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

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WHO guidelines for the treatment

of Neisseria gonorrhoeae*

Web annex E

Systematic reviews

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1 WHO Library Cataloguing-in-Publication Data

WHO guidelines for the treatment of Neisseria gonorrhoeae.

Contents: Web annex D: Evidence profiles and evidence-to-decision framework -- Web annex E: Systematic reviews -- Web annex F: Summary of conflicts of interest

1.Neisseria gonorrhoeae - drug therapy. 2.Gonorrhea - drug therapy.

3.Drug Resistance, Microbial. 4.Guideline. I.World Health Organization.

ISBN 978 92 4 154969 1 (NLM classification: WC 150)

(http://www.who.int) or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; email: [email protected]).

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WHO Press through the WHO website (http://www.who.int/about/licensing/copyright_form/index.html).

The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part

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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.

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*The full guidelines and annexes are available at:

www.who.int/reproductivehealth/publications/rtis/gonorrhoea-treatment-guidelines/en/

For more information, please contact:

Department of Reproductive Health and Research E-mail: [email protected]

www.who.int/reproductivehealth

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Recommendation 1

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

Criteria

Population Intervention Comparator Outcome

Adults and adolescents, HIV-positive patients, MSM with uncomplicated genital (cervix, urethra) and anorectal gonococcal infections

Ceftriaxone

≥ 250 mg IM × 1

Single therapy:

Azithromycin 1–2 g po × 1 Cefixime 400 mg po × 1 Cefixime 800 mg po × 1 Cefixime 400 mg po × 2 Gentamicin 240 mg IM × 1 Spectinomycin 2 g IM × 1 Kanamycin 2 g IM × 1

Quinolones (just in vitro resistance data) Ceftriaxone 125 mg IM × 1

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

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

IM: intramuscular; po: by mouth (orally)

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 2004 to February 2015. Keywords used included gonorrhoea, gonorrhea, gonococcal, ophthalmia neonatorum. The search found 111 citations. Some reviews were used to verify the included studies. Five systematic reviews were found.

For randomized and non-randomized studies

We used one search of the databases to find articles for all five questions. We searched all databases up to March 2015: MEDLINE (from 1946), Embase (from 1980) and CENTRAL (Cochrane Central Register of Controlled Trials) and LILACS from inception. The search strategy included keywords and text words for gonorrhoea and medications.

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

Search strategy 1 gonorrhea.mp.

2 gonorrhoea.mp.

3 gonococcal.mp.

4 ophthalmia neonatorum.mp.

5 or/1-4

6 ceftriaxone.mp.

7 Azithromycin.mp.

8 cefixime.mp.

9 gentamicin.mp.

10 spectinomycin.mp.

11 kanamycin.mp.

12 quinolone*.mp.

13 doxycycline.mp.

14 erythromycin.mp.

15 silver nitrate.mp.

16 chloramphenicol.mp.

17 tetracycline*.mp.

18 povidone iodine.mp.

19 gemifloxacin.mp.

20 cephalosporin*.mp.

21 macrolide*.mp.

22 or/6-21 23 5 and 22 24 (th or tu).xs.

25 (co or cn or dr or dt or rh or si or th).fs.

26 24 or 25 27 23 and 26

28 limit 27 to (book or book series or editorial or letter or note or “review” or case reports or meta-analysis or news or systematic reviews) [Limit not valid in Ovid MEDLINE®, Ovid MEDLINE® Daily Update, Ovid MEDLINE® In-Process; records were retained]

29 case report/

30 27 not (28 or 29)

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

Screening of studies and data extraction

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

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

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

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

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Methods of analysis

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

narratively.

When available, we pooled and report data for subgroups by HIV status, drug dosage and type of infection.

The heterogeneity of pooled results is reported using the I² statistic.

Results

We found five reviews: Bai et al., 2012; Bignell & Unemo, 2012; Dowell & Kirkcaldy, 2012; Hathorn et al., 2014;

and Tapsall, 2002 (see below). The reviews did not cover all of the interventions and populations, but we used the search results from these reviews to confirm the studies to include. From our comprehensive search of electronic databases, we included 108 studies (including foreign language articles): 14 randomized and 94 non-randomized studies (including three non-randomized studies with two or more groups and 91 non-randomized studies with one group).

1. Bai ZG, Bao XJ, Cheng WD, Yang KH, Li YP. Efficacy and safety of ceftriaxone for uncomplicated gonorrhoea:

a meta-analysis of randomized controlled trials. Int J STD AIDS. 2012;23(2):126-32.

doi:10.1258/ijsa.2009.009198.

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

3. Dowell D, Kirkcaldy RD. Effectiveness of gentamicin for gonorrhoea treatment: systematic review and meta- analysis. Sex Transm Infect. 2012;88(8):589-94. doi:10.1136/sextrans-2012-050604.

