WHO GUIDELINES FOR THE Treatment of Chlamydia trachomatis WHO Library Cataloguing-in-Publication Data WHO guidelines for the treatment of Chlamydia trachomatis. &RQWHQWV:HEDQQH['(YLGHQFHSURnjOHVDQGHYLGHQFHWRGHFLVLRQ framework -- Web annex E: Systematic reviews -- Web annex F: Summary RIFRQǍLFWVRILQWHUHVW 1.Chlamydia trachomatis. 2.Chlamydia Infections - drug therapy. 3.Sexually Transmitted Diseases. 4.Guideline. I.World Health Organization. ,6%1 1/0FODVVLnjFDWLRQ:& © World Health Organization 2016 All rights reserved. Publications of the World Health Organization are DYDLODEOHRQWKH:+2ZHEVLWH KWWSZZZZKRLQW RUFDQEHSXUFKDVHG IURP:+23UHVV:RUOG+HDOWK2UJDQL]DWLRQ$YHQXH$SSLD 1211 Geneva 27, Switzerland WHOID[HPDLOERRNRUGHUV#ZKRLQW  Requests for permission to reproduce or translate WHO publications – whether for sale or for non-commercial distribution– should be addressed to WHO Press through the WHO website (http://www.who.int/about/licensing/ FRS\ULJKWBIRUPLQGH[KWPO  The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. 7KHPHQWLRQRIVSHFLnjFFRPSDQLHVRURIFHUWDLQPDQXIDFWXUHUVšSURGXFWV does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. Printed by the WHO Document Production Services, Geneva, Switzerland WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS i

CONTENTS

Acknowledgements iii Abbreviations and acronyms iv Executive summary 1 Overview of the guidelines for the prevention, treatment and management of STIs 6 67,HSLGHPLRORJ\DQGEXUGHQ  :K\QHZJXLGHOLQHVIRUWKHSUHYHQWLRQWUHDWPHQWDQGPDQDJHPHQWRI67,V"  Approach to the revision of STI guidelines 8 References 9 WHO guidelines for the treatment of Chlamydia trachomatis 10 1. Introduction 10  (SLGHPLRORJ\EXUGHQDQGFOLQLFDOFRQVLGHUDWLRQV   &OLQLFDOSUHVHQWDWLRQ  Laboratory diagnosis 11 1.2 Rationale for new recommendations 11 1.3 Objectives 11 1.4 Target audience 11 1.5 Structure of the guidelines 11 2. Methods 12  *XLGHOLQH'HYHORSPHQW*URXS *'*   2.2 Questions and outcomes 12 2.3 Reviews of the evidence 12 2.4 Making recommendations 13  0DQDJHPHQWRIFRQǍLFWVRILQWHUHVW  3. Dissemination, updating and implementation of the guidelines 15 3.1 Dissemination 15 3.2 Updating the STI guidelines and user feedback 15 3.3 Implementation of the WHO guidelines for the treatment of C. trachomatis 15 Adaptation, implementation and monitoring 15  ,GHQWLI\LQJDQGSURFXULQJ67,GUXJV 

4. Recommendations for treatment of chlamydial infections 17 4.1 Uncomplicated genital chlamydia 17 Recommendation 1 17 4.2 Anorectal chlamydial infection 18 Recommendation 2 18 4.3 Chlamydial infection in pregnant women 19 Recommendation 3a 19 Recommendation 3b 19 Recommendation 3c 19  /\PSKRJUDQXORPDYHQHUHXP /*9    5HFRPPHQGDWLRQ  ii WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

&217(176 &217,18('

 2SKWKDOPLDQHRQDWRUXP   5HFRPPHQGDWLRQ   5HFRPPHQGDWLRQ  Recommendation 7 21 References 22 Annex A: STI guideline development teams 23 Annex B: Detailed methods for guideline development 32 Questions and outcomes 32 Review of the evidence 35 Applying the GRADE approach to making the recommendations 38 Annex C: Lists of references for reviewed evidence 39 Recommendation 1 39 5HFRPPHQGDWLRQ  Recommendation 3a, 3b, 3c 41 Recommendation 4 42 Recommendation 5 43 5HFRPPHQGDWLRQVDQG 

Web annexes available at: www.who.int/reproductivehealth/publications/rtis/chlamydia-treatment-guidelines/en/

:HEDQQH['(YLGHQFHSURnjOHVDQGHYLGHQFHWRGHFLVLRQIUDPHZRUNV Web annex E: Systematic reviews for chlamydia guidelines :HEDQQH[)6XPPDU\RIFRQǍLFWVRILQWHUHVW WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS iii

ACKNOWLEDGEMENTS

The Department of Reproductive Health and Research Members:

ABBREVIATIONS AND ACRONYMS

AIDS DFTXLUHGLPPXQHGHnjFLHQF\V\QGURPH

AMR antimicrobial resistance

DALY disability-adjusted life year

DFA GLUHFWǍXRUHVFHQWDQWLERG\

DOI declaration of interests

ELISA enzyme-linked immunosorbent assays

GDG Guideline Development Group

GRADE Grading of Recommendations Assessment, Development and Evaluation

GUD genital ulcer disease

HIV KXPDQLPPXQRGHnjFLHQF\YLUXV

HPV human papillomavirus

HRP UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction

+69 herpes simplex virus type 2

LGV lymphogranuloma venereum

MSH Management Sciences for Health

MSM men who have sex with men

NAATs QXFOHLFDFLGDPSOLnjFDWLRQWHVWV 1$$7V

PICO population, intervention, comparator, outcome

POCT point-of-care test

STI sexually transmitted infection

UNAIDS Joint United Nations Programme on HIV/AIDS

UNFPA United Nations Population Fund

UNICEF 8QLWHG1DWLRQV&KLOGUHQšV)XQG

WHO World Health Organization WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS 1

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

EXECUTIVE SUMMARY

Sexually transmitted infections (STIs) are a PDMRUSXEOLFKHDOWKSUREOHPZRUOGZLGHDNjHFWLQJ TXDOLW\RIOLIHDQGFDXVLQJVHULRXVPRUELGLW\ and mortality. STIs have a direct impact on UHSURGXFWLYHDQGFKLOGKHDOWKWKURXJKLQIHUWLOLW\ FDQFHUVDQGSUHJQDQF\FRPSOLFDWLRQVDQG WKH\KDYHDQLQGLUHFWLPSDFWWKURXJKWKHLUUROH LQIDFLOLWDWLQJVH[XDOWUDQVPLVVLRQRIKXPDQ LPPXQRGHnjFLHQF\YLUXV +,9 DQGWKXVWKH\ also have an impact on national and individual economies. More than a million STIs are acquired every day. In 2012, an estimated 357 million new FDVHVRIFXUDEOH67,V JRQRUUKRHDFKODP\GLD V\SKLOLVDQGWULFKRPRQLDVLV RFFXUUHGDPRQJ Ş\HDUROGVZRUOGZLGHLQFOXGLQJPLOOLRQ cases of chlamydial infection. 2 WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

Chlamydial infection, caused by Chlamydia trachomatis, OBJECTIVES is the most common bacterial STI and results in The objectives of these guidelines are: substantial morbidity and economic cost worldwide. Occurring most commonly among young sexually active • to provide evidence-based guidance on treatment adults, C. trachomatis causes cervicitis in women and of infection with C. trachomatisDQG urethritis in men, as well as extra-genital infections, • to support countries to update their national including rectal and oropharyngeal infections. guidelines for treatment of chlamydial infection. Asymptomatic infections are common in both men and women. Untreated chlamydial infection may cause severe complications in the upper reproductive METHODS tract, primarily in young women, including ectopic These guidelines were developed following the pregnancy, salpingitis and infertility. Lymphogranuloma PHWKRGVRXWOLQHGLQWKH:+2KDQGERRNIRU YHQHUHXP /*9 FDXVHGE\DPRUHLQYDVLYHVHURYDU guideline development. The Guideline Development of C. trachomatis, is increasingly prevalent among *URXS *'* LQFOXGHGLQWHUQDWLRQDO67,H[SHUWV PHQZKRKDYHVH[ZLWKPHQ 060 LQVRPHVHWWLQJV clinicians, researchers and programme managers. Maternal infection is associated with serious adverse The GDG prioritized questions and outcomes related outcomes in neonates, such as preterm birth, low birth to treatment of chlamydial infections to include weight, conjunctivitis, nasopharyngeal infection and in this update, and a methodologist and a team of pneumonia. C. trachomatis can be diagnosed by culture, systematic reviewers from McMaster University, the GLUHFWLPPXQRǍXRUHVFHQFHDVVD\V ')$V DQGHQ]\PH WHO Collaborating Centre for Evidence-Informed OLQNHGLPPXQRVRUEHQWDVVD\V (/,6$V EXWQXFOHLFDFLG Policy, independently conducted systematic reviews DPSOLnjFDWLRQWHVWV 1$$7V DUHSUHIHUUHGGXHWRWKHLU RIWKHHNjHFWLYHQHVVRIGLNjHUHQWWUHDWPHQWVIRU superior performance characteristics. chlamydial infections. The evidence was assessed using the Grading of Recommendations Assessment, RATIONALE FOR THE GUIDELINES 'HYHORSPHQWDQG(YDOXDWLRQ *5$'( DSSURDFKDQG SUHVHQWHGWRWKH*'*&RQǍLFWVRILQWHUHVWZHUH Since the publication of the World Health Organization managed according to WHO guidelines and declared :+2 *XLGHOLQHVIRUWKHPDQDJHPHQWRIVH[XDOO\ before the recommendations were discussed and WUDQVPLWWHGLQIHFWLRQVLQFKDQJHVLQWKH njQDOL]HG5HVHDUFKLPSOLFDWLRQVZHUHDOVRGHYHORSHG epidemiology of STIs and advancements in prevention, by the GDG. diagnosis and treatment necessitate changes in STI management. These guidelines provide updated treatment recommendations for common infections RECOMMENDATIONS caused by C. trachomatis based on the most recent The current guidelines provide nine treatment HYLGHQFHWKH\IRUPRQHRIVHYHUDOPRGXOHVRI recommendations for genital infections and LGV JXLGHOLQHVIRUVSHFLnjF67,V2WKHUPRGXOHVZLOOIRFXV caused by C. trachomatis. The recommendations on treatments for Neisseria gonorrhoeae JRQRUUKRHD  summarized in Table 1 apply to adults, adolescents KHUSHVVLPSOH[YLUXVW\SH +69JHQLWDOKHUSHV  Ş\HDUVRIDJH SHRSOHOLYLQJZLWK+,9DQG and Treponema pallidum V\SKLOLV ,QDGGLWLRQIXWXUH key populations, including sex workers, MSM and work will provide guidance for syphilis screening and WUDQVJHQGHUSHUVRQV6SHFLnjFUHFRPPHQGDWLRQVKDYH treatment of pregnant women, STI syndromic approach, also been developed for genital chlamydial infection in clinical management, STI prevention, and treatments of pregnant women and for prophylaxis and treatment other STIs. It is strongly recommended that countries of ophthalmia neonatorum caused by C. trachomatis. take updated global guidance into account as they establish standardized national protocols, adapting this guidance to the local epidemiological situation and antimicrobial susceptibility data. WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS 3

Table 1. Summary of recommendations for treatment of chlamydial infections

Recommendations Strength of recommendation and quality of evidence Uncomplicated genital chlamydia Recommendation 1 Conditional recommendation, The WHO STI guideline suggests treatment with one of the following options: moderate quality • azithromycin 1 g orally as a single dose evidence • GR[\F\FOLQHPJRUDOO\WZLFHDGD\IRUGD\V or one of these alternatives: • WHWUDF\FOLQHPJRUDOO\IRXUWLPHVDGD\IRUGD\V • HU\WKURP\FLQPJRUDOO\ four times a day for 7 days • RǍR[DFLQŞPJRUDOO\WZLFHDGD\IRUGD\V Remarks::KLOHJRRGSUDFWLFHEDVHGRQHYLGHQFHRIODUJHQHWEHQHnjWGLFWDWHVWKDW patients should be treated for chlamydial infection, the choice of treatment may depend on the convenience of dosage, the cost and quality of the medicines in GLNjHUHQWVHWWLQJVDQGHTXLW\FRQVLGHUDWLRQV:KHQKLJKYDOXHLVSODFHGRQUHGXFLQJ FRVWVGR[\F\FOLQHLQDVWDQGDUGGRVHPD\EHWKHEHVWFKRLFHZKHQKLJKYDOXH is placed on convenience, azithromycin in a single dose may be the best choice. A delayed-release doxycycline formulation may be an alternative to twice daily dosing of doxycycline, but the high cost of the delayed-release formulation may SURKLELWLWVXVH1RWHWKDWGR[\F\FOLQHWHWUDF\FOLQHDQGRǍR[DFLQDUHFRQWUDLQGLFDWHG LQSUHJQDQWZRPHQ VHHUHFRPPHQGDWLRQVbDŞF  Anorectal chlamydial infection Recommendation 2 Conditional recommendation, 7KH:+267,JXLGHOLQHVXJJHVWVWUHDWPHQWZLWKGR[\F\FOLQHPJRUDOO\WZLFHD low quality evidence GD\IRUGD\VRYHUD]LWKURP\FLQbJRUDOO\DVDVLQJOHGRVH Remarks: This recommendation applies to people with known anorectal infection and to people with suspected anorectal infections with genital co-infection. Clinicians should ask men, women and key populations (e.g. men who have sex ZLWKPHQWUDQVJHQGHUSHUVRQVDQGIHPDOHVH[ZRUNHUV DERXWDQDOVH[DQG treat accordingly. Doxycycline should not be used in pregnant women because RIDGYHUVHHNjHFWV VHHUHFRPPHQGDWLRQVbDŞF  4 WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

Genital chlamydial infection in pregnant women Recommendation 3a Strong recommendation, The WHO STI guideline recommends treatment with azithromycin over erythromycin. moderate quality evidence Recommendation 3b The WHO STI guideline suggests treatment with azithromycin over amoxicillin. Conditional recommendation, low quality evidence Recommendation 3c The WHO STI guideline suggests treatment with amoxicillin over erythromycin. Conditional recommendation, Dosages: low quality evidence • azithromycin 1 g orally as a single dose • DPR[LFLOOLQPJRUDOO\WKUHHWLPHVDGD\IRUGD\V • HU\WKURP\FLQPJRUDOO\ four times a day for 7 days. Remarks: $]LWKURP\FLQLVWKHnjUVWFKRLFHRIWUHDWPHQWEXWPD\QRWEHDYDLODEOH in some settings. Azithromycin is less expensive than erythromycin and since it is provided as a single dose, may result in better adherence and therefore better outcomes. Lymphogranuloma venereum (LGV) Recommendation 4 Conditional recommendation, very 7KH:+267,JXLGHOLQHVXJJHVWVWUHDWPHQWZLWKGR[\F\FOLQHPJRUDOO\WZLFHGDLO\ low quality evidence IRUGD\VRYHUD]LWKURP\FLQbJRUDOO\ZHHNO\IRUZHHNV Remarks: *RRGSUDFWLFHGLFWDWHVHNjHFWLYHWUHDWPHQWRI/*9LQSDUWLFXODUIRUPHQZKR have sex with men and for people living with HIV. When doxycycline is contraindicated, azithromycin should be provided. When neither treatment is available, erythromycin PJRUDOO\IRXUWLPHVDGD\IRUGD\VLVDQDOWHUQDWLYH'R[\F\FOLQHVKRXOGQRWEH XVHGLQSUHJQDQWZRPHQEHFDXVHRIDGYHUVHHNjHFWV VHHUHFRPPHQGDWLRQVbDŞF  Ophthalmia neonatorum Recommendation 5 Strong recommendation, very low quality evidence In neonates with chlamydial conjunctivitis, the WHO STI guideline recommends WUHDWPHQWZLWKD]LWKURP\FLQbPJNJGD\RUDOO\RQHGRVHGDLO\IRUGD\VRYHU HU\WKURP\FLQbPJNJGD\RUDOO\LQIRXUGLYLGHGGRVHVGDLO\IRUGD\V Remarks: This is a strong recommendation given the potential for the risk of pyloric stenosis with the use of erythromycin in neonates. In some settings, azithromycin suspension is not available and therefore erythromycin may be used. 6LGHHNjHFWVVKRXOGEHPRQLWRUHGZLWKWKHXVHRIHLWKHUPHGLFDWLRQ WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS 5

Recommendation 6 Strong recommendation, low quality evidence For all neonates, the WHO STI guideline recommends topical ocular prophylaxis for the prevention of gonococcal and chlamydial ophthalmia neonatorum.

