009.2 Establishment of the gonorrhoea mouse model for pre-clinical testing of antimicrobial agents againstneisseria gonorrhoeae

Abstract

Introduction New antibiotics for gonorrhoea are needed due to the emergence of resistance to the extended-spectrum cephalosporins (ESCs) in Neisseria gonorrhoeae . Here we established the 17β-estradiol mouse model of gonococcal genital tract infection for testing antibiotics against gonorrhoea by defining the in vivo efficacy of cefixime (CFX) and ceftriaxone (CRO) against strain FA1090 (ESC S ) and the multi-drug resistant strain H041 (ESC R ). Methods Estradiol-treated female BALB/c mice were inoculated vaginally with FA1090 or H041 bacteria. PBS or different doses of CFX or CRO were administered two days later (n = 9 mice/group) and vaginal swabs were quantitatively cultured for N. gonorrhoeae for 8 consecutive days. The percentage of mice colonised over time was compared among groups using the Log-rank test. Results A single oral dose of 60, 12, 6 or 3 mg/kg CFX showed significant activity against strain FA1090 with the two highest doses clearing infection within 48 hr. One or two mice in the groups that received 6 or 3 mg/kg CFX did not clear infection. None of four higher concentrations (120, 60, 12, and 6 mg/kg) of CFX cleared H041 infection, but gentamycin (48 mg/kg, i.p. injection, 5 days, q24h) was effective compared to PBS. Five concentrations (30, 15, 5, 1.5, and 0.5 mg/kg) of a single i.p. dose of CRO had significant activity against FA1090, while 60, 30, 15, or 1.5 mg/kg had no effect against H041. Conclusion The gonorrhoea mouse model shows a dose-dependent response for CRO and CFX against an ESC S strain with in vivo break-points less than 0.5 and 3 mg/kg, respectively. Higher doses of these antibiotics were not effective against an ESC R strain. We are currently correlating in vivo efficacy with pharmacokinetic analyses to further strengthen the usefulness of this model to test antimicrobial compounds against gonorrhoea. Disclosure of interest statement This work was supported by NIH/NIAID (Interagency Agreement AAI14024–001) and USUHS (USU-DOD MIC73–2493).