Treating Genitourinary and Pharyngeal Gonorrhoea with Single Dose Ceftriaxone

Genitourin Med: first published as 10.1136/sti.65.1.14 on 1 January 1989. Downloaded from

Genitourin Med 1989;65:14-17

Treating genitourinary and pharyngeal gonorrhoea with single dose ceftriaxone

J CHRISTOPHERSEN,* A C BOLLERUP,t E FROM,$ J 0 R0NNE-RASMUSSEN,§ K QUITZAUII From the *Department ofDermatovenereology, Gentofte Hospital, Hellerup; the tNeisseria Department, Statens Seruminstitut, Copenhagen; the tDepartment ofDermatovenereology, Marselisborg Hospital, Aarhus; the §Department ofDermatovenereology, Bispebjerg Hospital, Copenhagen; and the IlDepartment ofClinical Research, Roche, Denmark suMMARY The efficacy of ceftriaxone 250 mg given as a single intramuscular dose to treat genitourinary and pharyngeal gonorrhoea is compared with the outcome of the Danish standard treatment for uncomplicated genitourinary gonorrhoea, pivampicillin 1-4 g and probenecid 1 g, both given by mouth. The study comprised 327 patients for whom the diagnosis ofgonorrhoea was made by microscopy of a methylene blue stained smear at their first visit to the clinic and for whom the diagnosis was later confirmed by culture of Neisseria gonorrhoeae. One hundred and seventy patients with genitourinary gonorrhoea (18 with and 152 without concomitant pharyngeal infection) were treated with ceftriaxone. One hundred and fifty seven (17 with and 140 without concomitant pharyngeal infection) were treated with pivampicillin. One week after treatment N gonorrhoeae was isolated from none of 18, 1/152, (1%), 11/17 (65%), and 6/140 (4%) patients, respectively. At a second attendance two weeks after treatment no further treatment failure was found. During the study period, a further 52 patients with pharyngeal infection (with or without concomitant genitourinary infection) that was shown by culture only were treated with a single http://sti.bmj.com/ intramuscular injection of 250 mg ceftriaxone. No treatment failure was observed in this group. Only minor adverse drug reactions were seen. Ceftriaxone 250 mg as a single intramuscular injection is therefore safe and effective in treating gonorrhoea, including pharyngeal infection. on September 26, 2021 by guest. Protected copyright. In some parts of the world single dose regimens of against N gonorrhoeae, and has minimum inhibitory penicillin and probenecid for treating uncomplicated concentrations (MICs) within the range 0.0004-0.03 genitourinary gonorrhoea can still be recommended.' pg/ml.'6 This exceptional activity, combined with high The increasing prevalence of penicillinase producing blood concentrations, pronounced tissue penetration, strains of Neisseria gonorrhoeae (PPNG), strains with and a plasma half life of eight hours, make it chromosomally mediated resistance, and spectino- particularly favourable for treating gonorrhoea. mycin resistant strains, have stressed the need for Clinical trials using single doses of 125-250 mg alternative treatment regimens.2 Moreover, single ceftriaxone have produced cure rates of 100% in dose antibiotic regimens have so far been unsatis- uncomplicated gonorrhoea in men and women.'9 The factory for treating pharyngeal gonorrhoea.34 effect of single dose ceftriaxone in pharyngeal gonorr- Ceftriaxone, a new extended range cephalosporin, is hoea is not well known, but results obtained by Judson one of the most active of all antimicrobial agents et al were promising. A single intramuscular dose of 125 mg ceftriaxone cured 30 (93.8%) of 32 pharyngeal Address for reprints: Dr J Christophersen, Department of infections.' Dermatovenereology, Gentofte Hospital, DK-2900 Hellerup, Denmark The present study aimed to evaluate the efficacy ofa single dose regimen of 250 mg ceftriaxone in pharyn- Accepted for publication 17 August 1988 geal gonorrhoea and to compare the cure rate and the 14 Genitourin Med: first published as 10.1136/sti.65.1.14 on 1 January 1989. Downloaded from