Recommendation 7 Conditional recommendation, low For ocular prophylaxis, the WHO STI guideline suggests one of the following options quality evidence for topical application to both eyes immediately after birth: • tetracycline hydrochloride 1% eye ointment • HU\WKURP\FLQH\HRLQWPHQW • povidone iodine 2.5% solution • silver nitrate 1% solution • chloramphenicol 1% eye ointment. Remarks: 5HFRPPHQGDWLRQVDQGDSSO\WRWKHSUHYHQWLRQRIERWKFKODP\GLDODQG gonococcal ophthalmia neonatorum. Cost and local resistance to erythromycin, tetracycline and chloramphenicol in gonococcal infection may determine the choice of medication. Caution should be taken to avoid touching eye tissue when applying the topical treatment and to provide a water-based solution of povidone iodine. '212786($/&2+2/%$6('329,'21(,2',1(62/87,21 6 WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

OVERVIEW OF THE GUIDELINES FOR THE PREVENTION, TREATMENT AND MANAGEMENT OF STIs

STI EPIDEMIOLOGY AND BURDEN 6H[XDOO\WUDQVPLWWHGLQIHFWLRQV 67,V DUHDPDMRU Both ulcerative and non-ulcerative STIs are associated SXEOLFKHDOWKSUREOHPZRUOGZLGHDNjHFWLQJTXDOLW\ with a several-fold increased risk of transmitting or of life and causing serious morbidity and mortality. acquiring HIV (7, 8). Infections causing genital ulcers STIs have a direct impact on reproductive and child DUHDVVRFLDWHGZLWKWKHKLJKHVW+,9WUDQVPLVVLRQULVN health through infertility, cancers and pregnancy in addition to curable ulcer-causing STIs (e.g. syphilis complications, and they have an indirect impact through DQGFKDQFURLG KLJKO\SUHYDOHQW+69LQIHFWLRQV their role in facilitating sexual transmission of human substantially increase that risk (9). Non-ulcerative LPPXQRGHnjFLHQF\YLUXV +,9 DQGWKXVWKH\DOVRKDYH STIs, such as gonorrhoea, chlamydia and trichomoniasis, an impact on national and individual economies. The have been shown to increase HIV transmission through prevention and control of STIs is an integral component genital shedding of HIV (10). Treating STIs with the of comprehensive sexual and reproductive health right medicines at the right time is necessary to reduce services that are needed to attain the related targets HIV transmission and improve sexual and reproductive XQGHU6XVWDLQDEOH'HYHORSPHQW*RDO 6'* 1R health (11)(NjRUWVVKRXOGWKHUHIRUHEHWDNHQWR (Ensure healthy lives and promote well-being for all at all strengthen STI diagnosis and treatment. DJHV LQFOXGLQJWDUJHWŞWRHQGSUHYHQWDEOHGHDWKV RIQHZERUQVDQGFKLOGUHQXQGHU\HDUVRIDJHWDUJHW WHY NEW GUIDELINES FOR THE PREVENTION, – to end the epidemics of AIDS and other communicable GLVHDVHVWDUJHWŞWRUHGXFHSUHPDWXUHPRUWDOLW\ TREATMENT AND MANAGEMENT OF STIs? from noncommunicable diseases and promote mental Since the publication of the World Health Organization KHDOWKDQGZHOOEHLQJWDUJHWŞWRHQVXUHXQLYHUVDO :+2 *XLGHOLQHVIRUWKHPDQDJHPHQWRIVH[XDOO\ DFFHVVWRVH[XDODQGUHSURGXFWLYHKHDOWKFDUHVHUYLFHV WUDQVPLWWHGLQIHFWLRQVLQFKDQJHVLQWKH and target 3.8 – to achieve universal health coverage. epidemiology of STIs and advancements in prevention, Worldwide, more than a million curable STIs are diagnosis and treatment necessitate changes in STI DFTXLUHGHYHU\GD\,QWKHUHZHUHDQHVWLPDWHG management. Indeed, 88% of countries have updated 357 million new cases of curable STIs among adults aged their national STI guidelines or recommendations since 15–49 years worldwide: 131 million cases of chlamydia, (12)8SGDWHGJOREDOJXLGDQFHUHǍHFWLQJWKHPRVW PLOOLRQFDVHVRIJRQRUUKRHDPLOOLRQFDVHVRI recent evidence and expert opinion is therefore needed syphilis and 142 million cases of trichomoniasis (1). to assist countries to incorporate new developments The prevalence of some viral STIs is similarly high, with LQWRDQHNjHFWLYHQDWLRQDODSSURDFKWRWKHSUHYHQWLRQ an estimated 417 million people infected with herpes and treatment of STIs. VLPSOH[YLUXVW\SH +69 (2), and approximately There is an urgent need to update global treatment 291 million women harbouring human papillomavirus UHFRPPHQGDWLRQVWRHNjHFWLYHO\UHVSRQGWRWKH +39 DWDQ\SRLQWLQWLPH(3). The burden of STIs FKDQJLQJDQWLPLFURELDOUHVLVWDQFH $05 SDWWHUQV varies by region and gender, and is greatest in of STIs, especially for Neisseria gonorrhoeae. resource-poor countries. (NjHFWLYHWUHDWPHQWSURWRFROVWKDWWDNHLQWRDFFRXQW When left undiagnosed and untreated, curable STIs global and local resistance patterns are essential to can result in serious complications and sequelae, reduce the risk of further development of AMR. VXFKDVSHOYLFLQǍDPPDWRU\GLVHDVHLQIHUWLOLW\ High-level gonococcal resistance to quinolones, ectopic pregnancy, miscarriage, fetal loss and DSUHYLRXVO\UHFRPPHQGHGnjUVWOLQHWUHDWPHQW FRQJHQLWDOLQIHFWLRQV,QDQHVWLPDWHG is widespread and decreased susceptibility to the PDWHUQDOV\SKLOLVLQIHFWLRQVUHVXOWHGLQDGYHUVH H[WHQGHGVSHFWUXP WKLUGJHQHUDWLRQ FHSKDORVSRULQV pregnancy outcomes, including stillbirths, neonatal DQRWKHUnjUVWOLQHWUHDWPHQWIRUJRQRUUKRHDLVRQ deaths, preterm births and infected infants (4). the rise (13). Low-level resistance to Trichomonas Curable STIs accounted for the loss of nearly 11 million vaginalis has also been reported for nitroimidazoles, GLVDELOLW\DGMXVWHGOLIH\HDUV '$/tetracyclines and macrolides in the treatment of gender-based violence (6). Chlamydia trachomatis (14, 15). WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS 7

A WHO STI expert consultation recommended 1HZUDSLGSRLQWRIFDUHGLDJQRVWLFWHVWV 32&7V DUH XSGDWLQJWKH:+2JXLGHOLQHVIRUWKHnjUVWDQG changing STI management. Rapid syphilis diagnostic second-line treatments for C. trachomatis, increasing tests are now widely available, making syphilis screening WKHGRVDJHRIFHIWULD[RQHWRPJIRUWUHDWPHQW more widely accessible and allowing for earlier initiation of N. gonorrhoeae with continued monitoring of RIWUHDWPHQWIRUWKRVHZKRWHVWSRVLWLYH(NjRUWVDUH antimicrobial susceptibility, and consideration of under way to develop POCTs for other STIs that will ZKHWKHUD]LWKURP\FLQ JVLQJOHGRVH VKRXOGEH augment syndromic management of symptomatic recommended in early syphilis (16). cases and increase the ability to identify asymptomatic infections (12). Updated guidelines are needed that The epidemiology of STIs is changing, with viral incorporate rapid tests into syndromic management pathogens becoming more prevalent than bacterial of STIs and provide algorithms for testing and HWLRORJLHVIRUVRPHFRQGLWLRQVWKLVPHDQVWKDWXSGDWHG screening (16). information is required to inform locally appropriate prevention and treatment strategies. An increasing Although recent technological advances in diagnostics, proportion of genital ulcers are now due to viral WKHUDSHXWLFVYDFFLQHVDQGEDUULHUPHWKRGVRNjHUEHWWHU infections as previously common bacterial infections, opportunities for the prevention and care of STIs, access such as chancroid, approach elimination in many to these technologies is still limited, particularly in areas countries (16, 17). As recommended during the STI where the burden of infection is highest. For optimal expert consultation, treatment guidelines for genital HNjHFWLYHQHVVJOREDOJXLGHOLQHVIRUWKHPDQDJHPHQW XOFHUGLVHDVH *8' VKRXOGEHXSGDWHGWRLQFOXGH+69 of STIs need to include approaches for settings with treatment and a longer treatment duration for HSV-2 limited access to modern technologies, as well as for should be explored. In addition, suppressive therapy settings in which these technologies are available. for HSV-2 should be considered in areas with high HIV It is strongly recommended that countries take prevalence (16). The chronic, lifelong nature of viral updated global guidance into account as they establish infections also requires that renewed attention be paid standardized national protocols, adapting this guidance WRGHYHORSLQJHNjHFWLYHSUHYHQWLRQVWUDWHJLHVLQFOXGLQJ to the local epidemiological situation and antimicrobial expanding accessibility to available vaccines for HPV susceptibility data. Standardization ensures that all and development of new vaccines for HSV-2. patients receive adequate treatment at every level ,QWKH:+2JXLGHOLQHVDV\QGURPLFDSSURDFK of health-care services, optimizes the training and was recommended for the management of STIs. supervision of health-care providers and facilitates The approach guides the diagnosis of STIs based on procurement of medicines. It is recommended that LGHQWLnjFDWLRQRIFRQVLVWHQWJURXSVRIV\PSWRPVDQG QDWLRQDOJXLGHOLQHVIRUWKHHNjHFWLYHPDQDJHPHQWRI easily recognized signs and indicates treatment for STIs be developed in close consultation with local STI, the majority of organisms that may be responsible public health and laboratory experts. for producing the syndrome. The syndromic management algorithms need to be updated in response to the changing situation. In addition to changes to the GUD algorithm, other syndromes need to be re-evaluated, particularly vaginal discharge. The approach to syndromes for key populations also needs to be updated. For example, addition of a syndromic management algorithm for anorectal LQIHFWLRQVLQPHQZKRKDYHVH[ZLWKPHQ 060 DQG sex workers is urgently needed since a substantial number of these infections go unrecognized and untreated in the absence of guidelines (16). 8 WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

APPROACH TO THE REVISION OF STI GUIDELINES 7RHQVXUHHNjHFWLYHWUHDWPHQWIRUDOO67,V:+2SODQV a phased approach to updating the STI guidelines to address a range of infections and issues. Four phases have been proposed by the WHO STI Secretariat and agreed upon by the STI Guideline Development Group *'* PHPEHUV VHH$QQH[$IRUPHPEHUVRIWKHVH JURXSV 7DEOHVXPPDUL]HVWKHSURSRVHGSKDVHV and timeline.

Table 2: Phases for development of the STI guidelines

Phases Topics Timeframe Phase 1 7UHDWPHQWRIVSHFLnjF67,VChlamydia trachomatis 1RYHPEHUŞ$SULO FKODP\GLD Neisseria gonorrhoeae JRQRUUKRHD +69  JHQLWDOKHUSHV DQGTreponema pallidum V\SKLOLV

Syphilis screening and treatment of pregnant women

STI syndromic approach 0D\Ş'HFHPEHU Clinical management package  Phase 2 STI prevention: condoms, behaviour change Ş communication, biomedical interventions and vaccines Phase 3 7UHDWPHQWRIVSHFLnjF67,VDQGUHSURGXFWLYHWUDFW Ş LQIHFWLRQV 57,V QRWDGGUHVVHGLQ3KDVH7ULFKRPRQDV YDJLQDOLV WULFKRPRQLDVLV EDFWHULDOYDJLQRVLV&DQGLGD DOELFDQV FDQGLGLDVLV +HPRSKLOXVGXFUH\L FKDQFURLG  .OHEVLHOODJUDQXORPDWLV GRQRYDQRVLV KXPDQ SDSLOORPDYLUXV +39JHQLWDOZDUWVFHUYLFDOFDQFHU  6DUFRSWHVVFDELHL VFDELHV DQG3KWKLUXVSXELV SXELFOLFH Phase 4 STI laboratory diagnosis and screening Ş

Phase 1 will focus on treatment recommendations In addition, guidelines for the STI syndromic approach IRUVSHFLnjF67,VDVZHOODVRWKHULPSRUWDQWDQGXUJHQW and a clinical management package will be developed STI issues. Recommendations for the treatment of later in Phase 1. Phase 2 will focus on guidelines for STI VSHFLnjFLQIHFWLRQVZLOOEHGHYHORSHGDQGSXEOLVKHG prevention. The independent Phase 1 and 2 modules as independent modules: will later be consolidated into one document and published as comprehensive WHO guidelines on STI • Chlamydia trachomatis FKODP\GLD case management. Phase 3 will address treatment of • Neisseria gonorrhoeae JRQRUUKRHD additional infections, including Trichomonas vaginalis • +69 JHQLWDOKHUSHV WULFKRPRQLDVLV EDFWHULDOYDJLQRVLV&DQGLGDDOELFDQV • Treponema pallidum V\SKLOLV FDQGLGLDVLV +HPRSKLOXVGXFUH\L FKDQFURLG .OHEVLHOOD JUDQXORPDWLV GRQRYDQRVLV +39 JHQLWDOZDUWVFHUYLFDO • Syphilis screening and treatment of pregnant women. FDQFHU 6DUFRSWHVVFDELHL VFDELHV DQG3KWKLUXVSXELV SXELFOLFH 3KDVHZLOOSURYLGHJXLGDQFHRQODERUDWRU\ diagnosis and screening of STIs. WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS 9

REFERENCES

1. Newman L, Rowley J, Vander Hoorn S, Wijesooriya NS, Unemo M, Low N et al. Global estimates of the SUHYDOHQFHDQGLQFLGHQFHRIIRXUFXUDEOHVH[XDOO\WUDQVPLWWHGLQIHFWLRQVLQEDVHGRQV\VWHPDWLF UHYLHZDQGJOREDOUHSRUWLQJ3/R62QH  HGRLMRXUQDOSRQH

2. Looker KJ, Magaret AS, Turner KME, Vickerman P, Gottlieb SL, Newman LM. Global estimates of SUHYDOHQWDQGLQFLGHQWKHUSHVVLPSOH[YLUXVW\SHLQIHFWLRQVLQ3/R62QH  H GRLMRXUQDOSRQH

 'H6DQMRV«6'LD]0&DVWHOOVDJX«;&OLNjRUG*%UXQL/0X³R]1%RVFK);:RUOGZLGHSUHYDOHQFH and genotype distribution of cervical human papillomavirus DNA in women with normal cytology: DPHWDDQDO\VLV/DQFHW,QIHFW'LV  Ş

4. Wijesooriya NS, Rochat RW, Kamb ML, Turlapati P, Broutet N, Newman L. Declines in maternal and FRQJHQLWDOV\SKLOLVIURPWRSURJUHVVWRZDUGVHOLPLQDWLRQRIPRWKHUWRFKLOGWUDQVPLVVLRQ RIV\SKLOLV/DQFHW*OREDO+HDOWK LQSUHVV 

5. Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C et al. Disability-adjusted life \HDUV '$/

 *RWWOLHE6//RZ11HZPDQ/0%RODQ*.DPE0%URXWHW17RZDUGJOREDOSUHYHQWLRQRIVH[XDOO\ WUDQVPLWWHGLQIHFWLRQV 67,V WKHQHHGIRU67,YDFFLQHV9DFFLQH  ŞGRLM YDFFLQH

 :DVVHUKHLW-1(SLGHPLRORJLFDOV\QHUJ\LQWHUUHODWLRQVKLSVEHWZHHQKXPDQLPPXQRGHnjFLHQF\YLUXV LQIHFWLRQVDQGRWKHUVH[XDOO\WUDQVPLWWHGGLVHDVHV6H[7UDQVP'LV  Ş

8. Sexton J, Garnett G, Røttingen J-A. Metaanalysis and metaregression in interpreting study variability in the impact of sexually transmitted diseases on susceptibility to HIV infection. Sex Transm Dis.   Ş

9. \Glynn JR, Biraro S, Weiss HA. Herpes simplex virus type 2: a key role in HIV incidence. AIDS.   ŞGRL4$'EHHH

 -RKQVRQ/)/HZLV'$7KHHNjHFWRIJHQLWDOWUDFWLQIHFWLRQVRQ+,9VKHGGLQJLQWKHJHQLWDO WUDFWDV\VWHPDWLFUHYLHZDQGPHWDDQDO\VLV6H[7UDQVP'LV  ŞGRL 2/4EHG

11. Cohen MS. Classical sexually transmitted diseases drive the spread of HIV-1: back to the future. -,QIHFW'LV  ŞGRLLQIGLVMLV

12. Progress report of the implementation of the global strategy for prevention and control of sexually WUDQVPLWWHGLQIHFWLRQVŞ*HQHYD:RUOG+HDOWK2UJDQL]DWLRQ KWWSDSSVZKRLQW LULVELWVWUHDPBHQJSGIDFFHVVHG0D\ 

13. Ndowa FJ, Ison CA, Lusti-Narasimhan M. Gonococcal antimicrobial resistance: the implications for SXEOLFKHDOWKFRQWURO6H[7UDQVP,QIHFW 6XSSO LYŞGRLVH[WUDQV

14. Gottlieb SL, Low N, Newman LM, Bolan G, Kamb M, Broutet N. Toward global prevention of sexually WUDQVPLWWHGLQIHFWLRQV 67,V WKHQHHGIRU67,YDFFLQHV9DFFLQH  ŞGRLM YDFFLQH

 0DEH\'(SLGHPLRORJ\RIVH[XDOO\WUDQVPLWWHGLQIHFWLRQVZRUOGZLGH0HGLFLQH  Ş GRLMPSPHG

 5HSRUWRIWKHH[SHUWFRQVXOWDWLRQDQGUHYLHZRIWKHODWHVWHYLGHQFHWRXSGDWHJXLGHOLQHVIRUWKH PDQDJHPHQWRIVH[XDOO\WUDQVPLWWHGLQIHFWLRQV*HQHYD:RUOG+HDOWK2UJDQL]DWLRQ :+2 5+5KWWSDSSVZKRLQWLULVELWVWUHDP:+2B5+5BBHQJSGI DFFHVVHG0D\ 

 6WHHQ5(UDGLFDWLQJFKDQFURLG%XOO:RUOG+HDOWK2UJDQ  Ş 10 WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

CLINICAL PRESENTATION Genital infections due to C. trachomatis are DV\PSWRPDWLFLQDSSUR[LPDWHO\RIZRPHQDQG  RIPHQ (2). Symptoms of uncomplicated chlamydial infection in women include abnormal vaginal discharge, dysuria, and post-coital and intermenstrual bleeding. Common clinical signs on speculum examination include cervical friability and discharge. Symptomatic INTRODUCTION men usually present with urethral discharge and dysuria, sometimes accompanied by testicular pain. If left untreated, most genital infections will resolve spontaneously with no sequelae but they may result in severe complications, mainly in young women. Infection can ascend to the upper reproductive tract and can FDXVHSHOYLFLQǍDPPDWRU\GLVHDVHHFWRSLFSUHJQDQF\ salpingitis and tubal factor infertility in women (3) and epididymitis in men (4). The risk of complications may increase with repeated infection. Infections at non-genital sites are common. Rectal infection may manifest as a rectal discharge, rectal pain or blood in the stools, but is asymptomatic in most cases. Oropharyngeal infections can manifest as pharyngitis and mild sore throat, but symptoms are rare. Chlamydial infection in pregnancy is associated with 1.1 EPIDEMIOLOGY, BURDEN AND CLINICAL preterm birth and low birth weight. Infants of mothers CONSIDERATIONS with chlamydia can be infected at delivery, resulting in Chlamydial infection, caused by Chlamydia trachomatis, neonatal conjunctivitis and/or nasopharyngeal infection is the most common bacterial sexually transmitted (3). Symptoms of ophthalmia include ocular discharge LQIHFWLRQ 67, DQGUHVXOWVLQVXEVWDQWLDOPRUELGLW\ and swollen eyelids. In newborns, nasopharyngeal and economic cost worldwide. The World Health infection can lead to pneumonitis. 2UJDQL]DWLRQ :+2 HVWLPDWHVWKDWLQ LGV, caused by a more invasive serovar of million new cases of chlamydia occurred among adults C. trachomatisDNjHFWVWKHVXEPXFRVDOFRQQHFWLYH and adolescents aged 15–49 years worldwide, with a tissue and can spread to regional lymph nodes. JOREDOLQFLGHQFHUDWHRISHUIHPDOHVDQG It commonly presents as a unilateral, tender SHUPDOHV7KHHVWLPDWHGPLOOLRQSUHYDOHQW inguinal or femoral lymph node and a genital ulcer cases of chlamydia result in an overall prevalence of or papule (5). Anorectal exposure may result in 4.2% for females and 2.7% for males, with the highest proctitis, rectal discharge, pain, constipation or prevalence in the WHO Region of the Americas and the tenesmus. Left untreated, LGV can lead to rectal :+2:HVWHUQ3DFLnjF5HJLRQ(1). In many countries, the njVWXODRUVWULFWXUH incidence of chlamydia is highest among adolescent girls aged 15–19 years, followed by young women aged Ş\HDUV7KHWKUHHELRYDUVRIC. trachomatis, each consisting of several serovars or genotypes, cause genital infections, lymphogranuloma venereum (LGV: DJHQLWDOXOFHUGLVHDVH>*8'@WKDWDNjHFWVO\PSKRLG WLVVXH DQGWUDFKRPD H\HLQIHFWLRQ  WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS 11

