Comparative study of the mutant prevention concentrations of vancomycin alone and in combination with levofloxacin, rifampicin and fosfomycin against methicillin-resistant Staphylococcus epidermidis

Abstract

No mutant-prevention concentration (MPC) with methicillin-resistant Staphylococcus epidermidis (MRSE) has been reported. The study aimed to evaluate the propensity of vancomycin individually and in combination to prevent MRSE from mutation. A total of 10 MRSE clinical isolates were included in the study. Susceptibility testing demonstrated that the susceptibility rates to vancomycin, rifampicin, levofloxacin and fosfomycin were 100, 100, 50 and 90%, respectively. The fractional inhibition concentration indices (FICI) for vancomycin combined with rifampicin, levofloxacin or fosfomycin were X1.5 but p2, X1.5 but p2, and 40.5 but p1.5, respectively, implying indifferent interactivity. The MPC with susceptible strains was determined to be the lowest antibiotic concentration inhibiting visible growth among 10 10 CFU on four agar plates (9 cm in diameter) after a 72-h incubation at 37 1C. The MPCs were 16B32, 464, X64 and 4B16 lg ml À1 for vancomycin, rifampicin, fosfomycin and levofloxacin, respectively. The vancomycin MPCs of combinations with fosfomycin (32 lg ml À1 ), levofloxacin (2 lg ml À1 ) and rifampicin (2 or 4 lg ml À1 ) were 1B4, 16B32 and 16B32 lg ml À1 , respectively. Against mutants selected by vancomycin, rifampicin, levofloxacin and fosfomycin individually, antibiotics had standard MICs of 2B4 lg ml À1 for vancomycin, 464 lg ml À1 for rifampicin, 4B8 lg ml À1 for levofloxacin and X64 lg ml À1 for fosfomycin. Thus single-step mutation can lead to resistance of MRSE to rifampicin, levofloxacin and fosfomycin, rather than non-susceptibility to vancomycin. Vancomycin-fosfomycin combination might be a superior alternative to vancomycin in blocking the growth of MRSE mutants, especially for high-organism-burden infections.

Synergistic combination of two antimicrobial agents closing each other’s mutant selection windows to prevent antimicrobial resistance

“…2 ). Analysis of various combinations reported 12 – 14 , 17 , 18 , we empirically put forward a tentative idea that antimicrobial agents targeting identical macromolecular biosynthesis with different sites likely presented remarkable synergistic activities. Thereby, RM, DC, VM, OX and FF were selected for three combinations RM/DC, VM/OX and VM/FF including seven proportions of each combination.…”

“…Simultaneously, the drug concentration will unavoidably fall into its MSW (The range from minimal concentration inhibiting colony formation by 99% (MIC 99% ) to MPC). Inspired by the analyses of combination therapies reported 12 – 14 , 17 , 18 , we empirically deduced that synergistic validity was likely a key to prevent antimicrobial resistance and balance these factors during combination therapy. Theoretically, the more remarkable the synergistic effect of two antimicrobial agents in a combination was, the more probable their MSWs were to close each other.…”

Fosfomycin

“…The effectiveness of these combinations was confirmed histologically (by disappearance of biofilm-like structures, marked decrease in necrosis, and formation of granular tissue) in the aforementioned studies. Finally, synergy between fosfomycin and vancomycin against methicillin-resistant S. epidermidis in vitro (by checkerboards) was not reported (167).…”

Validation of the mutant selection window hypothesis with fosfomycin against Escherichia coli and Pseudomonas aeruginosa: an in vitro and in vivo comparative study

“…[9][10][11][12] It is generally believed that this hypothesis may have broad applications for fighting the growing problem of antimicrobial resistance, and then the clinical applications of MSW were investigated quite intensively in recent years. [13][14][15][16] However, the applicability of the MSW to most of these antimicrobial-pathogen combinations was investigated only with in vitro model. In previous studies, this concept has also been proven to be relevant for vancomycin, but our in silico simulation results truly questioned the anti-mutant pharmacokinetics/pharmacodynamics (PK/PD) index derived from in vitro experiments.…”