Evaluation of Daptomycin Pharmacodynamics and Resistance at Various Dosage Regimens against Staphylococcus aureus Isolates with Reduced Susceptibilities to Daptomycin in an In Vitro Pharmacodynamic Model with Simulated Endocardial Vegetations

Abstract

The need to investigate novel dosing regimens and combinations is essential in combating poor treatment outcomes for Staphylococcus aureus bacteremia and endocarditis. We evaluated the impact of simulated standard-and high-dose daptomycin in combination with gentamicin or rifampin against daptomycin-susceptible and nonsusceptible matched strains of S. aureus. These strains were collected from the daptomycin bacteremia and endocarditis clinical trial and consisted of three susceptible strains (MIC, 0.25 mg/liter) and four nonsusceptible isolates (MICs, 2 to 4 mg/liter). Daptomycin regimens of 6 and 10 mg/kg of body weight daily alone and in combination with gentamicin at 5 mg/kg daily or rifampin at 300 mg every 8 h were evaluated using an in vitro model with simulated endocardial vegetations over 96 h. Rapid bactericidal activity, identified by time to 99.9% kill, was displayed in all regimens with the daptomycin-susceptible strains. Concentrationdependent activity was noted by more-rapid killing with the 10-mg/kg/day dose. The addition of gentamicin improved activity in the majority of susceptible isolates. Daptomycin 6-mg/kg/day monotherapy displayed bactericidal activity for only one of the nonsusceptible isolates and for only two isolates with increased doses of 10 mg/kg/day. Combination regimens demonstrated improvement with some but not all nonsusceptible isolates. Three isolates developed a reduction in daptomycin susceptibility with 6-mg/kg/day monotherapy, but this was suppressed with both combination therapy and high-dose daptomycin. These results suggest that high-dose daptomycin therapy and combination therapy may be reasonable treatment options for susceptible isolates; however, more investigations are needed to confirm the variability of these regimens with nonsusceptible isolates.The poor treatment outcomes associated with serious methicillin-resistant Staphylococcus aureus (MRSA) infections reflect the need for alternative effective treatment options. For decades, the mainstay of therapy for MRSA has been vancomycin. However, increasing reports of clinical vancomycin treatment failure along with reduced vancomycin susceptibility and vancomycin tolerance may be consequences of its longterm use (6,15,16,20,22). Although S. aureus, including MRSA, continues to be a major cause of bacteremia and endocarditis, alternative treatment options to vancomycin with proven efficacy remain minimal. Several in vitro studies indicate the potential of synergy with agents such as aminoglycosides in combination with vancomycin, but this has not been clearly elucidated in the clinical setting.Daptomycin is a lipopeptide antibiotic with potent activity against gram-positive organisms, including multidrug-resistant S. aureus (25,26,30). Multiple reports have displayed the bactericidal and concentration-dependent activity of daptomycin in vitro. In the advent of serious S. aureus infections, some studies advocate the importance of rapid inoculum reduction and bactericidal activity (9,22). Daptomycin has been approved i...

Activity of Daptomycin or Linezolid in Combination with Rifampin or Gentamicin against Biofilm-Forming Enterococcus faecalis or E. faecium in an In Vitro Pharmacodynamic Model Using Simulated Endocardial Vegetations and an In Vivo Survival Assay Using Galleria mellonella Larvae

“…In a retrospective cohort study of VRE bloodstream infections, treatment with daptomycin or linezolid demonstrated no difference in mortality; however, infection with E. faecium and concurrent treatment with rifampin or gentamicin were independent risk factors for mortality (54). Antagonistic activity is often observed when rifampin is added to bactericidal agents in high-inoculum infections, due to high rates of mutations conferring resistance (ϳ1 in 10 6 ) (31,55,56). The in vitro model demonstrated antagonism with rifampin.…”

“…As described previously, organism stocks containing approximately 10 10 CFU/ml were prepared by inoculating 5-ml test tubes of normal saline with colonies harvested from fresh overnight growth on TSA (20,22,24,31,32). Simulated endocardial vegetations (SEVs) containing 10 9 CFU/g were prepared by combining 0.05 ml of the organism suspension with 0.4 ml of human cryoprecipitated antihemolytic factor (AHF) from volunteer donors (Rhode Island Blood Bank, Providence, RI), 0.05 ml of an aprotinin suspension, and 0.025 ml of a platelet suspension (platelets mixed with normal saline; 250,000 to 500,000 platelets per clot) in 1.5-ml Eppendorf tubes.…”

Relationship of In Vitro Synergy and Treatment Outcome with Daptomycin plus Rifampin in Patients with Invasive Methicillin-Resistant Staphylococcus aureus Infections

“…In cases of primary treatment failure with S. aureus infections, rifampin has been recommended as an adjunctive therapeutic agent (3). Studies with in vitro and in vivo pharmacodynamic models of biofilm-associated infection support the use of daptomycin in combination with rifampin, where synergistic activity has been associated primarily with preventing the emergence of daptomycin-nonsusceptible strains (4)(5)(6). We have recently reported a high rate of success with daptomycin in combination with rifampin for treatment of complicated bone and joint infections (7), and in this study, we report the relationship between treatment outcome and in vitro synergy with complex deep MRSA infections.…”

“…Daptomycin in combination with adjunctive antibiotics, such as rifampin, aminoglycosides, or co-trimoxazole, may improve antimicrobial killing or inhibit the emergence of resistance compared to daptomycin alone (5,14). New Infectious Diseases Society of America (IDSA) guidelines for the treatment of prosthetic joint infections recommend combining rifampin with primary therapy (15), but published clinical experiences with daptomycin combined with rifampin have been very limited.…”

Updated Antimicrobial Therapy for the Prevention and Treatment of Endocarditis: Focus on Daptomycin

“…50,51 In vitro pharmacodynamic modelling with simulated endocarditis vegetations has demonstrated rapid bactericidal activity with daptomycin-susceptible strains, with more rapid killing at a dose of 10 mg/kg. 52 These authors reported an improvement in activity with combination regimens against some, but not all, isolates, and suggest that in the presence of strains with reduced susceptibility high-dose daptomycin or combination therapy may be a reasonable treatment option. Cunha et al have reported a successful clinical outcome using high-dose (12 mg/kg) daptomycin after continuing bacteraemia and mitral valve IE following 10 days of daptomycin (6 mg/kg) in combination with linezolid (600 mg 12 h).…”