Capability ofEnterococcus faecalisto shield Gram-negative pathogens from aminoglycoside exposure

Abstract

Background Enterococcus faecalis commonly produce aminoglycoside-modifying enzymes (AMEs) and are implicated in polymicrobial infections. Objectives To determine if AME-producing E. faecalis is capable of protecting Enterobacteriaceae and Pseudomonas aeruginosa from gentamicin exposure. Methods Two Klebsiella pneumoniae isolates, two Escherichia coli isolates, and two Pseudomonas aeruginosa isolates were investigated in monoculture time–kill experiments, and each Gram-negative organism was also evaluated during co-culture with either AME-producing or AME-deficient E. faecalis. A pharmacokinetic/pharmacodynamics analysis that utilized Log Ratio Areas and a Hill-type mathematical model was used to determine if the maximal killing or potency of gentamicin against the Gram-negative organisms was altered by the presence of the E. faecalis. Results The maximal killing and potency of gentamicin was the same during monoculture and co-culture experiments for both K. pneumoniae isolates and one E. coli isolate (P > 0.05). In contrast, the maximal killing of gentamicin was attenuated against one E. coli isolate and both P. aeruginosa isolates during co-culture with E. faecalis (P < 0.05). The potency of gentamicin was variable against the three aforementioned isolates. Against the E. coli isolate, the potency of gentamicin was significantly reduced by the presence of either E. faecalis isolate (EC50 95% CI = 4.23–4.43 mg/L monoculture versus 3.86–4.19 mg/L and 3.55–3.96 mg/L during co-culture with AME-producing and AME-deficient E. faecalis, respectively). The potency of gentamicin increased or decreased for P. aeruginosa depending on which E. faecalis isolate was investigated. Conclusions The AME-producing E. faecalis did not provide a consistent protective effect from aminoglycosides for the Gram-negative pathogens.

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

“…One variable that may impact the magnitude of a protective effect conferred by the production of drug-altering enzymes may be whether the β-lactamases are released into the extracellular space (Liao et al, 2014;Liao et al, 2015). In a prior in vitro investigation, aminoglycoside modifying enzyme-producing E. faecalis was not capable of appreciably protecting neighbouring gram-negative pathogens from gentamicin despite exposure of E. faecalis to lethal concentrations of ampicillin in an attempt to liberate intracellular enzymes (McMurtry et al, 2021). The relationship between resistance mechanisms and the pharmacodynamics of antibacterials during polymicrobial infections is therefore complex, and investigations of specific pathogen relationships and resistance mechanisms are likely needed to optimize antibacterial selection during polymicrobial infections.…”

“…In order to integrate the data obtained from time-killing experiments into a single quantifiable analysis, a mathematical approach was used to calculate maximum antibacterial activity during monoculture and co-culture conditions as described previously (McMurtry et al, 2021). In brief, the area under the CFU curve was calculated for each ampicillin or cefazolin concentration in each timekilling experiment using Systat Software version 14.0.…”

Enterococcus Virulence and Resistant Traits Associated with Its Permanence in the Hospital Environment

“…Another noteworthy reference is the fact that there is a possibility that, in polymicrobial infections, modifying enzyme-producing enterococci could possibly shield other bacteria from aminoglycoside action, increasing the MIC values necessary to inhibit bacterial multiplication [ 146 ].…”

Coumarin Glycosides Reverse Enterococci-Facilitated Enteric Infections

“…Given that multidrug-resistant enterococci are prone to overgrow in the gut after antibiotic treatments [ 12 , 13 ], enterococci-associated polymicrobial infections are difficult to eradicate by routine antibiotics. Seriously, the ability of enterococci to promote the proliferation, pathogenesis, and persistence of various pathogens further compromises the efficacy of existing antibiotics [ 14 , 15 ]. As an example, Enterococcus faecalis fuels the rapid autoaggregation and growth of E. coli , thus reinforcing dual-species biofilms to withstand harsh stresses including antibiotic treatments [ 16 ].…”