to men with analysis cultures negative, if patients urethral gonorrhoea within the 2 failed to keep appointed follow-up weeks prior to enrolment visits 7 to 10 days following enrollment, or if patients took therapy effective against N. gonorrhoeae between the time of enrollment and follow-up evaluation. Verdon 1993, > 16 All patients were examined with a Not clear microbiological cure Cefixime 200 mg USA proctoscope and specimens were po × 1 taken for microscopy and culture. The diagnosis was confirmed by the finding of Gram-negative intracellular diplococci on the smear and by the isolation and identification of N. gonorrhoeae Waugh 1993, 16–60 Gonorrhoea patients If having antibiotics or had microbiological cure Azithromycin 1 g United complication po × 1 Kingdom Judson 1983, 23/32 > 18 Women 18 years of age or older with Women with histories of allergy microbiological cure, Ceftriaxone USA proven (culture-positive) or to P-lactam antibiotics, antimicrobial side-effects 250 mg IM × 1 suspected (history of exposure to a therapy within the preceding 2 weeks, man with documented gonococcal complications of gonorrhoea, or any urethritis) uncomplicated gonorrhoea recent serious illness were excluded. IM: intramuscular; po: by mouth (orally)

100

Web annex E – Systematic reviews

Effects of interventions

Other treatments vs ceftriaxone 250 mg IM × 1

Azithromycin 1–2 g po × 1 by person (number of people) Microbiological cure (pharyngeal)

Azithromycin 1-2 gm po x 1 Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 42.1.1 Microbiological cure (pharyngeal) RCTs by person Handsfield 1994 19 19 15 15 1.00 [0.89, 1.12] + + + – + – + + + ?

0.5 0.7 1 1.5 2 Favours [Ceftriaxone] Favours [Azithromycin]

Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators (clincal cuure and a/e) (G) Blinding of data Analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Azithromycin 1–2 g po × 1 by person (number of people) Microbiological cure (pharyngeal)

Azithromycin 1-2 gm po x 1 Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI 43.1.1 Microbiological cure (pharyngeal) non-RCTs by person Barbee 2013 13 15 40 44 0.95 [0.77, 1.19]

0.5 0.7 1 1.5 2 Favours [Ceftriaxone] Favours [Azithromycin]

Cefixime 400 mg po × 1 (number of people) Microbiological cure (pharyngeal)

Cefixime 400 mg po x 1 Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 42.2.1 Microbiological cure (pharyngeal) RCTs by person Handsfield 1991 8 8 6 7 1.16 [0.80, 1.68] + + + – + – + + + ?

0.5 0.7 1 1.5 2 Favours [Ceftriaxonel] Favours [Cefixime 400mg]

Ri k f bi l d

Cefixime 400 mg po × 1 (number of people)

Microbiological cure (pharyngeal) Cefixime 400 mg po x 1 Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI

43.2.1 Microbiological cure (pharyngeal) non-RCTs by person

Barbee 2013 19 24 40 44 0.87 [0.70, 1.09]

0.5 0.7 1 1.5 2 Favours [Ceftriaxonel] Favours [Cefixime 400mg]

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Cefixime 800 mg po × 1 (or cefixime 400 mg po × 2) by persons (number of people) Microbiological cure (pharyngeal)

Cefixime 800 mg po x 1 (or Cefixime 400 mg po X 2) Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 42.3.1 Microbiological cure (pharyngeal) RCTs by person Handsfield 1991 6 7 6 7 1.00 [0.65, 1.53] + + + – + – + + + ?

0.5 0.7 1 1.5 2 Favours [Ceftraxonel] Favours [Cefixime 800mg]

Ceftriaxone 250 mg IM × 1 vs spectinomycin 2 g IM × 1 by person (number of people)

Microbiological cure (pharyngeal)

Spectinomycin 2 gm IM x 1 Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 42.5.1 Microbiological cure (pharyngeal) RCTs by person Handsfield 1983 2 7 1 1 9.1% 0.42 [0.11, 1.53] + + + – + – + + + ? Judson 1985 6 14 30 32 41.2% 0.46 [0.25, 0.84] + + + + + + + + + ? Rompalo 1994 8 12 2 2 37.3% 0.78 [0.41, 1.49] + + + – + – + + + ? Tian 2002 2 5 6 7 12.4% 0.47 [0.15, 1.42] + ? + + + + + + + ? Subtotal (95% CI) 38 42 100.0% 0.56 [0.38, 0.82] Total events 18 39 Heterogeneity: Tau² = 0.00; Chi² = 2.06, df = 3 (P = 0.56); I² = 0% Test for overall effect: Z = 2.93 (P = 0.003)

Total (95% CI) 38 42 100.0% 0.56 [0.38, 0.82] Total events 18 39 Heterogeneity: Tau² = 0.00; Chi² = 2.06, df = 3 (P = 0.56); I² = 0% 0.1 0.2 0.5 1 2 5 10 Test for overall effect: Z = 2.93 (P = 0.003) Favours [ceftriaxone] Favours [Spectinomycin] Test for subgroup differences: Not applicable

Spectinomycin 2 g IM × 1 by infections (number of infection sites)

Microbiological cure (pharyngeal)

Spectinomycin 2 gm IM x 1 Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Risk of Bias

Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 42.6.2 Microbiological cure (pharyngeal) RCTs by infections Collier 1984 4 8 9 10 0.56 [0.27, 1.14] + + + + + – + + + ?

0.1 0.2 0.5 1 2 5 10 Favours [ceftriaxone] Favours [Spectinomycin]

× Ceftriaxone 125 mg IM 1 by person (number of people) Microbiological cure (pharyngeal)

Ceftriaxone 125 mg IM x 1 Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 42.8.1 Microbiological cure (pharyngeal) RCTs by person Handsfield 1983 1 2 1 1 0.67 [0.17, 2.67] + + + – + – + + + ?

0.1 0.2 0.5 1 2 5 10 Favours [Ceftriaxone] Favours [Ceftriaxone]

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Non-randomized studies with 2 or more groups Ceftriaxone + doxycycline or azithromycin (number of people) Microbiological cure (pharyngeal)

Ceftriaxone + dox or azith Ceftriaxone 250mg IM x 1 Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI 43.8.1 Microbiological cure (pharyngeal) non-RCTs by person with ceftriaxone + doxycycline vs Ceftriaxone Barbee 2013 2 2 40 44 0.93 [0.55, 1.55]

43.8.2 Microbiological cure (pharyngeal) non-RCTs by person with ceftriaxone + azithromycin vs Ceftriaxone Barbee 2013 53 60 40 44 0.97 [0.85, 1.11]

0.1 0.2 0.5 1 2 5 10 Favours [ceftriaxone] Favours [ceftr+dox or Az]

Non-randomized studies with two or more groups

For MSM Cefixime vs cefixime + doxycycline or azithromycin Microbiological cure (pharyngeal) by number of people

Cefixime Cefixime + dox or azith Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 43.9.1 Microbiological cure (pharyngeal) non-RCTs by person with cefixime vs cefixime+azithromycin Barbee 2013 19 24 47 50 64.7% 0.84 [0.68, 1.05] McMillan 2007 (1) 7 8 44 44 35.3% 0.84 [0.63, 1.13] Subtotal (95% CI) 32 94 100.0% 0.84 [0.71, 1.00] Total events 26 91 Heterogeneity: Tau² = 0.00; Chi² = 0.00, df = 1 (P = 1.00); I² = 0% Test for overall effect: Z = 1.93 (P = 0.05)

43.9.2 Microbiological cure (pharyngeal) non-RCTs by person with cefixime vs cefixime+doxycycline Barbee 2013 19 24 22 31 100.0% 1.12 [0.82, 1.51] Subtotal (95% CI) 24 31 100.0% 1.12 [0.82, 1.51] Total events 19 22 Heterogeneity: Not applicable Test for overall effect: Z = 0.70 (P = 0.48)

0.5 0.7 1 1.5 2 Favours [Cefixime] Favours [Cefx+dox or Azi]

Footnotes (1) MSM 68%

Cefixime vs cefixime + azithromycin Side-effects (pharyngeal)

Cefixime cefixime + azithromycin Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI McMillan 2007 0 9 0 44 Not estimable 0.5 0.7 1 1.5 2 Favours [Cefixime] Favours [ Cefixime + azithro]

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Non-randomized studies with one group

Ceftriaxone ≥ 250 mg IM × 1 by person (by number of people) Microbiological cure (pharyngeal) event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 44.1.1 Non-randomised with 1 group : Microbiological cure by person Baddour 1992 1 0.202412 1 1 0.3% 1.00 [0.60, 1.40] Christophersen 1989 1 0.044869 18 18 6.4% 1.00 [0.91, 1.09] Collier 1984 0.9 0.09854098 9 10 1.3% 0.90 [0.71, 1.09] Covino 1990 1 0.143241 3 3 0.6% 1.00 [0.72, 1.28] Covino 1993 1 0.167762 2 2 0.5% 1.00 [0.67, 1.33] Handsfield 1981 (1) 1 0.20241243 1 1 0.3% 1.00 [0.60, 1.40] Handsfield 1983 1 0.20241243 1 1 0.3% 1.00 [0.60, 1.40] Handsfield 1991 0.85714286 0.1243509 6 7 0.8% 0.86 [0.61, 1.10] Handsfield 1994 1 0.05201257 15 15 4.8% 1.00 [0.90, 1.10] Hook 1993 1 0.099577 6 6 1.3% 1.00 [0.80, 1.20] Judson 1983 1 0.11083967 5 5 1.1% 1.00 [0.78, 1.22] Judson 1985 0.9375 0.04698073 30 32 5.9% 0.94 [0.85, 1.03] McCormack 1993 1 0.07631448 9 9 2.2% 1.00 [0.85, 1.15] Muratani 2008 1 0.033979 25 25 11.2% 1.00 [0.93, 1.07] Pabst 1989 1 0.143241 3 3 0.6% 1.00 [0.72, 1.28] Portilla 1992 1 0.01511375 1 1 56.7% 1.00 [0.97, 1.03] Rompalo 1994 1 0.16776226 2 2 0.5% 1.00 [0.67, 1.33] Smith 1993 1 0.054928 14 14 4.3% 1.00 [0.89, 1.11] Tian 2002 0.85714286 0.1243509 6 7 0.8% 0.86 [0.61, 1.10] Subtotal (95% CI) 157 162 100.0% 0.99 [0.97, 1.01] Heterogeneity: Chi² = 5.02, df = 18 (P = 1.00); I² = 0% Test for overall effect: Z = 87.23 (P < 0.00001)

44.1.2 Non-randomised with 1 group : Microbiological cure by person:pharynx with or without genital concomitant Christophersen 1989 1 0.022353 40 40 100.0% 1.00 [0.96, 1.04] Subtotal (95% CI) 40 40 100.0% 1.00 [0.96, 1.04] Heterogeneity: Not applicable Test for overall effect: Z = 44.74 (P < 0.00001)

-2 -1 0 1 2 Favours [ceftriaxone] Favours [control]

Footnotes (1) Ceftriaxone dose 500mg

Azithromycin 1–2 g po × 1 by number of people Microbiological cure (pharyngeal)

Event total proportion proportion Study or Subgroup proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 45.1.1 Non-randomised with 1 group : Microbiological cure by person Handsfield 1994 1 0.04290418 19 19 1.00 [0.92, 1.08] Waugh 1993 1 0.167762 2 2 1.00 [0.67, 1.33]

-2 -1 0 1 2 Favours [Azithromycin] Favours [control]

Cefixime 400 mg po × 1 by number of people Microbiological cure (pharyngeal)

event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 43.3.1 Non-randomised with 1 group : Microbiological cure by person Handsfield 1991 1 0.08275909 8 8 32.5% 1.00 [0.84, 1.16] Hook 1997 0.8333333 0.102314 10 12 21.3% 0.83 [0.63, 1.03] McMillan 2007 0.88888889 0.1058969 8 9 19.9% 0.89 [0.68, 1.10] Mroczkowski 1997 0.6875 0.105693 11 16 19.9% 0.69 [0.48, 0.89] Verdon 1993 (1) 0.6666667 0.186443 2 3 6.4% 0.67 [0.30, 1.03] Subtotal (95% CI) 39 48 100.0% 0.86 [0.77, 0.95] Heterogeneity: Chi² = 6.74, df = 4 (P = 0.15); I² = 41% Test for overall effect: Z = 18.20 (P < 0.00001)

43.3.2 Non-randomised with 1 group : Microbiological cure by person among MSM Ota 2009 0.9098361 0.026318 111 122 100.0% 0.91 [0.86, 0.96] Subtotal (95% CI) 111 122 100.0% 0.91 [0.86, 0.96] Heterogeneity: Not applicable Test for overall effect: Z = 34.57 (P < 0.00001)

-2 -1 0 1 2 Favours [cefixime] Favours [control]

Footnotes (1) Cefixime dose 200mg oral

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Cefixime 800 mg po × 1 (or cefixime 400 mg po × 2) by number of people Microbiological cure (pharyngeal) event total proportion proportion Study or Subgroup proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 45.4.1 Non-randomised with 1 group : Microbiological cure by person Handsfield 1991 0.85714286 0.1243509 6 7 0.86 [0.61, 1.10] Megran 1990 0.75 0.132462 6 8 0.75 [0.49, 1.01]

-2 -1 0 1 2 Favours [cefixime] Favours [control]

Spectinomycin 2 g IM × 1 by number of people Microbiological cure (pharyngeal)

event total proportion proportion Study or Subgroup proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 44.5.1 Non-randomised with 1 group : Microbiological cure by person Spectinomycin dose 2gm Collier 1984 0.5 0.14529973 4 8 12.6% 0.50 [0.22, 0.78] Fiumara 1979 0.75 0.16678 3 4 9.6% 0.75 [0.42, 1.08] Handsfield 1983 0.5 0.17855321 2 4 8.4% 0.50 [0.15, 0.85] Hook 1986 0.6666667 0.109976 10 15 22.0% 0.67 [0.45, 0.88] Judson 1985 0.42857143 0.11742149 6 14 19.3% 0.43 [0.20, 0.66] Rompalo 1994 0.66666667 0.12022055 8 12 18.4% 0.67 [0.43, 0.90] Tian 2002 0.4 0.16624026 2 5 9.6% 0.40 [0.07, 0.73] Subtotal (95% CI) 35 62 100.0% 0.57 [0.47, 0.67] Heterogeneity: Chi² = 5.46, df = 6 (P = 0.49); I² = 0% Test for overall effect: Z = 11.00 (P < 0.00001)

44.5.2 Non-randomised with 1 group : Microbiological cure by person Spectinomycin dose 4gm Fiumara 1979 0.75 0.13246236 6 8 100.0% 0.75 [0.49, 1.01] Subtotal (95% CI) 6 8 100.0% 0.75 [0.49, 1.01] Heterogeneity: Not applicable Test for overall effect: Z = 5.66 (P < 0.00001)

-2 -1 0 1 2 Favours [spectinomycin] Favours [control]

Ceftriaxone 125 mg IM × 1 by number of people and sites of infections Microbiological cure (pharyngeal)

event total proportion proportion Study or Subgroup proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 44.6.1 Non-randomised with 1 group : Microbiological cure by person Freedman 1990 1 0.06186244 12 12 1.00 [0.88, 1.12] Handsfield 1987 1 0.042904 19 19 1.00 [0.92, 1.08]

44.6.2 Non-randomised with 1 group : Microbiological cure by infection sites Handsfield 1981 1 0.04391178 3 3 1.00 [0.91, 1.09]

-2 -1 0 1 2 Favours [ceftriaxonel] Favours [control]

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Risk of bias

Randomized studies: see forest plots Non-randomized studies (LOW: low risk of bias; MOD: moderate risk of bias; HIGH: high risk of bias; NI: no information)

STUDY INFORMATION OUTCOME INTERVENTION1 Risk of bias for non-RCTs Subgroups First author Selection of Measurement Intended Measurement Year reported Outcome Treatment Confounding Missing data Reporting Overall (last name only) participants of interventions interventions of outcomes separately? Microbiological Ceftriaxone MOD LOW LOW LOW LOW LOW LOW LOW Smith 1993 cure Microbiological Ceftriaxone MOD LOW LOW LOW LOW LOW LOW MOD Baddour 1992 cure Barbee 2013 MSM Microbiological Ceftriaxone LOW MOD LOW LOW LOW MOD MOD cure NI Barbee 2013 MSM Microbiological Cefixime LOW MOD LOW LOW LOW MOD MOD cure NI Barbee 2013 MSM Microbiological Cefixime LOW MOD LOW LOW LOW MOD MOD cure NI Barbee 2013 MSM Microbiological Ceftriaxone LOW MOD LOW LOW LOW MOD MOD cure NI Barbee 2013 MSM Microbiological Ceftriaxone + LOW MOD LOW LOW LOW MOD MOD cure Doxycyline NI Barbee 2013 MSM Microbiological Cefixime + LOW MOD LOW LOW LOW MOD MOD cure Azithromycin NI Barbee 2013 MSM Microbiological Cefixime + LOW MOD LOW LOW LOW MOD MOD cure Doxycyline NI McMillan Microbiological Cefixime MOD LOW LOW LOW LOW LOW LOW MOD 2007 cure McMillan Microbiological Cefixime MOD LOW LOW LOW LOW LOW LOW MOD 2007 cure McMillan Microbiological Cefixime MOD LOW LOW LOW LOW LOW LOW MOD 2007 MSM 32(68%) cure

