WHO guidelines for the treatment of Neisseria gonorrhoeae*

Transcription

1 WHO guidelines for the treatment of Neisseria gonorrhoeae* Web annex E: Systematic reviews June 26 * Full guidelines available at:

2 Contents Recommendation In adults and adolescents, HIV-positive patients and men who have sex with men (MSM) with uncomplicated genital (cervix, urethra) and anorectal gonococcal infections, should other treatments or ceftriaxone be used to treat gonorrhoea (genital or cervix)?... 5 Criteria... 5 Search... 5 For systematic reviews... 5 For randomized and non-randomized studies... 5 Screening of studies and data extraction... 6 Methods of analysis... 7 Results... 7 PRISMA... 8 Characteristics of included studies... 9 Effects of interventions Risk of bias References In pregnant women with uncomplicated genital (cervix, urethra) and anorectal gonococcal infections, what are the effects of ceftriaxone compared to other treatments? Criteria Search For systematic reviews For randomized and non-randomized studies Screening of studies and data extraction Methods of analyses Results PRISMA Characteristics of included studies Effects of intervention Risk of bias References Patient values, preferences and acceptability Gonococcal infections Characteristics of included studies Findings: acceptability Other conditions: syphilis Search Result Characteristics of included studies Findings References Other conditions Findings: Values References Recommendation In adults and adolescents, with gonococcal oropharyngeal infections, should ceftriaxone compared to other treatments be recommended?... 9 Criteria... 9 Search... 9 For systematic reviews

3 For randomized and non-randomized studies... 9 Screening of studies and data extraction... 9 Methods of analyses... 9 Results PRISMA Characteristics of included studies Effects of interventions Risk of bias... 3 References... 7 Recommendation In adults and adolescents with treatment failure of N. gonorrhoeae (genital or oropharyngeal) with any medication, what treatments should be used?... 9 Criteria... 9 Search... 9 For systematic reviews... 9 For randomized and non-randomized studies... 9 Screening of studies and data extraction... Methods of analyses... Results... PRISMA... 2 Characteristics of included studies... 3 Effects of interventions... 6 Risk of bias... 6 References... 7 Recommendation For treatment of gonococcal ophthalmia neonatorum in neonates, should one treatment versus another be recommended?... 2 Criteria... 2 Search... 2 For systematic reviews... 2 For randomized and non-randomized studies... 2 Screening of studies and data extraction... 2 Methods of analyses... 2 Results... 2 PRISMA Characteristics of included studies Effects of intervention Risk of bias References Recommendation 5 and For prevention of ophthalmia neonatorum in neonates, what are the effects of different interventions? Criteria Search For systematic reviews For randomized and non-randomized studies Screening of studies and data extraction Methods of analyses Results PRISMA Characteristics of included studies Effects of interventions

4 Risk of bias References

5 Recommendation. In adults and adolescents, HIV-positive patients and men who have sex with men (MSM) with uncomplicated genital (cervix, urethra) and anorectal gonococcal infections, should other treatments or ceftriaxone be used to treat gonorrhoea (genital or cervix)? Criteria Population Intervention Comparator Outcome Adults and adolescents, HIV-positive patients, MSM with Ceftriaxone 25 mg IM Single therapy: Azithromycin 2 g po Cefixime 4 mg po Cefixime 8 mg po Cefixime 4 mg po 2 uncomplicated Gentamicin 24 mg IM genital (cervix, Spectinomycin 2 g IM urethra) and Kanamycin 2 g IM anorectal Quinolones (just in vitro resistance data) gonococcal Ceftriaxone 25 mg IM infections Dual therapy versus single therapy: And multiple combinations of Cefixime + doxycycline (or azithromycin) versus cefixime alone And multiple combinations of Ceftriaxone + doxycycline (or azithromycin) versus ceftriaxone alone IM: intramuscular; po: by mouth (orally) Critical: Microbiological cure, STI complications, clinical cure, transmission to partners, compliance, N. gonorrhoeae antimicrobial in vitro resistance, side-effects (including allergy, toxicity) Important: HIV transmission and acquisition, quality of life Search For systematic reviews To identify pre-existing synthesized evidence, the Cochrane Library suite of databases (Cochrane Database of Systematic Reviews [CDSR], Health Technology Assessment [HTA] database and the American College of Physicians [ACP] Journal Club) was searched for recent systematic reviews and for protocols for reviews from 24 to February 25. Keywords used included gonorrhoea, gonorrhea, gonococcal, ophthalmia neonatorum. The search found citations. Some reviews were used to verify the included studies. Five systematic reviews were found. For randomized and non-randomized studies We used one search of the databases to find articles for all five questions. We searched all databases up to March 25: MEDLINE (from 946), Embase (from 98) and CENTRAL (Cochrane Central Register of Controlled Trials) and LILACS from inception. The search strategy included keywords and text words for gonorrhoea and medications. We excluded letters, editorial, comments, review articles and guidelines. We did not restrict by language. We also reviewed reference lists of relevant studies, guidelines and systematic reviews. Search strategy gonorrhea.mp. 5

6 2 gonorrhoea.mp. 3 gonococcal.mp. 4 ophthalmia neonatorum.mp. 5 or/-4 6 ceftriaxone.mp. 7 Azithromycin.mp. 8 cefixime.mp. 9 gentamicin.mp. spectinomycin.mp. kanamycin.mp. 2 quinolone*.mp. 3 doxycycline.mp. 4 erythromycin.mp. 5 silver nitrate.mp. 6 chloramphenicol.mp. 7 tetracycline*.mp. 8 povidone iodine.mp. 9 gemifloxacin.mp. 2 cephalosporin*.mp. 2 macrolide*.mp. 22 or/ and (th or tu).xs. 25 (co or cn or dr or dt or rh or si or th).fs or and limit 27 to (book or book series or editorial or letter or note or review or case reports or meta-analysis or news or systematic reviews) [Limit not valid in Ovid MEDLINE, Ovid MEDLINE Daily Update, Ovid MEDLINE In- Process; records were retained] 29 case report/ 3 27 not (28 or 29) The electronic database search for primary studies found 3295 non-duplicate records. After title and abstract screening, we retrieved 488 articles in full text and excluded 287 as not relevant. Overall we found 26 studies that provided data for the five questions: 23 randomized and 3 non-randomized studies. The number of studies providing data for each question are listed in the respective sections (see Figure for the PRISMA Study Flow diagram). Screening of studies and data extraction Two investigators independently screened titles and abstracts for relevant studies. The full texts of potentially relevant studies were retrieved and the full text was screened by two investigators. Screening forms were developed and piloted by at least two investigators. We excluded studies that were published before 97. Data were abstracted by one investigator and verified by another. We collected data about the study (date of data collection, type of study design, inclusion and exclusion criteria, country, funding sources), population or patient characteristics (type of population: adult/adolescent, pregnant women, neonates at risk, MSM, HIV-positive, people with treatment failures, age), infection (culture positive, types of infection: genital including cervical, urethral, rectal, anal), coinfection and treatment failure, treatments (number of doses, amount, method of treatment, cointervention), follow-up and outcomes of interest (including measures for cure rate by person and sites of infections, treatment results based on return day of visit, and types of adverse effects). We used a pretested data abstraction form. Most studies did not provide details about the number of people randomized to each group or the losses to followup in each group, or did not include people who did not comply with protocol; we therefore collected data for a per- 6

