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Clinical ORIGINAL ARTICLE Effectiveness of gentamicin for gonorrhoea treatment: systematic review and meta-analysis Deborah Dowell, Robert D Kirkcaldy ▸ Additional data are published online only. To view these files please visit the journal online (http://dx.doi.org/ 10.1136/sextrans-2012050604). Division of STD Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA Correspondence to Dr Deborah Dowell, New York City Department of Health and Mental Hygiene, Office of the Co
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  ORIGINAL ARTICLE Effectiveness of gentamicin for gonorrhoeatreatment: systematic review and meta-analysis Deborah Dowell, Robert D Kirkcaldy ▸  Additional data arepublished online only. To viewthese  󿬁 les please visit the journal online (http://dx.doi.org/ 10.1136/sextrans-2012-050604).Division of STD Prevention,Centers for Disease Control andPrevention, Atlanta, Georgia,USA Correspondence to Dr Deborah Dowell, New YorkCity Department of Health andMental Hygiene, Of   󿬁 ce of theCommissioner, 42-09 28thStreet, 8-62, Queens,New York 11101, USA;ddowell1@health.nyc.govAccepted 19 July 2012Published Online First23 August 2012 ABSTRACTObjectives  The development of resistance to multipleantimicrobial agents has limited treatment options forgonorrhoea. The potential emergence of cephalosporinresistance in  Neisseria gonorrhoeae  and cephalosporinallergy in some patients make it necessary to evaluatethe effectiveness of other available antimicrobial agents.Gentamicin is widely available in the USA and is used forgonorrhoea treatment in several countries. We conducteda systematic review of the medical literature to assessthe effectiveness of gentamicin for treatment of uncomplicated urogenital gonococcal infections. Methods  Two reviewers assessed relevant articles andindependently selected studies that met prespeci  󿬁 edselection criteria (including systematic enrolment andassignment to treatment and culture-con  󿬁 rmed diagnosisand outcome). Summary measures for selected studieswere pooled using inverse variance-weighted averageswith  󿬁 xed effects. Heterogeneity was assessed using I 2 ,which estimates proportion (0 – 100%) of variabilityattributable to heterogeneity between studies. Pooledpercentage with negative follow-up culture wascompared with Centers for Disease Control andPrevention (CDC) criteria for selection of recommendedtherapy (lower 95% CI of ef   󿬁 cacy  ≥ 95%). Results  Twenty-nine potentially relevant studies wereidenti  󿬁 ed; three met inclusion criteria. Two studies used240 mg intramuscular gentamicin and one used 280 mg.Percentages with negative culture after single-dosetreatment were 90.7% (n=86), 91.4% (n=220) and95.0% (n=40). Pooled percentage with negative cultureafter single-dose treatment was 91.5% (95% CI 88.1% to94.0%, I 2 =0%). Conclusions  Gentamicin does not meet current CDCcriteria for recommended treatment of gonorrhoea.However, if cephalosporin resistance emerges,gentamicin may be a useful alternative agent. Evaluationof additional regimens, including combination therapy, iswarranted. BACKGROUND  Neisseria gonorrhoeae  has demonstrated the ability todevelop resistance to several antibiotics. Penicillin,tetracycline and  󿬂 uoroquinolones are no longerconsidered suf  󿬁 ciently effective for the treatment of gonococcal infections after the emergence of resist-ance to these antibiotics. Spectinomycin is ef  󿬁 ca-cious but is no longer available in the USA. TheCenters for Disease Control and Prevention (CDC)currently recommends dual therapy for gonorrhoeawith a cephalosporin (preferably ceftriaxone) andazithromycin or doxycycline to ensure treatment of co-occurring pathogens and re 󿬂 ecting concern aboutemerging cephalosporin resistance. 1 Cephalosporinminimum inhibitory concentrations (MIC) havebeen increasing in Asia, Europe and the USA, and agrowing number of failures of gonorrhoea treatmentwith ce 󿬁 xime have been reported worldwide. 