4. Hathorn E, Dhasmana D, Duley L, Ross JD. The effectiveness of gentamicin in the treatment of Neisseria gonorrhoeae: a systematic review. Syst Rev. 2014;3:104. doi:10.1186/2046-4053-3-104.

5. Tapsall J. Current concepts in the management of gonorrhoea. Expert Opin Pharmacother. 2002;3(2):147-57.

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PRISMA

Figure 1: PRISMA Study Flow diagram

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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 2009, Jeddah, Saudi Arabia

2009 adult/adolescents 184/200 genital (urethra) or anorectal

14–55 Gonorrhoea patients Unclear microbiological

cure Ceftriaxone 250 mg IM × 1, spectinomycin 2 g IM × 1

Tian 2002,

China 2002 adult/adolescents 217/225 genital (cervix) 18–52 Gonorrhoea patients Not mentioned microbiological

cure, clinical cure

Ceftriaxone 250 mg IM × 1, spectinomycin 2 g IM × 1

Cheng 2001, China (in Chinese)

2001 adult/adolescents 93/94 genital (cervix) 18–56 Gonorrhoea patients Unclear microbiological

cure, clinical cure, side-effect

Handsfield 1994,

USA 1994 adult/adolescents 541/549 genital (cervix) not mentioned Men and women with

uncomplicated gonorrhoea Pregnant and nursing women microbiological

cure, side-effect Ceftriaxone 250 mg IM × 1, azithromycin 2 g po × 1 Rompalo 1994,

USA 1994 adult/adolescents 38/107 genital (cervix) 15–60 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.

microbiological

cure, side-effect Spectinomycin 2 g IM × 1, ceftriaxone 250 mg IM × 1

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7 Randomized studies with two or more comparison groups

Mroczkowski

1993, USA 1993 adult/adolescents 11/16 genital

(urethra) 23.6 (18–36) Patients with uncomplicated

gonorrhoea Patients under 18 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

microbiological cure, clinical cure, side- effects

Portilla 1992,

USA 1992 adult/adolescents genital (cervix) 23.3 (18–44) 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

microbiological cure, side- effects

Ceftriaxone 250 mg IM × 1, cefixime 400 mg po × 1, 800 mg po × 1 (or cefixime 400 mg po × 2)

Plourde 1992,

Kenya 1992 adult/adolescents 181/184 genital (cervix) 18–65 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

Cefixime 400 mg po × 1, ceftriaxone 250 mg IM × 1

Handsfield 1991,

USA 1991 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

Cefixime 400 mg po × 1, cefixime 800 mg po × 1 (or cefixime 400 mg po × 2)

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Judson 1985,

Denver, USA 1985 adults/adolescents

and MSM 41/41 genital (cervix) > 19 Patients who had positive smears for anogenital gonorrhoea and/or a documented exposure to gonorrhoea were considered

Patients with histories of allergy to beta-lactam antibiotics or who had antimicrobial therapy within the preceding 2 weeks, or complications of gonorrhoea, or any serious illness were excluded

Panikabutra

1985, Thailand 1985 adults/adolescents 190/190 genital (cervix) not mentioned Women with uncomplicated

gonorrhoea Not mentioned microbiological

cure, side- effects

Spectinomycin 2 g IM × 1, ceftriaxone 250 mg IM × 1

Collier 1984,

USA 1984 adults/adolescents 13/18 genital (cervix) 22.6 ± 4.3 The presence of intracellular Gram- negative 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

Handsfield 1983,

USA 1983 adult/adolescents 4/10 genital (cervix) 27.6 Men aged ≥ 16 years with uncomplicated gonorrhoea urethritis or anorectal infections

Patients with complicated gonorrhoea, had other antibiotics for preceding 2 weeks, allergic to B-lactam antibiotics

Ceftriaxone125 mg IM × 1, ceftriaxone 250 mg IM × 1, spectinomycin 2 g IM × 1 Handsfield 1981,

USA 1981 adult/adolescents 4/4 genital (cervix) 26.9 ± 7.7 years

(16–57) Men aged ≥ 16 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 beta- lactam antibiotics, with complications of gonorrhoea, or who had received antimicrobial therapy within the preceding 2 weeks

Ceftriaxone 125 mg IM × 1, ceftriaxone 250 mg IM × 1, 500 mg IM × 1

Non-randomized studies with two comparison groups

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Schumacher

2013, USA 2013 adult/adolescents 394/485 genital (cervix) Diagnosed as having uncomplicated

