Predicting antibiotic combination effects on the selection of resistant Staphylococcus aureus: In vitro model studies with linezolid and gentamicin

MPC-Based Prediction of Anti-Mutant Effectiveness of Antibiotic Combinations: In Vitro Model Study with Daptomycin and Gentamicin against Staphylococcus aureus

“…Daptomycin concentrations were simulated to achieve subtherapeutic AUCs, and to provide higher probability of the emergence of S. aureus resistance to daptomycin, while gentamicin was dosed to simulate therapeutic AUCs that correspond to once daily high-level doses of 5 and 7 mg/kg. Previous studies have documented that enrichment of gentamicin-resistant cells occurs even at high peak aminoglycoside concentrations [13,15,17]. As a result, when mono-treatments with daptomycin and gentamicin were simulated in the dynamic model, enrichment of resistant S. aureus mutants was observed.…”

“…The daptomycin-to-gentamicin concentration ratios, at which MPCs of antibiotics were determined, were equal to the respective daptomycin-to-gentamicin AUC ratios used in the pharmacokinetic simulations. This pharmacokinetic-based approach to MPC determination has been used in previous studies with the following antibiotic combinations: linezolid-rifampicin [18], daptomycinrifampicin [19], linezolid-gentamicin [17] and linezolid-daptomycin [16]. In the current study the increased T >MPC s for each antibacterial in the presence of the second agent were consistent with enhanced anti-mutant effects of daptomycin and gentamicin in combination and consequently with decreased areas under the bacterial mutant concentration-time curve (AUBC M s) of daptomycin (AUBC M(D) ) and gentamicin (AUBC M(G) ), respectively.…”

“…Antibiotics 2021, 10, 1148 6 of 10 previous studies with the following antibiotic combinations: linezolid-rifampicin [18], daptomycin-rifampicin [19], linezolid-gentamicin [17] and linezolid-daptomycin [16]. In the current study the increased T>MPCs for each antibacterial in the presence of the second agent were consistent with enhanced anti-mutant effects of daptomycin and gentamicin in combination and consequently with decreased areas under the bacterial mutant concentration-time curve (AUBCMs) of daptomycin (AUBCM(D)) and gentamicin (AUBCM(G)), respectively.…”

“…The exposures of daptomycin were simulated to provide subtherapeutic doses of the lipopeptide and to allow higher probability of daptomycinresistant S. aureus mutant growth. In contrast, gentamicin-pharmacokinetics were simulated at therapeutic exposures, according to previous in vitro studies that reported high intensity of growth of gentamicin-resistant mutants, even at high-dose aminoglycoside regimens [13,15,17]. As referenced above [16], the MPCs of one antibiotic, in the presence of the other, were determined at a pharmacokinetic-based daptomycin-to-gentamicin concentration ratio, which was equal to the ratio of the AUC of daptomycin to the AUC of gentamicin in pharmacokinetic simulations of the combined treatments.…”

Verification of a Novel Approach to Predicting Effects of Antibiotic Combinations: In Vitro Dynamic Model Study with Daptomycin and Gentamicin against Staphylococcus aureus

“…As therapeutic daptomycin exposures were characterized by a pronounced effect against staphylococci [ 28 ], subtherapeutic doses, which provide low antibacterial activity, were used in the present study. In contrast, gentamicin pharmacokinetics were simulated at therapeutic exposures, given previous in vitro studies that reported low [ 25 , 26 ] or moderate [ 29 , 30 ] anti-staphylococcal efficacy even at high peak concentrations at extended dosing interval regimens.…”