In vitro activity and time‐kill curve analysis of sitafloxacin against a global panel of antimicrobial‐resistant and multidrug‐resistant Neisseria gonorrhoeae isolates

Abstract

J€ onsson A, Foerster S, Golparian D, Hamasuna R, Jacobsson S, Lindberg M, Jensen JS, Ohnishi M, Unemo M. In vitro activity and time-kill curve analysis of sitafloxacin against a global panel of antimicrobial-resistant and multidrug-resistant Neisseria gonorrhoeae isolates. APMIS 2018; 126: 29-37 Treatment of gonorrhoea is a challenge worldwide because of emergence of resistance in N. gonorrhoeae to all therapeutic antimicrobials available and novel antimicrobials are imperative. The newer-generation fluoroquinolone sitafloxacin, mostly used for respiratory tract infections in Japan, can have a high in vitro activity against gonococci. However, only a limited number of recent antimicrobial-resistant isolates from Japan have been examined. We investigated the sitafloxacin activity against a global gonococcal panel (250 isolates cultured in 1991-2013), including multidrug-resistant geographically, temporally and genetically diverse isolates, and performed time-kill curve analysis for sitafloxacin. The susceptibility to sitafloxacin (agar dilution) and seven additional therapeutic antimicrobials (Etest) was determined. Sitafloxacin was rapidly bactericidal, and the MIC range, MIC 50 and MIC 90 was ≤0.001-1, 0.125 and 0.25 mg/L, respectively. There was a high correlation between the MICs of sitafloxacin and ciprofloxacin; however, the MIC 50 and MIC 90 of sitafloxacin were 6-fold and >6-fold lower, respectively. Sitafloxacin might be an option for particularly dual antimicrobial therapy of gonorrhoea and for cases with ceftriaxone resistance or allergy. However, further in vitro and particularly in vivo evaluations of potential resistance, pharmacokinetics/pharmacodynamics and ideal dosing for gonorrhoea, as well as performance of randomized controlled clinical, trials are crucial.

Multiresistant Neisseria gonorrhoeae: a new threat in second decade of the XXI century

“…zoliflodacin and gepotidacin. Examples of protein synthesis inhibitors are new drugs that entered clinical trials: lefamulin and solithromycin and drugs only in preclinical tests: apramycin (aminoglycoside) and aminomethyl spectinomycins [11][12][13][14][15][16][17][18]. Another candidate for gonorrhoea treatment with a new mechanism of action, a small antimicrobial molecule SMT-571, demonstrated in vitro high activity against all investigated strains of N. gonorrhoeae [19].…”

New treatment options for Neisseria gonorrhoeae in the era of emerging antimicrobial resistance

“…34 Some of the more modern fluoroquinolones, such as gemifloxacin, sitafloxacin and delafloxacin, have been evaluated as components of dual therapy regimens on account of their improved activity against N. gonorrhoeae over secondgeneration fluoroquinolones, such as ciprofloxacin. 30,[36][37][38] While in vitro studies suggest good activity, clinical evaluations of these drugs as sole therapeutic agents for gonorrhoea are lacking. It is inherently problematic to assign an effective clinical outcome to any one antimicrobial agent that is administered to patients or research participants in the context of dual therapy for gonorrhoea, as typically both drugs are highly effective in their own rights.…”

“…37 The implication of this observation is that sitafloxacin would not be a suitable monotherapeutic agent for gonorrhoea in those areas of the world where ciprofloxacin-resistant gonorrhoea is highly prevalent; however, it could potentially be a valuable component of a dual therapy regimen designed to manage cephalosporinresistant gonorrhoea or gonorrhoea occurring in a patient with cephalosporin allergy. 36,37 Delafloxacin is a somewhat unusual fluoroquinolone in that it demonstrates a more balanced activity against both DNA gyrase and topoisomerase IV in the context of both Gram-negative and Gram-positive infections. 39 Delafloxacin possesses activity against N. gonorrhoeae in vitro and, importantly, a low tendency to select spontaneous mutants in the laboratory setting.…”

Future Prospects for Neisseria gonorrhoeae Treatment

“…For this reason, the scientific community has turned to trying new combinations of already existing antibiotics as the fastest way to fight multi-resistant superbugs. Along these lines, Jönsson et al studied the viability of introducing sitafloxacin, a newer-generation broad spectrum fluoroquinolone mostly used for respiratory infections, as part of a dual therapy against gonococci [ 20 ]. In the study, sitafloxacin was tested against a global gonococcal panel of 250 isolates, showing a rapid bactericidal effect with a Minimum Inhibitory Concentration (MIC) range of ≤0.001–1 mg/L.…”