7 protocol analysis. The data extraction form was developed and piloted by at least two investigators. Methods of analysis We present the synthesized results by outcome in the results section. We analysed the data using Review Manager (RevMan) [ Computer Program]. Version 5.3. Copenhagen: The Nordic Cochrane Center, The Cochrane Collaboration, 24) and when available we have included the forest plots of the statistical analyses. For dichotomous outcomes, we pooled the relative risks (e.g. risk ratios and odds ratios) from randomized studies and pooled relative risks from non-randomized studies with two comparison groups. When a study included only one group, we calculated the risk of an event (or proportion) of an outcome and then pooled the proportions from each study weighted by the generic inverse variance. When results could not be pooled we summarized the results from the individual studies narratively. When available, we pooled and report data for subgroups by HIV status, drug dosage and type of infection. The heterogeneity of pooled results is reported using the I 2 statistic. Results We found five reviews: Bai et al., 22; Bignell & Unemo, 22; Dowell & Kirkcaldy, 22; Hathorn et al., 24; and Tapsall, 22 (see below). The reviews did not cover all of the interventions and populations, but we used the search results from these reviews to confirm the studies to include. From our comprehensive search of electronic databases, we included 8 studies (including foreign language articles): 4 randomized and 94 non-randomized studies (including three non-randomized studies with two or more groups and 9 non-randomized studies with one group).. Bai ZG, Bao XJ, Cheng WD, Yang KH, Li YP. Efficacy and safety of ceftriaxone for uncomplicated gonorrhoea: a meta-analysis of randomized controlled trials. Int J STD AIDS. 22;23(2): doi:.258/ijsa Bignell C, Unemo M; European STI Guidelines Editorial Board. Azithromycin in the treatment of infection with Neisseria gonorrhoeae. Int J STD AIDS. 23;24(2): doi:.77/ Dowell D, Kirkcaldy RD. Effectiveness of gentamicin for gonorrhoea treatment: systematic review and metaanalysis. Sex Transm Infect. 22;88(8): doi:.36/sextrans Hathorn E, Dhasmana D, Duley L, Ross JD. The effectiveness of gentamicin in the treatment of Neisseria gonorrhoeae: a systematic review. Syst Rev. 24;3:4. doi:.86/ Tapsall J. Current concepts in the management of gonorrhoea. Expert Opin Pharmacother. 22;3(2):

8 PRISMA Figure : PRISMA Study Flow diagram 8

9 Characteristics of included studies Randomized studies with two or more comparison groups STUDY YEAR POPULATION N INFECTION AGE (mean and/or range, if not indicated) INCLUSION EXCLUSION OUTCOMES TREATMENTS Shams 29, Jeddah, Saudi Arabia 29 adult/adolescents 84/2 genital (urethra) or anorectal 4 55 Gonorrhoea patients Unclear cure Ceftriaxone 25 mg IM, spectinomycin 2 g IM Tian 22, China 22 adult/adolescents 27/225 genital (cervix) 8 52 Gonorrhoea patients Not mentioned cure, clinical cure Ceftriaxone 25 mg IM, spectinomycin 2 g IM Cheng 2, China (in Chinese) 2 adult/adolescents 93/94 genital (cervix) 8 56 Gonorrhoea patients Unclear cure, clinical cure, side-effect Ceftriaxone 25 mg IM, spectinomycin 2 g IM Handsfield 994, USA 994 adult/adolescents 54/549 genital (cervix) not mentioned Men and women with uncomplicated gonorrhoea Pregnant and nursing women cure, side-effect Ceftriaxone 25 mg IM, azithromycin 2 g po Rompalo 994, USA 994 adult/adolescents 38/7 genital (cervix) 5 6 Patients who had Gram-stained urethral, rectal or endocervical smears showing Gram-negative diplococci within polymorphonuclear cells were eligible for enrolment. Also, women with a history of recent exposure to a sexual partner with gonorrhoea. If they had a history of allergy to any of the drug regimens administered, were pregnant or nursing, had co-existing syphilis, myasthenia gravis, or complicated gonococcal infections (i.e. disseminated gonorrhoea, pelvic inflammatory disease, or septic arthritis), received antibiotic therapy within 48 hours before clinic presentation, active kidney disease, had bleeding disorders, or active liver disease. Participants were excluded from treatment analysis if cultures obtained at enrolment were negative for N. gonorrhoeae, if patients failed to keep appointment for follow-up or took any other antibiotic between the time of enrolment and follow-up evaluation. cure, side-effect Spectinomycin 2 g IM, ceftriaxone 25 mg IM 9

