Gentamicin as an alternative treatment for gonorrhoea
Authors: Robert D Kirkcaldy, Kimberly A Workowski
Journal: The Lancet (2019)

A high gonorrhoea disease burden, increasing rates, and growing antimicrobial resistance portend a developing global public health crisis.1WHOReport on global sexually transmitted infection surveillance 2015. World Health Organization, Geneva2015Google Scholar Gonorrhoea can cause reproductive complications such as pelvic inflammatory disease and infertility, blindness in infants born to infected mothers, and can facilitate HIV acquisition and transmission. Effective treatment prevents sequelae and transmission. Yet Neisseria gonorrhoeae has developed resistance to each antimicrobial used for treatment.2Bolan GA Sparling PF Wasserheit JN The emerging threat of untreatable gonococcal infection.New Engl J Med. 2012; 366: 485-487Crossref PubMed Scopus (206) Google Scholar Development of new antimicrobials has not kept pace. Ceftriaxone is the only remaining recommended agent that reliably cures gonorrhoea at all anatomic sites.3Workowski KA Bolan GA Sexually transmitted diseases treatment guidelines, 2015.MMWR Recomm Rep. 2015; 64: 1-137PubMed Google Scholar Declining cephalosporin susceptibility in the USA and elsewhere in 2009–12 raised concern about emerging ceftriaxone resistance;2Bolan GA Sparling PF Wasserheit JN The emerging threat of untreatable gonococcal infection.New Engl J Med. 2012; 366: 485-487Crossref PubMed Scopus (206) Google Scholar in response, strategies to prolong ceftriaxone effectiveness included recommendations for use of ceftriaxone rather than oral cephalosporins (based on pharmacokinetic principles and site-specific differences in treatment efficacy) and combination therapy to potentially mitigate resistance.3Workowski KA Bolan GA Sexually transmitted diseases treatment guidelines, 2015.MMWR Recomm Rep. 2015; 64: 1-137PubMed Google Scholar Concerningly, azithromycin susceptibility has now also declined in many countries.4Unemo M del Rio C Shafer WM Antimicrobial resistance expressed by Neisseria gonorrhoeae: a major global public health problem in the 21st century.Microbiol Spectrum. 2016; 4 (EI10-0009-2015.)PubMed Google Scholar A ceftriaxone-resistant and azithromycin-resistant strain of N gonorrhoeae was recently identified in the UK, and international transmission of a different ceftriaxone-resistant strain was recently described.5Eyre DW Sanderson ND Lord E et al.Gonorrhoea treatment failure caused by a Neisseria gonorrhoeae strain with combined ceftriaxone and high-level azithromycin resistance, England, February 2018.Euro Surveill. 2018; DOI:10.2807/1560-7917Crossref PubMed Scopus (195) Google Scholar, 6Lahra MM Martin I Demczuk W et al.Cooperative recognition of internationally disseminated ceftriaxone-resistant Neisseria gonorrhoeae strain.Emerg Infect Dis. 2018; 24: 735-743Crossref Scopus (129) Google Scholar Although ceftriaxone remains effective in the USA, the threat of ceftriaxone resistance and challenge of treating cephalosporin-allergic patients drives the search for additional treatments. Results of phase 2 trials of new antimicrobials (gepotidacin and zoliflodacin)7Taylor SN Morris DH Avery AK et al.Gepotidacin for the treatment of uncomplicated urogenital gonorrhea: a phase 2, randomized, dose-ranging, single-oral dose evaluation.Clin Infect Dis. 2018; 67: 504-512Crossref PubMed Scopus (84) Google Scholar, 8Taylor SN Marrazzo J Batteiger BE et al.Single-dose zoliflodacin (ETX0914) for treatment of urogenital gonorrhea.N Engl J Med. 2018; 379: 1835-1845Crossref PubMed Scopus (104) Google Scholar are encouraging, but commercial availability of these agents is not imminent. If ceftriaxone is not an option, identification of existing drugs that are effective and well tolerated is needed. We have previously investigated available drugs for gonorrhoea treatment; one regimen of the trial