Treating genitourinary andpharyngeal gonorrhoea with single dose ceftriaxone 15 acceptability ofceftriaxone with those of our standard immunofluorescence test or carbohydrate (glucose, initial treatment of non-PPNG infections acquired in maltose, and sucrose) utilisation tests, or both and by a Denmark (1.4 g pivampicillin by mouth given with 1 g Gram stained smear. probenecid). IN VITRO SUSCEPTIBILITY TESTING Patients and methods Susceptibility to ceftriaxone and penicillin was tested by a plate dilution method with twofold dilution steps The study was undertaken as an open randomised of the antibiotics; the results are expressed as the comparative multicentre study. All patients aged over minimum inhibitory concentrations (MICs). The con- 18 who attended the clinics during March 1986 to centrations of ceftriaxone ranged from 0.064 to February 1987 were invited to participate. We in- 000025 jg/ml and for penicillin from 2-4 to 0 0094 cluded patients who gave their informed consent and pg/ml. Isolates requiring an MIC of penicillin of 1.2 for whom a diagnosis of genitourinary or rectal jg/ml or more were examined for the production of gonorrhoea was made by microscopy of a methylene penicillinase by the chromogenic cephalosporin test. blue stained smear at the initial visit. Patients were During the study period, isolates from all patients excluded if they had received antibiotics in the attending two of the participating dermatovenereo- previous seven days, if they had known or suspected logical outpatient clinics were stored in liquid nitrogen hypersensitivity to cephalosporins, penicillins, or for susceptibility testing. From a third clinic, however, lidocaine or if they had known renal or hepatic only isolates from patients who entered the study were insufficiency. stored. A total of 393 patients were randomised to treatment with either ceftriaxone 250 mg given as an Results intramuscular injection or pivampicillin 14 g plus probenecid 1 g given by mouth. Before treatment Table 1 shows the demographic characteristics of the specimens were taken for culture as follows: one each study population. Of 393 patients enrolled in the from the urethra and the rectum and two from the study, 327 (83%), whose diagnosis was confirmed by tonsillar region of each patient; an additional culture ofNgonorrhoeae and who returned for the first specimen was taken from the cervix of each woman. follow up visit, constituted the final study population. Patients for whom the cultures for Ngonorrhoeae were Of the remaining 66 patients, 42 were excluded negative were subsequently excluded from the study. because N gonorrhoeae was not isolated from the Follow up visits were planned on days 7 and 14 after specimens taken at the initial visit, three were not

treatment. On each occasion specimens were taken for treated according to the protocol, and 21 did not http://sti.bmj.com/ culture. Ifgonococci persisted or reappeared within 14 return for follow up. days after treatment and the patient had not had The two treatment groups were comparable for age further sexual intercourse, the treatment was con- and sex. Genitourinary infection without pharyngeal sidered to have failed. The reappearance ofgonococci infection was diagnosed in 243 (90%) of 269 men and after negative cultures on two occasions was con- 49 (84%) of 58 women. The remaining 26 (10%) men sidered to be due to reinfection irrespective of the patient's history. on September 26, 2021 by guest. Protected copyright. During the study period a further 52 patients with Table 1 Characteristics ofthe study population of393 pharyngeal infection with or without concomitant patients (figures are numbers (percentages) except where genitourinary or rectal infection, which was shown stated) only by culture, were treated with a single intra- Treatment muscular injection of 250 mg ceftriaxone. The regimen schedule for control visits and cultures was similar to Cefiriaxone Pivampicillin 2SOmg by 1.4 g and that for the first 393 patients. intramuscular probenecid I g injection by mouth CULTURE OF NGONORRHOEAE No treated 198 195 Specimens were transported from the clinics to the Noevaluable* 170 (86) 157 (81) laboratories on charcoal impregnated sterile wooden Sex distribution: applicators in a modified Stuart's medium. Each swab Men 143 (84) 126 (80) Women 27 (16) 31 (20) was streaked on a selective chocolate agar medium Median (range) age (years): containing amphotericin B (2 ug/ml), polymyxin B Men 26 (18-63) 27 (18-56) sulphate (25 IU/mI), lincomycin (1 pg/ml), and Women 23 (18-65) 24 (18-39) trimethoprim lactate (3 sg/ml). Gonococcus like *Patients for whom diagnosis was confirmed by culture of Neisseria oxidase positive colonies were identified by a direct gonorrhoeae and who returned for follow up. Genitourin Med: first published as 10.1136/sti.65.1.14 on 1 January 1989. Downloaded from

16 Christophersen, Bollerup, From, Ronne-Rasmussen, Quitzau Table 2 Outcome oftreatment with cefiriaxone or Table 4 Minimwn inhibitory concentrations ofpenicillinfor pivampicilin andprobenecid in 327patients with 17 strains ofNeisseria gonorrhoeae isolatedfrom patients genitourinary gonorrhoea, 35 with and 292 without with gonorrhoea not cured by treatment with pivampicillin concomitant pharyngeal infection (figures are numbers 1*4 gplusprobenecid 1 g (percentages) ofpatients not cured out ofnumbers treated) No ofisolatesfrom: Treatment regimen MIC (Ug/ml) Genitourinary Pharyngeal Ceftriaxone 250 g by Pivampicillin 1*4 g and ofpenicillin infection infection Infection intramuscular injection probenecid 1 g by mouth <0-15 Susceptible 0 5 Genitourinary 1/152 (1) 6/140 (4) 0-30-0-60 Less Pharyngeal 0/18 (0) 11/17 (65) susceptible 4 3 1-2-2-40 Resistant 2 3