10 Randomized studies with two or more comparison groups STUDY YEAR POPULATION N INFECTION AGE (mean and/or range, if not indicated) INCLUSION EXCLUSION OUTCOMES TREATMENTS Mroczkowski 993, USA 993 adult/adolescents /6 genital (urethra) 23.6 (8 36) Patients with uncomplicated gonorrhoea Patients under 8 years of age, pregnant or breastfeeding women, patients with active liver or kidney disease, myasthenia gravis, bleeding disorders or known allergy to spectinomycin or beta-lactam antibiotic. None of the study patients had been treated with trospectomycin or other antibiotics within 72 hours prior to enrolment cure, clinical cure, side-effects Ceftriaxone 25 mg IM, spectinomycin 2 g IM Portilla 992, USA 992 adult/adolescents genital (cervix) 23.3 (8 44) Patients with clinical evidence of uncomplicated gonorrhoea. Initial screening included examination of those who had recent sexual contact with a person who had documented gonorrhoea. If Gram-negative, intracellular diplococci consistent with N. gonorrhoeae were positive, the patients were enrolled in the study. An allergy to penicillin or cephalosporins, chronic bowel disorders, more than one bacterial infection, evidence of chancroid, syphilis or AIDS, severe systematic disease such as congestive heart failure or hepatic or renal failure, or those who were pregnant cure, side-effects Ceftriaxone 25 mg IM, cefixime 4 mg po, 8 mg po (or cefixime 4 mg po 2) Plourde 992, Kenya 992 adult/adolescents 8/84 genital (cervix) 8 65 Men were enrolled if a Gram stain of their urethral discharge showed intracellular Gram-negative diplococci. Women were enrolled if a culture of their cervical discharge was positive for N. gonorrhoeae. Patients with complicated gonococcal infection such as pelvic inflammatory disease, hypersensitivity to penicillins or cephalosporins, any other STDs or pregnancy cure, side-effects Cefixime 4 mg po, ceftriaxone 25 mg IM Handsfield 99, USA 99 adult/adolescents 4/4 genital (urethra) or anorectal 27.2 Patients with Gram-stained urethral or endocervical smears showing Gram-negative diplococci within polymorphonuclear leukocytes or, in women, a history of sexual exposure to a man with urethral gonorrhoea Patients who had symptoms or signs of pelvic inflammatory disease or other complications of gonorrhoea, gave a history of allergy to beta-lactam antibiotics or spectinomycin, had received antimicrobial therapy in the preceding 7 days, or were pregnant or nursing cure, side-effects Cefixime 4 mg po, cefixime 8 mg po (or cefixime 4 mg po 2) Judson 985, Denver, USA 985 adults/adolescents and MSM 4/4 genital (cervix) > 9 Patients who had positive smears for anogenital gonorrhoea and/or a documented exposure to gonorrhoea were considered Patients with histories of allergy to betalactam antibiotics or who had antimicrobial therapy within the preceding 2 weeks, or complications of gonorrhoea, or any serious illness were excluded cure, side-effects Ceftriaxone 25 mg IM, spectinomycin 2 g IM

11 Randomized studies with two or more comparison groups STUDY YEAR POPULATION N INFECTION AGE (mean and/or range, if not indicated) INCLUSION EXCLUSION OUTCOMES TREATMENTS Panikabutra 985, Thailand 985 adults/adolescents 9/9 genital (cervix) not mentioned Women with uncomplicated gonorrhoea Not mentioned cure, side-effects Spectinomycin 2 g IM, ceftriaxone 25 mg IM Collier 984, USA 984 adults/adolescents 3/8 genital (cervix) 22.6 ± 4.3 The presence of intracellular Gramnegative diplococci on a Gram-stained endocervical smear, untreated gonorrhoea documented by earlier isolation of N. gonorrhoeae, or a history of recent sexual intercourse with a man with urethral gonorrhoea Patients who had symptoms or signs of pelvic inflammatory disease or other complications of gonorrhoea, gave a history of allergy to beta-lactam antibiotics or spectinomycin, had received antimicrobial therapy in the preceding 7 days, or were pregnant or nursing. Patients from whom N. gonorrhoea was not isolated at entry visit were excluded from the analysis, but they were retained for toxicity analysis cure, clinical cure, side-effects Ceftriaxone 25 mg IM, spectinomycin 2 g IM Handsfield 983, USA 983 adult/adolescents 4/ genital (cervix) 27.6 Men aged 6 years with uncomplicated gonorrhoea urethritis or anorectal infections Patients with complicated gonorrhoea, had other antibiotics for preceding 2 weeks, allergic to B-lactam antibiotics cure, side-effects Ceftriaxone25 mg IM, ceftriaxone 25 mg IM, spectinomycin 2 g IM Handsfield 98, USA 98 adult/adolescents 4/4 genital (cervix) 26.9 ± 7.7 years (6 57) Men aged 6 years who attended a sexually transmitted disease clinic and who had presumptive gonococcal urethritis (urethral smear showing intracellular Gram-negative diplococci) or anorectal infection (positive Gram-stained smear or history of receptive rectal intercourse with a man with documented gonococcal urethritis) Patients with histories of allergy to betalactam antibiotics, with complications of gonorrhoea, or who had received antimicrobial therapy within the preceding 2 weeks cure, clinical cure, side-effects Ceftriaxone 25 mg IM, ceftriaxone 25 mg IM, 5 mg IM Non-randomized studies with two comparison groups Schumacher 23, USA 23 adult/adolescents 394/485 genital (cervix) Diagnosed as having uncomplicated N. gonorrhoeae infection Not mentioned cure Ceftriaxone + azithromycin, ceftriaxone + doxycycline Deguchi 23, Japan 23 adult/adolescents genital (cervix) Patients had symptoms and signs of acute urethritis. No patient had received antibiotic treatment before admission to the clinic. Not mentioned cure, side-effects Cefixime 2 mg po 2, cefixime 4 mg po Rajan 982, Singapore 982 adult/adolescents genital (cervix) Only those treated patients whose infections were confirmed by culture Patients with reinfections were excluded from the study cure, side-effects Ceftriaxone 25 mg IM, kanamycin 2 g IM