1 – 7  With few realistic prospects for novel antibiotics forgonorrhoea treatment, it is necessary to evaluate theef  󿬁 cacy of other currently available antibiotics.Gentamicin is chemically similar to spectinomycin,but unlike spectinomycin, is widely available in theUSA. Gentamicin is used for gonorrhoea treatmentin several countries, including Malawi. A recentstudy found continued susceptibility of gonococcalisolates in Malawi after 14 years of use as  󿬁 rst-linetreatment for urethritis. 8  We conducted a systematicreview of the medical literature and meta-analysis toassess the effectiveness of gentamicin for the treat-ment of uncomplicated urogenital gonococcalinfections. METHODS  We developed and followed a review protocol (seesupplementary text, available online only). Wesearched electronic databases (PubMed, EMBASE, theCochrane Central Register of Controlled Trials, Webof Science), registers of ongoing trials (Clinicaltrials.gov, 9 CenterWatch, 10 Current Controlled Trials 11 andthe WHO International Clinical Trials Registry Platform), 12 and reference lists of found articles forrelevant studies. The PubMed search strategy wasentered as  ‘ (gentamicin OR gentamicin(MeSHTerms)) AND (gonorrhoea OR gonococcal OR   N  gonorrhoeae  OR sexually transmitted diseases OR sexually transmitted infections OR urethritisOR cervicitis) OR (gonorrhoea OR   N gonorrhoeae  OR sexually transmitted diseases OR sexually transmit-ted diseases, bacterial(MeSH Terms)) ’ . Similarsearches were used for the other databases. Databaseswere last searched on 17 June 2012. We did not apply date or language restrictions. Abstracts were reviewed,and full text articles were retrieved for studies thatappeared to be trials of gentamicin in patients withgonococcal infection.Two reviewers (DD and RDK) assessed relevantarticles and independently selected studies thatmet prespeci 󿬁 ed selection criteria. We includedstudies of adolescents and/or adults with uncom-plicated urogenital gonococcal infection treatedwith single-dose intramuscular (IM) or intravenousgentamicin (any dose). Patients were considered tohave complicated gonococcal infection if they weredescribed as having a diagnosis of pelvic in 󿬂 amma-tory disease or disseminated gonococcal infection. We required included studies to have used urethral Sex Transm Infect   2012; 88 :589 – 594. doi:10.1136/sextrans-2012-050604 589 Clinical  or cervical culture for diagnosis of   N gonorrhoeae  at the time of treatment and for follow-up cultures of   N gonorrhoeae  to havebeen obtained from the same anatomical site as the initialinfection between 2 and 21 days post-treatment. To minimiseselection bias, we included controlled trials in which assign-ment to the treatment group was random or systematic andnot based on the severity of symptoms or patient characteris-tics. In addition, because we believed controlled trials would berare, we included single-arm case series, provided that enrol-ment in the study was systematic (eg, enrolment offered toconsecutive patients) and that any exclusions were prespeci 󿬁 ed.Initial agreement and kappa for assessment of studies to beincluded was calculated. Discrepancies in judgements regardinginclusion were adjudicated by discussion. For included studies,data including numbers of culture-positive patients treated,numbers with negative test of cure and dose of gentamicinused were extracted and recorded independently by tworeviewers (DD and RDK) using a data extraction form. Datawere compared, and differences were resolved throughdiscussion.Treatment success was de 󿬁 ned as the percentage of negativecultures obtained from initially culture-positive anatomicalsites within 2 – 21 days post-treatment. In the primary analysiswe included all participants who received treatment and didnot exclude participants based on perceived re-exposure.Summary measures of treatment success for all selected studieswere pooled using inverse variance-weighted averages (in whichthe weight of each study is the reciprocal of the variance in thestudy  ’ s estimate of treatment effect) with  󿬁 xed effects. Fixedeffects were assumed because we hypothesised there would beminimal variability in effect of an antibiotic on different uro-genital infections caused by   N gonorrhoeae . Heterogeneity wasassessed using I 2 , which estimates proportion (0 – 100%) of vari-ability attributable to heterogeneity between studies. Pooledpercentage with negative follow-up culture was compared withCDC criteria for selection of recommended therapy (95% lower95% CI of ef  󿬁 cacy at least 95%) and for alternative treatments(ef  󿬁 cacy of at least 95% with a lower 95% CI of at least90%). 