In vitro activities of the novel bicyclolides modithromycin (EDP-420, EP-013420, S-013420) and EDP-322 against MDR clinical Neisseria gonorrhoeae isolates and international reference strains.

OBJECTIVES New antimicrobials are essential to prevent gonorrhoea becoming an untreatable infection. Herein, the in vitro activities of the novel bicyclolides modithromycin (EDP-420, EP-013420, S-013420) and EDP-322 against Neisseria gonorrhoeae strains were investigated and compared with antimicrobials currently or previously recommended for treatment of gonorrhoea. METHODS MICs (mg/L) were determined using an agar dilution method (modithromycin and EDP-322) or Etest (seven antimicrobials) for a large geographically, temporally and genetically diverse collection of clinical N. gonorrhoeae isolates (n = 225) and international reference strains (n = 29), including diverse MDR and XDR isolates. RESULTS The MIC range, modal MIC, MIC50 and MIC90 of modithromycin and EDP-322 were 0.004-256, 0.25, 0.25 and 1 mg/L and 0.008-16, 0.5, 0.5 and 1 mg/L, respectively. The activities of modithromycin and EDP-322 were mainly superior to those of azithromycin and additional antimicrobials investigated. In general, there was no cross-resistance with other antimicrobials. CONCLUSIONS Modithromycin and EDP-322 exhibited high levels of in vitro activities against N. gonorrhoeae, including isolates resistant to azithromycin, cefixime, ceftriaxone, spectinomycin, ampicillin, tetracycline and ciprofloxacin. However, some cross-resistance with high-level azithromycin resistance (MIC = 4096 mg/L) was observed. Modithromycin and EDP-322 could be effective options for treatment of gonorrhoea, particularly for cases resistant to extended-spectrum cephalosporins and as a part of an antimicrobial combination therapy regimen. Nevertheless, it is important to detail the in vitro selection, in vivo emergence and mechanisms of resistance, pharmacokinetics/pharmacodynamics in humans and optimal dosing, and perform appropriate randomized controlled clinical trials.