12 Randomized studies with two or more comparison groups STUDY YEAR POPULATION N INFECTION AGE (mean and/or range, if not indicated) INCLUSION EXCLUSION OUTCOMES TREATMENTS Non-randomized study with one group Takahashi 24, Japan 24 adult/adolescents 3/33 genital (cervix) 2 or more Heterosexual male patients with both gonococcal urethritis (GU) and nongonococcal urethritis (NGU) who were 2 years old. Diagnosis of GU was based on both symptoms: urethral pain and pus discharge Unclear cure, clinical cure Azithromycin 2 g po Kojima 28, Japan 28 adult/adolescents 23/2 genital (cervix) 32.3 (7 73) Male patients with uncomplicated gonococcal urethritis Not mentioned cure, clinical cure, side-effects Spectinomycin 2 g IM Muratani 28, Japan 28 adult/adolescents 25/25 oropharyngeal 28. Outpatients with uncomplicated gonorrhoea either symptomatic or asymptomatic, as well as sexual contacts of individuals with known gonorrhoea Not mentioned Microbiological cure Ceftriaxone 25 mg IM Khaki 27, India 27 adult/adolescents 22 genital (urethra) or anorectal 8 54 Males with urethritis, females with endocervicitis Antibiotic therapy within the preceding 4 weeks, known hypersensitivity to macrolide antibiotic, serious cardiac, renal or hepatic disease, clinical evidence of disseminated gonococcal infection, other complications of gonorrhoeae or untreated syphilis and any condition that might affect gastro-intestinal absorption of antibiotics (e.g. peptic ulcer disease, gastrectomy). cure, clinical cure, side-effects Azithromycin 2 g po Khrianin 26, Russia 26 adults/adolescents 9/9 genital (cervix) 8 45 Gonorrhoea patients Allergic to antibiotic, diagnosis something else, e.g. syphilis cure, clinical cure Ceftriaxone 25 mg IM 2

13 Randomized studies with two or more comparison groups STUDY YEAR POPULATION N INFECTION AGE (mean and/or range, if not indicated) INCLUSION EXCLUSION OUTCOMES TREATMENTS Habib 24, United Kingdom 24 adulst/adolescents 68/7 genital (cervix) 25.8 (4 56) Men and women were treated for N. gonorrhoeae on the basis of a Gram-stained smear showing polymorphonuclear leukocytes with intracellular Gram-negative diplococci in the initial visit or with cultureproven N. gonorrhoeae thereafter, or if there was a history of recent unprotected sexual intercourse with a partner infected with gonorrhoea regardless of Gram staining and before culture confirmation. Patients with negative culture results for N. gonorrhoeae who were initially treated were excluded from the study cure Azithromycin g po Rustomjee 22, South Africa 22 adults/adolescents 55/56 genital (urethra) or anorectal Not mentioned First visit, non-pregnant, female, clinic attendees if they had a mucopurulent cervical discharge with a diagnosis of non-gonococcal cervicitis (NGC), based on a routine vaginal wet mount and cervical Gram stain Not mentioned cure, clinical cure, compliance, sideeffects Azithromycin g po Aplasca 2, Philippines 2 adults/adolescents 25/26 genital (cervix) 22.3 ± 4.2 Women with positive results for N. gonorrhoeae by endocervical Gram staining or culture < 6 years, pregnant, signs suggestive of pelvic inflammatory diseases cure, side-effects Cefixime 4 mg po Jin Hong 2, China 2 adults/adolescents 77/77 genital (cervix) not mentioned Gonorrhoea patients Unclear cure, clinical cure, side-effects Ceftriaxone 25 mg IM Swanston 2, Trinidad 2 adults/adolescents 2/27 genital (cervix) 4 83 History of genital discharge Patients had antibiotics within the last 7 to days, with complicated gonorrhoea or chlamydial infection, pregnant, lactating cure, clinical cure, side-effects Azithromycin g po Ling 2, China 2 adults/adolescents 53/78 genital (cervix) 8 55 Gonorrhoea patients Not mentioned cure, clinical cure, side-effects Shi 2, China 2 adults/adolescents 28/3 genital (cervix) 25 (9 47) Gonorrhoea patients Unclear cure, clinical cure, side-effects Azithromycin g po Spectinomycin 2 g IM 3

14 Randomized studies with two or more comparison groups STUDY YEAR POPULATION N INFECTION AGE (mean and/or range, if not indicated) INCLUSION EXCLUSION OUTCOMES TREATMENTS Zhou, 2, China (in Chinese) 2 adults/adolescents 35/36 genital (cervix) 8 52 Gonorrhoea patient Allergic, pregnant, breastfeeding, cardinal, renal and liver complications cure, clinical cure, side-effects Spectinomycin 2 g IM Gruber 997, Croatia 997 adults/adolescents genital (cervix) 24.5 Gonorrhoea patient Allergic, pregnant, breastfeeding, cardinal, renal and liver complications cure, clinical cure, side-effects Azithromycin g po Hook 997, USA 997 adults/adolescents genital (cervix) 27 All participants were required to have a Gram stain of a urethral specimen showing Gram-negative diplococci within polymorphonuclear leukocytes or a recent culture positive for N. gonorrhoeae If they have a history of allergy to quinolone or cephalosporin antibiotics; had received antibiotics or any other investigational drug within 2 weeks before enrolment; had complicating infection or disease that would compromise treatment evaluation; received concomitant antimicrobial medication other than topical or antifungal agents; received chronic treatment with warfarin, diflunisal, fluconazole or theophylline; had taken antacids or sucralfate within 4 hours of dosing; or had a known Chlamydia trachomatis infection cure, side-effects Cefixime 4 mg po Mroczkowski 997, USA 997 adults/adolescents 24/25 genital (cervix) 5 54 Women aged 6 years or older were eligible for enrolment if they had a Gram-stained endocervical smear showing Gram-negative diplococci within polymorphonuclear leukocytes, a recent untreated culture positive for N. gonorrhoeae, or sexual exposure to men with urethral gonorrhoea within the 2 weeks prior to enrolment If they had concomitant infection(s), such as complicated gonococcal infection, or disease that would compromise treatment evaluation; were pregnant or nursing; were known to have hypersensitivity to quinolone or cephalosporin antibiotics; had received antibiotics or any investigational drug within 2 weeks of enrolment; needed concurrent antimicrobial medication other than topical or antifungal agents; had received chronic treatment with warfarin, diflunisal, fluconazole or theophylline; or had taken antacids or sucralfate within 4 hours of dosing. Patients with recent positive cultures for C. trachomatis were also excluded cure, side-effects Cefixime 4 mg po 4

