Pharmacodynamics of zoliflodacin and doxycycline in gonorrhea treatment
Antimicrobial resistance in the sexually transmitted bacterium Neisseria gonorrhoeae is threatening the treatment and control of gonorrhea globally. Optimized use and enhanced stewardship of current antimicrobials in addition to development of novel antimicrobials are essential. The first in class zoliflodacin (spiropyrimidinetrione, DNA Gyrase B inhibitor) is a promising novel antimicrobial in latest stage of clinical development for gonorrhea treatment, i.e., the phase III randomized controlled clinical trial finishes in mid-2023. Doxycycline, the first-line treatment for chlamydia and empiric treatment for non-gonococcal urethritis, will likely be frequently given together with zoliflodacin because gonorrhea and chlamydia coinfections are common. In a previous static in vitro study, it was indicated that doxycycline inhibited the gonococcal killing of zoliflodacin in six hours time-kill curve analysis. Herein, we used our dynamic in vitro Hollow Fiber Infection Model (HFIM) to evaluate combination therapies with zoliflodacin and doxycycline. Dose-range experiments using the three gonococcal strains WHO F (susceptible to all relevant antimicrobials), WHO X (extensively drug-resistant, including ceftriaxone resistant) and SE600/18 (zoliflodacin-susceptible strain with GyrB S467N substitution) were conducted simulating combination therapy with a single oral dose of zoliflodacin 0.5-4 g combined with a doxycycline daily oral dose of 200 mg administered as 100 mg twice a day, for 7 days (standard dose for chlamydia treatment). Compared to zoliflodacin 0.5-4 g single oral dose, combination therapy with zoliflodacin (0.5-4 g single oral dose) plus doxycycline (200 mg divided into 100 mg twice a day orally, for 7 days) appeared slightly more effective in N. gonorrhoeae killing and suppression of zoliflodacin resistance emergence. Accordingly, WHO F was eradicated by only 0.5 g single oral dose of zoliflodacin in combination with doxycycline and WHO X and SE600/18 were both eradicated by a 2 g single oral dose of zoliflodacin in combination with doxycycline, and no zoliflodacin-resistant populations occurring during the seven day experiment when using these zoliflodacin doses. When using suboptimal (0.5-1 g) zoliflodacin doses together with doxycycline, gonococcal mutants with increased zoliflodacin MICs, due to GyrB D429N and the novel GyrB T472P, emerged, but both these mutants had an impaired biofitness. The present study shows the efficacy of zoliflodacin plus doxycycline combination therapy. It additionally illustrates the benefits of using dynamic HFIM that more accurately and comprehensively simulate gonococcal infection and their treatment, i.e., compared to static in vitro models, such as short-time checkerboard experiments or time-kill analysis. Zoliflodacin plus doxycycline for treatment of both gonorrhea and chlamydia appears to be an effective combination.