AUTHOR=Smith Nicholas M. , Kaur Harpreet , Kaur Ravneet , Minoza Trisha , Kent Michael , Barekat Ayeh , Lenhard Justin R. 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 15 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1339858

DOI=10.3389/fphar.2024.1339858

ISSN=1663-9812

ABSTRACT=We sought to evaluate the pharmacodynamics of β-lactam antibacterials against polymicrobial communities of clinically relevant gram-positive and gram-negative pathogens.Methods: 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 βlactamase-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 coculture 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).Discussion: β-lactamase-producing E. coli were capable of protecting S. aureus and E.