LABORATORY DIAGNOSIS 1.4 TARGET AUDIENCE There have been major developments in the These guidelines are primarily intended for health-care diagnosis of C. trachomatisLQWKHODVWŞ\HDUV SURYLGHUVDWDOOOHYHOV SULPDU\VHFRQGDU\DQGWHUWLDU\  Although C. trachomatis can be diagnosed by of the health-care system involved in the treatment FXOWXUHGLUHFWLPPXQRǍXRUHVFHQFHDVVD\V ')$V  and management of people with STIs in low-, middle- and laboratory-based and point-of-care enzyme- and high-income countries. They are also intended for OLQNHGLPPXQRVRUEHQWDVVD\V (/,6$V QXFOHLFDFLG individuals working in sexual and reproductive health DPSOLnjFDWLRQWHVWV 1$$7V DUHVWURQJO\UHFRPPHQGHG programmes, such as HIV/AIDS, family planning, due to their superior performance characteristics. maternal and child health and adolescent health, to 1$$7VDUHKLJKO\VHQVLWLYHDQGVSHFLnjFDQGFDQEH ensure appropriate STI diagnosis and management. used for a wide range of samples, including urine and The guidelines are also useful for policy-makers, vulvovaginal, cervical and urethral swabs. Several PDQDJHUVSURJUDPPHRǎFHUVDQGRWKHUSURIHVVLRQDOV FRPPHUFLDO1$$7VXVLQJGLNjHUHQWWHFKQRORJLHVDUH in the health sector who are responsible for available. The increased sensitivity of NAATs compared implementing STI management interventions with other diagnostic tests, such as culture and antigen at regional, national and subnational levels. GHWHFWLRQPHWKRGV ')$DQG(/,6$ DOORZVWHVWLQJ of non-invasive specimens, which can be collected conveniently at the primary level of care. Commercially 1.5 STRUCTURE OF THE GUIDELINES available NAATs are not yet licensed for the diagnosis of extra-genital samples but have shown to be reliable These guidelines provide evidence-based for detection of chlamydial infection in rectal and UHFRPPHQGDWLRQVIRUWKHWUHDWPHQWRIVSHFLnjF pharyngeal swabs. Several commercially available tests clinical conditions caused by C. trachomatis. for chlamydia are combined with tests for gonorrhoea. These guidelines provide direction for countries as Further information is available in the WHO publication WKH\GHYHORSQDWLRQDOWUHDWPHQWUHFRPPHQGDWLRQV on laboratory diagnosis of STIs including HIV (6). however, national guidelines should also take into account the local pattern of AMR, as well as health service capacity and resources. 1.2 RATIONALE FOR NEW RECOMMENDATIONS Updated treatment recommendations based on The guidelines for treatment of chlamydial infections the most recent evidence are included for the need to be updated to respond to the changes in most important common conditions caused by epidemiology and antimicrobial susceptibility for C. trachomatis. Recommendations were not updated chlamydia that have occurred since the previous WHO for rare conditions and other conditions for which Guidelines for the management of sexually transmitted no new information has become available since the LQIHFWLRQVZHUHSXEOLVKHGLQ(7). LGV is increasingly :+267,JXLGHOLQHVZHUHLVVXHG SUHYDOHQWDPRQJPHQZKRKDYHVH[ZLWKPHQ 060 LQ Treatment recommendations for the following some settings, and treatment failure has been reported conditions caused by C. trachomatis are included ZLWKWHWUDF\FOLQHDQGPDFUROLGHVLQDSSUR[LPDWHO\ in these guidelines: of cases (8)0RUHRYHUWKH:+267,JXLGHOLQHVDUH the only international guidelines that still recommend • uncomplicated genital infections treating chlamydial infections with amoxicillin or • anorectal infections tetracycline. As recommended by the WHO STI • uncomplicated genital infections in pregnant women H[SHUWFRQVXOWDWLRQLQWKHnjUVWDQGVHFRQGOLQH treatment recommendations for C. trachomatis needed • LGV to be reviewed and revised based on the most recent • RSKWKDOPLDQHRQDWRUXP WUHDWPHQWDQGSURSK\OD[LV  available evidence.

1.3 OBJECTIVES The objectives of these guidelines are: • to provide evidence-based guidance on treatment of infection with C. trachomatisDQG • to support countries to update their national guidelines for treatment of chlamydial infection. 12 WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

2.2 QUESTIONS AND OUTCOMES ,Q'HFHPEHUWKHnjUVW*'*PHHWLQJZDVKHOG to identify and agree on the key PICO (population, LQWHUYHQWLRQFRPSDUDWRURXWFRPH TXHVWLRQVWKDW formed the basis for the systematic reviews and the  recommendations. Following this meeting, a survey of GDG members was conducted to prioritize the questions and outcomes according to clinical relevance DQGLPSRUWDQFH6L[3,&2TXHVWLRQVZHUHLGHQWLnjHGIRU the update on the treatment of genital and anorectal METHODS chlamydial infections, treatment of LGV, and prevention DQGWUHDWPHQWRIQHRQDWDORSKWKDOPLD VHH$QQH[%  These questions pertained to adults and other special populations, namely adolescents, pregnant women, people living with HIV, and populations at high risk of acquiring and transmitting STIs, such as men ZKRKDYHVH[ZLWKPHQ 060 DQGVH[ZRUNHUV Only outcomes that were ranked as critical or important to patients and decision-making were included: clinical DQGPLFURELRORJLFDOFXUHDQGDGYHUVHHNjHFWV LQFOXGLQJ PDWHUQDODQGIHWDOHNjHFWVLQSUHJQDQWZRPHQ 

2.3 REVIEWS OF THE EVIDENCE The systematic reviews for each priority question were conducted by McMaster University, the WHO Collaborating Centre for Evidence-Informed Policy. 7KHVHJXLGHOLQHVZHUHGHYHORSHGIROORZLQJWKH Evidence for desirable and undesirable outcomes, methods outlined in the 2014 edition of the patient values and preferences, resources, acceptability, :+2KDQGERRNIRUJXLGHOLQHGHYHORSPHQW(9) equity and feasibility were reviewed from published and (see Annex B for a detailed description). unpublished literature. Comprehensive searches for previously conducted systematic reviews, randomized controlled trials and non-randomized studies were 2.1 GUIDELINE DEVELOPMENT GROUP (GDG) SHUIRUPHGIURP0DUFKWR2FWREHU$GGLWLRQDO searches were conducted to identify studies on patient To update the WHO guidelines for the prevention, values and preferences (e.g. qualitative research treatment and management of STIs, a GDG was GHVLJQV DQGUHVRXUFHLPSOLFDWLRQV HJFRVWRI established, comprising 33 international STI experts, LQWHUYHQWLRQVFRVWŞEHQHnjWDQGFRVWŞHNjHFWLYHQHVV including clinicians, researchers and programme VWXGLHV 7ZRPHPEHUVRIWKH6\VWHPDWLF5HYLHZ7HDP PDQDJHUV $QQH[$ $FRUHVXEJURXSWRIRFXVRQ screened studies, extracted and analysed the data, the guidelines related to chlamydia was created and assessed the quality/certainty of the evidence within the GDG, to provide more intensive feedback using the Grading of Recommendations Assessment, WKURXJKRXWWKHSURFHVV $QQH[$ 7KH*'* 'HYHORSPHQWDQG(YDOXDWLRQ *5$'( DSSURDFK1 participated in meetings and teleconferences to prioritize the questions to be addressed, discuss the HYLGHQFHUHYLHZVDQGnjQDOL]HWKHUHFRPPHQGDWLRQV 7KH*'*UHYLHZHGDQGDSSURYHGWKHnjQDOYHUVLRQ of the guidelines.

1 For more information, see: http://www.gradeworkinggroup.org/ WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS 13

The quality/certainty of the evidence was assessed of the recommendations. Following the meeting, the at four levels: UHFRPPHQGDWLRQVZHUHnjQDOL]HGYLDWHOHFRQIHUHQFH DQGnjQDODSSURYDOZDVREWDLQHGIURPDOO*'*PHPEHUV • +LJKŞ:HDUHYHU\FRQnjGHQWWKDWWKHWUXHHNjHFWOLHV electronically. These guidelines were subsequently FORVHWRWKDWRIWKHHVWLPDWHRIWKHHNjHFW written up in full and then peer reviewed. The External • 0RGHUDWHŞ:HDUHPRGHUDWHO\FRQnjGHQWLQWKHHNjHFW Review Group approved the methods and agreed with HVWLPDWHWKHWUXHHNjHFWLVOLNHO\WREHFORVHWRWKH the recommendations made by the GDG (members HVWLPDWHRIWKHHNjHFWEXWWKHUHLVDSRVVLELOLW\WKDW DUHOLVWHGLQ$QQH[$  LWLVVXEVWDQWLDOO\GLNjHUHQW According to the GRADE approach, the strength • /RZŞ2XUFRQnjGHQFHLQWKHHNjHFWHVWLPDWHLVOLPLWHG of each recommendation was rated as either WKHWUXHHNjHFWPD\EHVXEVWDQWLDOO\GLNjHUHQWIURPWKH strong or conditional. Strong recommendations are HVWLPDWHRIWKHHNjHFW presented using the wording “The WHO STI guideline • 9HU\ORZŞ:HKDYHYHU\OLWWOHFRQnjGHQFHLQWKHHNjHFW recommends…”, while conditional recommendations HVWLPDWHWKHWUXHHNjHFWLVOLNHO\WREHVXEVWDQWLDOO\ are worded as “The WHO STI guideline suggests…” GLNjHUHQWIURPWKHHVWLPDWHRIHNjHFW throughout the guidelines. The implications of the In addition, the direct costs of medicines were estimated GLNjHULQJVWUHQJWKVRIUHFRPPHQGDWLRQVIRUSDWLHQWV XVLQJWKH0DQDJHPHQW6FLHQFHVIRU+HDOWK 06+  clinicians and policy-makers are explained in detail International drug price indicator guide (10). References in Table 3. for all the reviewed evidence are listed in Annex C. All evidence was summarized in GRADE evidence SURnjOHVDQGLQHYLGHQFHWRGHFLVLRQWDEOHV VHH:HE DQQH[HV'DQG( 

2.4 MAKING RECOMMENDATIONS Recommendations were developed during a second PHHWLQJRIWKH*'*LQ2FWREHUZKLFKZDV facilitated by two co-chairs, one with expertise in GRADE and the other with clinical STI expertise. The methodologist presented the GRADE evidence SURnjOHVDQGHYLGHQFHWRGHFLVLRQIUDPHZRUNVDWWKH meeting. When formulating the recommendations, the GDG considered and discussed the desirable and XQGHVLUDEOHHNjHFWVRIWKHLQWHUYHQWLRQVWKHYDOXH placed on the outcomes, the associated costs and use of resources, the acceptability of the interventions to DOOVWDNHKROGHUV LQFOXGLQJSHRSOHDNjHFWHGE\67,V  the impact on health equity and the feasibility of implementation. Treatments were judged according WRWKHDERYHFULWHULDDQGnjQDOGHFLVLRQVDQGJXLGHOLQH recommendations were agreed. The discussion was facilitated by the co-chairs with the goal of reaching consensus across the GDG. Disagreements among the GDG members were noted in the evidence-to-decision framework for each judgement. In the case of failure to reach consensus for a recommendation, the planned procedure was for the GDG to take a vote and record the results. However, no votes were taken because the GDG reached consensus during discussion for all 14 WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

Table 3. Implications of strong and conditional recommendations using the GRADE approach

Implications Strong recommendation Conditional recommendation “The WHO STI guideline recommends…” “The WHO STI guideline suggests…” For patients Most individuals in this situation would want The majority of individuals in this situation the recommended course of action, and only would want the suggested course of action, a small proportion would not. but many would not. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences. For clinicians Most individuals should receive the &OLQLFLDQVVKRXOGUHFRJQL]HWKDWGLNjHUHQW recommended course of action. choices will be appropriate for each individual and that clinicians must help each individual Adherence to this recommendation according arrive at a management decision consistent to the guidelines could be used as a quality ZLWKWKHLQGLYLGXDOšVYDOXHVDQGSUHIHUHQFHV criterion or performance indicator. Decision aids may be useful to help individuals make decisions consistent with their values and preferences. For policy- The recommendation can be adopted as policy Policy-making will require substantial debate makers in most situations. and involvement of various stakeholders.

2.5 MANAGEMENT OF CONFLICTS OF INTEREST 0DQDJHPHQWRIFRQǍLFWVRILQWHUHVWZDVDNH\SULRULW\ throughout the process of guideline development. WHO JXLGHOLQHVIRUGHFODUDWLRQRILQWHUHVWV '2, IRU:+2 experts were implemented (11). DOI statements were obtained from all GDG members prior to assuming their roles in the group. At the GDG meetings (December DQG2FWREHU WKHPHPEHUVGLVFORVHG their interests, if any, at the beginning of the meeting. Their DOI statements are summarized in Web annex F. After analysing each DOI, the STI team concluded WKDWQRPHPEHUKDGnjQDQFLDORUFRPPHUFLDOLQWHUHVWV UHODWHGWR67,WUHDWPHQW2WKHUQRWLnjHGLQWHUHVWVZHUH PLQRUWKH\ZHUHHLWKHUQRWUHODWHGWR67,RUZHUHQRQ commercial grants or interests. The STI team concluded WKDWWKHUHZHUHQRVLJQLnjFDQWFRQǍLFWVRILQWHUHVWWKDW would exclude any member from participating fully in the guideline development process. Therefore, options for conditional participation, partial or total exclusion of any GDG member were not discussed. WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS 15

$OOOHYHOVRI:+2 KHDGTXDUWHUVUHJLRQDORǎFHVDQG FRXQWU\RǎFHV ZLOOZRUNZLWKUHJLRQDODQGQDWLRQDO partners – including the United Nations Population )XQG 81)3$ WKH8QLWHG1DWLRQV&KLOGUHQšV)XQG 81,&() WKH-RLQW8QLWHG3URJUDPPHRQ+,9$,'6 81$,'6 QRQJRYHUQPHQWDORUJDQL]DWLRQV 1*2V DQG  other agencies implementing sexual and reproductive health and STI services – to ensure that the new DISSEMINATION, recommendations are integrated and implemented in sexual and reproductive health, family planning, and UPDATING AND maternal, neonatal, child and adolescent health services. Reference to this document will be made within other IMPLEMENTATION OF relevant WHO guidelines. These guidelines will also be THE GUIDELINES disseminated at major conferences related to STIs and HIV and the aforementioned programme areas.

3.2 UPDATING THE GUIDELINES AND USER FEEDBACK A system of monitoring relevant new evidence and XSGDWLQJWKHUHFRPPHQGDWLRQVDVQHZnjQGLQJV become available will be established within a year of implementing the guidelines. An electronic follow-up survey of key end-users of the STI guidelines will be conducted after the release of the guidelines. The results of the survey will be used to identify challenges and barriers to the uptake of the guidelines, 3.1 DISSEMINATION to evaluate their usefulness for improving service delivery, and to identify topics or gaps in treatment These guidelines will be made available as a printed that need to be addressed in future editions. publication, as a download on the website of the WHO Department of Reproductive Health and Research (where there will also be links to all supporting 3.3 IMPLEMENTATION OF THE WHO GRFXPHQWDWLRQ 2, and in the WHO Reproductive GUIDELINES FOR THE TREATMENT OF +HDOWK/LEUDU\ 5+/ 3. The recommendations will also C. TRACHOMATIS EHDYDLODEOHLQDJXLGHOLQHDSSOLFDWLRQ ţDSSŤ FUHDWHG with the GRADEpro GDT software. The guidelines ADAPTATION, IMPLEMENTATION AND MONITORING will be announced in the next edition of the RHL newsletter and in the Reproductive Health and These guidelines provide recommendations for Research departmental newsletter, and other treatment of chlamydial infection based on the best relevant organizations will be requested to copy global evidence available at the time of compilation. the announcement in their respective newsletters. However, the epidemiology and AMR of STIs vary by geographical location and are constantly changing, :+2KHDGTXDUWHUVZLOOZRUNZLWK:+2šVUHJLRQDO sometimes rapidly. It is recommended that countries RǎFHVDQGFRXQWU\RǎFHVWRHQVXUHWKDWFRXQWULHV conduct good quality studies to gather the information receive support in the adaptation, implementation needed to adapt these guidelines to the local STI and monitoring of these guidelines using the WHO situation as they update their national guidelines. Department of Reproductive Health and Research In areas lacking local data as a basis for adaptation, JXLGDQFHRQ,QWURGXFLQJ:+2šVUHSURGXFWLYHKHDOWK the recommendations in these guidelines can be guidelines and tools into national programmes (12). adopted as presented.

2 These guidelines and all supporting documents will be available at: www.who.int/reproductivehealth/publications/rtis/chlamydia-treatment-guidelines/en/ 3 RHL is available at: http://apps.who.int/rhl/en/ 16 WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

For further guidance on adaptation, implementation In order to estimate the quantity of medicines needed, and monitoring of national guidelines please refer to it will be necessary to review the medicines that are ,QWURGXFLQJ:+2šVUHSURGXFWLYHKHDOWKJXLGHOLQHV recommended for treatment, their unit prices, the and tools into national programmes: principles and quantity required per treatment and the epidemiological processes of adaptation and implementation (12). information on the prevalence of infection. One can estimate medicine needs by multiplying the estimated In adapting the guidelines for national use, number of cases by the total quantity of medicine UHFRPPHQGHGWUHDWPHQWVVKRXOGKDYHDQHǎFDF\ VSHFLnjHGIRUWUHDWPHQWRIRQHFDVH7KHVHnjJXUHV of at least 95%. The criteria to be considered for can be derived from health centres providing care but the selection of medicines are listed in Box 1. WKH\PXVWEHYHULnjHGWRDYRLGZDVWHIXORYHURUGHULQJ Recommended medicines should meet as many of the criteria as possible, taking into account local availability, Budgeting for medicines is critical. If the national HǎFDF\URXWHDQGIUHTXHQF\RIDGPLQLVWUDWLRQ ministry of health does not provide medicines for free DQGWKHSDWLHQWFDQQRWDNjRUGWREX\WKHPHGLFLQHV then there will essentially be no possibility of BOX 1. CRITERIA FOR THE SELECTION OF curtailing the spread of infection and the occurrence MEDICINES FOR THE TREATMENT OF STIS of complications. At the national level it is important • +LJKHǎFDF\ DWOHDVWFXUHUDWH WKDWGHFLVLRQPDNHUVSROLWLFLDQVDQGnjVFDOFRQWUROOHUV understand the need to subsidize STI medicines. • +LJKTXDOLW\ SRWHQWDFWLYHLQJUHGLHQW Low-cost STI medicines can be obtained through • Low cost international vendors of generic products, non- • Low toxicity levels SURnjWRUJDQL]DWLRQVZLWKSURFXUHPHQWVFKHPHVVXFK • Organism resistance unlikely to develop as UNICEF, UNFPA and UNHCR, and through joint or likely to be delayed medicine procurement schemes. By way of such schemes, national programmes can join other national • Single dose programmes to jointly procure medicines, thus reducing • Oral administration the overall costs by sharing the overhead costs and • Not contraindicated for pregnant or taking advantage of discounts for purchasing in bulk. lactating women Placing STI medicines on national lists of essential medicines increases the likelihood of achieving a Appropriate medicines should be included in the supply of these medicines at low cost. national essential medicines lists. When selecting medicines, consideration should be given to the competencies and experience of health-care providers.