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STUDY INFORMATION OUTCOME INTERVENTION1 Risk of bias for non-RCTs Subgroups First author Selection of Measurement Intended Measurement Year reported Outcome Treatment Confounding Missing data Reporting Overall (last name only) participants of interventions interventions of outcomes separately? McMillan Side-effects Cefixime MOD LOW LOW LOW LOW LOW MOD MOD 2007 (including allergy Microbiological Cefixime MOD LOW LOW LOW LOW LOW LOW MOD Ota 2009 MSM (100%) cure Microbiological Ceftriaxone MOD LOW LOW LOW LOW LOW LOW MOD Christophersen 1989 cure Microbiological Ceftriaxone MOD LOW LOW LOW LOW LOW LOW MOD Christophersen 1989 cure Microbiological Ceftriaxone MOD LOW LOW LOW LOW LOW LOW MOD Covino 1993 cure Microbiological Ceftriaxone MOD LOW LOW LOW LOW LOW LOW MOD Covino 1990 cure Side-effects Ceftriaxone LOW LOW LOW LOW LOW MOD MOD MOD Covino 1990 (including allergy Side-effects Ceftriaxone LOW LOW LOW LOW LOW MOD MOD MOD Covino 1990 (including allergy Fiumara 1979 Microbiological Spectinomycin MOD LOW LOW LOW LOW LOW LOW MOD cure Freedman 1990 Microbiological Ceftriaxone MOD LOW LOW MOD MOD MOD LOW MOD cure Handsfield 1987 Microbiological Ceftriaxone MOD LOW LOW MOD MOD MOD LOW MOD MSM cure Hook 1997 Microbiological Cefixime LOW LOW LOW LOW LOW LOW LOW LOW cure Hook 1993 Microbiological Ceftriaxone LOW LOW LOW LOW LOW LOW LOW LOW cure Hook 1986 Side-effects Spectinomycin LOW LOW LOW LOW LOW MOD MOD MOD (including allergy McCormack 1993 Microbiological Ceftriaxone LOW LOW LOW LOW LOW LOW LOW LOW cure

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1 arm from randomized studies with 2 or more comparison groups Handsfield 1981 Microbiological Ceftriaxone MOD LOW LOW LOW LOW LOW MOD cure NI Hansfield 1983 Microbiological Ceftriaxone, MOD LOW LOW LOW LOW LOW MOD cure spectinomycin, NI Handsfield 1994 Microbiological Ceftriaxone, MOD LOW LOW LOW LOW LOW MOD cure azithromycin NI Handsfield 1991 Microbiological Ceftriaxone, MOD LOW LOW LOW LOW LOW MOD cure cefixime NI Judson 1985 Microbiological Ceftriaxone, MOD LOW LOW LOW LOW LOW MOD cure spectinomycin NI 108

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References 1. Barbee LA, Kerani RP, Dombrowski JC, Soge OO, Golden MR. A retrospective comparative study of 2-drug oral and intramuscular cephalosporin treatment regimens for pharyngeal gonorrhea. Clinical Infectious Diseases. 2013;56(11):1539-45. 2. Christophersen J, Bollerup AC, From E, Ronne-Rasmussen JO, Quitzau K. Treating genitourinary and pharyngeal gonorrhoea with single dose ceftriaxone. Genitourin Med. 1989;65(1):14-7. 3. Collier AC, Judson FN, Murphy VL, Leach LA, Root CJ, Handsfield HH. Comparative study of ceftriaxone and spectinomycin in the treatment of uncomplicated gonorrhea in women. Am J Med. 1984;77(4C):68-72. 4. Covino JM, Cummings M, Smith B, Benes S, Draft K, McCormack WM. Comparison of ofloxacin and ceftriaxone in the treatment of uncomplicated gonorrhea caused by penicillinase-producing and non- penicillinase-producing strains. Antimicrob Agents Chemother. 1990;34(1):148-9. 5. Covino JM, Smith BL, Cummings MC, Benes S, Draft K, McCormack WM. Comparison of enoxacin and ceftriaxone in the treatment of uncomplicated gonorrhea. Sex Transm Dis. 1993;20(4):227-9. 6. Fiumara NJ. Pharyngeal infection with Neisseria gonorrhoeae. Sex Transm Dis. 1979;6(4):264-6. 7. Freedman LD. Reduced dosage of ceftriaxone for uncomplicated gonorrhea in women. J. 1990;31(2):201-2. 8. Handsfield HH, Dalu ZA, Martin DH, Douglas JM, Jr., McCarty JM, Schlossberg D. Multicenter trial of single- dose azithromycin vs. ceftriaxone in the treatment of uncomplicated gonorrhea. Azithromycin Gonorrhea Study Group. Sex Transm Dis. 1994;21(2):107-11. 9. Handsfield HH, Hook IEW. Ceftriaxone for treatment of uncomplicated gonorrhea: Routine use of a single 125-mg dose in a sexually transmitted disease clinic. Sex Transm Dis. 1987;14(4):227-30. 10. Handsfield HH, Murphy VL. Comparative study of ceftriaxone and spectinomycin for treatment of uncomplicated gonorrhoea in men. Lancet. 1983;2(8341):67-70 11. Handsfield HH, Murphy VL, Holmes KK. Dose-ranging study of ceftriaxone for uncomplicated gonorrhea in men. Antimicrob Agents Chemother. 1981;20(6):839-40. 12. Hook EW, 3rd, Jones RB, Martin DH, Bolan GA, Mroczkowski TF, Neumann TM, et al. Comparison of ciprofloxacin and ceftriaxone as single-dose therapy for uncomplicated gonorrhea in women. Antimicrob Agents Chemother. 1993;37(8):1670-3. 13. Hook EW, 3rd, McCormack WM, Martin D, Jones RB, Bean K, Maroli AN. Comparison of single-dose oral grepafloxacin with cefixime for treatment of uncomplicated gonorrhea in men. The STD Study Group. Antimicrob Agents Chemother. 1997;41(8):1843-5. 14. Hook EW, 3rd, Judson FN, Verdon MS, Ehret JM, Handsfield HH. Comparative study of cefoperazone and spectinomycin for treatment of uncomplicated gonorrhea in men. Antimicrob Agents Chemother. 1986;30(4):619-21. 15. Judson FN, Ehret JM, Handsfield HH. Comparative study of ceftriaxone and spectinomycin for treatment of pharyngeal and anorectal gonorrhea. JAMA. 1985;253(10):1417-9. 16. Judson FN, Ehret JM, Root CJ. Comparative study of ceftriaxone and aqueous procaine penicillin g in the treatment of uncomplicated gonorrhea in women. Antimicrob Agents Chemother. 1983;23(2):218-20. 17. McCormack WM, Mogabgab WJ, Jones RB, Hook EW, 3rd, Wendel GD, Jr., Handsfield HH. Multicenter, comparative study of cefotaxime and ceftriaxone for treatment of uncomplicated gonorrhea. Sex Transm Dis. 1993;20(5):269-73. 18. McMillan A, Young H. The treatment of pharyngeal gonorrhoea with a single oral dose of cefixime. Int J STD AIDS. 2007;18(4):253-4. 19. Megran DW, Lefebvre K, Willetts V, Bowie WR. Single-dose oral cefixime versus amoxicillin plus probenecid for the treatment of uncomplicated gonorrhea in men. Antimicrob Agents Chemother. 1990;34(2):355-7. 20. Mroczkowski TF, Hook IEW, Jones RB, McCormack WM, Martin DH. Grepafloxacin versus cefixime as single- dose therapy for uncomplicated gonorrhea in women. Inf Dis Obstet Gynecol. 1997;5(6):370-5. 21. Muratani T, Inatomi H, Ando Y, Kawai S, Akasaka S, Matsumoto T. Single dose 1 g ceftriaxone for urogenital and pharyngeal infection caused by Neisseria gonorrhoeae. Int J Urol. 2008;15(9):837-42. 22. Ota KV, Fisman DN, Tamari IE, Smieja M, Ng LK, Jones KE, et al. Incidence and treatment outcomes of pharyngeal Neisseria gonorrhoeae and Chlamydia trachomatis infections in men who have sex with men: A 13-year retrospective cohort study. Clin Infect Dis. 2009;48(9):1237-43.

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23. Pabst KM, Siegel NA, Smith S, Black JR, Handsfield HH, Hook EW 3rd. Multicenter, comparative study of enoxacin and ceftriaxone for treatment of uncomplicated gonorrhea. Sex Transm Dis. 1989;16(3):148-51. 24. Portilla I, Lutz B, Montalvo M, Mogabgab WJ. Oral cefixime versus intramuscular ceftriaxone in patients with uncomplicated gonococcal infections. Sex Transm Dis. 1992;19(2):94-8. 25. Rompalo AM, Colletta L, Caine VA, Linnemeier P, Neumann T, Hook EW 3rd, et al. Efficacy of 250 mg trospectomycin sulfate i.m. vs. 250 mg ceftriaxone i.m. for treatment of uncomplicated gonorrhea. Sex Transm Dis. 1994;21(4):213-6. 26. Tian Hq DLY. Ceftriaxone in treating one hundred and fifteen patients with gonorrhea. Chinese J New Drugs Clinical Remedies. 2002;21(8):487-8. 27. Verdon MS, Douglas Jr JM, Wiggins SD, Handsfield HH. Treatment of uncomplicated gonorrhea with single doses of 200 mg cefixime. Sex Transm Dis. 1993;20(5):290-3. 28. Waugh MA. Open study of the safety and efficacy of a single oral dose of azithromycin for the treatment of uncomplicated gonorrhoea in men and women. J Antimicrob Chemother. 1993;31(Suppl E):193-8.

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Recommendation 3

In adults and adolescents with treatment failure of N. gonorrhoeae (genital or oropharyngeal) with any medication, what treatments should be used?

Criteria

Population Intervention and comparator Outcome Adults and Gentamicin 240 mg IM × 1 + azithromycin 2 g po × 1 Critical: Microbiological cure, adolescents Gentamicin 240 mg IM + azithromycin 1 g po × 1 compliance, STI complications, with treatment Spectinomycin 2 g IM + azithromycin 2 g po × 1 clinical cure, gonorrhoea failure of antimicrobial in vitro resistance, Gemifloxacin 1 g IM + azithromycin 2 g × 1 N. gonorrhoeae transmission to partners, side- (genital or Ceftriaxone 1 g + azithromycin 2 g × 1 effects (including allergy, oropharyngeal) Gentamicin 240 mg IM + spectinomycin 2 g IM × 1 toxicity), HIV transmission to cephalosporins Azithromycin 2 g po × 1 and acquisition

Important: Quality of life IM: intramuscular; po: by mouth (orally)

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13 doxycycline.mp. 14 erythromycin.mp. 15 silver nitrate.mp. 16 chloramphenicol.mp. 17 tetracycline*.mp. 18 povidone iodine.mp. 19 gemifloxacin.mp. 20 cephalosporin*.mp. 21 macrolide*.mp. 22 or/6-21 23 5 and 22 24 (th or tu).xs. 25 (co or cn or dr or dt or rh or si or th).fs. 26 24 or 25 27 23 and 26 28 limit 27 to (book or book series or editorial or letter or note or “review” or case reports or meta-analysis or news or systematic reviews) [Limit not valid in Ovid MEDLINE®, Ovid MEDLINE® Daily Update, Ovid MEDLINE® In-Process; records were retained] 29 case report/ 30 27 not (28 or 29)

Data were abstracted by one investigator and verified by another. We collected data about the study (date of data collection, type of study design, inclusion and exclusion criteria, country, funding sources), population or patient characteristics (type of population – adult/adolescent, pregnant women, neonates at risk, MSM, HIV-positive, people with treatment failures, age), infection (culture positive, types of infection – genital including cervix, urethral, oropharyngeal, neonatal ophthalmia, coinfection), treatments (number of doses, amount, method of treatment, co-intervention), follow-up and outcomes of interest (including measures for cure rate by person and sites of infections, treatment results based on return day of visit, and types of adverse effects). We used a pre-tested data abstraction form.

Most studies did not provide details about the number of people randomized to each group, the losses to follow-up in each group, or did not include people who did not comply with protocol, we therefore collected data for a per- protocol analysis. The data extraction form was developed and piloted by at least two investigators.

Methods of analyses We present the synthesized results by outcome in the results section. We analysed the data using RevMan 5.2 (RevMan, Computer Program, Copenhagen: The Nordic Cochrane Center, The Cochrane Collaboration, 2012) and when available we have included the forest plots of the statistical analyses. For dichotomous outcomes, we pooled the relative risks (e.g. risk ratios and odds ratios) from randomized studies and pooled relative risks from non-randomized studies with two comparison groups. When a study included only one group, we calculated the risk of an event (or proportion) of an outcome and then pooled the proportions from each study weighted by the generic inverse variance. When results could 113

WHO guidelines for the treatment of Neisseria gonorrhoeae

not be pooled we summarized the results from the individual studies narratively.

When available, we pooled and report data for subgroups by HIV status, drug dosage and type of infection. The heterogeneity of pooled results is reported using the I2 statistic.

Results We found five reviews: Bai et al., 2012; Bignell and Unemo, 2012; Dowell and Kirkcaldy, 2012; Hathorn et al., 2014; and Tapsall, 2002 (see below). The reviews did not cover all of the interventions and populations, but we used the search results from these reviews to confirm the studies to include. From the comprehensive search of electronic databases, we went through all 126 included studies and could include 25 studies, and we also included nine studies from other sources.

1. Dowell D, Kirkcaldy RD. Effectiveness of gentamicin for gonorrhoea treatment: systematic review and meta- analysis. Sex Transm Infect. 2012;88(8):589-94. doi:10.1136/sextrans-2012-050604. 2. Bai ZG, Bao XJ, Cheng WD, Yang KH, Li YP. Efficacy and safety of ceftriaxone for uncomplicated gonorrhoea: a meta-analysis of randomized controlled trials. Int J STD AIDS. 2012;23(2):126-32. doi:10.1258/ijsa.2009.009198. 3. Bignell C, Unemo M; European STI Guidelines Editorial Board. Azithromycin in the treatment of infection with Neisseria gonorrhoeae. Int J STD AIDS. 2013;24(2):85-92. doi:10.1177/0956462412472837. 4. Publication No. 10-05146. Rockville (MD): Agency for Healthcare Research and Quality; 2010. 5. Hathorn E, Dhasmana D, Duley L, Ross JD. The effectiveness of gentamicin in the treatment of Neisseria gonorrhoeae: a systematic review. Syst Rev. 2014;3:104. doi:10.1186/2046-4053-3-104. 6. Tapsall J. Current concepts in the management of gonorrhoea. Expert Opin Pharmacother. 2002;3(2):147-57.