15 Randomized studies with two or more comparison groups STUDY YEAR POPULATION N INFECTION AGE (mean and/or range, if not indicated) INCLUSION EXCLUSION OUTCOMES TREATMENTS Gruber 995, Croatia 995 adults/adolescents 49 genital (cervix) 24.5 Adults (>8 years) with clinical signs of gonorrhoea (urethral or cervical discharge, but some of the women were asymptomatic partners of men with gonorrhea). Presence of intracellular Gram-negative diplococci in the Gram-stained urethral or endocervical smear and/or positive culture for Neisseria gonorrhoeae Patients were excluded if they had received antibiotic pretreatment within 2 weeks before enrollment, if they were allergic to macrolides or quinolones, if they had other concomitant sexually transmitted infections (except chlamydial infection), if they had pharyngeal or rectal gonorrhea, if a female was pregnant, if they were unlikely to return for follow-up, were known alcohol or drug abusers, or had gastrointestinal diseases that might affect absorption of the drugs. cure, clinical cure, side-effects Azithromycin g po Mogabgab 994 cost data available, USA 994 adults/adolescents 48/48 genital (cervix) 23.9 Aged > 8 years with laboratory diagnosis of uncomplicated gonorrhoea Pregnant and lactating women, complicated gonorrhoea patients, allergic to penicillin or cephalosporin and received any antibiotic therapy within last 2 weeks cure, clinical cure, side-effects Ceftriaxone 25 mg IM Steingrimsson 994, Iceland 995 adults/adolescents 55 genital (urethra) 24.7 (7 58) The patients showed signs or symptoms of STD or were contacts of patients with STD Women of child bearing potential, patients who had received antibiotics or other experimental drugs within 2 weeks prior to visit, and patients with serious renal, cardiac or hepatic disease cure, side-effects Azithromycin g po Covino 993, USA 993 adults/adolescents 3/3 genital (cervix) > 8 Male patients with urethral gonorrhoea, female participants with positive culture. Recent sexual contact with person with recently documented gonorrhoea. Pregnant and lactating women, complicated gonorrhoea patients, allergic to penicillin or cephalosporin and received any antibiotic therapy within last 2 weeks cure Ceftriaxone 25 mg IM 5

16 Randomized studies with two or more comparison groups STUDY YEAR POPULATION N INFECTION AGE (mean and/or range, if not indicated) INCLUSION EXCLUSION OUTCOMES TREATMENTS Hook 993, USA 993 adults/adolescents 6/6 genital (cervix) 8 5 Women aged 8 to 5 years were eligible for enrolment if they gave a history of sexual exposure to a man with urethral gonorrhoea, if they had a Gram-stained endocervical smear showing Gram-negative diplococci within polymorphonuclear leukocytes, or if they had a history of an untreated culture positive for N. gonorrhoeae They were pregnant or nursing, had been previously enrolled in the study, gave a history of allergy to carboxyquinolone or cephalosporin antibiotics, had signs or symptoms of complicated gonococcal infection (pelvic inflammatory disease), had a chronic or acute intercurrent illness which would compromise treatment evaluation, had evidence of other acute STDs requiring treatment at the time of initial evaluation, or had received systemic antimicrobial therapy with an agent known to be active against N. gonorrhoeae during the 2 weeks prior to study enrolment cure, side-effects Ceftriaxone 25 mg IM McCormack 993, USA 993 adults/adolescents 3/5 genital (cervix) 24.4 Male patients with urethral gonorrhoea, female participants with positive culture. Recent sexual contact with person with recently documented gonorrhoea Pregnant and lactating women, complicated gonorrhoea patients, allergic to penicillin or cephalosporin and received any antibiotic therapy within past 2 weeks cure, side-effects Ceftriaxone 25 mg IM Odugbemi 993, Nigeria 993 adults/adolescents 4/23 genital (cervix) 6 52 Outpatients over 4 years old, diagnosed as STI by clinical signs and laboratory tests had not been on any antibiotic 2 weeks before being enrolled in this study Pregnant or lactating women, patients who gave a history of sensitivity to penicillin, and patients who had received other antimicrobial therapy during the preceding week. Patients who were included in the study whose cultures did not contain gonococci were not included cure, clinical cure, side-effects Azithromycin g po Smith 993, USA 993 adults/adolescents 24/24 genital (urethra) or anorectal 26.5 (8 58) Men and women 8 years. Men were enrolled if a Gram stain of their urethral discharge showed intracellular Gram-negative diplococci. Women were enrolled if a culture of their cervical discharge was positive for N. gonorrhoea Patients with complicated gonococcal infection such as pelvic inflammatory disease, hypersensitivity to penicillins or cephalosporins, any other STDs or pregnancy cure, side-effects Ceftriaxone 25 mg IM Tupasi 993 and 984 had the same data, the Philippines 993 adults/adolescents 52/2 genital (cervix) 3 3 Patients with culture-positive gonorrhoea Not mentioned cure, side-effects Spectinomycin 2 g IM 6

17 Randomized studies with two or more comparison groups STUDY YEAR POPULATION N INFECTION AGE (mean and/or range, if not indicated) INCLUSION EXCLUSION OUTCOMES TREATMENTS Verdon 993, USA 993 adults/adolescents 93/98 genital (cervix) > 6 All patients were examined with a proctoscope and specimens were taken for microscopy and culture. The diagnosis was confirmed by the finding of Gram-negative intracellular diplococci on the smear and by the isolation and identification of N. gonorrhoeae Unclear cure, side-effect Cefixime 2 mg po Waugh 993, United Kingdom 993 adults/adolescents 89/93 genital (cervix) 6 6 Male and female patients between 6 and 6 years of age with a diagnosis of gonorrhoea Patients were excluded from the study if they had received antibiotics, or any other investigational drug, within 2 weeks before the study (except where treatment failure was documented). Other exclusion criteria were terminal illness or any other condition which might preclude the patient from completing the study, known hypersensitivity to macrolides, concurrent treatment with ergotamine or carbamazepine, chronic diarrhoea, or any gastrointestinal condition which might affect absorption of azithromycin. Patients with clinical and serological evidence of primary or secondary syphilis were also excluded from the study. cure, clinical effect, sideeffects Azithromycin g po Baddour 992, Tennessee, USA 992 adults/adolescents 35/35 genital (cervix) 23.3 (8 47) Patients were8 years of age or older If they were pregnant, other complications, had antibiotics in previous weeks cure, side-effects Ceftriaxone 25 mg IM Dunnett/ Dunnel 992, USA 992 adults/adolescents 7/73 genital (cervix) > 8 Male patients with urethral gonorrhoea, female participants with positive culture. Recent sexual contact with person with recently documented gonorrhoea Pregnant and lactating women, complicated gonorrhoea patients, allergic to penicillin or cephalosporin and received any antibiotic therapy within past 2 weeks cure, side-effects Cefixime 4 mg po Goldstein 99, USA 99 adults/adolescents genital (cervix) 2 4 Documented urethritis, not allergic to penicillin and/or cephalosporin antibiotics Allergic to penicillin and/or cephalosporin antibiotics cure, side-effects Ceftriaxone 25 mg IM 7