IDENTIFYING AND PROCURING STI DRUGS It is important not only to identify medicines that will EHUHFRPPHQGHGDVnjUVWOLQHWUHDWPHQWIRU67,VEXW also the estimated quantities of the medicines that will be required. Quantifying medication needs is important in order to estimate costs, to reconcile njQDQFLDOUHTXLUHPHQWVZLWKDYDLODEOHEXGJHWDQGWR make orders in advance so that the unit and freight costs can be minimized. WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS 17

Remarks: While good practice based on evidence RIODUJHQHWEHQHnjWGLFWDWHVWKDWSDWLHQWVVKRXOGEH treated for chlamydial infection, the choice of treatment may depend on the convenience of dosage, the cost and TXDOLW\RIWKHPHGLFLQHVLQGLNjHUHQWVHWWLQJVDQGHTXLW\ considerations. When high value is placed on reducing  costs, doxycycline in a standard dose may be the best FKRLFHZKHQKLJKYDOXHLVSODFHGRQFRQYHQLHQFH RECOMMENDATIONS azithromycin in a single dose may be the best choice. A delayed-release formulation of doxycycline may be FOR TREATMENT an alternative to twice daily dosing of doxycycline, but the high cost of the delayed-release formulation may OF CHLAMYDIAL prohibit its use. Note that doxycycline, tetracycline INFECTIONS DQGRǍR[DFLQDUHFRQWUDLQGLFDWHGLQSUHJQDQWZRPHQ VHHUHFRPPHQGDWLRQVDŞF  Research implications: The potential for resistance to azithromycin, doxycycline and other treatment options should be investigated. Future research could compare these treatments and recommended dosages in randomized controlled trials measuring important outcomes such as clinical cure, microbiological cure, FRPSOLFDWLRQVVLGHHNjHFWV LQFOXGLQJDOOHUJ\WR[LFLW\ JDVWURLQWHVWLQDOHNjHFWV FRPSOLDQFHTXDOLW\RIOLIH+,9 transmission and acquisition, and partner transmission of chlamydia. Studies are also needed that evaluate DPR[LFLOOLQ PJWKUHHWLPHVDGD\IRUGD\V 

7KHIROORZLQJQLQHUHFRPPHQGDWLRQVDSSO\ SUMMARY OF THE EVIDENCE WRDGXOWVDGROHVFHQWV Ş\HDUVRIDJH  Evidence from a Cochrane systematic review was used. SHRSOHOLYLQJZLWK+,9DQGNH\SRSXODWLRQV This review included 25 randomized studies comparing LQFOXGLQJVH[ZRUNHUVPHQZKRKDYHVH[ tetracycline, quinolones and macrolides. There are no ZLWKPHQ 060 DQGWUDQVJHQGHUSHUVRQV data available for amoxicillin. Overall, there is moderate 6SHFLnjFUHFRPPHQGDWLRQVKDYHDOVREHHQ to low quality evidence for most comparisons of developed for ophthalmia neonatorum treatments. Moderate quality evidence shows trivial caused by C. trachomatis. GLNjHUHQFHVEHWZHHQD]LWKURP\FLQJDQGGR[\F\FOLQH PJRUDOO\WZLFHDGD\IRUGD\VLQWKHQXPEHUV of people microbiologically cured and experiencing DGYHUVHHYHQWV7KHUHZHUHIHZHUSHRSOHSHU 4.1 UNCOMPLICATED GENITAL CHLAMYDIA cured with azithromycin versus doxycycline, ranging IURPIHZHUWRPRUH ULVNUDWLR>55@ RECOMMENDATION 1 FRQnjGHQFHLQWHUYDO>&,@WR ,QDGGLWLRQWKHUH For people with uncomplicated genital chlamydia, ZHUHPRUHDGYHUVHHYHQWVSHUSHRSOHZLWK the WHO STI guideline suggests one of the azithromycin versus doxycycline, ranging from 42 fewer following options: WRPRUH 55&,WR 6LPLODUUHVXOWV are shown in a recently published randomized study. • azithromycin 1 g orally as a single oral dose Delayed-release doxycycline hyclate probably leads • GR[\F\FOLQHPJRUDOO\WZLFHDGD\IRUGD\V WROLWWOHWRQRGLNjHUHQFHLQWKHSURSRUWLRQRISHRSOH or one of these alternatives: microbiologically cured but probably has fewer side- HNjHFWVWKDQVWDQGDUGGRVHGR[\F\FOLQH2ǍR[DFLQPD\ • WHWUDF\FOLQHPJRUDOO\IRXUWLPHVDGD\IRUGD\V result in fewer cures but also slightly fewer adverse • HU\WKURP\FLQPJRUDOO\IRXUWLPHVDGD\IRUGD\V events compared to doxycycline. When comparing • RǍR[DFLQŞPJRUDOO\WZLFHDGD\IRUGD\V multiple high doses of azithromycin (1 g weekly for 3 ZHHNV WRDVLQJOHGRVHPRUHSHRSOHPD\EHFXUHGEXW Conditional recommendation, moderate quality evidence 18 WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

there are no data for adverse events related to Conditional recommendation, low quality evidence very high doses. Higher doses of any tetracycline Remarks: This recommendation applies to people compared with lower doses may lead to more cures with known anorectal infection and to people with but will probably also lead to more adverse events. suspected anorectal infections with genital co- Tetracyclines compared with quinolones may lead infection. Clinicians should ask men, women and key to fewer cures but also slightly fewer adverse events. populations (e.g. men who have sex with men [MSM], Erythromycin compared with quinolones may lead WUDQVJHQGHUSHUVRQVDQGIHPDOHVH[ZRUNHUV DERXW to fewer cures and more adverse events. anal sex and treat accordingly. Doxycycline should There is no evidence relating to patient values and not be used in pregnant women because of adverse preferences but the Guideline Development Group HNjHFWV VHHUHFRPPHQGDWLRQVDŞF  *'* DJUHHGWKDWWKHUHLVSUREDEO\QRYDULDELOLW\LQ Research implications: The global incidence of the values people place on the outcomes. Research chlamydial anorectal infections should be determined. related to other conditions indicates that adherence 0RUHUHVHDUFKLVQHFHVVDU\RQWKHHNjHFWVRIWUHDWPHQWV may be improved with simpler medication regimens. used for anorectal infections, particularly azithromycin, The GDG therefore agreed that azithromycin may be which is currently not on the WHO essential medicines more acceptable to patients since it is a single dose list for anorectal chlamydial infections (13)(NjHFWV regimen (a majority of the GDG members considered should be assessed in both men and women, and in single-dose regimens to be preferable for patient key populations (e.g. MSM, transgender persons and FRPSOLDQFHRYHUPXOWLGRVHUHJLPHQV 7KHUHLV IHPDOHVH[ZRUNHUV  little to no evidence for equity issues and feasibility. Resistance in other infections (e.g. gonorrhoea and SUMMARY OF THE EVIDENCE 0\FRSODVPDJHQLWDOLXP WKDWRIWHQFRRFFXUZLWK chlamydia may restrict the use of some medicines, There is low quality evidence from eight non- VXFKDVRǍR[DFLQ)RUPDQ\RIWKHVHPHGLFLQHVFRVWV UDQGRPL]HGVWXGLHV njYHGLUHFWFRPSDULVRQVDQGWKUHH PD\GLNjHUEHWZHHQFRXQWULHVLQSODFHVZLWKKLJK VLQJOHDUPVWXGLHV WKDWHYDOXDWHGGR[\F\FOLQHDQG LQFLGHQFHRIFKODP\GLDWKHFRVWGLNjHUHQFHVEHWZHHQ D]LWKURP\FLQ VHH:HEDQQH[HV'DQG( 7KHUHDUH azithromycin and doxycycline may be large due to no data for amoxicillin, erythromycin and quinolones. greater numbers of people requiring treatment. (YLGHQFHVKRZHGWKDWWKHUHPD\EHIHZHU PLFURELRORJLFDOFXUHVSHUSHRSOHZLWKD]LWKURP\FLQ In summary, there was moderate quality evidence FRPSDUHGZLWKGR[\F\FOLQH 55&, IRUWULYLDOGLNjHUHQFHVLQEHQHnjWVDQGKDUPVEHWZHHQ WR (YLGHQFHIURPVWXGLHVRIJHQLWDOLQIHFWLRQV azithromycin and doxycycline, and although the cost VKRZVOLWWOHWRQRGLNjHUHQFHLQVLGHHNjHFWVZLWKWKHVH of azithromycin is higher, the single dose may make WUHDWPHQWV 55&,WR $OWKRXJK it more convenient to use than doxycycline. While the there are fewer women than men in the studies, the GLNjHUHQFHVDUHDOVRWULYLDOZLWKWKHRWKHUPHGLFLQHV HYLGHQFHVXJJHVWHGOLWWOHGLNjHUHQFHLQHNjHFWVEHWZHHQ the evidence is low quality and these are therefore men and women. There is no evidence relating to patient provided as alternatives, with the exception of delayed- values and preferences, but the GDG agreed that release doxycycline, which is currently expensive. there are no known reasons to suspect values would See Annex C for list of references of reviewed evidence, YDU\IRUGLNjHUHQWSHRSOH7KHUHLVOLWWOHWRQRHYLGHQFH and Web annex D for details of the evidence reviewed, for acceptability, but research in other conditions LQFOXGLQJHYLGHQFHSURnjOHVDQGHYLGHQFHWRGHFLVLRQ indicates that adherence may be improved with simpler IUDPHZRUNV SS  medication regimens. There is also little to no evidence for equity issues and feasibility, but azithromycin is more expensive and typically the cost is transferred 4.2 ANORECTAL CHLAMYDIAL INFECTION to consumers. The GDG agreed that equity may vary between the medicines depending on the population: RECOMMENDATION 2 in some populations, azithromycin may be more In people with anorectal chlamydial infection, the acceptable since it is a single-dose treatment, :+267,JXLGHOLQHVXJJHVWVXVLQJGR[\F\FOLQHPJ and some people may experience stigma related to orally twice daily for 7 days over azithromycin 1 g orally visibility of a multi-dose regimen with doxycycline. single dose. Therefore, suggesting doxycycline over azithromycin could create inequity for people sensitive to stigma related to multi-dose regimens. Azithromycin is currently not listed as an essential medicine for anorectal chlamydial infection. WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS 19

In summary, doxycycline may result in more cures, SUMMARY OF THE EVIDENCE but although it is less expensive than azithromycin, Overall, there is moderate to low quality evidence from azithromycin may be better accepted due to the 14 randomized controlled trials, two non-randomized single-dose treatment. comparative studies and two large cohort studies See Annex C for list of references of reviewed evidence, DVVHVVLQJWKHHNjHFWVRID]LWKURP\FLQHU\WKURP\FLQ and Web annex D for details of the evidence reviewed, and amoxicillin in pregnant women with chlamydial LQFOXGLQJHYLGHQFHSURnjOHVDQGHYLGHQFHWRGHFLVLRQ LQIHFWLRQV7KHGLNjHUHQFHVLQEHQHnjWVEHWZHHQWKHVH IUDPHZRUNV SS  GLNjHUHQWWUHDWPHQWVDUHVPDOODQGZLGHFRQnjGHQFH intervals included the possibility of greater or lesser EHQHnjWVZLWKD]LWKURP\FLQFRPSDUHGWRRWKHU 4.3 CHLAMYDIAL INFECTION IN PREGNANT medicines. Moderate quality evidence found that WOMEN there are probably 94 more people microbiologically FXUHGSHUZLWKD]LWKURP\FLQYHUVXVHU\WKURP\FLQ RECOMMENDATION 3A 55&,WR DQGORZTXDOLW\ In pregnant women with genital chlamydial infection, evidence found that there may be 72 more people the WHO STI guideline recommends using azithromycin FXUHGSHUZLWKD]LWKURP\FLQYHUVXVDPR[LFLOOLQ over erythromycin. 55&,WR 7KHUHDUHSUREDEO\ IHZHUSHRSOHPLFURELRORJLFDOO\FXUHGSHUZLWK Strong recommendation, moderate quality evidence HU\WKURP\FLQYHUVXVDPR[LFLOOLQ 55&, WR 7KHUHPD\EHVOLJKWO\IHZHUVLGHHNjHFWVZLWK RECOMMENDATION 3B azithromycin compared with erythromycin or amoxicillin In pregnant women with genital chlamydial infection, DSSUR[LPDWHO\IHZHU EXWWKHUHPD\EH the WHO STI guideline suggests using azithromycin VXEVWDQWLDOO\PRUHVLGHHNjHFWVZLWKHU\WKURP\FLQ over amoxicillin. YHUVXVDPR[LFLOOLQ DSSUR[LPDWHO\PRUH  Conditional recommendation, low quality evidence Much of the evidence was uncertain for fetal outcomes as it came from indirect comparisons in RECOMMENDATION 3C large cohort studies. There were few events, and FRQnjGHQFHLQWHUYDOVDURXQGWKHVPDOOGLNjHUHQFHV In pregnant women with genital chlamydial infection, included the potential for fewer or more events the WHO STI guideline suggests using amoxicillin between comparisons. over erythromycin. In summary, the GDG agreed that azithromycin is Conditional recommendation, low quality evidence preferred over erythromycin because of greater Dosages: HNjHFWLYHQHVVDQGORZHUFRVWDQGSUHIHUUHGRYHU DPR[LFLOOLQGXHWRJUHDWHUHNjHFWLYHQHVV$]LWKURP\FLQ • azithromycin 1 g orally as a single dose PD\DOVREHPRUHDFFHSWDEOHGXHWRVLQJOHGRVDJH • DPR[LFLOOLQPJRUDOO\WKUHHWLPHVDGD\IRUGD\V however, it may not be available in all settings due to • HU\WKURP\FLQPJRUDOO\IRXUWLPHVDGD\IRU misconceptions that it is costly. Amoxicillin is preferred days. over erythromycin as it is less costly and may result in JUHDWHUEHQHnjWVDQGIHZHUVLGHHNjHFWV Remarks: $]LWKURP\FLQLVWKHnjUVWFKRLFHRI treatment but may not be available in some settings. See Annex C for list of references of reviewed evidence, Azithromycin is less expensive than erythromycin and Web annex D for details of the evidence reviewed, and since it is provided as a single dose, may result in LQFOXGLQJHYLGHQFHSURnjOHVDQGHYLGHQFHWRGHFLVLRQ better adherence and therefore better outcomes. IUDPHZRUNV SS  Research implications: Research in pregnant women comparing these treatments and the recommended dosages should be conducted. Although these medicines are relatively safe in pregnancy, maternal and fetal complications (e.g. adverse pregnancy outcomes, IHWDOGHIHFWV ZLWKWKHXVHRIWKHVHWUHDWPHQWVIRU67,V and other infections should be monitored, collected and analysed to inform updated recommendations in the future. When conducting these studies, costs and acceptability of the treatments could be measured. 20 WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

4.4 LYMPHOGRANULOMA VENEREUM (LGV) agreed that these may be dependent on individuals and countries. Data for medicine prices and procurement RECOMMENDATION 4 indicate that doxycycline is cheaper than azithromycin and erythromycin, although the latter medicines are In adults and adolescents with LGV, the WHO STI still inexpensive. JXLGHOLQHVXJJHVWVXVLQJGR[\F\FOLQHPJRUDOO\ twice daily for 21 days over azithromycin 1 g orally, In summary, there is very low quality evidence for all weekly for 3 weeks. medicines for treatment of LGV. The evidence suggests ODUJHEHQHnjWVZLWKGR[\F\FOLQHRYHUD]LWKURP\FLQDQG Conditional recommendation, very low quality evidence WKHHNjHFWVRIHU\WKURP\FLQDUHXQNQRZQ,QDGGLWLRQ Remarks: Good practice dictates treatment of LGV, doxycycline is the least expensive. LQSDUWLFXODUIRUPHQZKRKDYHVH[ZLWKPHQ 060  See Annex C for list of references of reviewed evidence, and for people living with HIV. When doxycycline is and Web annex D for details of the evidence reviewed, contraindicated, azithromycin should be provided. LQFOXGLQJHYLGHQFHSURnjOHVDQGHYLGHQFHWRGHFLVLRQ When neither treatment is available, erythromycin IUDPHZRUNV SS  PJRUDOO\IRXUWLPHVDGD\IRUGD\VLVDQ alternative. Doxycycline should not be used in SUHJQDQWZRPHQEHFDXVHRIDGYHUVHHNjHFWV 4.5 OPHTHALMIA NEONATORUM VHHUHFRPPHQGDWLRQVDŞF  RECOMMENDATION 5 Research implications: Additional research for each of the treatments and the dosages recommended is In neonates with chlamydial conjunctivitis, the WHO needed, in particular for erythromycin and azithromycin. STI guideline recommends using oral azithromycin Randomized controlled trials should be conducted, PJNJGD\RUDOO\RQHGRVHGDLO\IRUGD\VRYHU measuring critical and important outcomes, such HU\WKURP\FLQPJNJGD\RUDOO\LQIRXUGLYLGHG as clinical cure, microbiological cure, complications, doses daily for 14 days. VLGHHNjHFWV LQFOXGLQJDOOHUJ\WR[LFLW\JDVWURLQWHVWLQDO Strong recommendation, very low quality evidence HNjHFWV TXDOLW\RIOLIH+,9WUDQVPLVVLRQDQGDFTXLVLWLRQ compliance and LGV transmission to partners. Remarks: This is a strong recommendation given 7KHHNjHFWVRIVKRUWHUFRXUVHVRIWUHDWPHQWVKRXOG the potential for the risk of pyloric stenosis with the also be investigated. use of erythromycin in neonates. In some settings, azithromycin suspension is not available and therefore SUMMARY OF THE EVIDENCE HU\WKURP\FLQPD\EHXVHG6LGHHNjHFWVVKRXOGEH monitored with the use of either medication. There is very low quality evidence from 12 non- randomized studies with no comparisons between Research implications: Additional research should be treatments. These studies assessed treatment FRQGXFWHGWRGHWHUPLQHWKHHNjHFWVRIWKHVHPHGLFLQHV with azithromycin and doxycycline for 21 days, and WRWUHDWRSKWKDOPLDQHRQDWRUXP7KHHNjHFWVRIRWKHU erythromycin for 14 days. Evidence for doxycycline medications such as trimethoprim should also be VKRZHGWKDWWKHUHPD\EHODUJHEHQHnjWV FOLQLFDODQG investigated. Pyloric stenosis should be monitored PLFURELRORJLFDOFXUHUDWHVJUHDWHUWKDQ DQG or research conducted to evaluate this risk with WULYLDOVLGHHNjHFWV HJSHUVLVWHQWPXFRXVPHPEUDQH the medicines suggested. DEQRUPDOLWLHVSHULUHFWDODEVFHVVDQGDOOHUJ\  7KHHNjHFWVRID]LWKURP\FLQDQGHU\WKURP\FLQZHUH SUMMARY OF THE EVIDENCE uncertain, with only 14 people receiving azithromycin There is low quality evidence for a cure rate of 98% with and 31 people receiving erythromycin in the studies. HU\WKURP\FLQPJNJGD\IRUGD\VDQGXQFHUWDLQ 6LGHHNjHFWVDUHOLNHO\WULYLDODQGVLPLODUWRWKHVLGH HNjHFWVRQWKHFXUHUDWHIRUD]LWKURP\FLQJLYHQWKH HNjHFWVRIWKHVHWUHDWPHQWVLQSHRSOHZLWKRWKHU small numbers of neonates receiving azithromycin in chlamydial infections. There is no evidence relating WKHVWXG\ VHH:HEDQQH[HV'DQG( 7KHUHLVYHU\ORZ to patient values and preferences, but the GDG quality evidence for 7 more instances of pyloric stenosis agreed that there are no known reasons to suspect SHUZLWKHU\WKURP\FLQ7KH*'*UHJDUGHGWKH YDOXHVZRXOGYDU\IRUGLNjHUHQWSHRSOH7KHUHLVOLWWOH ULVNRIS\ORULFVWHQRVLVDVDVHULRXVDGYHUVHHNjHFW to no evidence for acceptability, but research in other of erythromycin use in children. There are no data conditions indicates that adherence may be improved evaluating pyloric stenosis due to use of azithromycin. with simpler medication regimens. There is little 7KHUHDUHDOVRQRGDWDDVVHVVLQJWKHHNjHFWVRI evidence for equity issues and feasibility, but the GDG WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS 21