13 Prespeci 󿬁 ed sensitivity analyses were performed todetermine impact of the following on pooled treatment effectand precision of the estimate of treatment effect: excludingtrials that were not randomised, controlled trials; excludingresults for patients who reported sexual activity between genta-micin treatment and test of cure; and excluding results forpatients given doses other than 240 mg gentamicin IM.Sensitivity analyses were also planned to determine impacts of excluding women, of excluding results for patients given anti-biotics in addition to gentamicin between 7 days before treat-ment and culture test of cure, of excluding patients known tohave symptoms of gonorrhoea for more than 7 days beforetreatment, of excluding HIV-negative patients, and of excludingHIV-positive patients. RESULTS  We identi 󿬁 ed 913 records through database searches and refer-ence lists of found articles. We retrieved the full text for the 29studies among those that appeared to be trials of gentamicintreatment for gonorrhoea. After independent review and discus-sion, we agreed that 26 studies (table 1) did not meet prespeci- 󿬁 ed inclusion criteria because they were not treatment trials of single-dose gentamicin, because we could not con 󿬁 rm thatstudy enrolment or assignment to treatment was systematic, orbecause culture was not used for diagnosis and for test of cure( 󿬁 gure 1). Agreement for initial judgement on meetingselection criteria was good (93% agreement,  κ =0.713). Threestudies (table 2) met the inclusion criteria. One study was arandomised, controlled trial that enrolled men with urethraldischarge or dysuria presenting to an outpatient clinic inMalawi. 14 Two were single-arm case series: one that enrolledmen with complaints of urethral discharge presenting to one of two hospitals in Malawi, 15 and one that enrolled men withuncomplicated acute urethritis presenting to a sexually trans-mitted diseases clinic in Zambia. 16  Two studies used 240 mgand one study used 280 mg IM gentamicin for single-dosetreatment of gonorrhoea. In the three studies included, the per-centages of study participants with negative culture after treat-ment were 90.7% (95% CI 84.6% to 96.8%), 91.4% (95% CI87.7% to 95.1%) and 95.0% (95% CI 88.3% to 100.0%). Thepooled percentage with negative culture after single-dose treat-ment was 91.5% (95% CI 88.1% to 94.0%, I 2 =0%).The single randomised controlled trial had a treatment effectof 95%. A sensitivity analysis excluding patients considered by authors of the srcinal reports to have been re-exposed to gon-orrhoea between treatment and follow-up culture yielded atreatment effectiveness of 95.1% (95% CI 91.8% to 97.2%,I 2 =64%). Restricting analysis to patients treated with 240 mgIM gentamicin produced similar results (91.8% effectiveness,95% CI 85.4% to 95.5%, I 2 =0%) to those from the primary analysis. Sensitivity analysis excluding women was not donebecause no women were enrolled in the studies included. Analyses excluding results for patients given antibiotics in add-ition to gentamicin between 7 days before treatment andculture test of cure or excluding patients known to have symp-toms of gonorrhoea for more than 7 days before treatmentwere not done because no information was available in theincluded reports that would allow the determination of patients meeting these criteria. While one study reportedoverall numbers of HIV-positive patients enrolled in the trial,effectiveness of gentamicin among HIV-positive patients and of HIV-negative patients was not reported, so effects of