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PRISMA

Figure 4: PRISMA Study Flow diagram

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Characteristics of included studies STUDY RCT POPULATION N INFECTION AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS Brown 1974, no adult/adolescents 152 genital (cervix) not clear Adult male patients with acute uncomplicated Not mentioned microbiological Spectinomycin Canada gonorrhoeal urethritis cure, side- 2 g IM × 1 effects Cavenee yes pregnant women 168 genital 19.7; Patients with positive culture and pregnant women Negative pretreatment culture, patients with penicillin microbiological Ceftriaxone 1993, USA (urethra) or gestational allergy and who did not return for follow up after 14 days, cure, fatal 250 mg IM × 1, anorectal age had unprotected coitus neonatal spectinomycin 22.2 weeks outcome, 2 g IM × 1 reinfection, side-effects Duncan 1972, no adult/adolescents 159/212 genital (cervix) Patients proven to have gonococcal infection by Not mentioned microbiological Spectinomycin USA culture on Thayer–Martin selective medium were cure, side- 4 g IM × 1 selected for the study effects Fluker 1980, no adult/adolescents 56/68 genital (cervix) 30.3 (18–67) All patients were examined with a proctoscope and Not mentioned microbiological Spectinomycin United specimens were taken for microscopy and culture. cure 2 g IM × 1 Kingdom The diagnosis was confirmed by the finding of Gram- negative intracellular diplococci on the smear and by the isolation and identification of N. gonorrhoeae Habib 2004, no adult/adolescents 226/301 genital (cervix) 25.8 (14–56) Men and women were treated for N. gonorrhoeae on Patients with negative culture results for N. gonorrhoeae microbiological Azithromycin United the basis of a Gram-stained smear showing who were initially treated were excluded from the study. cure 1 g po × 1 Kingdom polymorphonuclear leukocytes with intracellular Gram-negative diplococci in the initial visit or with culture-proven N. gonorrhoeae thereafter, or if there was a history of recent unprotected sexual intercourse with a partner infected with gonorrhoea regardless of Gram staining and before culture confirmation Hira 1985, yes adult/adolescents 302+113 genital Those with uncomplicated acute urethritis and who Men with a previous history of urethral discharge or microbiological Kanamycin 2 g Zambia (urethra) had Gram-negative intracellular diplococci in smears recurrent urethritis were excluded, as were those who cure, side- IM × 1, of their urethral discharge were enrolled in the study had recently received antibiotics. Although treatment effects gentamicin was started on the basis of Gram stain results, culture 240 mg IM × 1 specimens were taken before treatment from all patients, and those with negative results. Holder 1972, no adult/adolescents 14 MSM genital (cervix) Homosexual patients were examined and Not mentioned microbiological Spectinomycin USA specimens were cultured for diagnosis of cure, clinical 2 g IM × 1 gonorrhoea cure Judson 1985, yes adult/adolescents 208 genital (cervix) Had positive smears for anogenital gonorrhoea Patients with histories of allergy to beta-lactam microbiological Ceftriaxone Denver, USA and/or a documented exposure to gonorrhoea antibiotics or who had antimicrobial therapy within the cure, side- 250 mg IM × 1, preceding 2 weeks, or complications of gonorrhoea, effects spectinomycin or any serious illness were excluded 2 g IM × 1

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STUDY RCT POPULATION N INFECTION AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS Karney 1977, yes adult/adolescents 704/971 genital All members of the study population had Not mentioned microbiological Spectinomycin USA (urethra) or uncomplicated gonococcal cervicitis cure, side- 2 g IM × 1 anorectal effects Kim 1984, yes adult/adolescents 44/58 genital (cervix) 25.6 (18–42) Gonorrhoea patients Excluded patients with other complications microbiological Spectinomycin Seoul, Korea cure, side- 2 g IM × 1 effects Kouri 1989, yes adult/adolescents 210 genital (cervix) 26 (18 –53) If they had signs or symptoms of genital infection and Pregnant or if they had a history of allergy to penicillin microbiological Spectinomycin Puerto Rico, Gram-negative intracellular diplococci on smear of or spectinomycin, evidence of coexistent syphilis, or had cure, side- 2 g IM × 1 Latin America the discharge or were contact cases from a culture- received antibiotics within the previous 2 weeks effects positive patient Kousa 1974, no adult/adolescents genital (cervix) not clear Gonorrhoea patients Not mentioned microbiological Spectinomycin Finland cure, side- 2 g IM × 1 effects McCann yes adult/adolescents 138/150;104/115 Total 15–57 Patients with uncomplicated gonorrhoea Not clear microbiological Spectinomycin 1977, Belfast cure, side- 2 g IM × 1, effects Meheus no adult/adolescents 210/228 genital (cervix) 23.9 Men with signs and symptoms of urethritis Allergic to the drugs under study, had received microbiological Spectinomycin 1984, Bangui, antimicrobial treatment within the preceding 2 weeks, cure, side- 2 g IM × 1 Central and had complication of the gonococcal infection effects African Republic. Mroczkowski yes adult/adolescents 114/144 genital 23.6 (18–36) Patients with uncomplicated gonorrhoea Patients under 18 years of age, pregnant or breastfeeding microbiological Ceftriaxone 1993, USA (urethra) women, patients with active liver or kidney disease, cure, clinical 250 mg IM × 1, myasthenia gravis, bleeding disorders or known allergy cure, side- to spectinomycin or beta-lactam antibiotic. None of the effects study patients had been treated with trospectomycin or other antibiotics within 72 hours prior to enrolment Mroczkowski yes adult/adolescents 131/189 genital (cervix) 15–54 Women aged 16 years or older were eligible for If they had concomitant infection(s), such as complicated microbiological Cefixime 1997, USA enrolment if they had a Gram-stained endocervical gonococcal infection, or disease that would compromise cure, side- 400 mg po × 1 smear showing Gram-negative diplococci within treatment evaluation; were pregnant or nursing; were effects polymorphonuclear leukocytes, a recent untreated known to have hypersensitivity to quinolone or culture positive for N. gonorrhoeae, or sexual cephalosporin antibiotics; had received antibiotics or any exposure to men with urethral gonorrhoea within investigational drug within 2 weeks of enrolment; needed the 2 weeks prior to enrolment concurrent antimicrobial medication other than topical or antifungal agents; had received chronic treatment with warfarin, diflunisal, fluconazole or theophylline; or had taken antacids or sucralfate within 4 hours of dosing. Patients with recent positive cultures for C. trachomatis were also excluded. Ota 2009, no adult/adolescents 169/178 oropharyngeal Not mentioned Not mentioned microbiological Cefixime Canada cure 400 mg po × 1

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STUDY RCT POPULATION N INFECTION AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS Pabst 1989, no adult/adolescents 75 genital (cervix) 23 Women aged 16 years or older were eligible for Allergy to penicillin or quinolone antibiotics; complicated microbiological Ceftriaxone USA enrolment if they had a Gram-stained endocervical gonococcal infection; known untreated syphilis; or cure, side- 250 mg IM × 1 smear showing Gram-negative diplococci within received antimicrobial therapy effective against N. effects polymorphonuclear leukocytes, a recent untreated gonorrhoeae in the 14 days preceeding initial evaluation. culture positive for N. gonorrhoeae, or sexual Patients excluded from analysis cultures negative, if exposure to men with urethral gonorrhoea within patients failed to keep appointed follow-up visits 7 to 10 the 2 weeks prior to enrolment days following enrollment, or if patients took therapy effective against N. gonorrhoeae between the time of enrollment and follow-up evaluation. Pandhi 1989, no adult/adolescents 55/65 all 21–40 and Patients with acute gonococcal urethritis Not mentioned microbiological Gentamicin India infections/total 11–20 cure, side- 240 mg IM × 1 effects Porter 1977, no adult/adolescents 75/110 genital (cervix) not clear Patients with acute gonococcal urethritis Not mentioned microbiological Spectinomycin cure, side- 2 g IM × 1, effects azithromycin 1 g po × 1 Rajan 1979, no adult/adolescents 342/356 genital (cervix) not clear Patients with complicated gonococcal infections Not mentioned microbiological Kanamycin 2 g Singapore cure, side- IM × 1 effects Ramus 2001, yes pregnant women 95/161 genital (cervix 19.1; All untreated women Not clear microbiological Cefixime USA gestational cure, Fatal 400 mg po × 1, age 21 weeks neonatal ceftriaxone outcome 125 mg IM × 1 Sands 1980, no adult/adolescents 25 genital (cervix) > 18 Only those cases in which a follow-up rectal culture Not mentioned microbiological Spectinomycin USA was done 3–14 days after completion of therapy were cure 2 g IM × 1 included. Only those follow-up culture-positive patients with physician histories specifically excluding reinfection were included among the treatment failures. Steingrimsson yes adult/adolescents 43/181 genital 24.7 (17–58) The patients showed signs or symptoms of STD or Women of child-bearing potential, patients who had microbiological Azithromycin 1990, Iceland (urethra) were contacts of patients with STD received antibiotics or other experimental drugs within cure, side- 500 g po × 2, 2 weeks prior to visit, and patients with serious renal, effects 1 g po × 1; cardiac or hepatic disease doxycycline Takahashi no adult/adolescents 33/55 genital (cervix) 20 or more Heterosexual male patients with both GU and NGU Not clear microbiological Azithromycin 2014, Japan who were 20 years or older. Diagnosis of GU was cure, clinical 2 g po × 1 done based on both symptoms: urethral pain and pus cure discharge IM: intramuscular; po: by mouth (orally)

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Effects of interventions

Risk of bias Non-randomized studies (LOW: low risk of bias; MOD: moderate risk of bias; HIGH: high risk of bias; NI: no information) STUDY INFECTION INTERVENTION1 Risk of bias for non-RCTs

First author Year Infection Treatment

(last name only)

Confounding Selection of participants Measurement of interventions Intended interventions Missing data Measurement outcomes of Reporting Overall

McCann 1977 urethra or anorectal Spectinomycin MOD LOW LOW NI LOW LOW LOW MOD

Steingrimsson 1990 genital (urethra) Spectinomycin LOW LOW LOW LOW LOW LOW LOW LOW

Karney 1977 urethra or anorectal Spectinomycin MOD LOW LOW NI LOW LOW LOW LOW

Kousa 1974 genital (cervix) Spectinomycin MOD LOW LOW LOW LOW LOW LOW MOD

Duncan 1972 genital (cervix) Spectinomycin MOD LOW LOW LOW LOW MOD LOW MOD

Rajan 1982 genital (cervix) Ceftriaxone MOD LOW LOW LOW LOW MOD LOW MOD

Karney 1977 urethra or anorectal Spectinomycin MOD LOW LOW LOW LOW MOD LOW MOD

Ota 2009 oropharyngeal Cefixime MOD LOW LOW LOW LOW LOW LOW MOD

Fluker 1980 genital (cervix) Spectinomycin MOD LOW LOW LOW LOW LOW LOW MOD

Habib 2004 genital (cervix) Azithromycin MOD MOD LOW MOD MOD MOD LOW MOD

Holder 1972 genital (cervix) Spectinomycin MOD LOW LOW MOD MOD MOD LOW MOD

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STUDY INFECTION INTERVENTION1 Risk of bias for non-RCTs

First author Year Infection Treatment

(last name only)

Confounding Selection of participants Measurement of interventions Intended interventions Missing data Measurement outcomes of Reporting Overall

Kim 1984 genital (cervix) Spectinomycin LOW LOW LOW LOW LOW LOW LOW LOW

Kouri 1989 genital (cervix) Spectinomycin LOW LOW LOW LOW LOW LOW LOW LOW

Meheus 1984 genital (cervix) Spectinomycin MOD MOD LOW LOW LOW LOW LOW MOD

Mroczkowski 1997 all infections/total Cefixime LOW LOW LOW LOW LOW MOD MOD MOD

Pabst 1989 genital (cervix) Ceftriaxone MOD LOW LOW LOW LOW MOD MOD MOD

Pandhi 1989 all infections/total Gentamicin MOD LOW LOW LOW LOW MOD MOD MOD

Porter 1977 genital (cervix) Spectinomycin MOD LOW LOW LOW LOW MOD MOD MOD

Rajan 1979 genital (cervix) kanamycin LOW LOW LOW LOW LOW MOD MOD MOD

Sands (a) 1980 genital (cervix) Spectinomycin MOD LOW MOD MOD MOD LOW MOD MOD

Takahashi 2014 genital (cervix) Ceftriaxone LOW LOW LOW LOW LOW MOD MOD MOD

Hira 1985 genital (cervix) Gentamicin LOW LOW LOW NI LOW LOW LOW MOD

References 1. Brown J, Tabert O, Hanna JD, Rentiers PL. Treatment of gonorrheal urethritis with spectinomycin hydrochloride. Can Med Assoc J. 1974;110(2):173 passim. 2. Cavenee MR, Farris JR, Spalding TR, Barnes DL, Castaneda YS, Wendel GD, Jr. Treatment of gonorrhea in pregnancy. Obstet Gynecol. 1993;81(1):33-8. 3. Duncan WC, Holder WR, Roberts DP, Knox JM. Treatment of gonorrhea with spectinomycin hydrochloride: comparison with standard penicillin schedules. Antimicrob Agents Chemother. 1972;1(3):210-4. 4. Fluker JL, Deherogoda P, Platt DJ, Gerken A. Rectal gonorrhoea in male homosexuals. Presentation and therapy. Br J Vener Dis. 1980;56(6):397-9. 5. Habib AR, Fernando R. Efficacy of azithromycin 1 g single dose in the management of uncomplicated gonorrhoea. Int J STD AIDS. 2004;15(4):240-2. 6. Hira SK, Attili VR, Kamanga J, Mkandawire O, Patel JS, Patel MI. Efficacy of gentamicin and kanamycin in the treatment of uncomplicated gonococcal

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urethritis in Zambia. Sex Transm Dis. 1985;12(1):52-4. 7. Holder WR, Roberts DP, Duncan WC, Knox JM. Preliminary report on spectinomycin HCl in the treatment of gonorrhoea in homosexual men. Br J Vener Dis. 1972;48(4):274-6. 8. Judson FN, Ehret JM, Handsfield HH. Comparative study of ceftriaxone and spectinomycin for treatment of pharyngeal and anorectal gonorrhea. JAMA. 1985;253(10):1417-9. 9. Karney WW, Pedersen AH, Nelson M, Adams H, Pfeifer RT, Holmes KK. Spectinomycin versus tetracycline for the treatment of gonorrhea. N Engl J Med. 1977;296(16):889-94. 10. Kim JH. Comparison of thiamphenicol and spectinomycin in the treatment of uncomplicated gonorrhea in men. Sex Transm Dis. 1984;11(4 Suppl):386-90. 11. Kousa M, Lassus A, Jarvelainen R, Renkonen OV. Spectinomycin hydrochloride in the treatment of uncomplicated gonorrhoea in males and females. Br J Vener Dis. 1974;50(4):291-3. 12. Kouri YH, Gonzalez L, Perez M, Menar R, Gadea CR, Kraiselburd E, et al. Effect of penicillin and spectinomycin given for urethritis and cervicitis with Neisseria gonorrhoeae: high prevalence of penicillin-resistant isolates. Genitourin Med. 1989;65(5):342-6. 13. McCann JS, Horner T, Shepherd I, Quin N, Dougan H. Spectinomycin hydrochloride (Trobicin) in the treatment of gonorrhoea. Ir Med J. 1977;70(3):86-8. 14. Meheus A, Widy-Wirski R, D’Costa J, Van Dyck E, Delgadillo R, Piot P. Treatment of gonorrhoea in males in the Central African Republic with spectinomycin and procaine penicillin. Bull World Health Organ. 1984;62(1):89-94. 15. Mroczkowski TF, Hook IEW, Jones RB, McCormack WM, Martin DH. Grepafloxacin versus cefixime as single-dose therapy for uncomplicated gonorrhea in women. Infect Dis Obstet Gynecol. 1997;5(6):370-5. 16. Mroczkowski TF, Millikan LE, Martin DH, Leonik KJ. Treatment of gonococcal infections with a single 250 mg intramuscular injection of trospectomycin sulphate vs ceftriaxone sodium. Drugs Exp Clin Res. 1993;19(1):41-6. 17. Ota KV, Fisman DN, Tamari IE, Smieja M, Ng LK, Jones KE, et al. Incidence and treatment outcomes of pharyngeal Neisseria gonorrhoeae and Chlamydia trachomatis infections in men who have sex with men: A 13-year retrospective cohort study. Clin Infect Dis. 2009;48(9):1237-43. 18. Pabst KM, Siegel NA, Smith S, Black JR, Handsfield HH, Hook EW 3rd. Multicenter, comparative study of enoxacin and ceftriaxone for treatment of uncomplicated gonorrhea. Sex Transm Dis. 1989;16(3):148-51. 19. Porter IA, Rutherford HW. Treatment of uncomplicated gonorrhoea with spectinomycin hydrochloride (Trobicin). Br J Vener Dis. 1977;53(2):115-7. 20. Pandhi RK, Jayant D, Gupta A, Vaswani N, Sharma SD. Efficacy of gentamicin in gonococcal urethritis. Indian J Sex Transm Dis. 1989;10(2):48-50. 21. Rajan VS, Pang R, Tan NJ, Sng EH. Kanamycin in the treatment of penicillinase-producing gonococcal infections. Asian J Infect Dis. 1979;3(1):37-9. 22. Ramus RM, Sheffield JS, Mayfield JA, Wendel GD, Jr. A randomized trial that compared oral cefixime and intramuscular ceftriaxone for the treatment of gonorrhea in pregnancy. Am J Obstet Gynecol. 2001;185(3):629-32. 23. Sands M, Sellers T. Therapy of anorectal gonorrhea in men – Efficacy of oral antibiotic regimens. West J Med. 1980;133:469-471. 24. Steingrimsson O, Olafsson JH, Thorarinsson H, Ryan RW, Johnson RB, Tilton RC. Azithromycin in the treatment of sexually transmitted disease. J Antimicrob Chemother. 1990;25 Suppl A:109-14. 25. Takahashi S, Kiyota H, Ito S, Iwasawa A, Hiyama Y, Uehara T, et al. Clinical efficacy of a single two gram dose of azithromycin extended release for male patients with urethritis. Antibiotics. 2014;3(2):109-20. 26. Unemo M, Golparian D, Nicholas R, Ohnishi M, Gallay A, Sednaoui P. High-level cefixime- and ceftriaxone-resistant Neisseria gonorrhoeae in France: novel penA mosaic allele in a successful international clone causes treatment failure. Antimicrob Agents Chemother. 2012;56(3):1273-80. doi:10.1128/AAC.05760-11. Epub 2011 Dec 12. 121