18 Randomized studies with two or more comparison groups STUDY YEAR POPULATION N INFECTION AGE (mean and/or range, if not indicated) INCLUSION EXCLUSION OUTCOMES TREATMENTS Bryan 99, Zambia 99 adults/adolescents including HIV patients 64/65 genital (cervix) 27.5 Adult males between 8 and 5 years of age who presented with urethral discharge containing intracellular Gram-negative diplococci (as determined by microscopic exam) A history of antimicrobial treatment within 4 days, a history of allergy to beta-lactam antibiotics or quinolones, evidence of extra-urethral gonococcal disease or genital ulcer disease, or clinical evidence of immunodeficiency cure, side-effects Ceftriaxone 25 mg IM Lassus 99, Finland 99 adults/adolescents 4 genital (cervix) 44.9 Patients were enrolled on the basis of clinical diagnosis alone, although every attempt was made to isolate causative pathogens from swabs or pus Not mentioned cure, side-effects Azithromycin g po Covino 99, USA 99 adults/adolescents 4/42 genital (cervix) > 8 Heterosexual men or women at least 8 years old. Males had a urethral Gram stain showing gram-negative intracellular diplococci. Females had a known positive culture, a cervical Gram stain showing gram-negative intracellular diplococci, or recent exposure to a man with documented gonorrhea. Pregnant or nursing women; patients with a history of allergic reaction to carboxyquinolones, nalidixic acid, ceftriaxone, or cephalosporins; and patients who had received systemic antimicrobial therapy within the previous 24 h were excluded. cure, side-effects Ceftriaxone 25 mg IM Freedman 99, USA 99 adults/adolescents 5/5 genital (cervix not mentioned If pharynx and rectum are culture positive for gonococcus (by the patient s history) Not mentioned cure Ceftriaxone 25 mg IM Megran 99, Canada 99 adults/adolescents MSM 97/98 genital (cervix) > 8 Males aged 8 years and older with positive cultures for N. gonorrhoeae from any site or with Gram-negative intracellular diplococci from endourethral or rectal swabs Patients receiving antimicrobial therapy in the preceding 2 weeks were excluded from the study, as were persons with a history of hypersensitivity to penicillins or cephalosporins and those with serious underlying disorders cure, side-effects Cefixime 8 mg po Steingrimsson 99, Iceland 99 adults/adolescents 4/43 genital (urethra) 24.7 (7 58) The patients showed signs or symptoms of STD or were contacts of patients with STD Women of child-bearing potential, patients who had received antibiotics or other experimental drugs within 2 weeks prior to visit, and patients with serious renal, cardiac or hepatic disease cure, side-effects Azithromycin g po Wojtowicz 99, Polish 99 adults/adolescents 59/59 genital (cervix) not mentioned All comers Not mentioned cure Spectinomycin 2 g IM 8

19 Randomized studies with two or more comparison groups STUDY YEAR POPULATION N INFECTION AGE (mean and/or range, if not indicated) INCLUSION EXCLUSION OUTCOMES TREATMENTS Backhaus 99, Germany 99 adults/adolescents 4/4 genital (cervix) 39.4 Male Kidney failure, beta-lactam intolerance, severe illness, alcohol/drug abuse, other venereal disease, antibiotic use < 3 days prior cure, side-effects Cefixime 4 mg po Christophersen 989, Netherlands 989 adults/adolescents 4/4 genital (cervix) > 8 A diagnosis of genitourinary or rectal gonorrhoea was made by microscopy of a methylene blue-stained smear at the initial visit and test positives were included They had received antibiotics in the previous 7 days, if they had known or suspected hypersensitivity to cephalosporins, penicillins, or lidocaine or if they had known renal or hepatic insufficiency cure, side-effects Ceftriaxone 25 mg IM Korting 989 Germany 989 adults/adolescents 64/65 genital (cervix) > 8 Gonorrhoea patients As above and mental disability cure, side-effects Ceftriaxone 25 mg IM Kouri 989, Puerto Rico, Latin America 989 adults/adolescents 25/2 genital (cervix) 26 (8 53) If they had signs or symptoms of genital infection and Gram-negative intracellular diplococci on smear of the discharge or were contact cases from a culture-positive patient Pregnant or if they had a history of allergy to penicillin or spectinomycin, evidence of coexistent syphilis, or had received antibiotics within the previous 2 weeks cure, side-effects Spectinomycin 2 g IM Pabst 989, USA 989 adults/adolescents 4/5 genital (cervix) 23 Women aged 6 years or older were eligible for enrolment if they had a Gram-stained endocervical smear showing Gram-negative diplococci within polymorphonuclear leukocytes, a recent untreated culture positive for N. gonorrhoeae, or sexual exposure to men with urethral gonorrhoea within the 2 weeks prior to enrolment Allergy to penicillin or quinolone antibiotics; complicated gonococcal infection; known untreated syphilis; or received antimicrobial therapy effective against N. gonorrhoeae in the 4 days preceeding initial evaluation. Patients excluded from analysis cultures negative, if patients failed to keep appointed follow-up visits 7 to days following enrollment, or if patients took therapy effective against N. gonorrhoeae between the time of enrollment and follow-up evaluation. cure, side-effects Ceftriaxone 25 mg IM Pandhi 989, India 989 adults/adolescents 54/55 all infections/total 2 4 and 2 Patients with acute gonococcal urethritis Not mentioned cure, side-effects Gentamicin 24 mg IM Calderon 988, Mexico 988 adults/adolescents 4/4 genital (cervix) 25 ± 8.3 (6 47) Gonorrhoea patients Had history of sensitivity to quinolones, azaquinolones or cephalosporins, had received antibiotics in the previous 2 weeks, or failed to follow up test cure, clinical cure, side-effects Ceftriaxone 25 mg IM 9

