Influence of β-lactam pharmacodynamics on the systems microbiology of gram-positive and gram-negative polymicrobial communities

TL;DR

This study shows how β-lactamase-producing E. coli can protect other bacteria from β-lactam antibiotics in mixed infections.

Contribution

The study introduces a systems microbiology approach to quantify β-lactam antibiotic interactions in polymicrobial communities.

Findings

β-lactamase-producing E. coli reduced the effectiveness of ampicillin and cefazolin against co-cultured gram-positive bacteria.

Mathematical models revealed that E. coli protected S. aureus and E. faecalis by reducing antibiotic potency parameters like Kmax.

The presence of β-lactamase-producing E. coli significantly lowered the maximum killing (Emax) of β-lactam antibiotics.

Abstract

We sought to evaluate the pharmacodynamics of β-lactam antibacterials against polymicrobial communities of clinically relevant gram-positive and gram-negative pathogens.

Two Enterococcus faecalis isolates, two Staphylococcus aureus isolates, and three Escherichia coli isolates with varying β-lactamase production were evaluated in static time-killing experiments. Each gram-positive isolate was exposed to a concentration array of ampicillin (E. faecalis) or cefazolin (S. aureus) alone and during co-culture with an E. coli isolate that was β-lactamase-deficient, produced TEM-1, or produced KPC-3/TEM-1B. The results of the time-killing experiments were summarized using an integrated pharmacokinetic/pharmacodynamics analysis as well as mathematical modelling to fully characterize the antibacterial pharmacodynamics.

In the integrated analysis, the maximum killing of ampicillin (Emax) against both E. faecalis isolates was ≥ 4.11 during monoculture experiments or co-culture with β-lactamase-deficient E. coli, whereas the Emax was reduced to ≤ 1.54 during co-culture with β-lactamase-producing E. coli. In comparison to monoculture experiments, culturing S. aureus with KPC-producing E. coli resulted in reductions of the cefazolin Emax from 3.25 and 3.71 down to 2.02 and 2.98, respectively. Two mathematical models were created to describe the interactions between E. coli and either E. faecalis or S. aureus. When in co-culture with E. coli, S. aureus experienced a reduction in its cefazolin Kmax by 24.8% (23.1%RSE). Similarly, β-lactamase-producing E. coli preferentially protected the ampicillin-resistant E. faecalis subpopulation, reducing Kmax,r by 90.1% (14%RSE).

β-lactamase-producing E. coli were capable of protecting S. aureus and E. faecalis from exposure to β-lactam antibacterials.

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