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27. Unemo M, Golparian D, Stary A, Eigentler A. First Neisseria gonorrhoeae strain with resistance to cefixime causing gonorrhoea treatment failure in Austria, 2011. Euro Surveill. 2011 Oct 27;16(43). 28. Allen VG, Mitterni L, Seah C, Rebbapragada A, Martin IE, Lee C, et al. Neisseria gonorrhoeae treatment failure and susceptibility to cefixime in Toronto, Canada. JAMA. 2013;309(2):163-70. doi:10.1001/jama.2012.176575. 29. Unemo M, Golparian D, Potočnik M, Jeverica S. Treatment failure of pharyngeal gonorrhoea with internationally recommended first-line ceftriaxone verified in Slovenia, September 2011. Euro Surveill. 2012;17(25). 30. Yokoi S, Deguchi T, Ozawa T, Yasuda M, Ito S, Kubota Y, et al. Threat to cefixime treatment for gonorrhea. Emerg Infect Dis. 2007;13(8):1275-7. 31. Lewis DA, Sriruttan C, Müller EE, Golparian D, Gumede L, Fick D, et al. Phenotypic and genetic characterization of the first two cases of extended-spectrum- cephalosporin-resistant Neisseria gonorrhoeae infection in South Africa and association with cefixime treatment failure. J Antimicrob Chemother. 2013;68(6):1267-70. doi:10.1093/jac/dkt034. 32. Y Chen M, Stevens K, Tideman R, Zaia A, Tomita T, Fairley CK, Lahra M, Whiley D, Hogg G. Failure of 500 mg of ceftriaxone to eradicate pharyngeal gonorrhoea, Australia. J Antimicrob Chemother. 2013;68(6):1445-7. doi:10.1093/jac/dkt017. 33. Ison CA, Hussey J, Sankar KN, Evans J, Alexander S. Gonorrhoea treatment failures to cefixime and azithromycin in England, 2010. Euro Surveill. 2011;16(14). 34. Soge OO, Harger D, Schafer S, Toevs K, Raisler KA, Venator K, et al. Emergence of increased azithromycin resistance during unsuccessful treatment of Neisseria gonorrhoeae infection with azithromycin (Portland, OR, 2011). Sex Transm Dis. 2012;39(11):877-9. doi:10.1097/OLQ.0b013e3182685d2b.

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Recommendation 4

For treatment of gonococcal ophthalmia neonatorum in neonates, should one treatment versus another be recommended?

Criteria Population Intervention and comparator Outcome Neonates Ceftriaxone 50 mg/kg IM × 1 or × 2 or × 3 Critical: Microbiological cure, clinical cure, with neonatal Cefotaxime 100 mg/kg IM × 1 complications, side-effects (including allergy, conjunctivitis Spectinomycin 25 mg/kg IM × 1 toxicity, gastro), antimicrobial resistance, Kanamycin 25 mg/kg IM × 1 compliance Kanamycin + gentamicin ointment Kanamycin + tetracycline drop IM: intramuscular

For randomized and non-randomized studies We searched all databases up to September 2015: MEDLINE (from 1946), Embase (from 1980) and CENTRAL (Cochrane Central Register of Controlled Trials) and LILACS from inception. We did not restrict by language. We also reviewed reference lists of relevant studies, guidelines and systematic reviews.

Search strategy 1 ophthalmia neonatorum.tw. 2 newborn ophthalmia/ 3 ophthalmia neonatorum/ 4 exp conjunctivitis/ 5 conjunctivitis.tw. 6 4 or 5 7 (neonat* or newborn*).tw. 8 6 and 7 9 1 or 2 or 3 or 8 10 gonorrhea.mp. 11 gonorrhoea.mp. 12 gonococcal.mp. 13 or/10-12 14 9 and 13 15 remove duplicates from 14

The electronic database search for primary studies found 448 non-duplicate records for this question. After title and abstract screening, we retrieved 15 articles in full text and excluded the rest as not relevant (see Figure 5 for the PRISMA Study Flow diagram). 123

WHO guidelines for the treatment of Neisseria gonorrhoeae

Data were abstracted by one investigator and verified by another. We collected data about the study (date of data collection, type of study design, inclusion and exclusion criteria, country, funding sources), population or patient characteristics (type of population – neonates at risk, age), infection (culture positive, types of infection – neonatal ophthalmia), treatments (number of doses, amount, method of treatment, co-intervention), follow-up and outcomes of interest (including measures for cure rate, treatment results based on return day of visit, and types of adverse effects). We used a pre-tested data abstraction form.

Most studies did not provide details about the number of people randomized to each group, the losses to follow-up in each group, or did not include people who did not comply with protocol, we therefore collected data for a per- protocol analysis. The data extraction form was developed and piloted by at least two investigators.

Methods of analyses We present the synthesized results by outcome in the results section. We analysed the data using RevMan 5.2 (RevMan, Computer Program, Copenhagen: The Nordic Cochrane Center, The Cochrane Collaboration, 2012) and when available we have included the forest plots of the statistical analyses. For dichotomous outcomes, we pooled the relative risks (e.g. risk ratios and odds ratios) from randomized studies and pooled relative risks from non- randomized studies with two comparison groups. When a study included only one group, we calculated the risk of an event (or proportion) of an outcome and then pooled the proportions from each study weighted by the generic inverse variance. When results could not be pooled we summarized the results from the individual studies narratively.

When available, we pooled and report data for subgroups by drug dosage and type of infection. The heterogeneity of pooled results is reported using the I2 statistic.

Results The electronic database search for primary studies found 448 non-duplicate records for this question. After title and abstract screening, we included two randomized and 13 non-randomized studies.

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PRISMA

Figure 5: PRISMA Study Flow diagram

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Characteristics of included studies Study Study design No. patients Outcome(s) Follow-up Number Previous Intervention(s) First author, (enrolled or measured times (days) lost to prophylaxis? year, country diagnosed with follow-up Yes/no N. gonorrhoeae) Gururaj 1992 Non-randomized 58 Microbiological Not 0 No Spectinomycin 40 mg/kg IM (single dose) Malaysia cure, mean days mentioned Cefotaxime 100 mg/kg IM (single dose) of cure, side- Penicillin g IM effects Cefuroxime (single dose) IM Laga 1986, Kenya Randomized 122 Microbiological 3, 7 17 No Ceftriaxone 125 mg IM (single dose) control trial cure, clinical Kanamycin 75 mg IM (single dose) + 1% cure, mean tetracycline ointment (4 times daily for severity score 7 days) Kanamycin 75 mg IM (single dose) + 1% gentamicin ointment (4 times daily for 7 days) Fransen 1984, Randomized 117 Microbiological 3, 30 0 No Kanamycin 75 mg IM (single dose) + Kenya control trial cure, mean gentamicin ointment conjunctivitis Kanamycin 75 mg IM (single dose) + saline score, wash antimicrobial Kanamycin 150 mg IM (single dose) + resistance, post- gentamicin ointment gonococcal Kanamycin 150 mg IM (single dose) + saline conjunctivitis, wash compliance, side- Kanamycin 150 mg IM (single dose) + effects gentamicin ointment Kanamycin 150 mg IM (single dose) + chloramphenicol eyedrops Hoosen 2002, Non-randomized 6 2–7 0 No Ceftriaxone 62.5 mg IM (single dose) Canada Microbiological cure, clinical cure, compliance Lepage 1990, Non-randomized 211 Microbiological 2–7 0 Yes: 8; Cefotaxime 100 mg/kg IM single dose Rwanda cure, clinical No: 13 (without topical antibiotic therapy) cure, antimicrobial resistance, compliance, side- effects Lepage 1988, Non-randomized 9 Microbiological 3–7 0 Yes: 9 Cefotaxime 100 mg/kg IM single dose Rwanda cure, clinical (without topical antibiotic therapy) cure, side-effects Latif 1988, Non-randomized 219 Microbiological 72 hours, 7, 7 No Kanamycin 100 mg IM + hourly ocular Zimbabwe cure, clinical 28 irrigation with saline cure, postgonococcal conjunctivitis Ng SK 1987, Non-randomized 24 24 hours 0 No Kanamycin 500 mg/kg IM × 1 Singapore Microbiological Cefotaxime 100 mg/kg IM × 1 cure, compliance Ceftriaxone 50, 100, 150 mg/kg IM2 (all combined with 1% kanamycin eyedrops) Lockie 1986, Non-randomized 78 (including 2–14 0 No Penicillin (topical) + penicillin (systematic) 3 Malaysia 5 PPNG) Microbiological Results were cure Chloramphenicol Cefoperazone4 available for 5 PPNG cases only Spectinomycin (systematic)

Penicillin vs penicillin5 Gentamicin (topical) + kanamycin (systematic) Chloramphenicol (topical) + ampicillin (systematic)

Chloramphenicol (topical) + spectinomycin (systematic) 4 Chloramphenicol (topical) and single-dose spectinomycin (40 mg/kg) IM (systematic) 6

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Haase 1986, Non-randomized 7 Microbiological 0 No Ceftriaxone 125 mg IM × 1 (30–40 mg/kg) Canada cure, clinical 24 hours, 48– (without topical antibiotic therapy) cure, severity 72 hours, 7, score 10 Jarvis 1987, USA Non-randomized 37,8 Not 0 Yes Penicillin g (100 000 U/kg/day) IV followed Microbiological mentioned by topical penicillin drops (100 000 U/ml) cure, Cephazolin (parenteral) and topical gentamicin eyedrops Penicillin g (100 000 U/kg/day)

Gentamicin (6 mg/kg/day) IV Hira 1986, 45 7 0 No Kanamycin 250 mg IM stat + 1% tetracycline Zambia Non-randomized Microbiological eyedrops instilled every 4 hours for 7 days cure, clinical cure, side-effects Li 2009, China 62 Clinical cure, 30 0 Not Ceftriaxone 50 mg/kg/day 1 daily for 7 days Randomized conjunctival mentioned IV (topical Oflaxacin) vs Penicillin 50 000 controlled trial scarring units/kg/day twice daily 7 days IV (topical tobramycin+ oflaxacin) Rajan 1978, Non-randomized 60 3 0 Yes Local therapy as crystalline penicillin Singapore Microbiological eyedrops (10 000 units per ml) cure9 Local + systematic therapy as crystalline penicillin eyedrops (10 000 units per ml) + IM crystalline penicillin 100 000 units every 6 hours for 24 hours (i.e. a total of 400 000 units) Nsanze 1996, Non-randomized 1 N. gonorrhoeae Not 0 Not Ceftriaxone 50–125 mg IM in addition to United Arab case out of 81 Microbiological mentioned mentioned tropical therapy Emirates ophthalmia cure neonatum cases IM: intramuscular; IV: intravenous; PPNG: penicillinase-producing N. gonorrhoeae. 1 Eight patients (38%) had received previous antibiotic therapy (penicillin im and/or tetracydine eye ointment). 2 Ceftriaxone 100, 150 mg/kg IM were occasionally given when there were still symptoms of conjunctivitis present 24 hours after the institution of therapy. 3 Initial treatment of case 1 and case 4 was penicillin+penicillin and retreated with gentamicin+kanamycin and chloramphenicol+ampicillin, respectively. 4 Initial treatment of case 5 was chloramphenicol (tropical), cefoperazone and spectinomycin (systematic) and curative medications were chloramphenicol (tropical) and cefobid (unchanged from initial medication) spectinomycin (systematic) 5 **Case 3 had same treatments at the time of admission and discharged (penicillin). 6 Case 6 had same treatments at the time of admission and discharged 7 One of the three infants was treated with penicillin g (100 000 units/kg/day) intravenously. Local therapy consisted of frequent saline lavage followed by topical penicillin drops (100 000 U/ml). The eyes improved markedly within 12 hours, although subsequent improvement was slower than expected. Culture of the conjunctiva grew N. gonorrhoeae. The organism produced a β-lactamase and was resistant to penicillin (MIC greater than 20 µg/ml). 8 Includes one mixed infection (gonococcal and chlamydial) and intravenous penicillin and eyedrops with saline irrigation were begun, with dramatic improvement, not cured. The penicillin was stopped and the child was cured with sulphacetamide eyedrops. 9 Six treatment failures with local therapy were found to be clear of the infection on the third day after the additional treatment.

ǂ gave best result.

Effects of intervention

Kanamycin + tetracycline vs ceftriaxone Microbiological cure Kanamycin 75mg IM (single dose)+ 1 % tetracycline oinment Ceftriaxone 125mg IM (single dose) Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI 49.1.1 Microbiological cure Laga 1986 19 19 36 36 1.00 [0.92, 1.08]

49.1.2 Clinical cure Laga 1986 23 23 46 46 1.00 [0.94, 1.07]

0.1 0.2 0.5 1 2 5 10 Favours [ Ceftriaxone 125mg IM (single dose) Favours [ Kanamycin 75mg IM (single dose)+ 1 % tetracycline oinme

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Kanamycin + gentamicin vs ceftriaxone Microbiological cure

Kanamycin+gentamycin Ceftriaxone 125mg IM (single dose) Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI 49.2.1 Microbiological cure Laga 1986 17 17 36 36 1.00 [0.92, 1.09]

49.2.2 Clinical cure Laga 1986 19 19 46 46 1.00 [0.93, 1.08]

0.1 0.2 0.5 1 2 5 10 Favours [ Ceftriaxone 125mg IM (single dose) Favours [ Kanamycin +gen]

Spectinomycin 40 mg/kg vs cefotaxime 100 mg/kg Microbiological cure

cefotaxime 100 mg/kg Spectinomycin 40mg/kg Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI 49.3.1 Microbiological cure Gururaj 1992 24 24 31 32 1.03 [0.94, 1.13]

0.1 0.2 0.5 1 2 5 10 Favours cefotaxime 100 mg/kg Favours Spectinomycin 40mg/kg

Kanamycin 150 mg + gentamicin 1% ointment vs kanamycin 150 mg + chloramphenicol drop Microbiological cure

Kanamycin 150mg +Gentamycin 1% oint. Kanamycin 150mg + Chloramphenicol drop Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI 49.4.1 Microbiological cure Fransen 1984 23 23 12 12 1.00 [0.88, 1.13]

0.1 0.2 0.5 1 2 5 10 Favours Kanamycin 150mg + Chloramphenicol drop Favours Kanamycin 150mg +Gentamycin 1% oint.

Kanamycin 75 mg + gentamicin 1% ointment vs kanamycin 75 mg + saline Microbiological cure

Kanamycin 75mg +Gentamycin 1% oint. Kanamycin 75mg +saline Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI 49.5.1 Microbiological cure Fransen 1984 29 29 8 9 1.16 [0.89, 1.51]

0.1 0.2 0.5 1 2 5 10 Favours Kanamycin 75mg +saline Favours Kanamycin 75mg +Gentamycin 1% oint.