trimethoprim. There is no evidence for variation in SUMMARY OF THE EVIDENCE patient values and preferences, but compliance with Overall, the quality of evidence is low to very low treatments ranged from 77% to 89%. The costs for IURPVWXGLHVUDQGRPL]HGVWXGLHVDQGRQH treatments are relatively low and similar, and most non-randomized study with two comparison treatments are currently being used. JURXSV7KHUHDUHIHZDYDLODEOHGDWDIRUWKHHNjHFWV In summary, azithromycin is preferred over RIFKORUDPSKHQLFRO/DUJHEHQHnjWVZHUHUHSRUWHG erythromycin because of the potential risk of serious for prophylaxis compared with no prophylaxis, in adverse events with erythromycin, and there are no particular in babies born to women with known infection data for trimethoprim. DSSUR[LPDWHO\UHGXFWLRQLQFRQMXQFWLYLWLVZLWK SURSK\OD[LVXVLQJGLNjHUHQWPHGLFDWLRQV 7KHEHQHnjWV See Annex C for list of references of reviewed evidence, ZLWKGLNjHUHQWPHGLFDWLRQVDUHVLPLODUKRZHYHUWKHORZ and Web annex D for details of the evidence reviewed, WRYHU\ORZTXDOLW\HYLGHQFHLQGLFDWHVWKDWWKHEHQHnjWV LQFOXGLQJHYLGHQFHSURnjOHVDQGHYLGHQFHWRGHFLVLRQ of tetracycline hydrochloride, erythromycin or povidone IUDPHZRUNV SS  iodine may be slightly greater than for silver nitrate. 5(&200(1'$7,21 Few data are available for the incidence of non- infectious conjunctivitis after prophylaxis or no For all neonates, the WHO STI guideline recommends prophylaxis. Low quality evidence shows a slight topical ocular prophylaxis for the prevention of UHGXFWLRQRUOLWWOHGLNjHUHQFHDQGLQGLFDWHVWKDW gonococcal and chlamydial ophthalmia neonatorum. EHWZHHQDQGSHULQIDQWVKDYHQRQLQIHFWLRXV Strong recommendation, low quality evidence FRQMXQFWLYLWLVDIWHUDSSOLFDWLRQRIGLNjHUHQWSURSK\ODFWLF medications. There is little evidence relating to patient RECOMMENDATION 7 values and preferences, but the GDG agreed that WKHUHZRXOGOLNHO\EHOLWWOHGLNjHUHQFHLQWKHKLJKYDOXH For ocular prophylaxis, the WHO STI guideline suggests placed on avoiding long-term consequences of both one of the following options for topical application to gonococcal and chlamydial conjunctivitis. The GDG also both eyes immediately after birth: DJUHHGWKDWWKHUHZRXOGEHOLWWOHHNjHFWRQDFFHSWDELOLW\ • tetracycline hydrochloride 1% eye ointment equity and feasibility, as prophylaxis is currently used • HU\WKURP\FLQH\HRLQWPHQW in many countries. The GDG reported that alcohol- based povidone iodine has erroneously been used • SRYLGRQHLRGLQHVROXWLRQ ZDWHUEDVHG as prophylaxis resulting in serious harm to babies. • silver nitrate 1% solution Silver nitrate is the most expensive prophylaxis option. • chloramphenicol 1% eye ointment. ,QVXPPDU\WKHUHDUHODUJHEHQHnjWVIRUSURSK\OD[LVWR Conditional recommendation, low quality evidence SUHYHQWRSKWKDOPLDQHRQDWRUXPDQGWKHVHEHQHnjWV outweigh the risk of non-infectious conjunctivitis due Remarks: 5HFRPPHQGDWLRQVDQGDSSO\WRWKH to prophyalaxis with any of the topical medications. prevention of both chlamydial and gonococcal Some topical medications may provide greater ophthalmia neonatorum. Cost and local resistance protection (tetracycline hydrochloride, erythromycin to erythromycin, tetracycline and chloramphenicol RUSRYLGRQHLRGLQH EXWDOODUHIHDVLEOHWRSURYLGH in gonococcal infection may determine the choice of medication. Caution should be taken to avoid touching See Annex C for list of references of reviewed evidence, eye tissue when applying the topical treatment and and Web annex D for details of the evidence reviewed, to provide a water-based solution of povidone iodine. LQFOXGLQJHYLGHQFHSURnjOHVDQGHYLGHQFHWRGHFLVLRQ Alcohol-based povidone iodine solution must not be IUDPHZRUNV SS  applied. The topical application should be administered immediately after birth. Research implications: The prevalence of gonococcal ophthalmia should be determined given the high prevalence of maternal gonorrhoea in some settings. The state of resistance to the medications should be explored and it should be established whether these organisms would be killed by ocular prophylaxis despite resistant strains being established in the organisms. 0RUHUHVHDUFKFRPSDULQJWKHEHQHnjWVDQGKDUPV RIWKHGLNjHUHQWPHGLFDWLRQVLVQHHGHGLQSDUWLFXODU comparisons with chloramphenicol. 22 WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

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 :+2HVVHQWLDOPHGLFLQHVOLVWWKHGLWLRQ*HQHYD:RUOG+HDOWK2UJDQL]DWLRQ KWWSZZZ ZKRLQWVHOHFWLRQBPHGLFLQHVFRPPLWWHHVH[SHUW(0/BB),1$/BDPHQGHGB$8*SGI DFFHVVHG0D\  WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS 23

ANNEX A: STI GUIDELINE DEVELOPMENT TEAMS

WHO STI STEERING COMMITTEE

WHO regional STI focal points Region 1. Massimo Ghidinelli 5HJLRQRIWKH$PHULFDV $05 :DVKLQJWRQ'&Ş8QLWHG6WDWHVRI$PHULFD 86$ 2. Lali Khotenashvili (XURSHDQ5HJLRQ (85 Copenhagen – Denmark 3.

18. Lori Newman Department of Reproductive Health and Research Human Reproduction Team 19. Annette Mwansa Nkowane Department of Health Workforce  Anita Sands Essential Medicines and Health Products, 3UHTXDOLnjFDWLRQ7HDP 21. Igor Toskin Department of Reproductive Health and Research Human Reproduction Team 22. Marco Vitoria Department of HIV/AIDS Treatment and Care WHO STI Secretariat Department and Team 23. Ian Askew Department of Reproductive Health and Research Human Reproduction Team 24. 1DWKDOLH%URXWHW FROHDGRIWKH Department of Reproductive Health and Research development process) Human Reproduction Team 25. James Kiarie Department of Reproductive Health and Research Human Reproduction Team  Lee Sharkey Department of Reproductive Health and Research Human Reproduction Team 27. Teodora Elvira Wi (lead of the Department of Reproductive Health and Research development process) Human Reproduction Team

METHODOLOGIST Nancy Santesso Department of Clinical Epidemiology and Biostatistics McMaster University 0DLQ6WUHHW:HVW Hamilton, Ontario L8N 3Z5 Canada

SYSTEMATIC REVIEW TEAM: MCMASTER UNIVERSITY Team lead: Nancy Santesso Team members: Housne Begum, Janna-Lina Kerth, Gian Paolo Morgano, Kristie Poole, Nicole Schwab, Matthew Ventresca, Yuan Zhang, Andrew Zikic WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS 25

STI GUIDELINE DEVELOPMENT GROUP

Chairpersons: Judith Wasserheit, Holger Schünemann, Patricia Garcia

Name and address Region Sex 1.

9. 3DWULFLD*DUFLD &R&KDLU AMR F School of Public Health and Administration Universidad Peruana Cayetano Heredia $YH+RQRULR'HOJDGR 31 AP, 4314 Lima Peru  Suzanne Garland WPR F 5R\DO:RPHQšV+RVSLWDO/HYHO %OGJ%LR,QVWLWXWH Flemington Road, Parkville Victoria Australia 11. Sarah Hawkes EUR F University College London Institute for Global Health London United Kingdom 12. Mary Higgins EUR F International Confederation of Midwives /DDQYDQ0HHUGHUYRRUW 2517 AN The Hague The Netherlands 13. King Holmes AMR M Department of Global Health and Department of Medicine University of Washington Harborview Medical Center 325 9th Ave., Box 359931 6HDWWOH:$ USA 14. -HNjUH\.ODXVQHU AMR M Division of Infectious Diseases and Program in Global Health 'DYLG*HNjHQ6FKRRORI0HGLFLQHDQG)LHOGLQJ6FKRRORI3XEOLF+HDOWK University of California, Los Angeles USA 15. David Lewis WPR M Western Sydney Sexual Health Centre Marie Bashir Institute for Infectious Diseases and Biosecurity Sydney Medical School Westmead, University of Sydney Sydney Australia  Nicola Low EUR F Epidemiology and Public Health University of Bern Institute of Social and Preventive Medicine Finkenhubelweg 11 %HUQ Switzerland 17. David Mabey EUR M Communicable Diseases /RQGRQ6FKRRORI+\JLHQHDQG7URSLFDO0HGLFLQH /6+70 Keppel Street London WC1E 7HT United Kingdom WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS 27

18. Angelica Espinosa Miranda AMR F Núcleo de Doenças Infecciosas Universidade Federal do Espirito Santo Av. Marechal Campos 0DUX¯SH 9LWµULDŞ(6&(3 Brazil 19. Nelly Mugo AFR F Kenya Medical Research Institute Mbagathi Rd. 32%R[1DLUREL Kenya  Saiqa Mullick AFR F Implementation Science University of the Witwatersrand Hillbrow Health Precinct Hillbrow, Johannesburg South Africa 21. Francis Ndowa AFR M 7KDPHV5RDG Vainona, Harare Zimbabwe 22. Joel Palefsky AMR M Division of Infectious Diseases %R[ 3DUQDVVXV$YH5RRP6 University of California, San Francisco San Francisco, CA 94143 USA 23. .HLWK5DGFOLNjH EUR M European STI Guidelines Project ,QWHUQDWLRQDO8QLRQDJDLQVW6H[XDOO\7UDQVPLWWHG,QIHFWLRQV ,867, Royal Society of Medicine 1 Wimpole Street /RQGRQ:*$( United Kingdom 24. Ulugbek Sabirov EUR M National STI Program Republican Center for Dermato-Venereology Tashkent Uzbekistan 25. +ROJHU6FK¾QHPDQQ &R&KDLU AMR M Department of Clinical Epidemiology and Biostatistics McMaster University 0DLQ6WUHHW:HVW Hamilton, Ontario L8N 3Z5 Canada  Richard Steen EUR M Localitá Cassaluvo Diano San Pietro ,PSHULD Italy 28 WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

27. Judith Stephenson EUR F University College London Gower Street London United Kingdom 28. Magnus Unemo EUR M Department of Laboratory Medicine Microbiology Örebro University Hospital 6(˜UHEUR Sweden 29. Bea Vuylsteke EUR F Institute of Tropical Medicine Nationalestraat 155 $QWZHUS Belgium  Anna Wald AMR F University of Washington Virology Research Clinic Harborview Medical Center 325 9th Ave, Box 359928 6HDWWOH:$ USA 31. -XGLWK:DVVHUKHLW &R&KDLU AMR F Department of Global Health Professor of Global Health and Medicine Adjunct Professor of Epidemiology University of Washington +DUULV+\GUDXOLFV%XLOGLQJ5RRP' 1(3DFLnjF6WUHHW %R[ 6HDWWOH:$ USA 32. Thomas Wong AMR M Division of Community Acquired Infections Centre for Communicable Diseases and Infection Control Public Health Agency of Canada 5RRP(JODQWLQH'ULYHZD\ 7XQQH\šV3DVWXUH$/& 2WWDZD2QWDULR.$/ Canada 33. Kimberly A. Workowski AMR F &HQWHUVIRU'LVHDVH&RQWURODQG3UHYHQWLRQ &'& Division of Infectious Diseases Emory University School of Medicine &OLIWRQ5G $WODQWD*$ USA

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STI Guideline Development Group: Working group for chlamydia

1. Andrew Amato 2. Harrell Chesson 3. Craig Cohen 4. Patricia Garcia 5. Nicola Low  David Mabey 7. Angelica Miranda 8. Francis Ndowa 9. .HLWK5DGFOLNjH  Judith Stephenson 11. Magnus Unemo 12. Bea Vuylsteke 13. Judith Wasserheit

STI External Review Group: Working group for chlamydia

Name and address Region Sex 1. /DLWK$EX5DGGDG EMR M Biostatistics, Epidemiology and Biomathematics Research Core Infectious Disease Epidemiology Group Department of Public Health Weill Cornell Medical College Cornell University Qatar Foundation – Education City Qatar 2. $GHOH%HQDNHQ6FKZDUW] AMR F Ministry of Health STI, AIDS and Viral Hepatitis Department SAF Sul Trecho 2, Ed. Premium Torre I, Térreo, Sala 12 Ş%UDV¯OLDŞ') Brazil 3. Mircea Betiu EUR M 1LFRODH7HVWHPLņDQX6WDWH8QLYHUVLW\RI0HGLFLQHDQG3KDUPDF\ Republic of Moldova 4. Anupong Chitwarakorn SEAR M Department of Diseases Control Bureau of AIDS, TB and STIs Ministry of Public Health Nonthaburi Thailand 30 WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

5. Anjana Das SEAR F )+, New Delhi India  Carolyn Deal AMR F 1DWLRQDO,QVWLWXWHRI$OOHUJ\DQG,QIHFWLRXV'LVHDVHV 1,$,' United States Department of Health and Human Services National Institutes of Health Washington, DC USA 7. 0DUJDUHW*DOH5RZH AMR F Professional Guidelines and Public Health Practice Division Centre for Communicable Diseases and Infection Control Public Health Agency of Canada Ottawa, Ontario Canada 8. William M. Geisler AMR M Medicine and Epidemiology University of Alabama at Birmingham Division of Infectious Diseases WK6WUHHW6RXWK Zeigler Research Building, Room 242 %LUPLQJKDP$/ USA 9. Amina El Kettani EMR F 'LUHFWLRQGHOš(SLG«PLRORJLH Service des MST-sida Ministry of Health 71 Avenue Ibn Sinaa, Agdal Rabat Morocco  Ahmed Latif AFR M Public Health Consultant Zimbabwe 11. Mizan Kiros AFR M Disease Prevention and Control Directorate Federal Ministry of Health Ethiopia 12. Philippe Mayaud EUR M Clinical Research Department )DFXOW\bRI,QIHFWLRXVDQG7URSLFDO'LVHDVHV London School of Hygiene and Tropical Medicine Keppel Street London WC1E 7HT United Kingdom WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS 31

13. David McCartney EUR M Research and Technical Support ,QWHUQDWLRQDO3ODQQHG3DUHQWKRRG)HGHUDWLRQ ,33) 4 Newhams Row, London SE1 3UZ United Kingdom 14. Ali M. Mir SEAR M Population Council 1R6WUHHW6HFWRU) Islamabad Pakistan 15. Nuriye Ortayli AMR F 8QLWHG1DWLRQV3RSXODWLRQ)XQG 81)3$ 7KLUG$YHQXHUGǍRRU 1HZ

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ANNEX B: DETAILED METHODS FOR GUIDELINE DEVELOPMENT

QUESTIONS AND OUTCOMES E 67,FRQGLWLRQVQRWLQFOXGHGLQWKH:+267, guidelines that were selected by the GDG to be To determine which recommendations to update, reviewed and added in the new WHO STI guidelines. LQ'HFHPEHUWKH:RUOG+HDOWK2UJDQL]DWLRQ These are important and common conditions. :+2 'HSDUWPHQWRI5HSURGXFWLYH+HDOWKDQG Research reviewed current recommendations of key F 67,FRQGLWLRQVLQFOXGHGLQWKH:+267, international guidelines: guidelines that were not updated but were selected by the GDG to be included in the new WHO STI • Sexually transmitted diseases treatment guidelines, guidelines. These STI conditions are rare and 'HSDUWPHQWRI+HDOWKDQG+XPDQ6HUYLFHV diagnosis is not often made in the majority of United States Centers for Disease Control and settings, or it is unlikely that there is new information 3UHYHQWLRQ &'& 4 available as a basis for making any changes to the • United Kingdom national guidelines for the :+267,UHFRPPHQGDWLRQV management of sexually transmitted infections, British Association for Sexual Health and HIV G 67,FRQGLWLRQVQRWLQFOXGHGLQWKH:+267, %$6++ Ş5 guidelines that are part of other national guidelines, but were not selected by the GDG to be included • Canadian guidelines on sexually transmitted in the new WHO STI guidelines. These conditions infections, Public Health Agency of Canada, DUHUDUHDQGGLǎFXOWWRGLDJQRVHLQWKHPDMRULW\ Ş of settings, or it is unlikely that new research or • European sexually transmitted infections guidelines, LQIRUPDWLRQKDVEHFRPHDYDLODEOHWKHUHDUHH[LVWLQJ International Union of Sexually Transmitted recommendations for these conditions that can be ,QIHFWLRQV ,867, 7 applied in other settings (e.g. reference hospitals • National management guidelines for sexually WKDWPDQDJHFRPSOLFDWHGFRQGLWLRQV  transmissible infections, Sexual Health Society $PHHWLQJZDVKHOGLQ'HFHPEHUDWZKLFKWKH RI9LFWRULD$XVWUDOLD8 *XLGHOLQH'HYHORSPHQW*URXS *'* GLVFXVVHGDQG • National guideline for the management and control decided on the initial list of population, intervention, RIVH[XDOO\WUDQVPLWWHGLQIHFWLRQV 67,V 1DWLRQDO FRPSDUDWRUDQGRXWFRPH 3,&2 TXHVWLRQVLGHQWLnjHG 'HSDUWPHQWRI+HDOWK6RXWK$IULFD9 and by WHO. After the meeting, surveys pertaining to each • National guidelines on prevention, management of the four STI topic areas (i.e. gonorrhoea, chlamydia, and control of reproductive tract infections including V\SKLOLVDQGKHUSHVVLPSOH[YLUXVW\SH>+69@ ZHUH sexually transmitted infections, Ministry of Health administered among subgroups of the GDG members and Family Welfare, Government of India, with expertise relating to the relevant STIs. The goal $XJXVW of the surveys was to rank the population, interventions DQGRXWFRPHVIRUHDFKVSHFLnjF67,FRQGLWLRQE\ Based on the review, four proposed categories importance. The surveys required the members of RIVH[XDOO\WUDQVPLWWHGLQIHFWLRQ 67, FRQGLWLRQV the STI subgroups to rank the population, interventions were prioritized: and outcomes on a scale of 1 to 9, from lowest to D 67,FRQGLWLRQVLQFOXGHGLQWKH:+267, highest priority. guidelines11 that were selected by the GDG to be reviewed and updated in the new WHO STI guidelines. These are important and common conditions.