N. gonorrhoeae infection Not mentioned microbiological

cure Ceftriaxone + azithromycin, ceftriaxone + doxycycline Deguchi 2003,

Japan 2003 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 microbiological

cure, side- effects

Cefixime 200 mg po × 2, cefixime 400 mg po × 1

Rajan 1982,

Singapore 1982 adult/adolescents genital (cervix) Only those treated patients whose infections were confirmed by culture

Patients with reinfections were excluded

from the study microbiological

cure, side- effects

Ceftriaxone 250 mg IM × 1, kanamycin 2 g IM × 1

Non-randomized study with one group Takahashi 2014,

Japan 2014 adult/adolescents 30/33 genital (cervix) 20 or more Heterosexual male patients with both gonococcal urethritis (GU) and non-gonococcal urethritis (NGU) who were ≥ 20 years old. Diagnosis of GU was based on both symptoms: urethral pain and pus discharge

Unclear microbiological

cure, clinical cure

Azithromycin 2 g po × 1

Kojima 2008,

Japan 2008 adult/adolescents 203/210 genital (cervix) 32.3 (17–73) Male patients with uncomplicated

gonococcal urethritis Not mentioned microbiological

cure, clinical cure, side- effects

Spectinomycin 2 g IM × 1

Muratani 2008,

Japan 2008 adult/adolescents 25/25 oropharyngeal 28.1 Outpatients with uncomplicated gonorrhoea either symptomatic or asymptomatic, as well as sexual contacts of individuals with known gonorrhoea

Not mentioned Microbiological

cure Ceftriaxone 250 mg IM × 1

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Khaki 2007,

India 2007 adult/adolescents 22 genital (urethra) or anorectal

18–54 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).

Khrianin 2006,

Russia 2006 adults/adolescents 119/119 genital (cervix) 18–45 Gonorrhoea patients Allergic to antibiotic, diagnosis something

else, e.g. syphilis microbiological

cure, clinical cure

Ceftriaxone 250 mg IM × 1

Habib 2004,

United Kingdom 2004 adulst/adolescents 168/170 genital (cervix) 25.8 (14–56) 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 culture-proven N. gonorrhoeae thereafter, or if there was a history of recent unprotected sexual intercourse with a partner infected with gonorrhoea regardless of Gram staining and before culture confirmation.

Patients with negative culture results for N. gonorrhoeae who were initially treated were excluded from the study

microbiological

cure Azithromycin 1 g po × 1

Rustomjee 2002,

South Africa 2002 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

cure, clinical cure, compliance, side-effects

Aplasca 2001,

Philippines 2001 adults/adolescents 25/26 genital (cervix) 22.3 ± 4.2 Women with positive results for N. gonorrhoeae by endocervical Gram staining or culture

< 16 years, pregnant, signs suggestive

of pelvic inflammatory diseases microbiological cure, side- effects

Cefixime 400 mg po × 1

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Jin Hong 2001,

China 2001 adults/adolescents 77/77 genital (cervix) not mentioned Gonorrhoea patients Unclear microbiological

cure, clinical cure, side- effects

Swanston 2001,

Trinidad 2001 adults/adolescents 121/127 genital (cervix) 14–83 History of genital discharge Patients had antibiotics within the last 7 to 10 days, with complicated gonorrhoea or chlamydial infection, pregnant, lactating

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

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

Zhou, 2000, China (in Chinese)

2000 adults/adolescents 35/36 genital (cervix) 18–52 Gonorrhoea patient Allergic, pregnant, breastfeeding, cardinal,

renal and liver complications microbiological cure, clinical cure, side- effects

Gruber 1997,

Croatia 1997 adults/adolescents genital (cervix) 24.5 Gonorrhoea patient Allergic, pregnant, breastfeeding, cardinal,

renal and liver complications microbiological cure, clinical cure, side- effects

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Hook 1997, USA 1997 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

Mroczkowski

1997, USA 1997 adults/adolescents 124/125 genital (cervix) 15–54 Women aged 16 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

microbiological

cure, side-effects Cefixime 400 mg po × 1

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Gruber 1995,

Croatia 1995 adults/adolescents 49 genital (cervix) 24.5 Adults (>18 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.