20 Randomized studies with two or more comparison groups STUDY YEAR POPULATION N INFECTION AGE (mean and/or range, if not indicated) INCLUSION EXCLUSION OUTCOMES TREATMENTS Panikabutra 988, Bangkok and Singapore 988 adults/adolescents 24/243 genital (cervix) 25 (5 58) Men and non-pregnant women aged 6 58 years who had culture positive symptomatic or symptomless uncomplicated gonorrhoea of the urethra, cervix or rectum Patients with complicated gonococcal infections, known hypersensitivity to quinolones, known impaired kidney function (creatinine clearance less than 3 ml/min), known decreased liver function, blood disorders or coexistent syphilis, or those who had received concomitant treatment with any other antibacterial drugs, coumarin derivatives, phenytoin or methotrexate cure, side-effects Spectinomycin 2 g IM Yoon 988, Korea 988 adults/adolescents 64/25 genital (cervix) > 8 Gonorrhoea patients, and those who had contact with gonorrhoea patients Unclear cure Kanamycin 2 g IM, gentamicin 24 mg IM Handsfield 987, USA Monayar 987, Argentina 987 adults/adolescents 9/ genital (cervix) not mentioned Gonorrhoea patients Not mentioned cure, side-effects 987 adults/adolescents 59/6 genital (cervix) 5 47 Men with uncomplicated gonorrhoea Not mentioned cure Ceftriaxone 25 mg IM Spectinomycin 2 g IM Lassau 987, France 987 adults/adolescents genital (cervix) 3.5 Male with uncomplicated gonococcal urethritis The patients had received antibiotics at least 2 weeks prior to treatment cure Spectinomycin 2 g IM Davidson 986, USA 986 adults/adolescents 4/45 genital (cervix) not indicated Positive culture Not mentioned cure Spectinomycin 2 g IM Dixon 986, United Kingdom 986 adults/adolescents 4/4 genital (cervix) not clear Men had to have uncomplicated urethral or rectal gonorrhoea diagnosed by the presence of Gramnegative intracellular diplococci (GNICD) in smears. Women were included if GNICD were seen on urethral, cervical or rectal smears or if N. gonorrhoeae was cultured from urethral, cervical or rectal swabs Patients in whom the initial cultures for N. gonorrhoeae were negative were subsequently excluded from the trial. Patients were excluded if they had received antibiotics in the previous days or if they had undiagnosed genital ulcers or known renal or hepatic disease. Pregnant women and those not using adequate contraception (such as the contraceptive pill, an intrauterine device, or sterilization) and any woman with evidence of salpingitis on clinical examination cure Ceftriaxone 25 mg IM, 5 mg IM 2

21 Randomized studies with two or more comparison groups STUDY YEAR POPULATION N INFECTION AGE (mean and/or range, if not indicated) INCLUSION EXCLUSION OUTCOMES TREATMENTS Hook 986, USA 986 adults/adolescents genital (cervix) > 8 Men > 8 years of age who had either a smear of urethral or rectal exudate showing Gram-negative intracellular diplococci or culture isolation of N. gonorrhoeae With complicated gonococcal infection, with a history of allergy to spectinomycin or beta-lactam antibiotics, or who had taken antimicrobial therapy active against N. gonorrhoeae within 2 weeks of enrolment cure, side-effects Spectinomycin 2 g IM Stapinski 986, Polish 986 adults/adolescents 936/946 genital (cervix) all comers with gonorrhoea Not mentioned Not mentioned cure Spectinomycin 2 g IM Hira 985, Zambia 985 adults/adolescents 678/347 genital (urethra) Not mentioned Uncomplicated acute urethritis and those with Gram-negative intracellular diplococci in smears of their urethral discharge were enrolled in the study Men with a previous history of urethral discharge or recurrent urethritis were excluded, as were those who had recently received antibiotics. Although treatment was started on the basis of Gram-stain results, culture specimens were taken before treatment from all patients, and those with negative results cure, side-effects Kanamycin 2 g IM, gentamicin 24entamic Kim 984, Korea 984 adults/adolescents 44/44 genital (cervix) 25.6 (8 42) Gonorrhoea patients Excluded patients with other complications cure, side-effects Spectinomycin 2 g IM Meheus 984, Central African Republic 984 adults/adolescents 97/2 genital (cervix) 23.9 Men with signs and symptoms of urethritis Allergic to the drugs under study, had received antimicrobial treatment within the preceding 2 weeks, and had complication of gonococcal infection cure, side-effects Spectinomycin 2 g IM Tupasi 984, Philippines 984 adults/adolescents 52/52 genital (cervix) 3 3 Patients with culture-positive gonorrhoea. Not mentioned cure, side-effects Spectinomycin 2 g IM Judson 983, USA 983 adults/adolescents genital (cervix) > 8 Women 8 years of age or older with proven (culture-positive) or suspected (history of exposure to a man with documented gonococcal urethritis) uncomplicated gonorrhoea Women with histories of allergy to P- lactam antibiotics, antimicrobial therapy within the preceding 2 weeks, complications of gonorrhoea, or any recent serious illness were excluded cure, side-effects Ceftriaxone 25 mg IM Panikabutra 983, Thailand 983 adults/adolescents 9/92 genital (cervix) Not mentioned Uncomplicated gonorrhoea Not mentioned cure, side-effects Spectinomycin 2 g IM Reggiani 983, Italy 983 adults/adolescents genital (cervix) Not reported/no age restriction Gonorrhoea patients Not mentioned cure, side-effects Spectinomycin 4 g IM 2

