Gentamicin a potential treatment for ceftriaxone-resistant gonorrhoea
Gentamicin, while not as effective as ceftriaxone in clearing gonorrhoea infection, may be a suitable alternative treatment for patients who are intolerant or resistant to ceftriaxone, according to the G-ToG study.
“Our trial has found that gentamicin combined with azithromycin works almost as well as ceftriaxone with azithromycin for genital gonorrhoea but did not clear throat or rectal gonorrhoea as effectively,” said primary investigator Professor Jonathan Ross from the Birmingham University Hospitals NHS Foundation Trust, Birmingham, UK.
“We believe ceftriaxone should remain the first-line treatment for gonorrhoea, with gentamicin as an alternative particularly for patients with genital infection, and those who are allergic or intolerant to ceftriaxone,” said Ross.
Study participants were 720 patients aged 16–70 years who were diagnosed with uncomplicated genital (n=409), pharyngeal (n=256), or rectal gonorrhoea (n=306) at one of 14 sexual health clinics in England. They were randomized to receive a single dose of gentamicin (240 mg; n=358, mean age 30.4 years, 18 percent female) or ceftriaxone (500 mg; n=362, mean age 30.2 years, 19 percent female) intramuscularly plus a single dose of oral azithromycin (1 g). Of these, primary outcome data was available for 292 and 306 gentamicin and ceftriaxone recipients, respectively.
Two weeks post-treatment, the infection had cleared* in 98 percent of patients assigned to receive ceftriaxone compared with 91 percent of those assigned to receive gentamicin (adjusted risk difference [ARD], -6.4 percent, 95 percent confidence interval [CI], -10.4 to -2.4 percent). [Lancet 2019;doi:10.1016/S0140-6736(18)32817-4]
When assessed according to infection type, clearance of infection was greater in the ceftriaxone compared with the gentamicin group participants who had a genital infection (98 percent vs 94 percent, ARD, -4.4 percent, 95 percent CI, -8.7 to 0 percent), pharyngeal infection (96 percent vs 80 percent, ARD, -15.3 percent, 95 percent CI, -24.0 to -6.5 percent), or rectal infection (98 percent vs 90 percent, ARD, -7.8 percent, 95 percent CI, -13.6 to -2.0 percent).
Reduction in estimated glomerular filtration rate from baseline to follow up was comparable between the ceftriaxone and gentamicin groups (median difference, -1.3 vs -1.4 mL/min), as was the incidence of nausea (12 percent vs 14 percent), dizziness/unsteadiness (7 percent each), hearing reduction (2 percent vs 1 percent), vomiting (1 percent vs 4 percent), and skin rash (2 percent vs 4 percent). Injection-site pain was reported by a similar proportion of patients in the ceftriaxone and gentamicin groups (98 percent vs 99 percent), with a higher mean pain score in gentamicin recipients (36 vs 21).
The proportion of patients reporting adverse events (AEs) was similar between the ceftriaxone and gentamicin groups (15 percent vs 13 percent) and were mostly mild. The three severe AEs were grade 4 dizziness (ceftriaxone group), diarrhoea, and sickness (gentamicin group for the latter two).
“Our current antibiotic treatment for gonorrhoea is beginning to fail and experience with previous drugs strongly suggests that this could become a widespread problem,” said Ross.
Furthermore, the results showed that the CDC- and WHO-recommended addition of azithromycin at a 1 g dose, meant to help reduce the development of resistance, did not appear to provide “microbiological cover”, especially in extra-genital gonorrhoea, highlighting the need to review this strategy, said Ross and co-authors.
“[B]ecause of ongoing management challenges and emerging resistance, new drugs with efficacy at all anatomic sites are still needed,” said Drs Robert Kirkcaldy from the Centers for Disease Control and Prevention, and Kimberly Workowski from Emory University, Atlanta, Georgia, US, in a commentary. [Lancet 2019;doi:10.1016/S0140-6736(19)30244-2]
“Ceftriaxone is the only remaining recommended agent that reliably cures gonorrhoea at all anatomic sites,” they said.
“Because few treatment options exist, we might have to rethink existing efficacy standards for treatment recommendations. Strengthening prevention programmes and developing new approaches (including vaccines) is necessary, and staying ahead of the threat of gonococcal resistance requires sustained action,” they said.
Local treatment measures
According to Dr Candice Chan, a consultant at the Department of Infectious Diseases, Singapore General Hospital, the current recommended treatment for urogenital, rectal, or pharyngeal gonorrhoea in Singapore is a single dose of intramuscular ceftriaxone with oral azithromycin 1g, a regimen that has a cure rate exceeding 95 percent.
“The rationale for combination therapy is to improve treatment efficacy and potentially slow the emergence and spread of resistance to cephalosporins,” she said. [Clin Infect Dis 2015;61 Suppl 8:S759-S762]
“However, in April 2019, Singapore published its first case of ceftriaxone-resistant multidrug-resistant Neisseria gonorrhoea (N. gonorrhoea) in a female sex worker, [though the microbe] remained susceptible to azithromycin,” she continued. [Antimicrob Agents Chemother 2019;63]
“As Singapore is situated in Southeast Asia with a large transient population from foreign visitors, it is at high risk of importation and dissemination of multi-drug resistant N. gonorrhoea. The local microbiology laboratories and DSO [National Laboratories] are closely monitoring the trend of antimicrobial resistance and clinical failure of the current first-line regimen. If the treatment failure rate or drug-resistant N. gonorrhoea continue to rise, it may be an indication of emergence of resistant N. gonorrhoea and thus [bring about] a need to review current treatment regimens to safeguard public health,” Chan said.