was gentamicin 240 mg intramuscularly plus azithromycin 2 g orally.9Kirkcaldy RD Weinstock HW Moore PC et al.The efficacy and safety of gentamicin plus azithromycin and gemifloxacin plus azithromycin as treatment of uncomplicated gonorrhea.Clin Infect Dis. 2014; 59: 1083-1091Crossref PubMed Scopus (105) Google Scholar Cure was based on negative cultures 10–17 days post treatment. The gentamicin-based regimen showed 100% efficacy for urogenital gonorrhoea in a group of 202 patients. Extragenital infections were cured, but the sample only included ten participants with pharyngeal gonorrhoea and one with rectal gonorrhoea. Likely owing to the 2 g azithromycin dose, 56 (26%) participants in the gentamicin group had mild to moderate nausea and 15 (7%) had mild to moderate vomiting. Among all participants who received gentamicin and azithromycin, ten (3%) vomited within 1 h. Subsequently, the US Centers for Disease Control and Prevention's 2015 treatment guidelines for sexually transmitted diseases listed gentamicin and azithromycin combination therapy as an alternative option in the presence of cephalosporin allergy but noted that gastrointestinal intolerability might limit use.3Workowski KA Bolan GA Sexually transmitted diseases treatment guidelines, 2015.MMWR Recomm Rep. 2015; 64: 1-137PubMed Google Scholar In The Lancet, Jonathan Ross and colleagues10Ross JDC Brittain C Cole M et al.Gentamicin compared with ceftriaxone for the treatment of gonorrhoea (G-ToG): a randomised non-inferiority trial.Lancet. 2019; (published online May 2.)http://dx.doi.org/10.1016/S0140-6736(18)32817-4Summary Full Text Full Text PDF Scopus (65) Google Scholar advance our understanding of the potential utility of gentamicin. 720 participants with uncomplicated gonorrhoea were randomly assigned to 500 mg of intramuscular ceftriaxone or 240 mg of intramuscular gentamicin; all participants received azithromycin 1 g orally. The primary outcome was clearance of N gonorrhoeae by negative nucleic acid amplification testing (NAAT) 2 weeks post treatment. 409 participants had genital gonorrhoea (219 in the gentamicin group), 256 participants had pharyngeal gonorrhoea (128 in the gentamicin group), and 306 had rectal gonorrhoea (147 in the gentamicin group). At 2 weeks after treatment, infection had cleared for 299 (98%) of 306 participants in the ceftriaxone group compared with 267 (91%) of 292 participants in the gentamicin group (adjusted risk difference −6·4%, 95% CI −10·4% to −2·4%). Similarly, 151 (98%) of 154 participants with genital gonorrhoea were cleared of infection in the ceftriaxone group compared with 163 (94%) of 174 participants with genital gonorrhoea in the gentamicin group (adjusted risk difference −4·4%, −8·7 to 0). For participants with a pharyngeal infection, a greater proportion receiving ceftriaxone had clearance at follow-up (108 [96%] in the ceftriaxone group compared with 82 [80%] in the gentamicin group; adjusted risk difference −15·3%, −24·0 to −6·5). For participants with rectal infection, clearance at follow-up was also greater in the ceftriaxone group (134 [98%] in the ceftriaxone group compared with 107 [90%] in the gentamicin group; adjusted risk difference −7·8%, −13·6 to −2·0). Thus, efficacy of gentamicin for the treatment of gonorrhoea was inferior to efficacy of ceftriaxone. When recommending regimens, gonorrhoea treatment guidelines have traditionally used efficacy estimates of individual agents.11Newman LM Moran JS Workowski KA Update on the management of gonorrhea in adults in the United States.Clin Infect Dis. 2007; 44: S84-S101Crossref PubMed Scopus (141) Google Scholar Gentamicin efficacy in this trial might have been higher had culture rather than NAAT been used for treatment outcome. Additionally, some apparent treatment failures might have been reinfections; 47 (16%) participants in the gentamicin group reported interim condomless sex.10Ross JDC Brittain C Cole M et al.Gentamicin compared with ceftriaxone for the treatment of gonorrhoea (G-ToG): a randomised non-inferiority trial.Lancet. 