Pharmacokinetic/Pharmacodynamic Index Linked to In Vivo Efficacy of the Ampicillin-Ceftriaxone Combination against Enterococcus faecalis

Combination therapy with ampicillin plus ceftriaxone (AMP+CRO) is the first-line therapy for treating severe infections due to Enterococcus faecalis. However, the pharmacokinetic/pharmacodynamic (PK/PD) index linked to the in vivo efficacy of the combination is not yet defined, hindering dose optimization in the clinic. Because classical PK/PD indices are not directly applicable to antimicrobial combinations, two novel indices were tested in the optimized murine model of infection by E. faecalis to delineate the potentiation of AMP by CRO: the time above the CRO threshold (T_>threshold) and the time above the AMP instantaneous MIC (T_>MICi). The potential clinical relevance was evaluated by simulating human doses of AMP and CRO. Hill's equation fitted well the exposure-response data in terms of T_>threshold, with a CRO threshold of 1 mg/L. The required exposures were 46%, 49%, and 52% for stasis and 1- and 2-log₁₀ killing, respectively. Human ceftriaxone doses of 2 g every 12 h (q12h) would reach the target in >90% of strains with thresholds ≤64 mg/L. The AMP T_>MICi index also fitted well, and the required exposures were 37%, 41%, and 46% for stasis and 1- and 2-log₁₀ killing, respectively. In humans, the addition of CRO would allow use of lower AMP doses to reach the same T_>MICi and to treat strains with higher MICs. This is the first report of the PK/PD indices and required magnitudes linked to AMP+CRO against E. faecalis; these results can be used as the basis to guide the design of clinical trials to improve combined therapy against enterococci.