22 Randomized studies with two or more comparison groups STUDY YEAR POPULATION N INFECTION AGE (mean and/or range, if not indicated) INCLUSION EXCLUSION OUTCOMES TREATMENTS Tupasi 983, The Philippines 983 adults/adolescents 52/52 genital (cervix) 2 (3 3) Culture-positive patients Unclear cure, side-effects Spectinomycin 2 g IM Zajdowicz 983, USA 983 adults/adolescents 6/6 genital (cervix) not mentioned Recent sexual exposure, signs or symptoms of urethritis, and the presence of polymorphonuclear neutrophils and intracellular Gramnegative diplococci in a Gram-stained smear of urethral exudate Had a history of a severe immediate reaction to penicillin or any type of allergic reaction to any of the cephalosporins; hypersensitivity to lignocaine or probenecid; evidence of coexisting syphilis or gonococcal infection other than uncomplicated urethritis; or any disease which might require additional antibiotic treatment cure, clinical cure, side-effects Ceftriaxone 25 mg IM Ratnam 982, Zambia 982 adults/adolescents 5/6 genital (cervix) > 8 Men > 8 years of age who had either a smear of urethral or rectal exudate showing Gram-negative intracellular diplococci or culture isolation of N. gonorrhoeae With complicated gonococcal infection, with a history of allergy to spectinomycin or beta-lactam antibiotics, or who had taken antimicrobial therapy active against N. gonorrhoeae within 2 weeks of enrolment cure, side-effects Spectinomycin 2 g IM Fluker 98, United Kingdom 98 adults/adolescents 53/56 genital (cervix) 3.3 (8 67) All patients were examined with a proctoscope and specimens were taken for microscopy and culture. The diagnosis was confirmed by the finding of Gram-negative intracellular diplococci on the smear and by the isolation and identification of N. gonorrhoeae Not mentioned cure Spectinomycin 2 g IM Sands 98, USA 98 adults/adolescents 25/5 genital (cervix) > 8 Only those cases in which a follow-up rectal culture was done 3 4 days after completion of therapy were included. Only those follow-up culture-positive patients with physician histories specifically excluding reinfection were included among the treatment failures Not mentioned cure Spectinomycin 2 g IM Rajan 979, Singapore 979 adults/adolescents genital (cervix) not clear Patients with complicated gonococcal infections Not mentioned cure, side-effects Kanamycin 2 g IM, Falman 978 USA 978 adults/adolescents genital (cervix) 28.9 Culture-positive patients from anal sample Not mentioned cure Spectinomycin 4 g IM 22

23 Randomized studies with two or more comparison groups STUDY YEAR POPULATION N INFECTION AGE (mean and/or range, if not indicated) INCLUSION EXCLUSION OUTCOMES TREATMENTS Karney 977, USA 977 adults/adolescents 25/245 urethral or anorectal not mentioned All members of the study population had uncomplicated gonococcal cervicitis Not mentioned cure, side-effects Spectinomycin 4 g IM McCann 977, Belfast 977 adults/adolescents 236/242 total 5 57 Patient with uncomplicated gonorrhoea Unclear cure, side-effects Spectinomycin 2 g IM, spectinomycin 4 g IM Porter 977, 977 adults/adolescents 74/75 genital (cervix) not clear Patients with acute gonococcal urethritis Not mentioned cure, side-effects Spectinomycin 2 g IM Jaffe 976, USA 976 adults/adolescents genital (cervix) not clear Patients with suspected of urethral and/or anorectal gonorrhoea had either a smear of urethral or rectal exudate showing Gram-negative intracellular diplococci or culture isolation of N. gonorrhoeae With gonococcal complications, has history of allergy with any of the medicines, pregnant women side-effects Spectinomycin 2 g IM Niunikova 976, Russia Dashevskii 975, Russia 976 adults/adolescents 98/98 genital (cervix) 8 52 Gonorrhoea patients Not mentioned cure, clinical cure, side-effects 975 adults/adolescents 59/62 genital (cervix) 8 4 Gonorrhoea patients Not mentioned cure, side-effects Kanamycin 2 g IM Kanamycin 2 g IM Finger 975, USA 975 adults/adolescents genital (cervix) 2.5 Culture-positive patients from anal sample Not mentioned cure Spectinomycin 2 g IM, 4 g IM Turanova 975, Russia 975 adults/adolescents 67/68 genital (cervix) 9 45 Gonorrhoea patients Not mentioned cure, clinical cure Kanamycin 2 g IM Bowie 974, Canada 974 adults/adolescents 44/48 genital (cervix) > 8 Patients with gonorrhoea, had contact with gonorrhoea patients Unclear cure, side-effects Gentamicin 24 mg IM Brown 974, Canada 974 adults/adolescents 46/52 genital (cervix) not clear Adult male patients with acute uncomplicated gonorrhoeal urethritis Not mentioned cure, side-effects Spectinomycin 2 g IM 23

24 Randomized studies with two or more comparison groups STUDY YEAR POPULATION N INFECTION AGE (mean and/or range, if not indicated) INCLUSION EXCLUSION OUTCOMES TREATMENTS Duancic 974, USA 974 adults/adolescents 7/26 genital (cervix) not mentioned Women who were suspected on clinical or epidemiological grounds of having uncomplicated gonococcal infection and who gave written informed consent were randomized Pregnant women, patients who gave a history of sensitivity to penicillin, and patients who had received other antimicrobial therapy during the preceding week. Patients who were included in the study whose cultures did not contain gonococci were not included in the analysis of the data. cure, side-effects Spectinomycin, 2 g IM, spectinomycin 4 g IM Judson 974, USA 974 adults/adolescents 224/242 genital (cervix) adolescents and adults Born at 37 weeks or more, healthy neonates without ocular malformations whose mothers were treated with neither systemic nor local antibiotics week before delivery Not mentioned cure, side-effects Spectinomycin 4 g IM Kousa 974, Finland 974 adults/adolescents 245/263 genital (cervix) not clear Gonorrhoea patients Not mentioned cure, side-effects Spectinomycin 2 g IM Willcox 974, United Kingdom 974 adults/adolescents 76/83 genital (cervix) Male patients with acute uncomplicated urethral gonorrhoea Unclear cure, side-effects Spectinomycin 2 g IM Meyer-Rohn 974, Germany 974 adults/adolescents 87/ genital (cervix) 24.5 Men and women with unknown duration of gonorrhoea infection Not mentioned cure, clinical cure, side-effects Spectinomycin 2 g IM Reeves 974, United Kingdom 974 adults/adolescents 67/78 genital (cervix) 26.5 (6 6) Patients with acute uncomplicated gonococcal urethritis attending the Bristol venereal diseases clinic Not mentioned cure Gentamicin 24 mg IM Same study as Morrison and Reeves 973 Hantschke 973, Germany 973 adults/adolescents 58/62 genital (cervix) not mentioned Gonorrhoea patients Not mentioned cure, side-effects Ceftriaxone 25 mg IM Morrison 973, United Kingdom 973 adults/adolescents 67/78 genital (cervix) 26.5 (6 6) Patients with acute uncomplicated gonococcal urethritis attending the Bristol venereal diseases clinic Not mentioned cure Gentamicin 24 mg IM 24