excludingHIV-negative patients and of excluding HIV-positive patientscould not be determined.Studies not meeting standards for inclusion but providingdata on gonorrhoea treatment outcomes following IM gentami-cin reported success rates ranging from 62.4% to 100.0% basedon clinical examination, Gram stain and/or culture (table 1).The six studies presenting results speci 󿬁 cally for women 17 – 22 reported successful treatment rates between 92.2% and 96.5%.Of note, two of these studies, one in English 17 and one inGerman 21 by the same primary author, contain similar descrip-tions of patients, and it is possible the same patients describedin one study  17 included the patients described in the otherstudy. 21 The two studies reporting treatment with other anti-biotics in addition to gentamicin 23 24 did not provide speci 󿬁 cinformation on gonorrhoea outcomes. None of the excludedstudies included information about gonorrhoea outcomes by HIV status. In several of the excluded studies, speci 󿬁 c criteriafor reporting successful treatment were not described. DISCUSSION  A systematic review of the medical literature for trials of single-dose gentamicin treatment of culture-con 󿬁 rmed uncomplicatedurogenital gonorrhoea found treatment ef  󿬁 cacy of greater than90% for all studies and a pooled ef  󿬁 cacy of 91.5% with a lower95% con 󿬁 dence limit for ef  󿬁 cacy of 88.1%. Only one study (arandomised, controlled trial) found a treatment ef  󿬁 cacy of 95%(with lower 95% con 󿬁 dence limit of 88%). 14 Based on ourprimary analysis, gentamicin does not meet current CDC 590  Sex Transm Infect   2012; 88 :589 – 594. doi:10.1136/sextrans-2012-050604 Clinical  Table 1  Studies considered but excluded from the systematic review Author Year Efficacy of gentamicin for gonorrhoea treatment Reason for exclusion Bartunek   et al  19 1974 95/100 Women (95.0%) with gonorrhoea successfully treated with 280 mggentamicin IM×1 based on clinical and microscopic exam and culture (specificcriteria for success not specified)Non-systematic enrolment or treatment assignment, or notdescribedBowie  et al  20 1974 47/51 Women (92.2%) with culture-proven gonorrhoea had negative culture after240 mg gentamicin IM×1Non-systematic enrolment or treatment assignment, or notdescribedBrown  et al  8 2007 Patient outcome data not presented. All 100  N gonorrhoeae  isolates tested frommen presenting with urethral discharge were  ‘ susceptible ’  to gentamicin (MIC ≤ 4)Culture not used systematically for diagnosis or outcomeBukharovich andRevunov 23 1991 114/116 Men with urethritis of different aetiologies including gonorrhoea had ‘ favourable ’  results following a combination of immunostimulation with  ‘ gonorrhoeavaccine, methyluracil and pyrogenal, ’  local therapy, gentamicin (840 mg pertreatment course) and doxycyclineGentamicin dosing was not single doseDanda  et al  w5 1976 18/19 Men (94.7%) with gonorrhoea treated with 320 mg IM of gentamicin and 9/ 10 men (90.0%) with gonorrhoea treated with 240 mg IM of gentamicin were ‘ cured ’  based on clinical exams and cultureNon-systematic enrolment or treatment assignment, or notdescribedFelarca  et al  29 1971 Men with gonococcal urethritis were treated with successively higher doses ofgentamicin IM up to 280 mg; all 34 patients (100.0%) given this dose (whoreturned for follow up) became asymptomaticGentamicin dosing was not single doseGomez-Medina w6 1969 12/14 Men (85.7%) with acute or subacute gonorrhoea treated with 1 mg/kggentamicin IM daily for 2 days had negative urethral smears within 3 days aftertreatmentGentamicin dosing was not single doseHantschke  et al  21 1973 40/43 Women (93.0%) and 13/14 men (92.9%) with gonococcal infection werecured (based on culture between 3rd and 10th day) after 5 mg/kg gentamicin IM;two women had salpingitis and one man had epididymitis (these three patientswith complications were among those cured)Non-systematic enrolment or treatment assignment, or notdescribed; included complicated gonorrhoeaHantschke  et al  17 1973 45/48 Women (93.8%) and 13/14 men (92.9%) with gonococcal