Single-dose solithromycin disappoints as first-line treatment for gonorrhoea
Oral solithromycin may not be a suitable substitute for ceftriaxone plus azithromycin in the first-line treatment of uncomplicated genital gonorrhoea, according to results of the phase III SOLITAIRE-U* trial.
“Combination ceftriaxone plus azithromycin is the recommended standard of care in the treatment of gonorrhoea in several regions. However, in view of increasing azithromycin resistance and the threat of more widespread ceftriaxone resistance, new drugs and combinations effective against gonorrhoea are required,” said the researchers.
“Solithromycin as a single 1000 mg dose is not a suitable first-line treatment for gonorrhoea,” they said.
Researchers of this open-label, noninferiority trial randomized 262 individuals aged ≥15 years (94 percent male) with untreated uncomplicated genital gonorrhoea (241 urethral and 12 cervical gonorrhoea infections) to receive either a single dose of oral solithromycin (1,000 mg; mean 30.1 years) or intramuscular ceftriaxone (500 mg) plus oral azithromycin (1,000 mg; mean age 29.4 years). Twelve, three, and nine percent of patients also had genital, pharyngeal, and rectal chlamydia infections, respectively.
The culture-determined eradication of genital Neisseria gonorrhoeae (N. gonorrhoeae) on day 7 (test of cure), occurred in a similar proportion of patients on solithromycin and ceftriaxone-azithromycin (80 percent vs 84 percent, difference -4.0, 95 percent confidence interval, -13.6 to 5.5; pnoninferiority=0.1082, with solithromycin not meeting the noninferiority criteria of a lower limit of the CI exceeding -10 percent). [Lancet Infect Dis 2019;19:833-842]
There was no evidence to suggest that re-infection with a different N. gonorrhoeae strain was responsible for treatment failure, the researchers said.
At test of cure, eight patients assigned to solithromycin had persistent genital gonorrhoea infection compared with none in the ceftriaxone-azithromycin group. In the 213 microbiologically evaluable patients**, 92, 94, and 83 percent of those treated with solithromycin tested negative for genital, pharyngeal, and rectal gonorrhoea on day 7, while all patients on ceftriaxone-azithromycin tested negative at all sites.
However, the number of extragenital gonorrhoea infections was relatively small and prevents any conclusions from being drawn on the efficacy of solithromycin for these infections, cautioned the researchers.
Adverse events (AEs) were more common among solithromycin compared with ceftriaxone-azithromycin recipients (53 percent vs 34 percent) and were primarily gastrointestinal (44 percent vs 24 percent) with diarrhoea (24 percent vs 15 percent) and nausea (21 percent vs 11 percent) the most frequently occurring AEs. Study drug-related AEs occurred in 43 and 25 percent of solithromycin and ceftriaxone-azithromycin recipients, respectively.
The importance of new treatments for gonorrhoea
The resistance of N. gonorrhoeae to all antibiotics prescribed for its treatment as well as the rise in resistance to azithromycin and ceftriaxone is cause for concern, said the researchers. [Nat Rev Microbiol 2014;12:223-229; Sex Transm Infect 2016;92:365-367; J Antimicrob Chemother 2015;70:1267-1268; Antimicrob Agents Chemother 2012;56:1273-1280] This is compounded by the shortage of drugs being developed for this condition, they added.
In this study, 24.9, 18.5, and 28.1 percent of the 313 N. gonorrhoeae isolates tested for susceptibility were resistant to ciprofloxacin, penicillin, and tetracycline, respectively.
“Once ceftriaxone becomes ineffective, no empirically proven successful treatment options exist for gonorrhoea,” commented Professor Henry J C de Vries and Dr Maarten F Schim-van der Loeff from Public Health Service Amsterdam, the Netherlands. [Lancet Infect Dis 2019;19:791-792]
The researchers acknowledged that some incidents of treatment failure could have been due to the short duration of treatment, and as such, a longer treatment duration may potentially improve the outcomes. “However, any further trials with longer dosing need to consider the potential risk of gastrointestinal effects and liver enzyme elevations,” they noted.
Furthermore, the impact of solithromycin on azithromycin-resistant N. gonorrhoeae could not be determined as only one isolate with decreased susceptibility to azithromycin was detected in a patient treated with ceftriaxone-azithromycin.
In addition, the study population was mostly men, particularly men who have sex with men; thus, the impact of solithromycin on genital infections in women may need re-evaluation.
“In all analyses, less than 95 percent of patients had eradication with solithromycin, which is below the minimum cure rate recommended by WHO,” said de Vries and van der Loeff. “[Nonetheless], the SOLITAIRE-U trial contributes important information in the further search for options to ensure gonorrhoea remains a treatable disease,” they said.