Activities of Daptomycin and Vancomycin Alone and in Combination with Rifampin and Gentamicin against Biofilm-Forming Methicillin-Resistant Staphylococcus aureus Isolates in an Experimental Model of Endocarditis

Abstract

The findings of clinical and in vitro research support the theory that infective endocarditis (IE)-causing bacteria form biofilms and that biofilms negatively affect treatment outcomes. The purpose of the present study was to quantify the biofilm formation of methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) isolates obtained from patients with IE and to evaluate the in vitro activities of daptomycin and vancomycin alone and in combination with rifampin (rifampicin) or gentamicin while monitoring the isolates for the development of resistance. A high-inoculum, stationary-phase infection model of IE was used to simulate the pharmacokinetics in humans of daptomycin at 6 mg/kg of body weight/day, vancomycin at 1.25 g every 12 h (q12h) alone and in combination with rifampin at 300 mg every 8 h, and gentamicin at 1.3 mg/kg q12h. Two randomly selected clinical MRSA isolates were obtained from patients with IE; both MRSA isolates quantitatively produced biofilms. The time to bactericidal activity in the presence of daptomycin was isolate dependent but was achieved by 24 h for both MRSA isolates. Vancomycin did not achieve bactericidal activity throughout the experiment. At 24, 48, and 72 h, daptomycin-containing regimens had significantly more activity (greater declines in the mean number of CFU/g) than any of the vancomycin-containing regimens (P ‫؍‬ 0.03). Rifampin and gentamicin antagonized or delayed the bactericidal activity of daptomycin (against MRSA B346846 for rifampin and against both isolates for gentamicin) in the first 24 h. Increases in the daptomycin and vancomycin MICs were not observed. We conclude that in an IE model of biofilm-forming MRSA, daptomycin monotherapy has better in vitro activity than daptomycin in combination with rifampin or gentamicin or any vancomycin-containing regimen studied within the first 24 h. Further investigations are needed to understand the initial delay in bactericidal activity observed when gentamicin or rifampin is combined with daptomycin.

XerC Contributes to Diverse Forms of Staphylococcus aureus Infection via agr -Dependent and agr -Independent Pathways

“…We chose daptomycin because it is a membrane-active agent that is relatively effective against stationary-phase and nondividing S. aureus cells (44). It was also shown to penetrate staphylococcal biofilms and exhibit a relatively high degree of efficacy in the context of an established biofilm (21,22,(45)(46)(47). Ceftaroline was chosen because it is a beta-lactam antibiotic with activity against methicillin-resistant S. aureus (48).…”

Central venous catheter-related biofilm infections: An up-to-date focus on meticillin-resistant Staphylococcus aureus

“…In combination therapy, daptomycin treatment with rifampicin or gentamicin has shown conflicting results, but its clinical use has proven successful against several forms of biofilm infections [48,49]. Finally, in a rat model study by Van Praagh et al, combined daptomycin ALT and systemic dosing resulted in clearance of S. aureus CVC-related infection after two daily ALT treatments [50].…”

Penetration of Daptomycin into Bone and Synovial Fluid in Joint Replacement

“…Second, daptomycin has a high and very rapid concentration-dependent bactericidal activity (8)(9)(10)(11), not affected by decreased susceptibility to vancomycin (12). Third, daptomycin shows an antimicrobial activity in an in vivo model of acute osteomyelitis (13) and penetrates rapidly into biofilms (14,15); also, due to its unique mechanism of action on cell membrane, daptomycin retains antimicrobial activity against both stationary-phase cultures of staphylococci within the biofilm and bacteria in the multiplication phase (16)(17)(18)(19)(20). Finally, the safety and tolerability of daptomycin have been established (21)(22)(23).…”