and nine (6%) women also had pharyngeal gonorr- 170 (6%)) patients treated with ceftriaxone than by hoea. those (3/157 (2%)) treated with pivampicillin and Table 2 shows that 151 (99%) of 152 patients with probenecid (p = 0.046). uncomplicated genitourinary infection treated with A total of 805 gonococcal strains were tested for ceftriaxone yielded negative cultures for N gonorr- susceptibility to ceftriaxone and penicillin (table 3), hoeae compared with 134 (96%) of 140 treated with 380 ofthem were from patients who entered the study. pivampicillin. Concomitant pharyngeal gonococcal A strong positive correlation (r = 0.93) was seen infection was eradicated in all 18 patients treated with except for PPNG strains. The ratios between the MICs ceftriaxone compared with six (35%) of 17 patients of penicillin and of ceftriaxone were 1:40 for strains treated with pivampicillin, a significant difference with MICs of penicillin of 0.15 sg/ml or less and 1:80 (p < 0 05, Fisher's exact test). Of five patients infec- for strains with MICs ofpenicillin ofless than 0.15 ig/ ted with PPNG strains, two had pharyngeal infection. ml. The MICs ofceftriaxone against isolates from the All were treated with and cured by ceftriaxone. patient who was not cured after treatment with Of the additional 52 patients with pharyngeal ceftriaxone were 0-002 pg/ml before and 0.004 ig/ml infection treated with ceftriaxone, seven were excluded after treatment. from analysis ofefficacy because ofnegative culture on Table 4 shows the MICs of penicillin for strains the day of treatment and five did not return for follow isolated from patients who were not cured by treat- up. These patients were similar to the main study ment with pivampicillin 1-4 g and probenecid 1 g. population in sex and age. All 20 evaluable women and None of them were PPNG strains. 20 evaluable men yielded negative cultures for N http://sti.bmj.com/ gonorrhoeae after treatment. In 14 of the patients the Discussion evaluation was based on a positive culture from the pharynx on the day of treatment. In 26 the positive The standard treatment ofuncomplicated gonorrhoea culture had been obtained within two weeks before (pivampicillin 1.4 g and probenecid 1 g by mouth) was treatment. successful in 96% of our patients. A similar cure rate No serious adverse drug reactions were seen after was found in a study from Copenhagen in 1983," and treatment with either ceftriaxone or pivampicillin. must be considered to be satisfactory. On the other on September 26, 2021 by guest. Protected copyright. Minor gastrointestinal complaints (mainly "loose hand, the standard regimen gave an unsatisfactory stools" or diarrhoea) were experienced by more (10/ cure rate (only 35%) for pharyngeal gonorrhoea as in

Table 3 Correlation between minimun inhibitory concentrations (MICs) ofceftriaxone andpenicillinfor 805 strains of Neisseria gonorrhoeae No ofnon-PPNG isolates with MICs (pug/mi) ofpenicillin of: MIC (pg/mi) No of ofceftriaxone <001-004 00O8-S15 0-30-0-60 1.2-2.4 > 2.4 PPNG isolates Total <0-00025 136 0 0 0 0 0 136 0 0005-0 001 252 5 2 0 0 0 259 0.002-00004 1 98 115 1 1 8 224 0.008-0.016 0 19 58 58 0 13 148 0032-0064 0 2 2 28 3 2 37 0.128 0 0 0 0 1 0 1 Total 389 124 177 87 5 23 805 PPNG = penicillinase producing Ngonorrhoeae. Genitourin Med: first published as 10.1136/sti.65.1.14 on 1 January 1989. Downloaded from