Kanamycin 75 mg + saline vs kanamycin 150 mg + saline Microbiological cure

Kanamycin 75mg +Saline Kanamycin 150mg +saline Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI 49.6.1 Microbiological cure Fransen 1984 8 9 14 14 0.88 [0.67, 1.16]

0.1 0.2 0.5 1 2 5 10 Favours Kanamycin 75mg +saline Favours Kanamycin 150mg +saline

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Ceftriaxone Microbiological cure

Event Total Proportion Proportion Study or Subgroup Proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 1.1.1 Microbiological cure with Ceftriaxone 50mg/kg x 1 Ng SK 1987 1 0.07080106 10 10 1.00 [0.86, 1.14]

1.1.2 Microbiological cure with Ceftriaxone 50mg/kg x 2 Ng SK 1987 1 0.20241243 1 1 1.00 [0.60, 1.40]

1.1.3 Microbiological cure with Ceftriaxone 50mg/kg x 3 Ng SK 1987 1 0.16776226 2 2 1.00 [0.67, 1.33]

1.1.4 Microbiological cure with Ceftriaxone 62.5mg at day 7 Hoosen 2002 1 0.03944996 21 21 1.00 [0.92, 1.08]

1.1.6 Microbiological cure with Ceftriaxone 125mg at day 0 Laga 1986 0 0.01511375 0 61 0.00 [-0.03, 0.03]

1.1.7 Microbiological cure with Ceftriaxone 125mg at day 3 Laga 1986 1 0.01665488 55 55 1.00 [0.97, 1.03]

1.1.8 Microbiological cure with Ceftriaxone 125mg at day 7 to 10 Haase 1986 0.85714286 0.1243509 6 7 0.86 [0.61, 1.10] Laga 1986 1 0.01966229 46 46 1.00 [0.96, 1.04] Nsanze 1996 1 0.20241243 1 1 1.00 [0.60, 1.40]

1.1.9 Microbiological cure with Ceftriaxone 125mg at day 14 Laga 1986 1 0.02459741 36 36 1.00 [0.95, 1.05]

-2 -1 0 1 2 Favours Favours [Ceftriaxone]

Cefotaxime Microbiological cure

Event Total Proportion Proportion Study or Subgroup Proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 1.2.1 Microbiological cure with cefotaxime 100 mg/kg day 7 Lepage 1988 1 0.07631448 9 9 17.4% 1.00 [0.85, 1.15] Lepage 1990 1 0.03944996 21 21 65.2% 1.00 [0.92, 1.08] Ng SK 1987 1 0.07631448 9 9 17.4% 1.00 [0.85, 1.15] Subtotal (95% CI) 39 39 100.0% 1.00 [0.94, 1.06] Heterogeneity: Chi² = 0.00, df = 2 (P = 1.00); I² = 0% Test for overall effect: Z = 31.40 (P < 0.00001)

Total (95% CI) 39 39 100.0% 1.00 [0.94, 1.06] Heterogeneity: Chi² = 0.00, df = 2 (P = 1.00); I² = 0% -2 -1 0 1 2 Test for overall effect: Z = 31.40 (P < 0.00001) Favours [Kana + Saline] Favours [control] Test for subgroup differences: Not applicable

Efotaxime in a single IM dose of 100 mg/kg Narrative findings Antimicrobial resistance Lepage, 1990: cefotaxime in a single IM dose of 100 mg/kg showed no resistance to PPNG and non-PPNG strains, both in neonates and older children. Otitis media Lepage, 1990: One neonate with concurrent otitis media was treated with cefotaxime for 5 days

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Kanamycin alone or different combinations Microbiological cure Event Total Proportion Proportion Study or Subgroup Proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 1.3.1 Microbiological cure with Kanamycin 500mg /kg x 1 Ng SK 1987 1 0.16776226 2 2 1.00 [0.67, 1.33]

1.3.2 Microbiological cure with Kanamycin 100mg + Saline day 28 Latif 1988 0.98584906 0.00917052 209 212 0.99 [0.97, 1.00]

1.3.3 Microbiological cure with Kanamycin 75mg + gentamycin ointment at day 0 Laga 1986 0 0.027342 0 32 0.00 [-0.05, 0.05]

1.3.4 Microbiological cure with Kanamycin 75mg + gentamycin ointment at day 3 Fransen 1984 1 0.02660036 33 33 1.00 [0.95, 1.05] Laga 1986 0.96153846 0.04645662 25 26 0.96 [0.87, 1.05]

1.3.5 Microbiological cure with Kanamycin 75mg + gentamycin ointment at day 7 Laga 1986 0.94736842 0.06046949 18 19 0.95 [0.83, 1.07]

1.3.6 Microbiological cure with Kanamycin 75mg + gentamycin ointment at day 14 Laga 1986 1 0.04702134 17 17 1.00 [0.91, 1.09]

1.3.7 Microbiological cure with Kanamycin + Tetracycline drop at day 0 Laga 1986 0 0.0298402 0 29 0.00 [-0.06, 0.06]

1.3.8 Microbiological cure with Kanamycin + Tetracycline drop at day 3 Laga 1986 1 0.03519913 24 24 1.00 [0.93, 1.07]

1.3.9 Microbiological cure with Kanamycin + Tetracycline drop at day 7 Laga 1986 0.95652174 0.05158148 22 23 0.96 [0.86, 1.06]

1.3.10 Microbiological cure with Kanamycin + Tetracycline drop at day 14 Laga 1986 1 0.04290418 19 19 1.00 [0.92, 1.08]

1.3.11 Microbiological cure with Kanamycin 250mg + 1% Tetracycline drop at day 7 Hira 1986 1 0.02006486 45 45 1.00 [0.96, 1.04]

1.3.12 Microbiological cure with Kanamycin 75mg + Saline at day 3 Fransen 1984 0.84615385 0.09670777 11 13 0.85 [0.66, 1.04]

1.3.13 Microbiological cure with Kanamycin 75mg + Saline at day 30 Fransen 1984 0.88888889 0.1058969 8 9 0.89 [0.68, 1.10]

1.3.14 Microbiological cure with Kanamycin 150mg + Saline at day 3 Fransen 1984 0.94736842 0.06046949 18 19 0.95 [0.83, 1.07]

1.3.15 Microbiological cure with Kanamycin 150mg + Saline at day 30 Fransen 1984 1 0.05492781 14 14 1.00 [0.89, 1.11]

1.3.16 Microbiological cure with Kanamycin 150mg + Gentamycin ointment 1% at day 3 Fransen 1984 1 0.0298402 29 29 1.00 [0.94, 1.06]

1.3.17 Microbiological cure with Kanamycin 150mg + Gentamycin ointment 1% at day 30 Fransen 1984 1 0.03651049 23 23 1.00 [0.93, 1.07]

1.3.18 Microbiological cure with Kanamycin 150mg + Chloramphenicol drop at day 3 Fransen 1984 0.92307692 0.08148859 12 13 0.92 [0.76, 1.08]

1.3.19 Microbiological cure with Kanamycin 150mg + Chloramphenicol drop at day 30 Fransen 1984 1 0.06186244 12 12 1.00 [0.88, 1.12]

-2 -1 0 1 2 Favours [Kana + Saline] Favours [control]

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Post gonococcal conjunctivitis Narrative findings: Latif, 1988: 22 (10.4%) were diagnosed as post-gonococcal conjunctivitis. Fransen, 1984: with A and C: 8 patients at day 3; with B: 2 had persistent gonococcal conjunctivitis at day 3 and 2 bacteriological and clinical relapses at day 10 and day 30; with D: 1 had a persistent gonococcal conjunctivitis at day 3 and relapsed bacteriological and clinical relapses at day 7.

Antimicrobial resistance Fransen, 1984: from in vitro susceptibility of 52 strains isolated from ophthalmia neonatorum infants, penicillinase production was detected in 23% of strains, while 9.3% of the penicillinase-negative isolates had a minimum inhibitory concentration of penicillin of 2 mg/l or more. All strains were moderately sensitive to kanamycin and gentamicin. Over half of the isolates had a minimum inhibitory concentration of tetracycline of 2–4 mg/l.

Spectinomycin 40 mg/kg Microbiological cure

Event Total Proportion Proportion Study or Subgroup Proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 1.4.1 Microbiological cure with Spectinomycin 40mg/kg Gururaj 1992 (1) 0.96875 0.03875213 31 32 0.97 [0.89, 1.04]

-2 -1 0 1 2 Favours Favours Spectinomycin

Footnotes (1) Mean days of cure 2.78

Crystalline penicillin eyedrops (10 000 units per ml) Microbiological cure

Event Total Proportion Proportion Study or Subgroup Proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 1.5.1 Microbiological cure with Crystalline penicillin eye-drops (10;000 units per ml) Rajan 1978 0.8125 0.06739814 26 32 0.81 [0.68, 0.94]

-2 -1 0 1 2 Favours Favours Crystalline penicillin eye-

Crystalline penicillin eyedrops (10 000 units per ml) +intramuscular crystalline penicillin 100 000 units every 6 hours for 24 hours (i.e. a total of 400 000 units) Microbiological cure

Event Total Proportion Proportion Study or Subgroup Proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 1.6.1 Microbiological cure with with Crystalline penicillin eye-drops (10;000 units per ml)+intramuscular crystalline penicillin 100,000 units every 6 hours for 24 hours (i.e. a total of 400,000 units) Rajan 1978 1 0.03077735 28 28 1.00 [0.94, 1.06]

-2 -1 0 1 2

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Penicillin g (100 000 units/kg/day) intravenously Microbiological cure

Event Total Proportion Proportion Study or Subgroup Proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 1.7.1 Microbiological cure with penicillin G (100 000units/kg/day) intravenously Jarvis 1987 0 0.20241243 0 1 0.00 [-0.40, 0.40]

-2 -1 0 1 2

Cephazolin and gentamicin eyedrops Microbiological cure

Event Total Proportion Proportion Study or Subgroup Proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 1.8.1 Microbiological cure with cephazolin and gentamicin eyedrops Jarvis 1987 1 0.20241243 1 1 1.00 [0.60, 1.40]

-2 -1 0 1 2

Penicillin g 100 000 units/kg/day + gentamicin 6 mg/kg/day Microbiological cure Event Total Proportion Proportion Study or Subgroup Proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 1.9.1 Microbiological cure with penicillin G 100000 units/kg/day + gentamicin 6mg/kg/day Jarvis 1987 1 0.20241243 1 1 1.00 [0.60, 1.40]

-2 -1 0 1 2

Penicillin IV + eyedrops with saline Microbiological cure

Event Total Proportion Proportion Study or Subgroup Proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 1.10.1 Microbiological cure with penicillin IV + eye drops with saline Jarvis 1987 0 0.20241243 1 1 0.00 [-0.40, 0.40]

-2 -1 0 1 2

Sulphacetamide eyedrops Microbiological cure

Event Total Proportion Proportion Study or Subgroup Proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 1.11.1 Microbiological cure with sulphacetamide eyedrops. Jarvis 1987 1 0.20241243 1 1 1.00 [0.60, 1.40]

-2 -1 0 1 2

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Penicillin + penicillin Microbiological cure (1st visit)

Event Total Proportion Proportion Study or Subgroup Proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 1.12.1 Microbiological cure with Penicillin+penicillin Lockie, 1986 0 0.16776226 0 2 0.00 [-0.33, 0.33]

-2 -1 0 1 2

Penicillin + penicillin Microbiological cure (2nd visit)

Event Total Proportion Proportion Study or Subgroup Proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 1.13.1 Microbiological cure with Penicillin+penicillin Lockie, 1986 1 0.20241243 1 1 1.00 [0.60, 1.40]

-2 -1 0 1 2

Chloramphenicol cefoperazone 75 mg IM twice daily for 5 days and spectinomycin 40 mg/kg single IM Microbiological cure

Event Total Proportion Proportion Study or Subgroup Proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 1.14.1 Microbiological cure with Chloramphenicol Cefoperazone 75 mg bd IM for 5 days & spectinomycin 40 mg/kg single IM Lockie, 1986 1 0.20241243 1 1 1.00 [0.60, 1.40]

-2 -1 0 1 2

Gentamicin + kanamycin 25 mg IM twice daily for 7 days Microbiological cure

Event Total Proportion Proportion Study or Subgroup Proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 1.15.1 Microbiological cure with Gentamicin + Kanamycin 25mg bd IM for 7 days Lockie, 1986 1 0.20241243 1 1 1.00 [0.60, 1.40]

-2 -1 0 1 2

Chloramphenicol + ampicillin Microbiological cure

Event Total Proportion Proportion Study or Subgroup Proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 1.16.1 Microbiological cure with Chloramphenicol + Ampicillin Lockie, 1986 1 0.20241243 1 1 1.00 [0.60, 1.40]

-2 -1 0 1 2

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Microbiological cure with chloramphenicol and single-dose spectinomycin 40 mg/kg single IM

Event Total Proportion Proportion Study or Subgroup Proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 1.17.1 Microbiological cure with Chloramphenicol and single-dose spectinomycin 40 mg/kg single IM Lockie, 1986 1 0.20241243 1 1 1.00 [0.60, 1.40]

-2 -1 0 1 2

Ceftriaxone 50 mg/kg × 1 for 7 days IV Clinical cure

Event Total proportion proportion Study or Subgroup proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI Li 2009 0.96774194 0.03985395 30 31 0.97 [0.89, 1.05] -2 -1 0 1 2 Favours [experimental] Favours [control]

Penicillin 50 000 units/kg/day × 2 for 7 days IV Clinical cure

Event Total proportion proportion Study or Subgroup proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI Li 2009 0.83870968 0.06515863 26 31 0.84 [0.71, 0.97] -2 -1 0 1 2 Favours [experimental] Favours [control]

Cefotaxime Clinical cure

Event Total Proportion Proportion Study or Subgroup Proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 2.1.1 Clinical cure with cefotaxime 100 mg/kg day 7 Lepage 1988 1 0.07631448 9 9 21.1% 1.00 [0.85, 1.15] Lepage 1990 1 0.03944996 21 21 78.9% 1.00 [0.92, 1.08] Subtotal (95% CI) 30 30 100.0% 1.00 [0.93, 1.07] Heterogeneity: Chi² = 0.00, df = 1 (P = 1.00); I² = 0% Test for overall effect: Z = 28.54 (P < 0.00001)

Total (95% CI) 30 30 100.0% 1.00 [0.93, 1.07] Heterogeneity: Chi² = 0.00, df = 1 (P = 1.00); I² = 0% -2 -1 0 1 2 Test for overall effect: Z = 28.54 (P < 0.00001) Favours [Cefotaxime Favours [control] Test for subgroup differences: Not applicable

Kanamycin Clinical cure

Event Total Proportion Proportion Study or Subgroup Proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI 2.2.1 Clinical cure with Kanamycin 250mg + 1% Tetracycline drop day 7 Hira 1986 0.9111111 0.0439357 41 45 0.91 [0.82, 1.00]

-2 -1 0 1 2 Favours [Kanamycin] Favours [control]

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Ceftriaxone 125 mg Clinical cure Narrative result: Laga, 1986: all had clinical improvement. Hoosen, 2002: This study demonstrated good clinical efficacy with single low-dose ceftriaxone for the management of gonococcal ophthalmia neonatorum.

Cefotaxime Side-effects

Event Total Proportion Proportion Study or Subgroup Proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 49.1.1 Side effects with cefotaxime 100 mg/kg day 7 Lepage 1988 0 0.07631448 0 9 21.1% 0.00 [-0.15, 0.15] Lepage 1990 0 0.03944996 0 21 78.9% 0.00 [-0.08, 0.08] Subtotal (95% CI) 0 30 100.0% 0.00 [-0.07, 0.07] Heterogeneity: Chi² = 0.00, df = 1 (P = 1.00); I² = 0% Test for overall effect: Z = 0.00 (P = 1.00)

Total (95% CI) 0 30 100.0% 0.00 [-0.07, 0.07] Heterogeneity: Chi² = 0.00, df = 1 (P = 1.00); I² = 0% -2 -1 0 1 2 Test for overall effect: Z = 0.00 (P = 1.00) Favours [Cef]otaxime Favours [control] Test for subgroup differences: Not applicable

Ceftriaxone 125 mg Side-effects Narrative result: Laga, 1984: Side-effects: High dose of ceftriaxone is associated with few adverse effects.

Kanamycin 75 mg + saline wash Side-effects Narrative result: Fransen, 1984: 1 infant with persistent infection, pneumonia, sepsis and a bilateral corneal ulcer developed.

Kanamycin 250 mg + 1% tetracycline drop every 4 hours for 7 days Side-effects Narrative result: Hira, 1986: 4 of 70 cases had signs of mild congestion of palpebral conjunctivae on the 7th day.

Spectinomycin 40 mg/kg IM (single dose); Cefotaxime 100 mg/kg IM (single dose); Penicillin G; Cefuroxime (single dose) Side-effects Narrative result: Gurujaj, 1992: Side-effects: there are no permanent sequelae in the form of corneal opacities in any of the 58 cases with all 4 antibiotics and none of the antibiotics produced any significant adverse effects.