 $YDLODEOHDWKWWSZZZFGFJRYVWGWUHDWPHQWVWGWUHDWPHQWUUSGI  $YDLODEOHDWKWWSZZZEDVKKRUJ%$6++*XLGHOLQHV*XLGHOLQHV%$6++*XLGHOLQHV*XLGHOLQHVDVS["KNH\ FHGHEEDFHIEGGH  $YDLODEOHDWKWWSZZZSKDFDVSFJFFDVWGPWVVWLLWVFJVWLOGFLWVLQGH[HQJSKS 7 Available at: http://www.iusti.org/regions/europe/euroguidelines.htm  0HOERXUQH6H[XDO+HDOWK&HQWUH7UHDWPHQW*XLGHOLQHVDYDLODEOHDWKWWSPVKFRUJDX+HDOWK3URIHVVLRQDO06+&7UHDWPHQW*XLGHOLQHVWDELG'HIDXOW  /HZLV'$0DUXPD(5HYLVLRQRIWKHQDWLRQDOJXLGHOLQHIRUnjUVWOLQHFRPSUHKHQVLYHPDQDJHPHQWDQGFRQWURORIVH[XDOO\WUDQVPLWWHGLQIHFWLRQVZKDWšVQHZ DQGZK\"6RXWK$IU-(SLGHPLRO,QIHFW   KWWSDSSVZKRLQWPHGLFLQHGRFVGRFXPHQWVVHQVHQSGIDFFHVVHG-XQH   $YDLODEOHDWKWWSZZZLORRUJZFPVSJURXSVSXEOLFHGBSURWHFWSURWUDYLORBDLGVGRFXPHQWVOHJDOGRFXPHQWZFPVBSGI  *XLGHOLQHVIRUWKHPDQDJHPHQWRIVH[XDOO\WUDQVPLWWHGLQIHFWLRQV*HQHYD:RUOG+HDOWK2UJDQL]DWLRQ KWWSZZZZKRLQWKLYSXEVWLHQ 67,*XLGHOLQHVSGIDFFHVVHG0D\  WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS 33

)RXUGLNjHUHQWSULRULW\67,VXUYH\VZHUHFRQGXFWHG The number of comparisons in each question was also DQGHDFKVXUYH\DWWDLQHGDŞUHVSRQVHUDWH UHGXFHGRQO\ţFULWLFDOŤLQWHUYHQWLRQVZHUHFRPSDUHG from the STI subgroup members. The survey results for with each other and with important interventions. priority populations, interventions and outcomes were Thus, “important” interventions were not compared analysed. Populations, interventions and outcomes with to each other. DQDYHUDJHUDWLQJRIWRZHUHFRQVLGHUHGţFULWLFDOŤ A revised list of questions was then compiled and all WKRVHZLWKDQDYHUDJHUDWLQJRIWRZHUHFRQVLGHUHG members of the full STI GDG were requested to review ţLPSRUWDQWŤDQGWKRVHZLWKDQDYHUDJHUDWLQJRIWR the priority questions. The priority questions were 3 were considered “not important” and were thus not then revised based on this feedback. covered in the guidelines. Some questions that scored less than 7 were kept for consistency. 6L[TXHVWLRQVZHUHLGHQWLnjHGIRUWKHXSGDWHRIWKH chlamydial infections guideline. Each question is framed using the PICO format (population, intervention, FRPSDUDWRUDQGRXWFRPH (DFKTXHVWLRQFRUUHVSRQGV to a recommendation.

PRIORITY QUESTIONS AND OUTCOMES FOR CHLAMYDIA TRACHOMATIS 1. Uncomplicated genital (cervix, urethra) chlamydial infections in adults and adolescents

Population Intervention Comparator Outcome Adults and Azithromycin 1 g orally Doxycycline extended release Critical: Clinical cure, adolescents with x 1 dose (5 PJGDLO\[GD\V microbiological cure, STI uncomplicated 'R[\F\FOLQHPJ (U\WKURP\FLQPJRUDOO\ FRPSOLFDWLRQVVLGHHNjHFWV genital (cervix, twice daily x 7 days four times daily x 7 days (including allergy, toxicity, XUHWKUD  Erythromycin ethylsuccinate JDVWUR FRPSOLDQFH chlamydial (6 PJRUDOO\IRXUWLPHV Important: Quality of life, HIV infections daily x 7 days transmission and acquisition, (U\WKURP\FLQPJRUDOO\ partner transmission WZLFHGDLO\[ŞGD\V $PR[LFLOOLQPJRUDOO\ thrice daily x 7 days Quinolones

2. Uncomplicated anorectal chlamydial infections in adults and adolescents, excluding lymphogranuloma venereum (LGV)

Population Intervention Comparator Outcome Adults and Azithromycin 1 g orally 'R[\F\FOLQH (5 PJGDLO\ Critical: Clinical cure, adolescents with x 1 dose x 7 days microbiological cure, STI uncomplicated 'R[\F\FOLQHPJ (U\WKURP\FLQPJRUDOO\ FRPSOLFDWLRQVVLGHHNjHFWV anorectal twice daily x 7 days four times daily x 7 days (including allergy, toxicity, chlamydial (U\WKURP\FLQ(6PJRUDOO\ JDVWUR FRPSOLDQFH infections four times daily x 7 days Important: Quality of life, HIV H[FOXGLQJ/*9 (U\WKURP\FLQPJRUDOO\ transmission and acquisition, WZLFHGDLO\[ŞGD\V partner transmission $PR[LFLOOLQPJRUDOO\WKULFH daily x 7 days Quinolones 34 WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

3a–c. Chlamydia in pregnancy

Population Intervention Comparator Outcome Pregnant women Azithromycin 1 g orally $PR[LFLOOLQPJRUDOO\WKULFH Critical: Fetal outcomes (e.g. with chlamydia x 1 dose daily x 7 days WHUDWRJHQLFLW\WR[LFLW\ IHWDO (U\WKURP\FLQPJ (U\WKURP\FLQPJRUDOO\ loss, prematurity/low birth orally, four times daily x twice daily x 14 days weight, chorioamnionitis, 7 days (U\WKURP\FLQPJRUDOO\ infant pneumonitis/neonatal four times daily x 14 days ophthamia, postpartum (U\WKURP\FLQ(6PJRUDOO\ endometritis, microbiological four times daily x 7 days FXUHVLGHHNjHFWV LQFOXGLQJ (U\WKURP\FLQ(6PJRUDOO\ DOOHUJ\WR[LFLW\JDVWUR FOLQLFDO four times daily x 14 days FXUH V\PSWRPV FRPSOLDQFH Important: HIV acquisition, quality of life, transmission to partner

4. Lymphogranuloma venereum (LGV) in all populations

Population Intervention Comparator Outcome Adults and 'R[\F\FOLQHPJ 'R[\F\FOLQHPJWZLFHGDLO\ Critical: Clinical cure, adolescents with twice daily x 21 days x 14 days microbiological cure LGV Azithromycin 1 g orally (U\WKURP\FLQEDVHPJ Important: STI complications, once a week x 1–3 orally, four times daily x 21 days VLGHHNjHFWV LQFOXGLQJDOOHUJ\ weeks WR[LFLW\JDVWUR TXDOLW\RI life, HIV transmission and acquisition, compliance, LGV transmission to partner

5. Ophthalmia neonatorum treatment

Population Intervention and comparator Outcome Neonates Erythromycin in 4 divided doses orally, daily x 14 days: Critical: Clinical cure, with neonatal bPJNJGD\bPJNJGD\RUbPJNJGD\ microbiological cure, conjunctivitis $]LWKURP\FLQPJNJGD\RUDOO\GDLO\[GD\V &RPSOLFDWLRQVVLGHHNjHFWV 7ULPHWKRSULPbPJVXOIDbPJRUDOO\WZLFHGDLO\ (including allergy, toxicity, [bGD\V JDVWUR DQWLPLFURELDO resistance, compliance

6 and 7. Ophthalmia neonatorum prophylaxis

Population Intervention and comparator Outcome Neonates at risk Ophthalmic ointment in each eye at the time of delivery: Critical: Absence of for ophthalmia (U\WKURP\FLQ conjunctivitis, keratitis, neonatorum Silver nitrate 1% complications, blindness, Chloramphenicol corneal scarring, antimicrobial Tetracycline 1% resistance Povidone iodine 2.5% WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS 35

REVIEWS OF THE EVIDENCE

SEARCH FOR EVIDENCE FOR EFFECTS Primary studies were searched for in the Cochrane OF INTERVENTIONS &HQWUDO5HJLVWHURI&RQWUROOHG7ULDOV &(175$/  MEDLINE and Embase databases. Search end dates for To avoid duplication of reviews that have been each PICO question varied between March and October previously published, evidence was searched using  VHHOLVWEHORZ 7KHVWUDWHJLHVLQFOXGHGVHDUFKLQJ DKLHUDUFKLFDODSSURDFK7KHWHDPnjUVWVHDUFKHGIRU for subject headings and text words that included synthesized evidence then searched the primary FKODP\GLDDQGVSHFLnjFLQWHUYHQWLRQV HJPHGLFDWLRQ studies for all the factors needed to complete the QDPHVDQGFODVVHV $GGLWLRQDOVWUDWHJLHVLQFOXGHG evidence-to-decision framework for each question checking reference lists and consulting with the GDG LHEHQHnjWVDQGKDUPVSDWLHQWYDOXHVDFFHSWDELOLW\ for any missed articles. We searched for RCTs for critical IHDVLELOLW\HTXLW\DQGFRVWV  and important outcomes, and non-randomized studies The hierarchical approach consisted of identifying for critical outcomes when no evidence was available pre-existing synthesized evidence, including from from RCTs. previously published guidelines that included systematic Search end dates: reviews of the literature. When synthesized evidence DERXWEHQHnjWVDQGKDUPVIRUDQLQWHUYHQWLRQZDVQRW • 8QFRPSOLFDWHGJHQLWDO FHUYL[XUHWKUD FKODP\GLDO available or the synthesized evidence was not up to date, LQIHFWLRQVLQDGXOWVDQGDGROHVFHQWVXSWR0DUFK a new systematic review of randomized controlled trials • Uncomplicated anorectal chlamydial infections 5&7V DQGQRQUDQGRPL]HGVWXGLHVZDVFRQGXFWHG H[FOXGLQJ/*9 LQDGXOWVDQGDGROHVFHQWVXSWR The search strategies were developed by an information -XQH specialist trained in systematic reviews. The strategies • &KODP\GLDLQSUHJQDQF\XSWR-XQHXSWR included the use of keywords from the controlled 'HFHPEHUIRUQRQUDQGRPL]HGFRPSDUDWLYH vocabulary of the database and text words based studies on the PICO questions. There were no restrictions • Lymphogranuloma venereum in all populations: based on language, publication status or study design. XSWR-XQH RCTs were included for critical and important outcomes, • 2SKWKDOPLDQHRQDWRUXPWUHDWPHQWXSWR0D\ and non-randomized studies for critical outcomes when no evidence was available from RCTs. Additional • Ophthalmia neonatorum prevention: up to strategies included contacting Cochrane review groups 2FWREHU and authors of study protocols. The Cochrane Library suite of databases (Cochrane Database of Systematic Reviews [CDSR], Database RI$EVWUDFWVRI5HYLHZVRI(NjHFWV>'$5(@+HDOWK Technology Assessment [HTA] database and the $PHULFDQ&ROOHJHRI3K\VLFLDQV>$&3@-RXUQDO&OXE  was searched for published systematic reviews and SURWRFROVIURPWR Search strategy: 1. chlamydia.mp. 2. trachomatis.mp. 3. ct infection*.tw. 4. or/1-3 36 WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

SCREENING STUDIES, DATA EXTRACTION PATIENT VALUES AND PREFERENCES, AND ANALYSIS ACCEPTABILITY, EQUITY AND FEASIBILITY Two researchers independently screened titles and Studies on patient values and preferences, acceptability, DEVWUDFWVRIV\VWHPDWLFUHYLHZVLGHQWLnjHGWKURXJK equity and feasibility were searched for and screened database searching to determine studies eligible for using two methods. First, while screening studies for inclusion in the analysis. Disagreements were resolved WKHHNjHFWVRIWUHDWPHQWVDQGFRVWVWZRLQYHVWLJDWRUV by discussing study inclusion with a third member of LGHQWLnjHGVWXGLHVRISRWHQWLDOUHOHYDQFHLQWKHVHDUHDV the research team. Data were extracted using a pilot- Secondly, a separate search was conducted in MEDLINE, tested form for patient characteristics (including the (PEDVHDQG3V\F,1)2IURP-DQXDU\WR-XO\ VXEJURXSVLGHQWLnjHGE\WKH*'* GLDJQRVLVWUHDWPHQW 7H[WZRUGVDQGNH\ZRUGVIRUWKHGLNjHUHQW67,VZHUH GRVHVFKHGXOHHWF VHWWLQJIROORZXSDQGRXWFRPHV used in combination with words such as “preference”, Two investigators independently abstracted data. “adherence”, “satisfaction”, “attitudes”, “health utilities” Risk of bias of each study was also assessed using risk and “value”, “equity” and “feasibility”. The results of bias tools appropriate for RCTs (http://handbook. LQFOXGHGXQLTXHUHIHUHQFHV7ZRLQYHVWLJDWRUV cochrane.org/chapter_8/8_assessing_risk_of_bias_ VFUHHQHGWKHVWXGLHVDQGVWXGLHVZHUHLGHQWLnjHG LQBLQFOXGHGBVWXGLHVKWP DQGXVLQJWKH5LVN2I%LDV,Q for full text retrieval. Any study design was included 1RQUDQGRPL]HG6WXGLHVRI,QWHUYHQWLRQV 52%,16, that addressed equity or feasibility. In addition, SUHYLRXVO\FDOOHG$&52%$7 WRROWRDVVHVVQRQ when adherence was measured in RCTs or non- UDQGRPL]HGVWXGLHV ZZZULVNRIELDVLQIR  randomized studies, the data were collected, V\QWKHVL]HGDQGSUHVHQWHGLQWKHHYLGHQFHSURnjOHV 7RPHDVXUHWKHWUHDWPHQWHNjHFWWKHGDWDZHUH for each PICO question. analysed using RevMan 5.2.12 The following study designs were included: For dichotomous outcomes, we calculated relative risks ZLWKFRQnjGHQFHLQWHUYDOV HJULVNUDWLRVDQGRGGV a. Patient utilities and health status values studies: UDWLRV E\SRROLQJUHVXOWVIURP5&7VDQGSRROLQJUHVXOWV These studies examine how patients value alternative IURPQRQUDQGRPL]HGVWXGLHVXVLQJWKHUDQGRPHNjHFWV health states and their experiences with treatment. PRGHO0RGHUDWHWRKLJKKHWHURJHQHLW\ ,! ZDV The measurement techniques used can include: H[SORUHG(NjHFWVZHUHFRQYHUWHGWRDEVROXWHHNjHFWV VWDQGDUGJDPEOHWLPHWUDGHRNjYLVXDODQDORJXH XVLQJWKHFDOFXODWHGUHODWLYHHNjHFWDQGDUHSUHVHQWDWLYH scale, or mapping results based on generic surveys EDVHOLQHULVN DJUHHGXSRQE\WKH*'* :KHQQRQ (XUR4ROnjYHGLPHQVLRQVKHDOWKTXHVWLRQQDLUH>(4 randomized studies with one group were included, a '@RUWKH,WHP6KRUW)RUP+HDOWK6XUYH\>6)@  SRROHGSURSRUWLRQRIDQHYHQW DQGFRQnjGHQFHLQWHUYDOV  RUVSHFLnjFPHDVXUHPHQW HJ6W*HRUJH5HVSLUDWRU\ were calculated across the studies using the generic 4XHVWLRQQDLUH RIKHDOWKUHODWHGTXDOLW\RIOLIH inverse variance. For continuous outcomes, a mean E 6WXGLHVRISDWLHQWVšGLUHFWFKRLFHVZKHQSUHVHQWHG GLNjHUHQFHRUDVWDQGDUGL]HGPHDQGLNjHUHQFH ZKHQ with decision aids: These studies examine the VWXGLHVXVHGGLNjHUHQWVFDOHVWRPHDVXUHDQRXWFRPH  choices patients make when presented with decision was calculated. When possible, the forest plots of the aids for management options (i.e. probabilistic meta-analyses were made available to the GDG. WUDGHRNjWHFKQLTXHV  When data could not be pooled across studies, narrative c. Studies on non-utility measurement of health states: synthesis methods were used (see http://methods. 7KHVHVWXGLHVTXDQWLWDWLYHO\H[DPLQHSDWLHQWVš FRFKUDQHRUJVLWHVPHWKRGVFRFKUDQHRUJnjOHV views, attitudes, satisfaction or preferences through 0FNHQ]LHSGI 5HVXOWVZHUHSUHVHQWHGLQWDEOHV TXHVWLRQQDLUHVRUVFDOHVWKHVHDUHQHLWKHUXWLOLW\ HJPHGLDQHNjHFWVZLWKLQWHUTXDUWLOHUDQJHV RUZHUH VWXGLHVQRUVWXGLHVRISDWLHQWVšUHVSRQVHVWR QDUUDWLYHO\GHVFULEHGE\GLUHFWLRQRIWKHHNjHFWRUE\ decision aids. Patients are asked about how VWDWLVWLFDOVLJQLnjFDQFHDVUHSRUWHGLQWKHSULPDU\VWXG\ desirable or aversive a particular outcome is for them. This category includes some studies that use questionnaires or scales. G 4XDOLWDWLYHVWXGLHV7KHVHVWXGLHVH[SORUHSDWLHQWVš views, attitudes, satisfactions or preferences related WRGLNjHUHQWWUHDWPHQWRSWLRQVEDVHGRQTXDOLWDWLYH research methods including focus group discussions, interviews, etc.

