Influence of Inoculum Effect on the Efficacy of Daptomycin Monotherapy and in Combination with β-Lactams against Daptomycin-Susceptible Enterococcus faecium Harboring LiaSR Substitutions

Abstract

isolates that harbor LiaFSR substitutions but are phenotypically susceptible to daptomycin (DAP) by current breakpoints are problematic, since predisposition to resistance may lead to therapeutic failure. Using a simulated endocardial vegetation (SEV) pharmacokinetic/pharmacodynamic (PK/PD) model, we investigated DAP regimens (6, 8, and 10 mg/kg of body weight/day) as monotherapy and in combination with ampicillin (AMP), ceftaroline (CPT), or ertapenem (ERT) against HOU503, a DAP-susceptible strain that harbors common LiaS and LiaR substitutions found in clinical isolates (T120S and W73C, respectively). Of interest, the efficacy of DAP monotherapy, at any dose regimen, was dependent on the size of the inoculum. At an inoculum of ∼10 CFU/g, DAP doses of 6 to 8 mg/kg/day were not effective and led to significant regrowth with emergence of resistant derivatives. In contrast, at an inoculum of ∼10 CFU/g, marked reductions in bacterial counts were observed with DAP at 6 mg/kg/day, with no resistance. The inoculum effect was confirmed in a rat model using humanized DAP exposures. Combinations of DAP with AMP, CPT, or ERT demonstrated enhanced eradication and reduced potential for resistance, allowing de-escalation of the DAP dose. Persistence of the LiaRS substitutions was identified in DAP-resistant isolates recovered from the SEV model and in DAP-resistant derivatives of an initially DAP-susceptible clinical isolate of (HOU668) harboring LiaSR substitutions that was recovered from a patient with a recurrent bloodstream infection. Our results provide novel data for the use of DAP monotherapy and combinations for recalcitrant infections and pave the way for testing these approaches in humans.

Impact of Daptomycin Dose Exposure Alone or in Combination with β-Lactams or Rifampin against Vancomycin-Resistant Enterococci in an In Vitro Biofilm Model

“…Here, we demonstrated that selected ␤-lactams and RIF provided enhancement to DAP efficacy and led to reduced resistance in the presence of biofilm. This is in agreement with previous studies that have shown similar levels of synergetic activity in comparisons between DAP, AMP, CPT, and ERT in time-kill assays and enhanced killing in PK/PD simulated endocardial vegetation models (37) as well as animal models (20,21,25,38). Furthermore, in the current study, we revealed that addition of RIF enhanced DAP activity, allowing bactericidal activity to be produced against VREfm strains, which is in good agreement with a previous study which demonstrated synergetic activity between DAP and RIF by Etest and time-kill assays (39,40).…”

“…These observations are in agreement with studies reported by Hindler et al and Diaz et al, who demonstrated that AMP plus DAP yielded the most consistent eradication activity but did so only for isolates with liaFSR mutations (32,44). Furthermore, Kebriaei et al reported that the combination of DAP plus AMP is active against HOU503 in the planktonic state (simulated endocardial vegetation model) with enhanced killing (reaching the detection limit in 24 h) (25). Of interest, their unpublished data reveal the same pattern of efficacy of DAP plus AMP against R497, another E. faecium strain which harbors mutations in the liaFSR operon (45).…”

“…Due to the static nature of MIC and time-kill experiments, these methods may not predict the achieved concentrations in the PK/PD models using humanized antibiotic exposures. However, they offer a screening methodology to determine the potential for antibiotic combination to impact the DAP MIC (25,40,42,43).…”

Daptomycin Dose-Ranging Evaluation with Single-Dose versus Multidose Ceftriaxone Combinations against Streptococcus mitis /oralis in an Ex Vivo Simulated Endocarditis Vegetation Model

“…We have previously demonstrated that combinations of DAP plus ceftaroline (CPT) or ceftriaxone (CRO) are synergistic both in vitro and in the simulated endocardial vegetation (SEV) model against two well-characterized DAP-S S. mitis/oralis parental strains (the penicillin-resistant S. mitis/oralis strain, 351, and the penicillin-susceptible strain S. mitis/oralis SF100) (19). This model has the advantage of being able to precisely simulate human antibiotic concentrations to replicate therapeutic regimens used to treat specific infections (19)(20)(21)(22)(23). In this SEV model, not only did the combination of standard dose DAP (6 mg/kg) plus either CPT or CRO significantly reduce SEV CFU, but it also prevented the emergence of DAP-R over a 96-h exposure period in both strains (2,24).…”

Optimizing the Dosing Regimens of Daptomycin Based on the Susceptible Dose-Dependent Breakpoint against Vancomycin-Resistant Enterococci Infection

“…Even though a 6 mg/kg/day dosing can achieve 90% PTA of MIC ≤ 1 µg/mL, concerns about treatment failure and higher mortality with a 6 mg/kg/day dosing should be considered. Mutations to the liaFSR system have been found [32]. At a MIC of about 2 µg/mL, we suggest a loading dose of 12 mg/kg followed by 10-12 mg/kg/day.…”