Ceftriaxone 50 mg/kg × 1 for 7 days IV Conjunctival scarring

Event Total proportion proportion Study or Subgroup proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI Li 2009 0 0.0281273 0 31 0.00 [-0.06, 0.06] -2 -1 0 1 2 Favours [experimental] Favours [control]

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Penicillin 50 000 units/kg/day × 2 for 7 days IV Conjunctival scarring

Event Total proportion proportion Study or Subgroup proportion SE Total Total IV, Fixed, 95% CI IV, Fixed, 95% CI Li 2009 0.06451613 0.04829476 2 31 0.06 [-0.03, 0.16] -2 -1 0 1 2 Favours [experimental] Favours [control]

Risk of bias Non-randomized studies- (LOW: low risk of bias; MOD: moderate risk of bias; HIGH: high risk of bias; NI: no information)

First author, year, country Confounding Selection of participants Measurement of interventions Intended interventions Missing data Measurement of outcomes Reporting Overall Gururaj 1992, India HIGH HIGH LOW LOW LOW HIGH LOW HIGH Laga 1986, Kenya MOD MOD LOW LOW LOW MOD LOW MOD Fransen 1984, Kenya MOD MOD LOW LOW LOW MOD LOW MOD Hoosen 2002, Canada HIGH HIGH LOW LOW LOW HIGH LOW HIGH Lepage 1990, Rwanda HIGH HIGH LOW LOW LOW HIGH LOW HIGH Lepage 1988, Rwanda HIGH MOD LOW LOW LOW HIGH LOW HIGH Latif 1988, Zimbabwe MOD MOD LOW LOW LOW MOD LOW MOD Ng SK 1987, Singapore HIGH MOD LOW LOW MOD HIGH LOW HIGH Lockie 1986, Malaysia HIGH HIGH LOW LOW LOW HIGH LOW HIGH Haase 1986, Canada MOD HIGH LOW LOW LOW MOD LOW MOD Jarvis 1987, USA MOD MOD LOW LOW HIGH HIGH LOW HIGH Hira 1986, Zambia HIGH MOD LOW LOW MOD HIGH LOW HIGH Li 2009 MOD MOD LOW LOW LOW MOD LOW MOD Rajan1978, Singapore HIGH MOD LOW LOW MOD HIGH LOW HIGH Nsanze 1996, UAE HIGH HIGH LOW LOW LOW HIGH LOW HIGH

References

1. Fransen L. Single-dose kanamycin therapy of gonococcal ophthalmia neonatorum. Lancet. 1984;2(8414):1234-7. 2. Gururaj AK, Ariffin WA, Vijayakumari S, Reddy TN. Changing trends in the epidemiology and management of gonococcal ophthalmia neonatorum. Singapore Med J. 1992;33(3):279-81. 3. Haase DA. Single-dose ceftriaxone therapy of gonococcal ophthalmia neonatorum. Sex Transm Dis. 1986;13(1):53-5. 4. Hira SK, Sheth J, Bhat S. Ophthalmia neonatorum in Zambia. Eur J Sex Transm Dis. 1986;3(2):103-6. 5. Hoosen AA. Single low-dose ceftriaxone for the treatment of gonococcal ophthalmia – implications for the national programme for the syndromic management of sexually transmitted diseases. South African Medical Journal. Suid-Afrikaanse Tydskrif Vir Geneeskunde. 92(3):238-40, 2002.

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6. Jarvis VN. Ophthalmia neonatorum: study of a decade of experience at the Mount Sinai Hospital. Br J Ophthalmol. 71(4):295-300, 1987. 7. Laga M, Naamara W, Brunham RC, D’Costa LJ, Nsanze H, Piot P, Kunimoto D, Ndinya-Achola JO, Slaney L, Ronald AR, et al. Single-dose therapy of gonococcal ophthalmia neonatorum with ceftriaxone. N Engl J Med. 1986;315(22):1382-5. 8. Latif A. Management of gonococcal ophthalmia neonatorum with single-dose kanamycin and ocular irrigation with saline. Sex Transm Dis. 1988;15(2):108-9. 9. Lepage P Single-dose cefotaxime intramuscularly cures gonococcal ophthalmia neonatorum. Br J Ophthalmol. 1988;72:518-20 10. Lepage P Treatment of gonococcal conjunctivitis with a single intramuscular injection of cefotaxime. J Antimicrob Chemother. 1990;26 Suppl A:23-7. 11. Li WY, Liu HJ, Gao XW, Dong XY, Yu HF. Clinical research on neonatal gonococcal conjunctivitis by ceftriaxone. Int J Ophthalmol. 2009;9(5):1000-1 (in Chinese). 12. Lockie P. Penicillinase-producing Neisseria gonorrhoea as a cause of neonatal and adult ophthalmia. ANZ J Ophthalmol. 1986;14(1):49-53. 13. Ng SK. Ophthalmia neonatorum – the Middle Road Hospital perspective. Ann Acad Med, Singapore. 16(4):645-7, 1987. 14. Nsanze, H. Ophthalmia neonatorum in the United Arab Emirates. Annals of Tropical Paediatrics. 1996;16(1):27-32. 15. Rajan VS, Pang R, Sng EH. An evaluation of treatment in gonococcal ophthalmia neonatorum. Singapore Med J. 1978;19(2):86-8.

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Recommendation 5 and 6

For prevention of ophthalmia neonatorum in neonates, what are the effects of different interventions?

Criteria Population Intervention and Comparator Outcome Neonates Ophthalmic ointment in each eye at the time of delivery: Critical: Absence of conjunctivitis, at risk for Erythromycin 0.5% keratitis, complications, blindness, ophthalmia Silver nitrate 1% corneal scarring, antimicrobial neonatorum Chloramphenicol resistance Tetracycline 1% Povidone iodine 2.5%

We found four potential reviews for inclusion. Two reviews we used to confirm included studies, and one was a protocol for a Cochrane review that is not in process. The other systematic review of randomized controlled trials for prevention of ophthalmic neonatorum was published with a search date up to January 2008.

For randomized and non-randomized studies We conducted a search for ophthalmia neonatorum due to chlamydia up to November 2015 and also used the search for ophthalmia neonatorum due to gonorrhoea (see Recommendation 4). We found 348 citations. We included 16 studies relevant to chlamydia, gonorrhoea and ophthalmia neonatorum (see Figure 6 for the PRISMA Study Flow diagram for chlamydia and Figure 5 for gonorrhoea).

Search strategy 1. ophthalmia neonatorum.tw. 2. newborn ophthalmia/ 3. ophthalmia neonatorum/ 4. exp conjunctivitis/ 5. conjunctivitis.tw. 6. 4 or 5 7. (neonat* or newborn*).tw. 8. 6 and 7 9. 1 or 2 or 3 or 8 10. chlamydia*.mp. 11. (antibacter* or antibiotic*).mp. 12. (erythro* or sliver or nitrate or chloramphenicol or tetracyclin* or providone or iodine).mp. 13. 9 and 10 and (11 or 12) 14. remove duplicates from 13

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Data were abstracted by one investigator and verified by another. We collected data about the study (date of data collection, type of study design, inclusion and exclusion criteria, country, funding sources), population or patient characteristics (type of population – neonatese), infection (culture positive, types of infection – neonatal ophthalmia, conjunctivitis), treatments (number of doses, amount, method of treatment, co-intervention), follow-up and outcomes of interest (including incidence of conjunctivitis, keratitis, complications, side-effects, blindness, corneal scarring, antimicrobial resistance). We used a pre-tested data abstraction form.

Most studies did not provide details about the number of people randomized to each group, the losses to follow-up in each group, or did not include people who did not comply with protocol, we therefore collected data for a per- protocol analysis. The data extraction form was developed and piloted by at least two investigators.

Methods of analyses We present the synthesized results by comparison and outcome in the results section. We analysed the data using RevMan 5.2 (RevMan, Computer Program, Copenhagen: The Nordic Cochrane Center, The Cochrane Collaboration, 2012) and when available we have included the forest plots of the statistical analyses. For dichotomous outcomes, we pooled the relative risks (e.g. risk ratios and odds ratios) from randomized studies and pooled relative risks from non-randomized studies with two comparison groups. When a study included only one group, we calculated the risk of an event (or proportion) of an outcome and then pooled the proportions from each study weighted by the generic inverse variance. When results could not be pooled we summarized the results from the individual studies narratively.

When available, we pooled and report data for subgroups by HIV status, drug dosage and type of infection. The heterogeneity of pooled results is reported using the I2 statistic.

Results We found three systematic reviews (Darling and McDonald, 2010; Mabry-Hernandez and Koenig, 2010; Zuppa et al., 2011) and one protocol by Kapoor, 2009 (see below). The reviews did not cover all of the interventions and populations, but we used the search results from these reviews to confirm the studies to include. From the comprehensive search of electronic databases, we included 16 (including foreign language articles) studies: 15 randomized and one non-randomized study with two comparison groups.

1. Darling EK, McDonald H. A meta-analysis of the efficacy of ocular prophylactic agents used for the prevention of gonococcal and chlamydial ophthalmia neonatorum. J Midwifery Womens Health. 2010;55(4):319-27. doi:10.1016/j.jmwh.2009.09.003. 2. Kapoor VS, Whyte R, LaRoche RR. Interventions for preventing ophthalmia neonatorum. Cochrane Database Syst Rev. 1999;(4):CD001862. doi:10.1002/14651858.CD001862 3. Mabry-Hernandez IR, Koenig HC. Ocular Prophylaxis for Gonococcal Ophthalmia Neonatorum: Evidence Update for the U.S. Preventive Services Task Force Reaffirmation Recommendation Statement. AHRQ Publication No. 10-05146. Rockville, MD: Agency for Healthcare Research and Quality; 2010. 4. Zuppa AA, Andrea VD, Catenazzi P, Corrano AS, Romannolic C. Ophthalmia neonatorum: what kind of prophylaxis? J Matern Fetal Neonatal Med. 2011;24(6):769–73.

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PRISMA

Figure 6: PRISMA Study Flow diagram

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Characteristics of included studies STUDY N AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS

Randomized studies with two or more comparison groups David 2011, 419 newborn The inclusion criteria included full-term Number of Tetracycline 1%, Israel (born after a pregnancy of 37 weeks or conjunctivitis, povidone iodine 2.5% more), healthy neonates without ocular side-effects malformations whose mothers were treated with neither systemic nor local antibiotics 1 week before delivery. Ramirez- 2004 infants Patients were enrolled from three rural Patients were excluded Number of Povidone iodine Ortiz 2007, hospitals in the highlands of Chiapas, a if they had eyelid conjunctivitis, eyedrops and Mexico marginalized area and well known for malformations that side-effects chloramphenicol active trachoma according to the World prevented appropriate Health Organization. All neonates born conjunctival evaluation by vaginal delivery or caesarean section or in the case of death were included. during the first month of life. Matinzadeh 657 newborn All newborns at that time of study. Not clear Number of Erythromycin 0.5%, 2007, Iran Included were 1002 healthy term conjunctivitis, no treatment newborns (weight over 2500 g and side-effects gestational age more than 37 weeks). These infants were classified into three groups. Selection of newborn for each group was done regardless of sex, kind of birth and exclusively done randomly. Tenth day visit of newborn was mandatory to diagnose or rule out conjunctivitis. Ali 2007, 220 newborn This randomized clinical trial was Complications Number of Erythromycin 0.5%, Iran performed in the Delivery Section of conjunctivitis, placebos Vali-e-Asr Hospital in Tehran. Inclusion side-effects criteria included healthy newborns without congenital eye anomalies, newborns of mothers who had not used any form of antibiotics within the last 48 hours prior to delivery, absence of rupture of membranes for more than 18 hours, and absence of meconium aspiration. Isenberg 719 newborn All babies born at the Presbyterian Infants were excluded Number of Povidone iodine 2.5% 2003, Kenya Church of East Africa Hospital in Kikuyu, if they had any obvious conjunctivitis Kenya, from January 2000 through ocular malformations, October 2001 were candidates for the the mother had received study. Only babies born by a vaginal antibiotics during the delivery were studied, since they have last month of pregnancy, previously proved that the eyes of babies or the mother was delivered by caesarean section are nearly unable to bring the always sterile. In certain regions of the infant back to the world, such as East Africa and South East hospital in the event that Asia, ophthalmia neonatorum remains conjunctivitis developed. a major problem. Ozkan 1999, 499 newborn Infants born over a period of 6 months in Not mentioned Number of Povidone iodine 2.5%, Turkey our hospital. Shortly after birth infants conjunctivitis control received a 2.5% solution of povidone- iodine or did not.

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STUDY N AGE INCLUSION EXCLUSION OUTCOMES TREATMENTS

Randomized studies with two or more comparison groups Isenberg 3117 newborn All newborns in the hospital. A masked, If infants had any type of Number of Erythromycin 0.5%, 1995, Kenya prospective trial involving 3117 infants ocular malformations, conjunctivitis povidone iodine, silver (quasi born over a period of 30 months in a the mother had received nitrate 1% randomized) hospital in Kenya. The frequency of the any antibiotics during disease ophthalmia neonatorum is as the last month of high as 23.2% where no prophylaxis is pregnancy, or the used. Babies whose mothers had mother was unable to infections had more bacterial infections bring the infant back to overall and more gonococcal infections in the hospital if the event particular. that conjunctivitis developed. Brussieux 900 newborn All neonates born at hospital during Not mentioned Number of Tetracycline 1%, silver 1991 study period conjunctivitis nitrate1%, placebo

Chen 1992, 4544 newborn All neonates born at hospital during Not mentioned Number of Erythromycin 0.5%, Taiwan study period conjunctivitis tetracycline 1%, silver (quasi) nitrate1%, placebo

Steigleder 3804 newborn All newborns in the hospital Not mentioned Number of Erythromycin 0.5%, 1989, USA +4468 conjunctivitis tetracycline 1%, silver (quasi) nitrate1%

Hammerschlag newborn All newborns in the hospital Not mentioned Number of Erythromycin 0.5%, 1989, USA conjunctivitis tetracycline 1%, silver (quasi) nitrate1%

Fischer 1988 359 newborn All neonates born at hospital during Not mentioned Number of Tetracycline 1%, silver study period conjunctivitis nitrate1%, placebo

Laga 1988, 71+66+ newborn All the mothers resided in a certain area, Not mentioned Number of Tetracycline 1%, Nairubi 67/82+ were in established labour and gave conjunctivitis silver nitrate 1%, (quasi RCT 93+67 verbal consent. Neonates at risk and no prophylaxis of silver infants exposed to N. gonorrhoeae during nitrate and delivery. The area has high prevalence of tetracycline; gonococcal ophthalmia. and historical control) Hammerschl 559 newborn Pregnant women registered at third Not mentioned Number of Silver nitrate eyedrops ag 1982, trimester. Cervical cultures for chlamydia conjunctivitis, (1%), erythromycin USA isolation and serum for chlamydia ointment antibodies studies were obtained from each woman. Hammerschl 559 newborn Pregnant women registered at third Not mentioned Number of Silver nitrate eyedrops ag 1980, trimester. Cervical cultures for chlamydia conjunctivitis (1%), erythromycin USA isolation and serum for chlamydia ointment antibodies studies were obtained from each woman. 60 infants born to chlamydia-positive women were followed-up.

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Non-randomized studies with 2 comparison groups

Zanoni newborn The charts of all infants delivered between Not mentioned Number of Erythromycin 0.5%, 1992, July 1984 and July 1989 at two teaching conjunctivitis silver nitrate 1% USA hospitals of the UCLA School of Medicine that were coded for diagnoses of ophthalmia neonatorum, chlamydial conjunctivitis or gonococcal conjunctivitis were reviewed. These codes, which were used for both inpatients and outpatients, were found to be the only relevant ones at each hospital. The diagnostic criteria generally were an erythematous conjunctiva with some discharge from the eye.

