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=15

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=<sec><title>Objectives</title><p>We sought to evaluate the pharmacodynamics of β-lactam antibacterials against polymicrobial communities of clinically relevant gram-positive and gram-negative pathogens.</p></sec><sec><title>Methods</title><p>Two <italic>Enterococcus faecalis</italic> isolates, two <italic>Staphylococcus aureus</italic> isolates, and three <italic>Escherichia coli</italic> 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 (<italic>E. faecalis</italic>) or cefazolin (<italic>S. aureus</italic>) alone and during co-culture with an <italic>E. coli</italic> 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.</p></sec><sec><title>Results</title><p>In the integrated analysis, the maximum killing of ampicillin (E<sub>max</sub>) against both <italic>E. faecalis</italic> isolates was ≥ 4.11 during monoculture experiments or co-culture with β-lactamase-deficient <italic>E. coli</italic>, whereas the E<sub>max</sub> was reduced to ≤ 1.54 during co-culture with β-lactamase-producing <italic>E. coli</italic>. In comparison to monoculture experiments, culturing <italic>S. aureus</italic> with KPC-producing <italic>E. coli</italic> resulted in reductions of the cefazolin E<sub>max</sub> from 3.25 and 3.71 down to 2.02 and 2.98, respectively. Two mathematical models were created to describe the interactions between <italic>E. coli</italic> and either <italic>E. faecalis</italic> or <italic>S. aureus</italic>. When in co-culture with <italic>E. coli</italic>, <italic>S. aureus</italic> experienced a reduction in its cefazolin K<sub>max</sub> by 24.8% (23.1%RSE). Similarly, β-lactamase-producing <italic>E. coli</italic> preferentially protected the ampicillin-resistant <italic>E. faecalis</italic> subpopulation, reducing K<sub>max,r</sub> by 90.1% (14%RSE).</p></sec><sec><title>Discussion</title><p>β-lactamase-producing <italic>E. coli</italic> were capable of protecting <italic>S. aureus</italic> and <italic>E. faecalis</italic> from exposure to β-lactam antibacterials.</p></sec>