To Örebro University

There is a pressing need for drug development for gonorrhea. Here we describe pharmacokinetics/pharmacodynamics (PK/PD) analysis of extended-spectrum cephalosporins (ESC) against drug-susceptible and drug-resistant gonococcal strains in a murine genital tract infection model. PK determined in uninfected mice displayed a clear dose response in plasma levels following single doses of ceftriaxone (CRO) (intraperitoneal) or cefixime (CFM) (oral). The observed doses required for efficacy against ESC^S strain FA1090 were 5 mg/kg (CRO) and 12 mg/kg (CFM); these doses had estimated therapeutic times (time of free drug above the MIC, fT_MIC) of 24 h and 37 h, respectively. No single dose of CRO or CFM was effective against the ESC^R strain H041. However, fractionation (TIDq8h) of a 120 mg/kg dose of CRO resulted in estimated therapeutic times in the range of 23 h and cleared H041 infection in a majority (90%) of mice, comparable to gentamicin. In contrast, multiple CFM doses of 120 or 300 mg/kg administered TIDq8h cleared infection in ≤ 50% of mice with therapeutic times estimated from single-dose PK data, of 13 and 27 h, respectively. This study reveals a clear relationship between plasma ESC levels and bacterial clearance rates in the gonorrhea mouse model. The PK/PD relationships in mice reflected that observed in humans with in vivo efficacy against an ESC^S strain requiring doses that yielded an fT_MIC in excess of 20-24 h. PK data also accurately predicted the failure of single doses of ESCs against an ESC^R strain and were useful in designing effective dosing regimens.