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Effects of interventions Silver nitrate 1% vs erythromycin 0.5% Incidence of conjunctivitis among Infants exposed to chlamydia during delivery

silver nitrate erythromycin Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 1.1.1 RCTs Hammerschlag 1980 (1) 12 36 0 24 37.9% 16.89 [1.05, 272.49] + ? + + + + + + + ? Steigleder 1989 (2) 15 76 13 92 62.1% 1.40 [0.71, 2.75] + ? + + + + + + + ? Subtotal (95% CI) 112 116 100.0% 3.59 [0.25, 50.99] Total events 27 13 Heterogeneity: Tau² = 2.83; Chi² = 3.65, df = 1 (P = 0.06); I² = 73% Test for overall effect: Z = 0.94 (P = 0.35)

Total (95% CI) 112 116 100.0% 3.59 [0.25, 50.99] Total events 27 13 Heterogeneity: Tau² = 2.83; Chi² = 3.65, df = 1 (P = 0.06); I² = 73% 0.1 0.2 0.5 1 2 5 10 Test for overall effect: Z = 0.94 (P = 0.35) Favours silver nitrate Favours erythromycin Test for subgroup differences: Not applicable Footnotes Risk of bias legend (1) Hammerschlag 1982 same study (A) Random sequence generation (selection bias) (2) Same study as Hammerschlag 1989 (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Incidence of gonococcal conjunctivitis

silver nitrate erythromycin Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 1.2.1 RCTs Chen 1992 (1) 0 1082 0 1163 Not estimable + ? + + + + + + + ? Hammerschlag 1980 0 317 0 242 Not estimable + ? + + + + + + + ? Isenberg 1995 (2) 4 929 11 1112 78.7% 0.44 [0.14, 1.36] + + + + + + + + + ? Steigleder 1989 (3) 1 3804 4 4159 21.3% 0.27 [0.03, 2.44] + ? + + + + + + + ? Subtotal (95% CI) 6132 6676 100.0% 0.39 [0.14, 1.08] Total events 5 15 Heterogeneity: Tau² = 0.00; Chi² = 0.14, df = 1 (P = 0.71); I² = 0% Test for overall effect: Z = 1.80 (P = 0.07)

1.2.2 Non-RCTs Zanoni 1992 4 34772 0 12652 100.0% 3.27 [0.18, 60.82] Subtotal (95% CI) 34772 12652 100.0% 3.27 [0.18, 60.82] Total events 4 0 Heterogeneity: Not applicable Test for overall effect: Z = 0.80 (P = 0.43)

0.1 0.2 0.5 1 2 5 10 Favours silver nitrate Favours erythromycin

Footnotes Risk of bias legend (1) Outcome was measured 7 days to 28 days (A) Random sequence generation (selection bias) (2) Outcome was measured within 28 days (B) Allocation concealment (selection bias) (3) Same study as Hammerschlag 1989; outcome was measured at 2 weeks, 6 weeks and... (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Incidence of chlamydial conjunctivitis

silver nitrate erythromycin Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 1.3.1 RCTs Chen 1992 (1) 18 1082 17 1163 1.14 [0.59, 2.20] + ? + + + + + + + ? Chen 1992 (2) 18 1082 6 425 1.18 [0.47, 2.95] + ? + + + + + + + ? Hammerschlag 1982 (3) 12 371 0 242 16.33 [0.97, 274.55] Isenberg 1995 98 929 82 1112 1.43 [1.08, 1.89] + + + + + + + + + ?

1.3.2 Non-RCTs Zanoni 1992 4 34772 6 12652 0.24 [0.07, 0.86]

0.1 0.2 0.5 1 2 5 10 Favours silver nitrate Favours erythromycin

Footnotes Risk of bias legend (1) Erythromycin once (A) Random sequence generation (selection bias) (2) Erythromucin twice, Outcome was measured within 30days (B) Allocation concealment (selection bias) (3) Same population and results as Hammerschlag 1980. Outcome was measured 2... (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

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Incidence of infectious conjunctivitis

silver nitrate erythromycin Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 1.4.1 RCTs Isenberg 1995 (1) 163 929 169 1112 1.15 [0.95, 1.41] + + + + + + + + + ?

1.4.2 Non-RCTs Zanoni 1992 34 34772 32 12652 0.39 [0.24, 0.63]

0.1 0.2 0.5 1 2 5 10 Favours silver nitrate Favours erythromycin

Footnotes Risk of bias legend (1) outcome was measured within 30d (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Incidence of non-infectious conjunctivitis

silver nitrate erythromycin Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 1.5.1 RCTs Isenberg 1995 129 929 148 1112 1.04 [0.84, 1.30] + + + + + + + + + ?

1.5.2 Non-RCTs Zanoni 1992 16 34772 11 12652 0.53 [0.25, 1.14]

0.1 0.2 0.5 1 2 5 10 Favours silver nitrate Favours erythromycin

Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Tetracycline 1% vs erythromycin 0.5% Incidence of conjunctivitis among infants exposed to chlamydia during delivery

Tetracycline 1% Erythromycin 0.5% Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 2.1.1 RCTs Steigleder 1989 7 62 13 92 0.80 [0.34, 1.89] + ? + + + + + + + ?

0.1 0.2 0.5 1 2 5 10 Favours [Tetracycline] Favours []Erythromycin]

Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) ( ) Other bias J

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Incidence of gonococcal conjunctivitis

Tetracycline 1% Erythromycin 0.5% Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 2.2.2 RCTs Chen 1992 0 1156 0 1163 Not estimable + ? + + + + + + + ? Steigleder 1989 3 4468 4 4159 100.0% 0.70 [0.16, 3.12] + ? + + + + + + + ? Subtotal (95% CI) 5624 5322 100.0% 0.70 [0.16, 3.12] Total events 3 4 Heterogeneity: Not applicable Test for overall effect: Z = 0.47 (P = 0.64)

0.1 0.2 0.5 1 2 5 10 Favours [Tetracycline] Favours [Erythromycin]

Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Incidence of chlamydial conjunctivitis

Tetracycline 1% Erythromycin 0.5% Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 2.3.1 RCTs Chen 1992 (1) 15 1156 6 425 0.92 [0.36, 2.35] + ? + + + + + + + ? Chen 1992 (2) 15 1156 17 1163 0.89 [0.45, 1.77] + ? + + + + + + + ?

0.1 0.2 0.5 1 2 5 10 Favours [Tetracycline] Favours []Erythromycin]

Footnotes Risk of bias legend (1) Erythromycin twice (A) Random sequence generation (selection bias) (2) Erythromycin once (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Incidence of infectious conjunctivitis No study found.

Incidence of non-infectious conjunctivitis No study found.

Povidone iodine 2.5% vs erythromycin 0.5% Incidence of gonococcal conjunctivitis

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Povidone iodine Erythromycin Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 3.2.1 RCTs Ali 2007 (1) 0 100 0 103 Not estimable + + + + + + + + + ? Isenberg 1995 9 1076 11 1112 100.0% 0.85 [0.35, 2.03] + + + + + + + + + ? Subtotal (95% CI) 1176 1215 100.0% 0.85 [0.35, 2.03] Total events 9 11 Heterogeneity: Not applicable Test for overall effect: Z = 0.37 (P = 0.71)

0.1 0.2 0.5 1 2 5 10 Favours Povidone iodine 2.5% Favours erythromycin

Footnotes Risk of bias legend (1) Outcome was measured fisrt 24 hours to 14 days (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Incidence of chlamydial conjunctivitis

Povidone iodine Erythromycin Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 3.3.1 RCTs Ali 2007 2 100 1 103 1.8% 2.06 [0.19, 22.36] + + + + + + + + + ? Isenberg 1995 59 1076 82 1112 98.2% 0.74 [0.54, 1.03] + + + + + + + + + ? Subtotal (95% CI) 1176 1215 100.0% 0.76 [0.55, 1.04] Total events 61 83 Heterogeneity: Tau² = 0.00; Chi² = 0.69, df = 1 (P = 0.41); I² = 0% Test for overall effect: Z = 1.70 (P = 0.09)

0.1 0.2 0.5 1 2 5 10 Favours Povidone iodine 2.5% Favours erythromycin

Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Incidence of infectious conjunctivitis

Povidone iodine Erythromycin Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 3.4.1 RCTs Ali 2007 (1) 5 100 4 103 2.5% 1.29 [0.36, 4.66] + + + + + + + + + ? Isenberg 1995 141 1076 169 1112 97.5% 0.86 [0.70, 1.06] + + + + + + + + + ? Subtotal (95% CI) 1176 1215 100.0% 0.87 [0.71, 1.07] Total events 146 173 Heterogeneity: Tau² = 0.00; Chi² = 0.36, df = 1 (P = 0.55); I² = 0% Test for overall effect: Z = 1.32 (P = 0.19)

0.1 0.2 0.5 1 2 5 10 Favours Povidone iodine 2.5% Favours erythromycin

Footnotes Risk of bias legend (1) In erythromycin group out of 19 clinical conjunctivitis only 7 attended the laboratory (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Incidence of non-infectious conjunctivitis

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Povidone iodine Erythromycin Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 3.5.1 RCTs Ali 2007 (1) 4 100 15 103 35.1% 0.27 [0.09, 0.80] + + + + + + + + + ? Isenberg 1995 104 1076 148 1112 64.9% 0.73 [0.57, 0.92] + + + + + + + + + ? Subtotal (95% CI) 1176 1215 100.0% 0.52 [0.21, 1.28] Total events 108 163 Heterogeneity: Tau² = 0.32; Chi² = 3.05, df = 1 (P = 0.08); I² = 67% Test for overall effect: Z = 1.42 (P = 0.16)

0.1 0.2 0.5 1 2 5 10 Favours Povidone iodine 2.5% Favours erythromycin

Silver nitrate 1% vs tetracycline 1% Conjunctivitis among infants exposed to N. gonorrhoeae during delivery

Silver nitrate Tetracycline Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 4.1.1 RCTs Laga 1988 (1) 5 71 2 66 2.32 [0.47, 11.57] + ? + + + + + + + ?

0.1 0.2 0.5 1 2 5 10 Favours [Silver nitrate] Favours [Tetracycline]

Footnotes Risk of bias legend (1) Outcome was measured at 7 and 28 days (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) ( ) Other bias J

Incidence of conjunctivitis among infants exposed to chlamydia during delivery

Silver nitrate Tetracycline Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 4.2.1 RCTs Laga 1988 10 99 8 111 46.7% 1.40 [0.58, 3.41] + ? + + + + + + + ? Steigleder 1989 (1) 15 76 7 62 53.3% 1.75 [0.76, 4.02] + ? + + + + + + + ? Subtotal (95% CI) 175 173 100.0% 1.58 [0.86, 2.90] Total events 25 15 Heterogeneity: Tau² = 0.00; Chi² = 0.13, df = 1 (P = 0.72); I² = 0% Test for overall effect: Z = 1.47 (P = 0.14)

Total (95% CI) 175 173 100.0% 1.58 [0.86, 2.90] Total events 25 15 Heterogeneity: Tau² = 0.00; Chi² = 0.13, df = 1 (P = 0.72); I² = 0% 0.01 0.1 1 10 100 Test for overall effect: Z = 1.47 (P = 0.14) Favours [Silver nitrate] Favours [Tetracycline] Test for subgroup differences: Not applicable Footnotes Risk of bias legend (1) Same study as Hammerschlag 1989;Infant born to women with chlamydia infection (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Incidence of gonococcal conjunctivitis

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Silver nitrate Tetracycline Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 4.3.1 RCTs Brussieux 1991 (1) 0 425 0 475 Not estimable + + + + + + + + + ? Chen 1992 0 1082 0 1156 Not estimable + ? + + + + + + + ? Fischer 1988 0 236 0 123 Not estimable + ? + + + + + + + ? Laga 1988 (2) 6 1233 2 1499 56.7% 3.65 [0.74, 18.04] + ? + + + + + + + ? Steigleder 1989 (3) 1 3804 3 4468 43.3% 0.39 [0.04, 3.76] + ? + + + + + + + ? Subtotal (95% CI) 6780 7721 100.0% 1.39 [0.16, 12.13] Total events 7 5 Heterogeneity: Tau² = 1.49; Chi² = 2.50, df = 1 (P = 0.11); I² = 60% Test for overall effect: Z = 0.30 (P = 0.77)

0.1 0.2 0.5 1 2 5 10 Favours Silver nitrate Favours Tetracycline

Footnotes Risk of bias legend (1) Outcome was measured between day 7 and 30 of birth. (A) Random sequence generation (selection bias) (2) In silver nitrate group, 1 case is mixed with chlamydia and gonorrhoeae (B) Allocation concealment (selection bias) (3) Same study as Hammerschlag 1989;Infant born to women with chlamydia infection (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Incidence of chlamydial conjunctivitis

Silver nitrate Tetracycline Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 4.4.1 RCTs Brussieux 1991 (1) 0 425 1 475 2.9% 0.37 [0.02, 9.12] + + + + + + + + + ? Chen 1992 18 1082 15 1156 63.1% 1.28 [0.65, 2.53] + ? + + + + + + + ? Laga 1988 10 1233 8 1499 34.0% 1.52 [0.60, 3.84] + ? + + + + + + + ? Subtotal (95% CI) 2740 3130 100.0% 1.31 [0.76, 2.25] Total events 28 24 Heterogeneity: Tau² = 0.00; Chi² = 0.70, df = 2 (P = 0.71); I² = 0% Test for overall effect: Z = 0.98 (P = 0.33)

0.1 0.2 0.5 1 2 5 10 Favours Silver nitrate Favours Tetracycline

Footnotes Risk of bias legend (1) Outcome was measured between day 7 and 30 of birth. (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) ( ) Other bias J

Incidence of infectious conjunctivitis

149

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Silver nitrate Tetracycline Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 4.5.1 RCTs Brussieux 1991 (1) 35 425 29 475 27.6% 1.35 [0.84, 2.17] + + + + + + + + + ? Fischer 1988 0 236 0 123 Not estimable + ? + + + + + + + ? Laga 1988 91 1233 78 1499 72.4% 1.42 [1.06, 1.90] + ? + + + + + + + ? Subtotal (95% CI) 1894 2097 100.0% 1.40 [1.09, 1.79] Total events 126 107 Heterogeneity: Tau² = 0.00; Chi² = 0.03, df = 1 (P = 0.86); I² = 0% Test for overall effect: Z = 2.64 (P = 0.008)

0.1 0.2 0.5 1 2 5 10 Favours Silver nitrate Favours Tetracycline

Incidence of non-infectious conjunctivitis

Silver nitrate Tetracycline Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 4.6.1 RCTs Brussieux 1991 (1) 37 425 33 475 100.0% 1.25 [0.80, 1.97] + + + + + + + + + ? Fischer 1988 0 236 0 123 Not estimable + ? + + + + + + + ? Subtotal (95% CI) 661 598 100.0% 1.25 [0.80, 1.97] Total events 37 33 Heterogeneity: Not applicable Test for overall effect: Z = 0.98 (P = 0.33)

0.1 0.2 0.5 1 2 5 10 Favours Silver nitrate Favours Tetracycline

Footnotes Risk of bias legend (1) Outcome was measured before day 7 of birth. (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Povidone iodine 2.5% vs tetracycline 1% Incidence of gonococcal conjunctivitis

Povidone iodine Tetracycline Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 5.1.1 RCTs David 2011 0 201 0 193 Not estimable + ? + + + + + + + ?

0.1 0.2 0.5 1 2 5 10 Favours Povidone iodine Favours Tetracycline

Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Incidence of chlamydial conjunctivitis

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Povidone iodine Tetracycline Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 5.2.1 RCTs David 2011 0 201 0 193 Not estimable + ? + + + + + + + ?

0.1 0.2 0.5 1 2 5 10 Favours Povidone iodine Favours Tetracycline

Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Incidence of infectious conjunctivitis

Povidone iodine Tetracycline Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 5.3.1 RCTs David 2011 (1) 21 201 10 193 2.02 [0.97, 4.17] + ? + + + + + + + ?

0.1 0.2 0.5 1 2 5 10 Favours Povidone iodine Favours Tetracycline

Footnotes Risk of bias legend (1) Outcomes was measured by 14 days (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

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Incidence of non-infectious conjunctivitis

Povidone iodine Tetracycline Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 5.4.1 RCTs David 2011 10 201 0 193 20.17 [1.19, 341.82] + ? + + + + + + + ?

0.1 0.2 0.5 1 2 5 10 Favours Povidone iodine Favours Tetracycline

Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Side-effects and complications

Povidone iodine Tetracycline Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 5.5.1 RCTs David 2011 0 201 0 193 Not estimable + ? + + + + + + + ?

0.1 0.2 0.5 1 2 5 10 Favours Povidone iodine Favours Tetracycline

Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Povidone iodine 2.5% vs silver nitrate% Incidence of gonococcal conjunctivitis

Povidone iodine Silver nitrate Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 6.2.1 RCTs Isenberg 1995 9 1076 4 929 1.94 [0.60, 6.29] + + + + + + + + + ?

0.1 0.2 0.5 1 2 5 10 Favours Povidone iodine Favours Silver nitrate

Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

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Incidence of chlamydial conjunctivitis Povidone iodine Silver nitrate Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 6.3.1 RCTs Isenberg 1995 59 1076 98 929 0.52 [0.38, 0.71] + + + + + + + + + ?

0.1 0.2 0.5 1 2 5 10 Favours Povidone iodine Favours Silver nitrate

Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Incidence of infectious conjunctivitis

Povidone iodine Silver nitrate Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 6.4.1 RCTs Isenberg 1995 (1) 141 1076 163 929 0.75 [0.61, 0.92] + + + + + + + + + ?

0.1 0.2 0.5 1 2 5 10 Favours Povidone iodine Favours Silver nitrate

Footnotes Risk of bias legend (1) The infants may have more than one type of infection. (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Incidence of non-infectious conjunctivitis

Povidone iodine Silver nitrate Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 6.5.1 RCTs Isenberg 1995 (1) 104 1076 129 929 0.70 [0.55, 0.89] + + + + + + + + + ?

0.1 0.2 0.5 1 2 5 10 Favours Povidone iodine Favours Silver nitrate

Footnotes Risk of bias legend (1) Outcome was measured with in 30 days of birth (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

153

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Povidone iodine 2.5% vs chloramphenicol eyedrops Incidence of gonococcal conjunctivitis

Povidone iodine Chloramphenicol Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 7.1.1 RCTs Ramirez-Ortiz-2007 0 1032 0 972 Not estimable + + + + + + + + + ?