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From the search, we included 17 studies reporting LQIRUPDWLRQUHODWLQJWRGLNjHUHQW67,V,QPDQ\LQVWDQFHV data for all infections informed the evidence for FKODP\GLDVSHFLnjFDOO\

RESOURCES We searched the published literature for evidence on use of resources and obtained data on direct costs of medicines. %DVHGRQWKHOLVWRISRVVLEOHWUHDWPHQWVLGHQWLnjHGE\ the GDG, an estimate of the cost associated with each alternative was calculated. This costing estimate refers only to the actual market price of the medication and does not include the costs of other resources that could be involved, such as syringes, injection time or needle disposal. Data were presented in a table and included: treatment, dose per day, treatment duration, days, medicine cost per dose, medicine cost per full course of treatment, DQGRISURFXUHPHQWFRVWV DVGHnjQHGLQWKH 06+,QWHUQDWLRQDOGUXJSULFHLQGLFDWRUJXLGH 13$njQDO price for a full course of treatment for each medicine by dosage was calculated as the number of doses per day, multiplied by the number of days of the treatment, plus 25% of the procurement costs for the medicines used. The unit price of the medicine was obtained from the PHGLDQSULFHVSURYLGHGLQWKH06+,QWHUQDWLRQDO drug price indicator guide and information available on the Internet. In order to determine a precise and reliable estimate, the price per unit (all expressed in 86GROODUV ZDVSURYLGHGRQO\ZKHQWKHLQIRUPDWLRQ available matched the dosage of interest (grams per SLOORUXQLWVSHUYLDO 1RFDOFXODWLRQVZHUHPDGH based on assumptions about the cost per unit of hypothetical packaging not listed in the directory. The major medical databases were also searched (MEDLINE, Embase and the Cochrane Library for Economic Evaluation and Technology Assessment UHSRUWV IURP-DQXDU\WR-XO\7KUHHVWXGLHV DGGUHVVHGWKHFRVWHNjHFWLYHQHVVRIGLNjHUHQWWUHDWPHQW strategies for chlamydia. In addition, while screening VWXGLHVIRUWKHHNjHFWVRIWUHDWPHQWVWZRLQYHVWLJDWRUV DOVRLGHQWLnjHGVWXGLHVRISRWHQWLDOUHOHYDQFHIRUFRVWV and abstracted data regarding possible resources to be considered during the decision-making process.

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APPLYING THE GRADE APPROACH TO MAKING THE RECOMMENDATIONS

EVIDENCE PROFILES MAKING THE RECOMMENDATIONS $QHYLGHQFHSURnjOHZDVPDGHIRUHDFK3,&2TXHVWLRQ ,Q2FWREHUWKH*'*PHWWRPDNHWKH XVLQJWKH*5$'(SURVRIWZDUH ZZZJUDGHSURRUJ  recommendations. This meeting was facilitated by (DFKSURnjOHLQFOXGHGWKHFULWLFDODQGLPSRUWDQW two co-chairs – one with expertise in GRADE and the RXWFRPHVWKHUHODWLYHDQGDEVROXWHHNjHFWVDQGWKH other with clinical expertise of chlamydia. During the quality of evidence according to the GRADE domains PHHWLQJWKHHYLGHQFHSURnjOHVDQGHYLGHQFHWRGHFLVLRQ VHHWKH*5$'(KDQGERRN 14%ULHǍ\WKH*5$'( frameworks were presented by the methodologists. approach assesses the quality of evidence for treatment The GDG discussed each GRADE criterion and judged interventions using well-established criteria for ZKLFKLQWHUYHQWLRQZDVIDYRXUHG7KHQDnjQDOGHFLVLRQ the design, risk of bias, inconsistency, indirectness, and guideline recommendation was developed. LPSUHFLVLRQHNjHFWVL]HGRVHŞUHVSRQVHFXUYHDQG The goal was to arrive at agreement across all members RWKHUFRQVLGHUDWLRQVWKDWPD\DNjHFWWKHTXDOLW\RI of the GDG and this was facilitated by the chairpersons the evidence. Two investigators used the GRADE through discussion. When there was disagreement for approach to assess the quality and level of a criterion, it was noted in the evidence-to-decision FHUWDLQW\RIWKHHYLGHQFH7KHHYLGHQFHSURnjOHVIRU framework for the relevant judgement. If there was each recommendation are available in Web annex D. GLVDJUHHPHQWIRUDQ\RIWKHnjQDOUHFRPPHQGDWLRQV the plan was for the GDG to vote and the numbers to be recorded. Because there was no disagreement (9,'(1&(72'(&,6,21)5$0(:25.6 IRUDQ\RIWKHnjQDOUHFRPPHQGDWLRQVKRZHYHUYRWHV Evidence-to-decision frameworks were also developed were not taken or reported in these guidelines. XVLQJ*5$'(SURVRIWZDUH ZZZJUDGHSURRUJ  The GDG made a strong or conditional recommendation Evidence-to-decision frameworks present the desirable for or against each intervention and described special DQGXQGHVLUDEOHHNjHFWVRIWKHLQWHUYHQWLRQVWKHYDOXH circumstances in the remarks. Research implications of the outcomes, the costs and resource use, the were also developed and presented, based on the gaps acceptability of the interventions to all stakeholders, LGHQWLnjHGLQWKHHYLGHQFH)ROORZLQJWKHPHHWLQJWKH the impact on health equity, and the feasibility of UHFRPPHQGDWLRQVZHUHnjQDOL]HGYLDWHOHFRQIHUHQFH implementation (i.e. the GRADE criteria for making DQGnjQDODSSURYDOZDVREWDLQHGIURPWKH*'*PHPEHUV GHFLVLRQV 7KHHYLGHQFHWRGHFLVLRQIUDPHZRUNV electronically. All decisions and discussions from the are based on a population perspective for these GDG for each recommendation are available in the recommendations. All GRADE criteria were evidence-to-decision frameworks in Web annex D. considered from this perspective.

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ANNEX C: LISTS OF REFERENCES FOR REVIEWED EVIDENCE

RECOMMENDATION 1 11. Ibsen HH, Møller BR, Halkier-Sørensen L, From E. Treatment RIQRQJRQRFRFFDOXUHWKULWLVFRPSDULVRQRIRǍR[DFLQDQG HU\WKURP\FLQ6H[7UDQVP'LV   Treatments for adults and adolescents with uncomplicated genital (cervix, urethra) 12. Kitchen VS, Donegan C, Ward H, Thomas B, Harris JR, Taylor- 5RELQVRQ'&RPSDULVRQRIRǍR[DFLQZLWKGR[\F\FOLQHLQWKH chlamydial infections treatment of non-gonococcal urethritis and cervical chlamydial LQIHFWLRQ-$QWLPLFURE&KHPRWKHU 6XSSO'  Systematic review 13. Lauharanta J, Saarinen K, Mustonen MT, Happonen HP. 1. Páez-Canro C, Martinez-Martinez F, Alzate JP, Lethaby A, Gaitán Single-dose oral azithromycin versus seven-day doxycycline HG. Antibiotics for treating genital Chlamydia trachomatis in the treatment of non-gonococcal urethritis in males. J LQIHFWLRQLQPHQDQGQRQSUHJQDQWZRPHQ SURWRFRO  $QWLPLFURE&KHPRWKHU 6XSSO(  &RFKUDQH'DWDEDVH6\VW5HY  &' 14. Lister PJ, Balechandran T, Ridgway GL, Robinson AJ. Comparison of azithromycin and doxycycline in the treatment Included studies of non-gonococcal urethritis in men. J Antimicrob Chemother. 1. Bowie WR, Yu JS, Fawcett A, Jones HD. Tetracycline in  6XSSO(  nongonococcal urethritis. Comparison of 2 g and 1 g daily 15. Manhart LE, Gillespie CW, Lowens MS, Khosropour CM, IRUVHYHQGD\V%U-9HQHU'LV   Colombara DV, Golden MR, et al. Standard treatment regimens 2. Campbell WF, Dodson MG. Clindamycin therapy for Chlamydia for nongonococcal urethritis have similar but declining trachomatisLQZRPHQ$P-2EVWHW*\QHFRO   cure rates: a randomized controlled trial. Clin Infect Dis.    3. Cramers M, Kaspersen P, From E, Møller BR. Pivampicillin compared with erythromycin for treating women with  0DUWLQ'+0URF]NRZVNL7)'DOX=$0F&DUW\--RQHV genital Chlamydia trachomatis infection. Genitourin RB, Hopkins SJ, et al. A controlled trial of a single dose of 0HG   azithromycin for the treatment of chlamydial urethritis and cervicitis. The Azithromycin for Chlamydial Infections Study 4. Csángó PA, Gundersen T, Anestad G. Doxycycline in the *URXS1(QJO-0HG   treatment of chlamydial urethritis: a therapeutic study. 3KDUPDWKHUDSHXWLFD   17. McCormack WM, Dalu ZA, Martin DH, Hook EW 3rd, Laisi R, .HOO3HWDO7URYDǍR[DFLQ&KODP\GLDO8UHWKULWLV&HUYLFLWLV 5. Fong IW, Linton W, Simbul M, Thorup R, McLaughlin B, Rahm V, 6WXG\*URXS'RXEOHEOLQGFRPSDULVRQRIWURYDǍR[DFLQDQG HWDO7UHDWPHQWRIQRQJRQRFRFFDOXUHWKULWLVZLWKFLSURǍR[DFLQ doxycycline in the treatment of uncomplicated Chlamydial $P-0HG $  XUHWKULWLVDQGFHUYLFLWLV6H[7UDQVP'LV  

 *HLVOHU:0.ROWXQ:'$EGHOVD\HG1%XULJR-0HQD/7D\ORU 18. McCormack WM, Martin DH, Hook EW 3rd, Jones RB. Daily oral 61HWDO6DIHW\DQGHǎFDF\RI:&YHUVXVYLEUDP\FLQ JUHSDǍR[DFLQYVWZLFHGDLO\RUDOGR[\F\FOLQHLQWKHWUHDWPHQWRI for the treatment of uncomplicated urogenital Chlamydia Chlamydia trachomatis endocervical infection. Infect Dis Obstet trachomatis infection: a randomized, double-blind, double- DQG*\QHFRO   dummy active-controlled, multicenter trial. Clin Infect Dis.   GRLFLGFLV 19. Nilsen A, Halsos A, Johansen A, Hansen E, Tørud E, Moseng D, et al. A double blind study of single dose azithromycin and 7. Guven MA, Gunyeli I, Dogan M, Ciragil P, Bakaris S, Gul M. doxycycline in the treatment of chlamydial urethritis in males. 7KHGHPRJUDSKLFDQGEHKDYLRXUDOSURnjOHRIZRPHQZLWK *HQLWRXULQ0HG   cervicitis infected with Chlamydia trachomatis, Mycoplasma hominis and Ureaplasma urealyticum and the comparison of two  3HUHLUD&$0RQWDJQLQL6'$SURVSHFWLYHUDQGRPL]HGWULDORI PHGLFDOUHJLPHQV$UFK*\QHFRO2EVWHW RǍR[DFLQYVGR[\F\FOLQHLQWKHWUHDWPHQWRIQRQJRQRFRFFDO urethritis caused by Chlamydia trachomatis. Arquivos brasileiros 8. Hammerschlag MR, Golden NH, Oh MK, Gelling M, Sturdevant GHPHGLFLQD   M, Brown PR, et al. Single dose of azithromycin for the treatment of genital chlamydial infections in adolescents. J Pediatr. 21. Robson HG, Shah PP, Lalonde RG, Hayes L, Senikas VM.    Comparison of rosaramicin and erythromycin stearate for treatment of cervical infection with Chlamydia trachomatis. 9. Hawkins DA, Taylor-Robinson D, Evans RT, Furr PM, Harris JR. 6H[7UDQV'LV   Unsuccessful treatment of non-gonococcal urethritis with rosoxacin provides information on the aetiology of the disease. 22. Stamm WE, Hicks CB, Martin DH, Leone P, Hook EW 3rd, *HQLWRXULQ0HG   Cooper RH, et al. Azithromycin for empirical treatment of the nongonococcal urethritis syndrome in men. A randomized  +RRWRQ705RJHUV0(0HGLQD7*.XZDPXUD/((ZHUV& GRXEOHEOLQGVWXG\-$0$   5REHUWV3/HWDO&LSURǍR[DFLQFRPSDUHGZLWKGR[\F\FOLQH IRUQRQJRQRFRFFDOXUHWKULWLV,QHNjHFWLYHQHVVDJDLQVW 23. Thambar IV, Simmons PD, Thin RN, Darougar S, Yearsley P. Chlamydia trachomatis due to relapsing infection. JAMA. Double-blind comparison of two regimens in the treatment of    nongonococcal urethritis. Seven-day vs 21-day course of triple WHWUDF\FOLQF 'HWHFOR %U-9HQHU'LV   40 WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

24. Topic A, Skerk V, Puntaric A, Milavec Puretic V, Beus A, Begovac RECOMMENDATION 2 -$]LWKURP\FLQRUJUDPGRVHLQWKHWUHDWPHQWRI patients with asymptomatic urogenital chlamydial infections. J &KHPRWKHU   Treatments in adults and adolescents with uncomplicated anorectal chlamydial infections 25. van der Willigen AH, Polak-Vogelzang AA, Habbema L, :DJHQYRRUW-+&OLQLFDOHǎFDF\RIFLSURǍR[DFLQYHUVXV (excluding lymphogranuloma venereum doxycycline in the treatment of non-gonococcal urethritis LQPDOHV(XU-&OLQ0LFURELRO,QIHFW'LV   Systematic review 1. Kong FY, Tabrizi SN, Fairley CK, Vodstrcil LA, Huston WM, Chen 3DWLHQWYDOXHVDQGSUHIHUHQFHVDFFHSWDELOLW\DQGFRVWVSHFLnjFWR 0HWDO7KHHǎFDF\RID]LWKURP\FLQDQGGR[\F\FOLQHIRUWKH chlamydial infections treatment of rectal chlamydia infection: a systematic review DQGPHWDDQDO\VLV-$QWLPLFURE&KHPRWKHU   1. Dixon-Woods M, Stokes T, Young B, Phelps K, Windridge GRLMDFGNX K, Shukla R. Choosing and using services for sexual health: a qualitative study of women's views. Sex Transm Infect.    Included studies

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1. Kingston M, Carlin E. Treatment of sexually transmitted 4. Hathorn E, Opie C, Goold P. What is the appropriate treatment infections with single-dose therapy: a double-edged sword. for the management of rectal Chlamydia trachomatis in men 'UXJV   DQGZRPHQ"6H[7UDQV,QIHFW  GRL VH[WUDQV 2. Nagarkar A, Mhaskar P. A systematic review on the prevalence and utilization of health care services for reproductive tract 5. Khosropour CM, Dombrowski JC, Barbee LA, Manhart LE, infections/sexually transmitted infections: evidence from India. Golden MR. Comparing azithromycin and doxycycline for ,QGLDQ-6H[7UDQVP'LV  GRL the treatment of rectal chlamydial infection: a retrospective  FRKRUWVWXG\6H[7UDQVP'LV  GRL 2/4 3. Ryan R, Santesso N, Lowe D, Hill S, Grimshaw J, Prictor M, HWDO,QWHUYHQWLRQVWRLPSURYHVDIHDQGHNjHFWLYHPHGLFLQHV  .KRVURSRXU&0'XDQ50HWVFK/5)HDVWHU'-*ROGHQ use by consumers: an overview of systematic reviews. MR. Persistent/recurrent chlamydial infection among STD &RFKUDQH'DWDEDVH6\VW5HY&' clinic patients treated with CDC- recommended therapies. Abstracts of the STI and AIDS World Congress, Vienna, Additional references $XVWULD6H[7UDQVP,QIHFW 6XSSO $GRL VH[WUDQV 1. Amin A, Garcia Moreno C. Addressing gender-based violence WRUHGXFHULVNRI67,DQG+,96H[7UDQVP,QIHFW 7. Steedman NM, McMillan A. Treatment of asymptomatic rectal 6XSSO $GRLVH[WUDQV Chlamydia trachomatisLVVLQJOHGRVHD]LWKURP\FLQHNjHFWLYH",QW -67'$,'6  GRLLMVD  *OREDO%XUGHQRI'LVHDVH6WXG\&ROODERUDWRUV*OREDO regional, and national incidence, prevalence, and years lived 8. White JA. Manifestations and management of lymphogranuloma ZLWKGLVDELOLW\IRUDFXWHDQGFKURQLFGLVHDVHVDQGLQMXULHV YHQHUHXP&XUU2SLQ,QIHFW'LV  GRL LQFRXQWULHVDV\VWHPDWLFDQDO\VLVIRUWKH*OREDO 4&2EHDDH %XUGHQRI'LVHDVH6WXG\/DQFHW   GRL6   3DWLHQWYDOXHVDQGSUHIHUHQFHVDFFHSWDELOLW\DQGFRVWVSHFLnjFWR chlamydial infections 3. Holmes K. Sexually transmitted diseases, 4th edition. New York 1< 0F*UDZ+LOO 1. Dixon-Woods M, Stokes T, Young B, Phelps K, Windridge K, Shukla R. Choosing and using services for sexual health: 4. Newman L, Rowley J, Vander Hoorn S, Wijesooriya NS, Unemo a qualitative study of women's views. Sex Transm Infect. M, Low N, et al. Global estimates of the prevalence and    LQFLGHQFHRIIRXUFXUDEOHVH[XDOO\WUDQVPLWWHGLQIHFWLRQVLQ based on systematic review and global reporting. PLoS One.  ,QWHUQDWLRQDOGUXJSULFHLQGLFDWRUJXLGHHGLWLRQ XSGDWHG   HGRLMRXUQDOSRQH DQQXDOO\ 0HGIRUG 0$ 0DQDJHPHQW6FLHQFHVIRU+HDOWK KWWSHUFPVKRUJGPSJXLGHSGI'UXJ3ULFH*XLGHBSGI DFFHVVHG-XQH  WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS 41