Treating genitourinary andpharyngeal gonorrhoea with single dose ceftriaxone 17 previous studies.34 Our treatment failures were not Refereumes associated with decreased sensitivity to penicillin in 1 WHO Expert Committee on Venereal Diseases and Trepone- vitro (table 4). matoses. Sixth Report. WHO Tech Rep Ser 1986;No 736:118- Ceftriaxone as a single intramuscular dose of 250 23. mg was an effective treatment in men and women with 2 Centers for Disease Control. Antibiotic-resistant strains of uncomplicated five Neisseriagonorrhoeae. MMWR 1987;36/5S1-18. gonorrhoea (including patients 3 Washington AE. Update on treatment recommendations for infected with PPNG strains) and gave a cure rate of gonococcal infections. Rev Infect Dis 1982;4suppl:758-71. 99%. This finding confirmed the results of other 4 Bro-Jorgensen A, Jensen T. Gonococcal pharyngeal infections: studies that showed 100% efficacy of single doses of report of 110 cases. British Journal of Venereal Diseases 1973; 125-250 mg ceftriaxone for uncomplicated gonorr- 49:491-2. 5 Ng WS, Chau PY, Ling J, Echeverria P, Rockhill R, Arnold K. hoea.'9 Penicillinase-producing Neisseria gonorrhoeae isolates from Single dose ceftriaxone 250 mg was also highly different localities in south east Asia. British Journal of Venereal effective in treating pharyngeal gonorrhoea. All 58 Diseases 1983;59:232-6. patients, including 26 who yielded positive cultures 6 Zajdowicz TR, Sanches PL, Berg SW, Kerbs SBJ, Newquist RL, Harrison WO. Comparison ofceftriaxone with cefoxitin in the within two weeks before treatment and two infected treatment of penicillin-resistant gonococcal urethritis. British with PPNG strains, were cured. Judson et alfound 125 Journal of Venereal Diseases 1983;59:176-8. mg ceftriaxone to be effective in 30 (94%) of 32 7 Handsfield HH, Murphy VL. Comparative study of ceftriaxone pharyngeal infections.'` This might indicate that a and spectinomycin for treatment of uncomplicated gonorrhoea in men. Lancet 1983;ii:67-70. larger dose of250 mg ceftriaxone can improve the cure 8 Panikabutra K, Ariyarit C, Chitwarakorn A, Saensanoh C, rate of single dose treatment of pharyngeal gonorr- Wongba C. Randomised comparative study ofceftriaxone and hoea, although the numbers were too small to give a spectinomycin in gonorrhoea. Genitourin Med 1985;61:106-8. significant difference. (95% Confidence levels were 9 Dixon CA, Bittiner JB, Shahidullah M, Slack RCB, Sulaiman MZC. Randomised observer blind comparative trial of ceftri- 79.2-99.2 in the study by Judson et al' and 93.8-100.0 axone and penicillin in treating uncomplicated gonorrhoea in in our study). men and women. Genitourin Med 1986;62:78-81. Ceftriaxone is also superior to other single dose 10 Judson FN, Ehret JM, Handsfield HH. Comparative study of regimens for treating pharyngeal gonorrhoea. Treat- ceftriaxone and spectinomycin for treatment ofpharyngeal and anorectal gonorrhoea. JAMA 1985;253:1417-9. ment with spectinomycin 2 g or 4 g as a single dose had 11 Hagdrup H, Serup J. Treatment of gonorrhoea with a single dose a cure rate of only 43-46% of the pharyngeal infec- of pivampicillin and failure to cure. Ugeskr Lager 1985;147: tions treated.'012 A similar low cure rate was found for 1536-7. two second generation cephalosporins, cefonicid and 12 Wiesner PJ, Tronca E, Bonin P, Pedersen AHB, Holmes KK. 14 Clinical spectrum ofpharyngeal gonococcal infection. N EnglJ cefuroxime.'3 Med 1973;288:181-5. Epidemiological studies from the venereal diseases 13 Handsfield HH, Murphy VL. Treatment of uncomplicated http://sti.bmj.com/ clinics in Copenhagen'516 and the Neisseria Depart- gonorrhoea in women with single dose cefonicid. Sex Transm ment, Statens Seruminstitut'7 during recent years have Dis 1985;12:90-2. 14 Graudal C, Bollerup AC, Lange K, Seier K, Lind I. The outcome shown a constant incidence ofpharyngeal gonorrhoea ofsingle-dose cefuroxime treatment in patients with pharyngeal of 15% in patients examined for gonorrhoea, with the gonorrhoea. Sex Transm Dis 1985;12:49-51. highest incidence in women and homosexual men. 15 Hagdrup H, Serup J. Tonsillarand rectal gonorrhoea. The value of This indicates that pharyngeal gonorrhoea is a routine culture for gonococci from tonsils and the rectum.

Ugeskr Lager 1985;147:3607-9. on September 26, 2021 by guest. Protected copyright. numerically important problem. The clinical impor- 16 Worm AM, Fogh H, Petersen CS. The diagnosis and therapeutic tance and the contagiousness of pharyngeal gonorr- control of gonorrhoea. The effects and costs. Ugeskr Lager hoea has not been satisfactorily assessed. The infection 1986;148:2819-21. seems to give throat symptoms seldom,4 1819 and may in 17 Lind I, Bolierup AC, Gadeberg OV, Reimann K, Bentzon MW. some cases be self Pharyngeal gonorrhoea is Activities of the WHO collaborating centre for reference and limiting.'8 research in gonococci, Copenhagen, for the year 1986. WHOI thus a reservoir of N gonorrhoeae. Until it is proved VDT/RES/GON/87 1987;150:1-15. not to be contagious or a possible source ofdissemina- 18 Wallin J. Pharyngeal Neisseria gonorrhoeae: coloniser or tion, therefore, patients with pharyngeal gonorrhoea pathogen? Br MedJ 1979;: 1462-3. 19 Young H, Bain SSR. Neisserial colonisation of the pharynx. should be treated. British Journal of Venereal Diseases 1983;S9:228-31.