0.1 0.2 0.5 1 2 5 10 Favours Povidone iodine Favours Chloramphenicol

Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Incidence of chlamydial conjunctivitis

Povidone iodine Chloramphenicol Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 7.2.1 RCTs Ramirez-Ortiz-2007 30 1032 16 972 1.77 [0.97, 3.22] + + + + + + + + + ?

0.1 0.2 0.5 1 2 5 10 Favours Povidone iodine Favours Chloramphenicol

Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Incidence of infectious conjunctivitis

Povidone iodine Chloramphenicol Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 7.3.1 RCTs Ramirez-Ortiz-2007 111 1032 77 972 1.36 [1.03, 1.79] + + + + + + + + + ?

0.1 0.2 0.5 1 2 5 10 Favours Povidone iodine Favours Chloramphenicol

Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

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Incidence of non-infectious conjunctivitis

Povidone iodine Chloramphenicol Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 7.4.1 RCTs Ramirez-Ortiz-2007 0 1032 4 972 0.10 [0.01, 1.94] + + + + + + + + + ?

0.1 0.2 0.5 1 2 5 10 Favours Povidone iodine Favours Chloramphenicol

Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Narrative findings: Ramirez-Ortiz, 2007: Side-effects: Ocular side-effects were rare and self limiting in both groups.

Povidone iodine 2 drops vs povidone iodine 1 drop Incidence of gonococcal conjunctivitis

Povidone iodine 2 drops Povidone iodine 1 drop Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 8.1.2 RCTs Isenberg 2003 (1) 0 317 0 402 Not estimable + ? + + + + + + + ?

0.1 0.2 0.5 1 2 5 10 Favours Povidone iodine 2 Favours Povidone iodine 1

Footnotes Risk of bias legend (1) Outcome was measured within a month of birth (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Incidence of chlamydial conjunctivitis

Povidone iodine 2 drops Povidone iodine 1 drop Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 8.2.1 RCTs Isenberg 2003 3 317 3 402 1.27 [0.26, 6.24] + ? + + + + + + + ?

0.1 0.2 0.5 1 2 5 10 Favours Povidone iodine 2 Favours Povidone iodine 1

Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

155

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Incidence of infectious conjunctivitis

Povidone iodine 2 drops Povidone iodine 1 drop Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 8.3.1 RCTs Isenberg 2003 11 317 9 402 1.55 [0.65, 3.69] + ? + + + + + + + ?

0.1 0.2 0.5 1 2 5 10 Favours Povidone iodine 2 Favours Povidone iodine 1

Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Incidence of non-infectious conjunctivitis

Povidone iodine 2 drops Povidone iodine 1 drop Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 8.4.1 RCTs Isenberg 2003 69 317 68 402 1.29 [0.95, 1.74] + ? + + + + + + + ?

0.1 0.2 0.5 1 2 5 10 Favours Povidone iodine 2 Favours Povidone iodine 1

Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) ( ) Other bias J

Narrative findings: Isenberg, 2003: Inflammation (conjunctival redness, swelling and discharge: At the time of discharge, the eyelid oedema score of the double dose group was mildly, but significantly greater than the single dose group (scores 1.4. (67) vs 1.2. (73), P = 0.0002). There were no differences between the two groups for other indicators of inflammation (conjunctival redness, swelling and discharge).

One treatment versus no treatment

Silver nitrate 1% vs no treatment Conjunctivitis among Infants exposed to N. gonorrhoeae during delivery

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Silver nitrate No treatment Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J Laga 1988 5 71 28 67 0.17 [0.07, 0.41] + ? + + + + + + + ? 0.1 0.2 0.5 1 2 5 10 Favours [Silver nitrate] Favours [No treatment]

Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias Incidence of conjunctivitis among infants exposed to chlamydia during delivery

Silver nitrate No treatment Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J Laga 1988 10 99 63 201 0.32 [0.17, 0.60] + ? + + + + + + + ? 0.01 0.1 1 10 100 Favours [Silver nitrate] Favours [No treatment]

Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Incidence of gonococcal conjunctivitis

Silver nitrate no treatment Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 9.3.1 RCTs Chen 1992 0 1082 0 1143 Not estimable + ? + + + + + + + ? Fischer 1988 0 236 3 91 7.9% 0.06 [0.00, 1.06] + ? + + + + + + + ? Laga 1988 (1) 6 1233 34 1019 92.1% 0.15 [0.06, 0.35] + ? + + + + + + + ? Subtotal (95% CI) 2551 2253 100.0% 0.14 [0.06, 0.31] Total events 6 37 Heterogeneity: Tau² = 0.00; Chi² = 0.38, df = 1 (P = 0.54); I² = 0% Test for overall effect: Z = 4.73 (P < 0.00001)

0.1 0.2 0.5 1 2 5 10 Favours Silver nitrate Favours no treatment

Footnotes Risk of bias legend (1) In silver nitrate group, 1 case is mixed with chlamydia and gonorrhoeae (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Incidence of chlamydial conjunctivitis

Silver nitrate no treatment Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 9.4.1 RCTs Chen 1992 18 1082 18 1143 50.0% 1.06 [0.55, 2.02] + ? + + + + + + + ? Laga 1988 10 1233 69 1019 50.0% 0.12 [0.06, 0.23] + ? + + + + + + + ? Subtotal (95% CI) 2315 2162 100.0% 0.36 [0.04, 3.12] Total events 28 87 Heterogeneity: Tau² = 2.34; Chi² = 22.07, df = 1 (P < 0.00001); I² = 95% Test for overall effect: Z = 0.93 (P = 0.35)

Total (95% CI) 2315 2162 100.0% 0.36 [0.04, 3.12] Total events 28 87 Heterogeneity: Tau² = 2.34; Chi² = 22.07, df = 1 (P < 0.00001); I² = 95% 0.1 0.2 0.5 1 2 5 10 Test for overall effect: Z = 0.93 (P = 0.35) Favours Silver nitrate Favours no treatment Test for subgroup differences: Not applicable Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

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Incidence of infectious conjunctivitis

Silver nitrate no treatment Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 9.5.1 RCTs Fischer 1988 0 236 3 91 22.3% 0.06 [0.00, 1.06] + ? + + + + + + + ? Laga 1988 (1) 91 1233 181 1019 77.7% 0.42 [0.33, 0.53] + ? + + + + + + + ? Subtotal (95% CI) 1469 1110 100.0% 0.27 [0.05, 1.37] Total events 91 184 Heterogeneity: Tau² = 0.89; Chi² = 1.78, df = 1 (P = 0.18); I² = 44% Test for overall effect: Z = 1.58 (P = 0.11)

0.1 0.2 0.5 1 2 5 10 Favours Silver nitrate Favours no treatment

Footnotes Risk of bias legend (1) It might include non-infectious conjunctivitis (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) ( ) Other bias J

Incidence of non-infectious conjunctivitis No study found

Tetracycline 1% vs no treatment Conjunctivitis among infants exposed to N. gonorrhoeae during delivery

Tetracycline No treatment Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 10.1.1 RCTs Laga 1988 2 66 28 67 0.07 [0.02, 0.29] + ? + + + + + + + ?

0.1 0.2 0.5 1 2 5 10 Favours [Tetracycline] Favours [No treatment]

Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Incidence of conjunctivitis among Infants exposed to chlamydia during delivery

Tetracycline No treatment Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 10.2.1 RCTs Laga 1988 8 111 63 201 0.23 [0.11, 0.46] + ? + + + + + + + ?

0.01 0.1 1 10 100 Favours [Tetracycline] Favours [No treatment]

Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

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Incidence of gonococcal conjunctivitis

Tetracycline no treatment Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 10.3.1 RCTs Chen 1992 0 1156 0 1143 Not estimable + ? + + + + + + + ? Fischer 1988 (1) 0 123 3 91 18.9% 0.11 [0.01, 2.03] + ? + + + + + + + ? Laga 1988 (2) 2 1499 34 1019 81.1% 0.04 [0.01, 0.17] + ? + + + + + + + ? Subtotal (95% CI) 2778 2253 100.0% 0.05 [0.01, 0.17] Total events 2 37 Heterogeneity: Tau² = 0.00; Chi² = 0.34, df = 1 (P = 0.56); I² = 0% Test for overall effect: Z = 4.64 (P < 0.00001)

0.1 0.2 0.5 1 2 5 10 Favours Tetracycline Favours no treatment

Footnotes Risk of bias legend (1) Was not specified as infectious or non-infectious conjunctivitis (A) Random sequence generation (selection bias) (2) In silver nitrate group, 1 case is mixed with chlamydia and gonorrhoeae (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Incidence of chlamydial conjunctivitis Tetracycline no treatment Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 10.4.1 RCTs Chen 1992 15 1156 18 1143 50.2% 0.82 [0.42, 1.63] + ? + + + + + + + ? Laga 1988 (1) 8 1499 69 1019 49.8% 0.08 [0.04, 0.16] + ? + + + + + + + ? Subtotal (95% CI) 2655 2162 100.0% 0.26 [0.02, 2.69] Total events 23 87 Heterogeneity: Tau² = 2.76; Chi² = 22.35, df = 1 (P < 0.00001); I² = 96% Test for overall effect: Z = 1.14 (P = 0.26)

Total (95% CI) 2655 2162 100.0% 0.26 [0.02, 2.69] Total events 23 87 Heterogeneity: Tau² = 2.76; Chi² = 22.35, df = 1 (P < 0.00001); I² = 96% 0.1 0.2 0.5 1 2 5 10 Test for overall effect: Z = 1.14 (P = 0.26) Favours Tetracycline Favours no treatment Test for subgroup differences: Not applicable Footnotes Risk of bias legend (1) In silver nitrate group, 1 case is mixed with chlamydia and gonorrhoeae (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

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Incidence of infectious conjunctivitis

Tetracycline no treatment Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 10.5.1 RCTs Fischer 1988 (1) 0 123 3 91 0.7% 0.11 [0.01, 2.03] + ? + + + + + + + ? Laga 1988 (2) 78 1499 181 1019 99.3% 0.29 [0.23, 0.38] + ? + + + + + + + ? Subtotal (95% CI) 1622 1110 100.0% 0.29 [0.23, 0.37] Total events 78 184 Heterogeneity: Tau² = 0.00; Chi² = 0.45, df = 1 (P = 0.50); I² = 0% Test for overall effect: Z = 9.59 (P < 0.00001)

0.1 0.2 0.5 1 2 5 10 Favours Tetracycline Favours no treatment

Footnotes Risk of bias legend (1) Was not specified as infectious or non-infectious conjunctivitis (A) Random sequence generation (selection bias) (2) It might include non-infectious conjunctivitis (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Incidence of non-infectious conjunctivitis No study found.

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Erythromycin 0.5% vs no treatment Incidence of gonococcal conjunctivitis

Erythromycin no treatment Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 11.1.1 RCTs Ali 2007 0 100 0 107 Not estimable + + + + + + + + + ? Chen 1992 0 1163 0 1143 Not estimable + ? + + + + + + + ? Matinzadeh 2007 (1) 0 320 0 337 Not estimable + + + – + – + + + ? Subtotal (95% CI) 1583 1587 Not estimable Total events 0 0 Heterogeneity: Not applicable Test for overall effect: Not applicable

0.1 0.2 0.5 1 2 5 10 Favours Erythromycin Favours no treatment

Footnotes Risk of bias legend (1) Outcomee was measured within first 10 days of birth (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Incidence of chlamydial conjunctivitis

Erythromycin no treatment Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 11.2.1 RCTs Ali 2007 (1) 1 103 1 107 1.04 [0.07, 16.39] + + + + + + + + + ? Chen 1992 (2) 17 1163 18 1143 0.93 [0.48, 1.79] + ? + + + + + + + ? Chen 1992 (3) 6 425 18 1143 0.90 [0.36, 2.24] + ? + + + + + + + ?

0.1 0.2 0.5 1 2 5 10 Favours Erythromycin Favours no treatment

Footnotes Risk of bias legend (1) Out of 19 and 24 conjunctivitis cases in erythromycin and control groups... (A) Random sequence generation (selection bias) (2) Erythromycin once (B) Allocation concealment (selection bias) (3) Erythromycin twice (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Incidence of infectious conjunctivitis

Erythromycin no treatment Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 11.3.1 RCTs Ali 2007 (1) 4 103 5 107 0.83 [0.23, 3.01] + + + + + + + + + ?

0.1 0.2 0.5 1 2 5 10 Favours Erythromycin Favours no treatment

Footnotes Risk of bias legend (1) Out of 19 and 24 conjunctivitis cases in erythromycin and control groups... (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

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Incidence of non-infectious conjunctivitis

Erythromycin no treatment Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 11.4.1 RCTs Ali 2007 (1) 15 103 19 107 0.82 [0.44, 1.53] + + + + + + + + + ?

0.1 0.2 0.5 1 2 5 10 Favours Erythromycin Favours no treatment

Narrative: Matinzadeh, 2007: Incidence of non-infectious conjunctivitis: no significant differences between groups – clinical or culture – were observed. In drug-free group, 53 (38.4%) cases were observed, and in normal saline group, 44 cases (31.9%). Culture was performed for 111 newborns (11.1%), 91 cases (9.1%) were positive and 20 newborns (2%) negative. Greatest number negative cultures were in normal saline group and erythromycin group stood second.

Povidone iodine 2.5% vs no treatment Incidence of gonococcal conjunctivitis

Povidone iodine no treatment Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 12.2.1 RCTs Ali 2007 0 100 0 107 Not estimable + + + + + + + + + ? Ozkan 1999 0 282 0 217 Not estimable + ? + + + + + + + ? Subtotal (95% CI) 382 324 Not estimable Total events 0 0 Heterogeneity: Not applicable Test for overall effect: Not applicable

0.1 0.2 0.5 1 2 5 10 Favours Povidone iodine Favours no treatment

Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) (J) Other bias

Incidence of chlamydial conjunctivitis

Povidone iodine no treatment Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 12.3.1 RCTs Ali 2007 (1) 2 100 1 107 100.0% 2.14 [0.20, 23.24] + + + + + + + + + ? Ozkan 1999 0 282 0 217 Not estimable + ? + + + + + + + ? Subtotal (95% CI) 382 324 100.0% 2.14 [0.20, 23.24] Total events 2 1 Heterogeneity: Not applicable Test for overall effect: Z = 0.63 (P = 0.53)

0.1 0.2 0.5 1 2 5 10 Favours Povidone iodine Favours no treatment

Footnotes Risk of bias legend (1) Out of 24 conjunctivitis cases in control group only 7 attended lab test (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants (micro cure) (D) Blinding of participants (clinical cure and adverse events) (E) Blinding of investigators (micro cure) (F) Blinding of investigators ( clinical cure and a/e) (G) Blinding of data analyst (H) Incomplete outcome data (attrition bias) (I) Selective reporting (reporting bias) ( ) Other bias J

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Incidence of infectious conjunctivitis

Povidone iodine no treatment Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 12.4.1 RCTs Ali 2007 (1) 5 100 5 107 32.9% 1.07 [0.32, 3.59] + + + + + + + + + ? Ozkan 1999 12 282 9 217 67.1% 1.03 [0.44, 2.39] + ? + + + + + + + ? Subtotal (95% CI) 382 324 100.0% 1.04 [0.52, 2.08] Total events 17 14 Heterogeneity: Tau² = 0.00; Chi² = 0.00, df = 1 (P = 0.96); I² = 0% Test for overall effect: Z = 0.11 (P = 0.91)

0.1 0.2 0.5 1 2 5 10 Favours Povidone iodine Favours no treatment

Incidence of non-infectious conjunctivitis

Povidone iodine no treatment Risk Ratio Risk Ratio Risk of Bias Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G H I J 12.5.1 RCTs Ali 2007 (1) 4 100 19 107 46.2% 0.23 [0.08, 0.64] + + + + + + + + + ? Ozkan 1999 24 282 17 217 53.8% 1.09 [0.60, 1.97] + ? + + + + + + + ? Subtotal (95% CI) 382 324 100.0% 0.52 [0.11, 2.49] Total events 28 36 Heterogeneity: Tau² = 1.08; Chi² = 6.74, df = 1 (P = 0.009); I² = 85% Test for overall effect: Z = 0.81 (P = 0.42)

0.1 0.2 0.5 1 2 5 10 Favours Povidone iodine Favours no treatment

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Risk of bias Randomized studies: see the forest plots Non-randomized studies (LOW: low risk of bias; MOD: moderate risk of bias; HIGH: high risk of bias; NI: no information)

Confounding Selection of participants Measurement of interventions Intended interventions Missing data Measurement of outcomes Reporting Overall Zanoni 1992 MOD LOW LOW LOW MOD LOW MOD MOD

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