Mogabgab 1994 cost data available, USA

1994 adults/adolescents 48/48 genital (cervix) 23.9 Aged > 18 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

Steingrimsson

1994, Iceland 1995 adults/adolescents 55 genital

(urethra) 24.7 (17–58) 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

Covino 1993,

USA 1993 adults/adolescents 3/3 genital (cervix) > 18 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

microbiological

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Hook 1993, USA 1993 adults/adolescents 6/6 genital (cervix) 18–50 Women aged 18 to 50 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

McCormack

1993, USA 1993 adults/adolescents 113/115 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

Odugbemi 1993,

Nigeria 1993 adults/adolescents 114/123 genital (cervix) 16–52 Outpatients over 14 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

Smith 1993, USA 1993 adults/adolescents 24/24 genital (urethra) or anorectal

26.5 (18–58) Men and women ≥ 18 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

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Tupasi 1993 and 1984 had the same data, the Philippines

1993 adults/adolescents 52/2 genital (cervix) 13–30 Patients with culture-positive

gonorrhoea Not mentioned microbiological

cure, side- effects

Verdon 1993,

USA 1993 adults/adolescents 93/98 genital (cervix) > 16 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

cure, side-effect Cefixime 200 mg po × 1

Waugh 1993,

United Kingdom 1993 adults/adolescents 89/93 genital (cervix) 16–60 Male and female patients between 16 and 60 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.

microbiological cure, clinical effect, side- effects

Baddour 1992,

Tennessee, USA 1992 adults/adolescents 35/35 genital (cervix) 23.3 (18–47) Patients were18 years of age

or older If they were pregnant, other complications,

had antibiotics in previous weeks microbiological cure, side- effects

Dunnett/

Dunnel 1992, USA

1992 adults/adolescents 71/73 genital (cervix) > 18 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

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Goldstein 1991,

USA 1991 adults/adolescents genital (cervix) 20–40 Documented urethritis, not allergic to penicillin and/or cephalosporin antibiotics

Allergic to penicillin and/or cephalosporin

antibiotics microbiological

cure, side- effects

Bryan 1990,

Zambia 1990 adults/adolescents including HIV patients

164/165 genital (cervix) 27.5 Adult males between 18 and 50 years of age who presented with urethral discharge containing intracellular Gram-negative diplococci (as determined by microscopic exam)

A history of antimicrobial treatment within 14 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

Lassus 1990,

Finland 1990 adults/adolescents 40 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

cure, side- effects

Covino 1990,

USA 1990 adults/adolescents 41/42 genital (cervix) > 18 Heterosexual men or women at least 18 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.

Freedman 1990,

USA 1990 adults/adolescents 51/51 genital (cervix not mentioned If pharynx and rectum are culture positive for gonococcus (by the patient’s history)

Megran 1990,

Canada 1990 adults/adolescents

MSM 97/98 genital (cervix) > 18 Males aged 18 years and older with positive cultures for N. gonorrhoeae from any site or with Gram-negative intracellular diplococci from endo-urethral 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

(22)

Steingrimsson

1990, Iceland 1990 adults/adolescents 41/43 genital

(urethra) 24.7 (17–58) 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

Wojtowicz 1990,

Polish 1990 adults/adolescents 59/59 genital (cervix) not mentioned All comers Not mentioned microbiological

cure Spectinomycin 2 g IM × 1 Backhaus

1990, Germany

1990 adults/adolescents 14/14 genital (cervix) 39.4 ^Male Kidney failure, beta-lactam

intolerance, severe illness, alcohol/drug abuse, other venereal disease, antibiotic use < 3 days prior

Christophersen 1989, Netherlands

1989 adults/adolescents 40/40 genital (cervix) > 18 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

Korting 1989

Germany 1989 adults/adolescents 64/65 genital (cervix) > 18 Gonorrhoea patients As above and mental disability microbiological cure, side- effects

Kouri 1989, Puerto Rico, Latin America

1989 adults/adolescents 205/210 genital (cervix) 26 (18–53) 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

(23)

Pabst 1989, USA 1989 adults/adolescents 14/15 genital (cervix) 23 Women aged 16 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 14 days preceeding initial evaluation.

Patients excluded from analysis cultures negative, if patients failed to keep appointed follow-up visits 7 to 10 days following enrollment, or if patients took therapy effective against N. gonorrhoeae between the time of enrollment and follow- up evaluation.

Pandhi 1989,

India 1989 adults/adolescents 54/55 all

infections/total 21–40 and

11–20 Patients with acute gonococcal

urethritis Not mentioned microbiological

cure, side- effects

Gentamicin 240 mg IM × 1

Calderon 1988,

Mexico 1988 adults/adolescents 40/40 genital (cervix) 25 ± 8.3 (16–47) 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

Panikabutra 1988, Bangkok and Singapore

1988 adults/adolescents 241/243 genital (cervix) 25 (15–58) Men and non-pregnant women aged 16–58 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 30 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

Yoon 1988,

Korea 1988 adults/adolescents 164/251 genital (cervix) > 18 Gonorrhoea patients, and those who had contact with gonorrhoea patients

cure Kanamycin 2 g IM × 1, gentamicin 240 mg IM × 1

Handsfield 1987,

USA 1987 adults/adolescents 109/110 genital (cervix) not mentioned Gonorrhoea patients Not mentioned microbiological cure, side- effects