infection werecured (based on culture between 3rd and 10th day) after 5 mg/kg gentamicin IM;two women had salpingitis and one man had epididymitisNon-systematic enrolment or treatment assignment, or notdescribed; included complicated gonorrhoeaHantschke andMauss 22 1970 13/14 Women (92.9%) with gonococcal infection treated with 240 mg gentamicinIM×3 days and 9/9 men (100.0%) with gonococcal infection treated with 160 mggentamicin IM×3 days were cured based on microscopy and culture 2 and 3 daysafter treatmentGentamicin dosing was not single doseIskandar  et al  w7 1978 19/22 Men (86.4%) with gonococcal urethritis treated with 240 mg gentamicin IMwere free of discharge and had negative Gram stains at 7 daysCulture not used systematically for diagnosis or outcomeLawrence  et al  w8 1974 Among men with uncomplicated gonorrhoea, 96/111 (86.5%; 6/8 (75.0%) treatedwith 160 mg gentamicin IM, 89/101 (88.1%) treated with 240 mg gentamicin IMand 1/2 (50.0%) treated with 320 mg gentamicin IM) were cured based on Gramstain and culture at 1 day, 1 week and 2 weeksCulture not used systematically for diagnosis or outcomeMirarchi  et al  w9 1971 15/15 Male patients (100.0%) with acute gonococcal urethritis treated with 280 mggentamicin IM were cured based on clinical and bacteriological examNon-systematic enrolment or treatment assignment, or notdescribedMorrison andReeves w10 1973 Among men with acute uncomplicated gonococcal urethritis, 33/38 (86.8%) treatedwith 120 mg gentamicin IM daily×2 days and 35/40 (87.5%) treated withgentamicin 240 mg IM×1 had negative urethral smears at 1 week Culture not used systematically for diagnosis or outcomePandhi  et al  w11 1989 52/55 Men (94.5%) with acute gonococcal urethritis had negative urethral smearsat 3 – 5 days after treatment with 240 mg gentamicin IMCulture not used systematically for diagnosis or outcomePareek andChowdhury w12 1981 19/20 Patients (95.0%) with penicillin-resistant strains of gonorrhoea had negativecultures at 3 days, 1 week and 2 weeks following treatment with gentamicin160 mg IM×1Non-systematic enrolment or treatment assignment, or notdescribedPelfini and Bruni w13 1969 12/18 Patients with gonococcal urethritis (66.7%) had negative cultures 4 days aftertreatment with 80 mg gentamicin IM daily×3 daysNon-systematic enrolment or treatment assignment, or notdescribedPrice  et al  24 2003 Trial of metronidazole versus placebo along with 240 mg IM gentamicin IM×1 and100 mg doxycycline twice a day for 7 days among men with urethritis. 73.5% ofparticipants had gonorrhoea by urine sediment PCR at enrolment, but neitheroutcomes specific to these men nor follow-up tests for gonorrhoea were reportedCulture not used systematically for diagnosis or outcomeRajan w14 1983 Not a novel study (review)Reeves w15 1974 Not a novel study (review)Serri w16 1969 Not a novel study (review)Siboulet w17 1972 93/105 Male patients (88.6%) successfully treated (criteria for successful treatmentnot described) with 240 mg gentamicin IM×1Non-systematic enrolment or treatment assignment, or notdescribed; culture not used systematically for diagnosis oroutcomeStrauss andHantschke w18 1973 58/62 Patients (93.5%) with gonorrhoea were cured (criteria not specified) with5 mg/kg gentamicin IMCulture not used systematically for diagnosis or outcomeTan  et al  18 1980 83/86 Women (96.5%) and 10/10 men (100.0%) with penicillinase-producing  N  gonorrhoeae  had negative cultures at 3 days, 1 week and 2 weeks after treatmentwith gentamicin 280 mg IM×1Non-systematic enrolment or treatment assignment, or notdescribed Yoon  et al  w19 1988 78/125 Male patients (62.4%) with uncomplicated gonococcal infection treatedwith gentamicin 240 mg IM×1 had negative Gram stain and culture results at 3 – 5 daysCulture not used systematically for diagnosis or outcomeZabaneh  et al  w20 1980 15/15 Men (100.0%) with gonococcal urethritis had disappearance of urethraldischarge and a negative culture 3 days after treatment with gentamicin 280 mgIM×1Non-systematic enrolment or treatment assignment, or notdescribed IM, intramuscular. Sex