Patient values and preferences, acceptability and cost: other 5. Bush MR, Rosa C. Azithromycin and erythromycin in the sexually transmitted infections and conditions treatment of cervical chlamydial infection during pregnancy. 2EVWHW*\QHFRO   1. Nagarkar A, Mhaskar P. A systematic review on the prevalence and utilization of health care services for reproductive tract  &URPEOHKROPH:56FKDFKWHU-*URVVPDQ0/DQGHUV'9 infections/sexually transmitted infections: evidence from India. Sweet RL. Amoxicillin therapy for Chlamydia trachomatis in ,QGLDQ-6H[7UDQVP'LV  GRL SUHJQDQF\2EVWHW*\QHFRO    7. Edwards MS, Newman RB, Carter SG, Leboeuf FW, Menard MK, 2. Ryan R, Santesso N, Lowe D, Hill S, Grimshaw J, Prictor M, Rainwater KP. Randomized clinical trial of azithromycin for the HWDO,QWHUYHQWLRQVWRLPSURYHVDIHDQGHNjHFWLYHPHGLFLQHV treatment of Chlamydia cervicitis in pregnancy. Infect Dis use by consumers: an overview of systematic reviews. 2EVWHW*\QHFRO   &RFKUDQH'DWDEDVH6\VW5HY&' 8. Jacobson GF, Autry AM, Kirby RS, Liverman EM, Motley RU. A randomized controlled trial comparing amoxicillin and Additional references azithromycin for the treatment of Chlamydia trachomatis in 1. Amin A, Garcia Moreno C. Addressing gender-based SUHJQDQF\$P-2EVWHW*\QHFRO   violence to reduce risk of STI and HIV. Sex Transm Infect. 9. Kacmar J, Cheh E, Montagno A, Peipert JF. A randomized  6XSSO $ trial of azithromycin versus amoxicillin for the treatment of  *OREDO%XUGHQRI'LVHDVH6WXG\&ROODERUDWRUV*OREDO Chlamydia trachomatis in pregnancy. Infect Dis Obstet Gynecol. regional, and national incidence, prevalence, and years lived    ZLWKGLVDELOLW\IRUDFXWHDQGFKURQLFGLVHDVHVDQGLQMXULHVLQ  0DJDW$+$OJHU/61DJH\'$+DWFK9/RYFKLN-&'RXEOH FRXQWULHVŞDV\VWHPDWLFDQDO\VLVIRUWKH*OREDO blind randomized study comparing amoxicillin and erythromycin %XUGHQRI'LVHDVH6WXG\/DQFHW   for the treatment of Chlamydia trachomatis in pregnancy. Obstet GRL6   *\QHFRO 3W 

3. Holmes K. Sexually transmitted diseases, 4th edition. New York 11. Martin DH, Eschenbach DA, Cotch MF, Nugent RP, Rao AV, 1< 0F*UDZ+LOO .OHEDQRNj0$HWDO'RXEOHEOLQGSODFHERFRQWUROOHGWUHDWPHQW 4. Newman L, Rowley J, Vander Hoorn S, Wijesooriya NS, Unemo trial of Chlamydia trachomatis endocervical infections in M, Low N, et al. Global estimates of the prevalence and SUHJQDQWZRPHQ,QIHFW'LV2EVWHW*\QHFRO   LQFLGHQFHRIIRXUFXUDEOHVH[XDOO\WUDQVPLWWHGLQIHFWLRQVLQ  1DGDnj0$EGDOL.+3DUVDQHMDG0(5DMDHH)DUG$5.DYLDQL0 based on systematic review and global reporting. PLoS One. A comparison of amoxicillin and erythromycin for asymptomatic   HGRLMRXUQDOSRQH Chlamydia trachomatis infection in pregnancy. Int J Gynaecol 2EVWHW   RECOMMENDATIONS 3A, 3B, 3C 13. Rahangdale L, Guerry S, Bauer HM, Packel L, Rhew M, Baxter R, et al. An observational cohort study of Chlamydia trachomatis WUHDWPHQWLQSUHJQDQF\6H[7UDQVP'LV   Treatments in pregnant women with chlamydial infections 14. Rosenn M, Macones GA, Silverman N. A randomized trial of erythromycin and azithromycin for the treatment of chlamydia LQIHFWLRQLQSUHJQDQF\$P-2EVWHW*\QHFRO Systematic review 15. Rosenn MF, Macones GA, Silverman NS. Randomized trial 1. Brocklehurst P, Gordon A, Heatley E, Milan SJ. Antibiotics for of erythromycin and azithromycin for treatment of treating bacterial vaginosis in pregnancy. Cochrane Database chlamydial infection in pregnancy. Infect Dis Obstet Gynecol. 6\VW5HY  &'   

Included studies  6LOYHUPDQ16+RFKPDQ06XOOLYDQ0:RPDFN0$UDQGRPL]HG prospective trial of amoxicillin versus erythromycin for the 1. Adair CD, Gunter M, Stovall TG, McElroy G, Veille JC, Ernest JM. treatment of chlamydia in pregnancy. Am J Obstet Gynecol. Chlamydia in pregnancy: a randomized trial of azithromycin and  HU\WKURP\FLQ2EVWHW*\QHFRO   17. Silverman NS, Sullivan M, Hochman M, Womack M, Jungkind 2. Alary M, Joly JR, Moutquin JM, Mondor M, Boucher M, Fortier A, DL. A randomized, prospective trial comparing amoxicillin and et al. Randomised comparison of amoxicillin and erythromycin in erythromycin for the treatment of Chlamydia trachomatis in treatment of genital chlamydial infection in pregnancy. Lancet. SUHJQDQF\$P-2EVWHW*\QHFRO      18. Turrentine MA, Troyer L, Gonik B. Randomized prospective  $OJHU/6/RYFKLN-&&RPSDUDWLYHHǎFDF\RIFOLQGDP\FLQYHUVXV study comparing erythromycin, amoxicillin and clindamycin for erythromycin in eradication of antenatal Chlamydia trachomatis. the treatment of Chlamydia trachomatis in pregnancy. Infect Dis $P-2EVWHW*\QHFRO   2EVWHW*\QHFRO  

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Reviews and studies for adverse outcomes RECOMMENDATION 4  0RUHQF\$0%XMROG(7KHHNjHFWRIVHFRQGWULPHVWHUDQWLELRWLF therapy on the rate of preterm birth. J Obstet Gynaecol Treatments for adults and adolescents with &DQ   lymphogranuloma venereum 2. Romøren M, Lindbæk M, Nordeng H. Pregnancy outcome after gestational exposure to erythromycin – a population- Included studies based register study from Norway. Br J Clin Pharmacol. 1. Ballard RC, Ye H, Matta A, Dangor Y, Radebe F. Treatment   GRLM[ of chancroid with azithromycin. Int J STD AIDS. 3. van den Broek NR, White SA, Goodall M, Ntonya C, Kayira E,  6XSSO  Kafulafula G, Neilson JP. The APPLe study: a randomized, 2. Collado CAM, Aguilar REB. Lymphogranuloma venereum. community-based, placebo-controlled trial of azithromycin for &OLQLFDODVSHFWVGLDJQRVWLFPHWKRGVDQGWUHDWPHQWRI the prevention of preterm birth, with meta-analysis. PLoS Med. SDWLHQWV'HUPDWRORJLD5HYLVWD0H[LFDQD     HGRLMRXUQDOSPHG 3. De Vries C, Smelov V, Middelburg JG, Pleijster J, Speksnijder 3DWLHQWYDOXHVDQGSUHIHUHQFHVDFFHSWDELOLW\DQGFRVWVSHFLnjFWR AG, Morré SA. Delayed microbial cure of lymphogranuloma chlamydial infections venereum proctitis with doxycycline treatment. Clin Infect Dis.   HHGRL 1. Dixon-Woods M, Stokes T, Young B, Phelps K, Windridge K, Shukla R. Choosing and using services for sexual health: 4. Heras E, Llibre JM, Martró E, Casabona J, Martin R, Sirera G. a qualitative study of women's views. Sex Transm Infect. [Lymphogranuloma venereum proctocolitis in men with HIV-1    LQIHFWLRQ@(QIHUP,QIHFF0LFURELRO&OLQ   LQ 6SDQLVK GRLMHLPF>FRUUHFWLRQLQ  ,QWHUQDWLRQDOGUXJSULFHLQGLFDWRUJXLGHHGLWLRQ XQGDWHG (QIHUP,QIHFF0LFURELRO&OLQ-XQ  @ DQQXDOO\ 0HGIRUG 0$ 0DQDJHPHQW6FLHQFHIRU+HDOWK KWWSHUFPVKRUJGPSJXLGHSGI'UXJ3ULFH*XLGHBSGI 5. Hevia H, Honeyman J, De la Parra M. [Treatment of early DFFHVVHG-XQH  syphilis and venereal lymphogranulomatosis with doxycycline]. 5HY0HG&KLO   LQ6SDQLVK  3. Pitsouni E, Iavazzo C, Athanasiou S, Falagas ME. Single-dose azithromycin versus erythromycin or amoxicillin for Chlamydia  +LOO6&+RGVRQ/6PLWK$$QDXGLWRQWKHPDQDJHPHQW trachomatis infection during pregnancy: a meta-analysis of lymphogranuloma venereum in a sexual health clinic in of randomised controlled trials. Int J Antimicrob Agents. /RQGRQ8.,QW-67'$,'6  GRL    LMVD 7. Kamarashev J, Riess CE, Mosimann J, Läuchlf S. Patient values and preferences, acceptability and cost: other Lymphogranuloma venereum in Zurich, Switzerland: Chlamydia sexually transmitted infections and conditions trachomatis serovar L2 proctitis among men who have sex with 1. Nagarkar A, Mhaskar P. A systematic review on the prevalence PHQ6ZLVV0HG:NO\  GRLVPZ and utilization of health care services for reproductive tract 8. Krishnamurthy VR, Johnson M, Rangasamy J, Murali RVK. infections/sexually transmitted infections: evidence from (ǎFDF\RIVWUHSWRP\FLQFKORUDPSKHQLFROFRWULPR[D]ROH ,QGLD,QGLDQ-6H[7UDQVP'LV   and doxycycline in lymphogranuloma venereum. Indian J Sex GRL 7UDQVP'LV  

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13. Vas A, Leighton J, Saxon C, Lebari D, Stott C, Ahmad S, et al. Audit of the clinical management of lymphogranuloma venereum in three inner-city genitourinary medicine clinics. International Journal of STD and AIDS, Conference, 11th Spring Meeting of WKH%ULWLVK$VVRFLDWLRQIRU6H[XDO+HDOWKDQG+,9 %$6++ Ş 0D\%ULVWRO8QLWHG.LQJGRP&RQIHUHQFH3XEOLFDWLRQ WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS 43

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2. Kakar S, Bhalla P, Maria A, Rana M, Chawla R, Mathur NB. RECOMMENDATION 5 Chlamydia trachomatis causing neonatal conjunctivitis in a WHUWLDU\FDUHFHQWHU,QGLDQ-0HG0LFURELRO   Treatment of chlamydial ophthalmia neonatorum GRL

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2. Fransen L, Nsanze H, D'Costa L. Oral erythromycin estolate Systematic reviews in nongonococcal neonatal conjunctivitis. Eur J Sex Transm 'LV    'DUOLQJ(.0F'RQDOG+$PHWDDQDO\VLVRIWKHHǎFDF\RIRFXODU prophylactic agents used for the prevention of gonococcal  +HJJLH$'-DNjH$&6WXDUW/$7KRPEUH366RUHQVHQ58 and chlamydial ophthalmia neonatorum. J Midwifery Womens Topical sulfacetamide vs oral erythromycin for neonatal +HDOWK  GRLMMPZK FKODP\GLDOFRQMXQFWLYLWLV$P-'LV&KLOG   2. Kapoor VS, Whyte R, LaRoche RR. Interventions for 4. Hammerschlag MR, Chandler JW, Alexander ER, English M, SUHYHQWLQJRSKWKDOPLDQHRQDWRUXP LQWHUYHQWLRQSURWRFRO  Koutsky L. Longitudinal studies on chlamydial infections in &RFKUDQH'DWDEDVH6\VW5HY  &' WKHnjUVW\HDURIOLIH3HGLDWU,QIHFW'LV   3. Mabry-Hernandez IR, Koenig HC. Ocular prophylaxis for 5. Hammerschlag,MR, Gelling M., Roblin PM, Kutlin A, Jule gonococcal ophthalmia neonatorum: evidence update JE. Treatment of neonatal chlamydial conjunctivitis with IRUWKH863UHYHQWLYH6HUYLFHV7DVN)RUFH5HDǎUPDWLRQ D]LWKURP\FLQ3HGLDWU,QIHFW'LV-   5HFRPPHQGDWLRQ6WDWHPHQW$+543XEOLFDWLRQ1R  3DWDPDVXFRQ355HWWLQJ3-)DXVW./.XVPLHV]+7 5RFNYLOOH 0' $JHQF\IRU+HDOWKFDUH5HVHDUFKDQG Nelson JD. Oral v topical erythromycin therapies for 4XDOLW\ FKODP\GLDOFRQMXQFWLYLWLV$P-'LV&KLOG    =XSSD$$'š$QGUHD9&DWHQD]]L36FRUUDQR$5RPDJQROL 7. Rosenman MB, Mahon BE, Downs SM, Kleiman MB. C. Ophthalmia neonatorum: what kind of prophylaxis? Oral erythromycin prophylaxis vs watchful waiting in -0DWHUQ)HWDO1HRQDWDO0HG  GRL caring for newborns exposed to Chlamydia trachomatis.  $UFK3HGLDWU$GROHVF0HG   44 WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

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5. Brussieux J, Boisivon A, Théron HP, Faidherbe C, Machado 2. Isenberg SJ, Apt L, Wood M. A controlled trial of povidone iodine N, Michelon B. [Prevention of neonatal conjunctivitis. A as prophylaxis against ophthalmia neonatorum. N Engl J Med. comparative clinical and bacteriologic study of 2 eyedrops: Ş VLOYHUQLWUDWHDQGR[\WHWUDF\FOLQH@$QQ3HGLDWU    LQ)UHQFK  3. Ison CA, Terry P, Bendayna K, Gill MJ, Adams J, Woodford N. 7HWUDF\FOLQHUHVLVWDQWJRQRFRFFLLQ8./DQFHWŞ  &KHQ-<3URSK\OD[LVRIRSKWKDOPLDQHRQDWRUXPFRPSDULVRQ of silver nitrate, tetracycline, erythromycin and no prophylaxis. 4. Knapp JS, Zenilman JM, Biddle JW, Perkins GH, DeWitt WE, 3HGLDWU,QIHFW'LV-   Thomas ML, et al. Frequency and distribution in the United States of strains of Neisseria gonorrhoeae with plasmid-  'DYLG05XPHOW6:HLQWUDXE=(ǎFDF\FRPSDULVRQEHWZHHQ mediated, high-level resistance to tetracycline. J Infect Dis. povidone iodine 2.5% and tetracycline 1% in prevention of  RSKWKDOPLDQHRQDWRUXP2SKWKDOPRORJ\   5. Schwarcz SK, Zenilman JM, Schnell D, Knapp JS, Hook EW 8. Fischer PR, Reta BB. Prevention of neonatal conjunctivitis in 3rd, Thompson S, et al. National surveillance of antimicrobial =DLUH$QQ7URS3DHGLDWU   resistance in Neisseria gonorrhoeae. The Gonococcal Isolate 6XUYHLOODQFH3URMHFW-$0$ 9. Hammerschlag MR, Cummings C, Roblin PM, Williams TH, 'HONH,(ǎFDF\RIQHRQDWDORFXODUSURSK\OD[LVIRUWKHSUHYHQWLRQ of chlamydial and gonococcal conjunctivitis. N Engl J Med. References related to patient values and preferences,    acceptability and cost

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11. Hammerschlag MR, Chandler JW, Alexander ER, English M, 2. Keenan JD, Eckert S, Rutar T. Cost analysis of povidone-iodine Koutsky L. Longitudinal studies on chlamydial infections in for ophthalmia neonatorum prophylaxis. Arch Ophthalmol. WKHnjUVW\HDURIOLIH3HGLDWU,QIHFW'LV     

12. Isenberg SJ, Apt L, Del Signore M, Gichuhi S, Berman NG.  ,QWHUQDWLRQDO'UXJ3ULFH,QGLFDWRU*XLGH(GLWLRQ XSGDWHG A double application approach to ophthalmia neonatorum DQQXDOO\ 0HGIRUG 0$ 0DQDJHPHQW6FLHQFHVIRU+HDOWK SURSK\OD[LV%U-2SKWKDOPRO   KWWSHUFPVKRUJGPSJXLGHSGI'UXJ3ULFH*XLGHBSGI DFFHVVHG-XQH  13. Isenberg SJ, Apt L, Wood M. A controlled trial of povidone-iodine as prophylaxis against ophthalmia neonatorum. N Engl J Med. Additional references     'DUOLQJ(.0F'RQDOG+$PHWDDQDO\VLVRIWKHHǎFDF\RIRFXODU 14. Laga M, Plummer FA, Plot P, Datta P, Namaara W, Neinya-Achola prophylactic agents used for the prevention of gonococcal JO, et al. Prophylaxis of gonococcal and chlamydial ophthalmia and chlamydial ophthalmia neonatorum. J Midwifery Womens neonatorum. A comparison of silver nitrate and tetracycline. +HDOWK  GRLMMPZK 1(QJO-0HG   2. Kakar S, Bhalla P, Maria A, Rana M, Chawla R, Mathur NB. 15. Matinzadeh ZK, Beiragdar F, Kavemanesh Z, Abolgasemi H, Chlamydia trachomatis causing neonatal conjunctivitis in a $PLUVDODUL6(ǎFDF\RIWRSLFDORSKWKDOPLFSURSK\OD[LV WHUWLDU\FDUHFHQWHU,QGLDQ-0HG0LFURELRO   in prevention of ophthalmia neonatorum. Trop Doct. GRL   

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17. Ramirez-Ortiz MA, Rodriguez-Almaraz M, Ochoa-Diazlopez H, Diaz-Prieto P, Rodriguez-Suárez RS. Randomised equivalency trial comparing 2.5% povidone-iodine eye drops and ophthalmic chloramphenicol for preventing neonatal conjunctivitis in a trachoma endemic area in southern Mexico. Br J Ophthalmology.   

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19. Zanoni D, Isenberg SJ, Apt L. A comparison of silver nitrate with erythromycin for prophylaxis against ophthalmia neonatorum. &OLQ3HGLDWU