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

Abstract

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.

Keywords: Enterococcus; PK/PD index; antibiotic combination; antimicrobial combinations; pharmacodynamics; pharmacokinetics; synergism.

FIG 1

AMP instantaneous MIC profile. Model fitting ampicillin MIC data for E. faecalis ATCC 29212 in the presence of escalating ceftriaxone concentrations (R² = 0.96). Open circles indicate experimental data, and the line represents the predicted MIC.

FIG 2

Simulation of murine AMP and CRO pharmacokinetics and ampicillin MIC_i profile. The ampicillin concentration-time profile at 150 mg/kg/day q3h (black line), ceftriaxone concentration-time profile at 25 mg/kg/day q3h (green line), and AMP MIC_i profile (red line) are shown.

FIG 3

In vivo pharmacodynamics of ampicillin plus ceftriaxone in terms of T_>MICi against E. faecalis ATCC 29212. The exposures required were 37.3% for stasis, 40.9% for 1-log₁₀ killing, and 45.7% for 2-log₁₀ killing.

FIG 4

Pharmacodynamics of AMP+CRO in terms of T_>threshold against E. faecalis ATCC 29212. The solid lines represent a significant and valid regression with CRO thresholds of 1 mg/L (black curve and circles) and 2 mg/L (red curve and circles); the CRO threshold of 4 mg/L yielded invalid parameters (gray dotted line and squares), and Hill’s equation did not fit the CRO threshold of 0.5 mg/L (gray triangles, no curve). The chosen threshold was 1 mg/L.

FIG 5

Probability of target attainment of AMP+CRO against E. faecalis ATCC 29212 at CRO doses of 0.5 g q12h (black), 1 g q12h (blue), 2 g q12 h (green), and 2 g q24 h (red) for targets in terms of T_>thresholds necessary for stasis (a), 1-log₁₀ killing (b), and 2-log₁₀ killing (c) with a range of CRO thresholds from 0.5 to 256 mg/L.

FIG 6

Simulation of human ampicillin total concentration profile (black lines), ceftriaxone total concentration profile (green lines), and ampicillin MIC_i (red line). (a) Ampicillin at 500 mg q6h; (b and c) ampicillin at 25 mg q6h + CRO at 500 mg q12h. Panel c is a closeup of panel b in the 0-to-2.5-mg/L concentration range for better visualization.