Transm Infect   2012; 88 :589 – 594. doi:10.1136/sextrans-2012-050604 591 Clinical  criteria for the recommended or alternative treatment of gonorrhoea.Gentamicin has several advantages for the treatment of gon-orrhoea. Gentamicin is an aminoglycoside with concentration-dependent bactericidal activity against Gram-negative bacteria.It binds at the 30S bacterial ribosomal subunit and interfereswith bacterial protein synthesis and initiation of DNA replica-tion. 25 26  The mechanism of action differs from that of otherantibiotics recommended for the treatment of gonorrhoea, sug-gesting that resistance to other antibiotic classes will notconfer resistance to gentamicin. Gentamicin is widely availableand inexpensive. However, gentamicin is only able to be admi-nistered intravenously or intramuscularly. In addition, gentami-cin is associated with oto and nephrotoxity at high doses andwhen used for extended periods of treatment, because toxicity depends on prolonged  ‘ trough ’  concentration levels. 27  Althoughdata on the risks of toxicity with single-dose therapy arelimited, the risks appear to be minimal. 16  – 18 28 29 Oto ornephrotoxicity were not observed among the participants of the studies we included in our analysis, although audiometry and creatinine clearance were not measured systematically. As apregnancy risk category D agent, gentamicin should not beused for pregnant or breast-feeding women. Although the ef  󿬁 cacy of gentamicin does not meet CDC cri-teria for a recommended (lower 95% CI of ef  󿬁 cacy   ≥ 95%) oralternative ( ≥ 95% ef  󿬁 cacy with lower 95% CI of 90%) treat-ment, it could potentially prove to be a treatment option if cephalosporin resistance emerges or for patients with severecephalosporin allergy. In an era of dwindling treatment options,the current CDC criteria for recommended and alternative treat-ment may need to be reconsidered. It is also worth noting thatthe CDC criteria for recommended treatment of gonorrhoeahave been applied to pooled estimates 30 including trials thatexcluded re-exposed patients in determining ef  󿬁 cacy, 31 – w2 andthat these pooled estimates may have been lower if all studieswere analysed according to assigned treatment (intent-to-treat)without the exclusion of patients who were consideredre-exposed. As an example, the authors of one study that weincluded retrospectively excluded patients deemed re-infected. 16  Our analysis, based on an intent-to-treat approach, found alower ef  󿬁 cacy (91.4%) than the srcinal study authors (98.0%),because we included all patients who were enrolled and receivedthe study drug. Although it may seem logical to exclude patientswho were re-exposed to  N gonorrhoeae  after treatment, retro-spectively excluding these patients may introduce bias into theresults, particularly when patients who had positive follow-upcultures were retrospectively evaluated for re-exposure whilepatients with negative cultures were not.Our  󿬁 ndings are subject to several limitations. First, wefound a small number of studies that met selection criteria Figure 1  Flow of studies included inthe systematic review. Table 2  Efficacy of single-dose gentamicin for the treatment of gonococcal urethritis Author Year Study design PopulationGentamicindosage OutcomeWeight in pooledanalysisEfficacy of gentamicin(95% CI) Daly  et al  15 1997 Single-arm caseseries107 Men withgonococcal urethrisin Malawi240 mg IM Culture onpost-treatmentday 727.4% 90.7% (84.6 to 96.8%)Hira  et al  16 1985 Controlled trial, withtreatment assignedto alternateconsecutive patients220 Men withgonococcal urethritisin Zambia280 mg IM Culture onpost-treatmentday 1465.4% 91.4% (87.7 to 95.1%)Lule  et al  14 1994 Randomisedcontrolledtrial40 Men withgonococcal urethrisin Malawi240 mg IM Culture onpost-treatmentday 8 – 107.2% 95.0% (88.3% to 100.0%)Pooled inverse weightedaverages of includedstudies100% 90.7% (88.1% – 94.0%) IM, intramuscular. 592  Sex Transm Infect   2012; 88 :589 – 594. doi:10.1136/sextrans-2012-050604 Clinical

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