2019; (published online May 2.)http://dx.doi.org/10.1016/S0140-6736(18)32817-4Summary Full Text Full Text PDF Scopus (65) Google Scholar Adverse events following treatment with gentamicin and azithromycin were relatively uncommon; 41 (14%) of 298 participants had nausea and renal function was not compromised. These data support the role of gentamicin 240 mg plus azithromycin 1 g as an alternative regimen for urogenital and possibly rectal gonorrhoea for people with cephalosporin allergy. However only 82 (80%) of 102 participants with pharyngeal gonorrhoea were cleared of infection, so gentamicin plus azithromycin is not a reliable treatment. Treatment of pharyngeal gonorrhoea is challenging; pharyngeal infections can be more difficult to eradicate than infections at other sites, and the pharynx might serve as a reservoir of asymptomatic infection and resistant gonococci.12Weinstock HW Workowski KA Pharyngeal gonorrhea: an important reservoir of infection?.Clin Infect Dis. 2009; 49: 1798Crossref PubMed Scopus (42) Google Scholar The work by Ross and colleagues10Ross JDC Brittain C Cole M et al.Gentamicin compared with ceftriaxone for the treatment of gonorrhoea (G-ToG): a randomised non-inferiority trial.Lancet. 2019; (published online May 2.)http://dx.doi.org/10.1016/S0140-6736(18)32817-4Summary Full Text Full Text PDF Scopus (65) Google Scholar is a welcome step forward. However, because of ongoing management challenges and emerging resistance, new drugs with efficacy at all anatomic sites are still needed. Pharmacokinetic and pharmacodynamic studies of new drugs are needed to understand tissue penetration (especially at extragenital sites) and inform treatment duration. Because few treatment options exist, we might have to rethink existing efficacy standards for treatment recommendations.11Newman LM Moran JS Workowski KA Update on the management of gonorrhea in adults in the United States.Clin Infect Dis. 2007; 44: S84-S101Crossref PubMed Scopus (141) Google Scholar Strengthening prevention programmes and developing new approaches (including vaccines) is necessary, and staying ahead of the threat of gonococcal resistance requires sustained action. This online publication has been corrected. The corrected version first appeared at thelancet.com on June 20, 2019 This online publication has been corrected. The corrected version first appeared at thelancet.com on June 20, 2019 We declare no competing interests. The findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Gentamicin compared with ceftriaxone for the treatment of gonorrhoea (G-ToG): a randomised non-inferiority trialGentamicin is not appropriate as first-line treatment for gonorrhoea but remains potentially useful for patients with isolated genital infection, or for patients who are allergic or intolerant to ceftriaxone, or harbour a ceftriaxone-resistant isolate. Further research is required to identify and test new alternatives to ceftriaxone for the treatment of gonorrhoea. Full-Text PDF Open AccessDepartment of ErrorKirkcaldy RD, Workowski KA. Gentamicin as an alternative treatment for gonorrhoea. Lancet 2019; 393: 2474–75—This Comment (published Online First on May 2) should have been published under a CC BY-NC-ND Open Access licence. This correction has been made to the online version as of June 20, 2019. Full-Text PDF Open AccessDepartment of ErrorRoss JDC, Brittain C, Cole M, et al. Gentamicin compared with ceftriaxone for the treatment of gonorrhoea (G-ToG): a randomised non-inferiority trial. Lancet 2019; 393: 2511–20—This Article (published Online First on May 2) should have been published under a CC BY-NC-ND Open Access licence. This correction has been made to the online version as of June 20, 2019. Full-Text PDF Open Access