A new pharmacodynamic approach to study antibiotic combinations against enterococci in vivo: Application to ampicillin plus ceftriaxone.

Ivone Jimenez-Toro,Carlos A Rodriguez,Julian D Otalvaro,Omar Vesga,Andres F Zuluaga,Yung-Fu Chang

doi:10.1371/journal.pone.0243365

Ivone Jimenez-Toro, Carlos A Rodriguez + Show 4 more

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https://doi.org/10.1371/journal.pone.0243365

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Abstract

The combination of ampicillin (AMP) and ceftriaxone (CRO) is considered synergistic against Enterococcus faecalis based on in vitro tests and the rabbit endocarditis model, however, in vitro assays are limited by the use of fixed antibiotic concentrations and the rabbit model by poor bacterial growth, high variability, and the use of point dose-effect estimations, that may lead to inaccurate assessment of antibiotic combinations and hinder optimal translation. Here, we tested AMP+CRO against two strains of E. faecalis and one of E. faecium in an optimized mouse thigh infection model that yields high bacterial growth and allows to define the complete dose-response relationship. By fitting Hill's sigmoid model and estimating the parameters maximal effect (Emax) and effective dose 50 (ED50), the following interactions were defined: synergism (Emax increase ≥2 log10 CFU/g), antagonism (Emax reduction ≥1 log10 CFU/g) and potentiation (ED50 reduction ≥50% without changes in Emax). AMP monotherapy was effective against the three strains, yielding valid dose-response curves in terms of dose and the index fT>MIC. CRO monotherapy showed no effect. The combination AMP+CRO against E. faecalis led to potentiation (59-81% ED50 reduction) and not synergism (no changes in Emax). Against E. faecium, the combination was indifferent. The optimized mouse infection model allowed to obtain the complete dose-response curve of AMP+CRO and to define its interaction based on pharmacodynamic parameter changes. Integrating these results with the pharmacokinetics will allow to derive the PK/PD index bound to the activity of the combination, essential for proper translation to the clinic.

Highlights

Enterococci are the third leading cause of hospital-associated infections [1]
The combination of AMP at concentrations of 1 mg/L and higher with CRO fixed at 4 mg/L was synergistic against E. faecalis ATCC 29212, increasing the bacterial killing 4.94 log10 CFU/mL at AMP 1 mg + CRO, and 2.62 log10 CFU/mL at AMP 2 mg/L + CRO compared with AMP alone (Fig 1 panel a)
In vivo, using the optimized mouse thigh infection model, we were able to obtain a complete dose-response curve of AMP monotherapy, with valid parameters derived from Hill’s sigmoid model to quantify its efficacy and potency, and the magnitude of the PK/PD index that drives its activity for stasis, 1 log10 kill and 2 log10 kill

Summary

Introduction

Enterococci are the third leading cause of hospital-associated infections [1]. They display intrinsic and acquired resistance to a wide variety of antibiotics in clinical use, including newer agents used to treat vancomycin resistant enterococcus (VRE) infections. Compounds considered bactericidal against other Gram-positive cocci are usually

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