Fosfomycin-daptomycin and other fosfomycin combinations as alternative therapies in experimental foreign-body infection by methicillin-resistant Staphylococcus aureus.

The efficacy of daptomycin, imipenem, or rifampin with fosfomycin was evaluated and compared with that of daptomycin-rifampin in a tissue cage model infection caused by methicillin-resistant Staphylococcus aureus (MRSA). Strain HUSA 304 was used. The study yielded the following results for MICs (in µg/ml): fosfomycin, 4; daptomycin, 1; imipenem, 0.25; and rifampin, 0.03. The study yielded the following results for minimum bactericidal concentration (MBC) (in µg/ml): fosfomycin, 8; daptomycin, 4; imipenem, 32; and rifampin, 0.5. Daptomycin-rifampin was confirmed as the most effective therapy against MRSA foreign-body infections. Fosfomycin combinations with high doses of daptomycin and rifampin were efficacious alternative therapies in this setting. Fosfomycin-imipenem was relatively ineffective and did not protect against resistance.

Efficacy of tigecycline alone and with rifampin in foreign-body infection by methicillin-resistant Staphylococcus aureus.

OBJECTIVES: Tigecycline appears as an alternative therapy against methicillin-resistant Staphylococcus aureus (MRSA) with limited clinical experience. We evaluate the efficacy of tigecycline and its combination with rifampin in comparison to that for vancomycin in a rat model of foreign-body infection by MRSA. METHODS: A tissue-cage infection model were used; therapy with tigecycline, vancomycin, rifampin, tigecycline plus rifampin and vancomycin plus rifampin was administered intraperitoneally for 7 days. The antibiotic efficacy was evaluated in the tissue-cage fluid and in the coverslips (attached bacteria); the emergence of resistance was screened. RESULTS: Among monotherapies rifampin was the best treatment (decrease in log CFU/ml of tissue-cage fluid, 2.75) (P < 0.05). The addition of rifampin improved the efficacy of vancomycin (decrease, 2.28) and tigecycline (decrease, 1.56) in solitary; there were not significantly differences between tigecycline-rifampin (decrease, 3.39) and vancomycin-rifampin (decrease, 3.70), but only the latter was better than rifampin alone (P < 0.05). Resistant strains were only detected using rifampin alone. CONCLUSIONS: tigecycline alone was the least effective treatment. Tigecycline-rifampin prevented the emergence of rifampin resistance, thus allowing the benefits of rifampin over time against staphylococcal foreign-body infections, but its efficacy needs to be evaluated in comparison with other anti-MRSA combined therapies.

Efficacy of usual and high doses of daptomycin in combination with rifampin versus alternative therapies in experimental foreign-body infection by methicillin-resistant Staphylococcus aureus.

The treatment of prosthetic joint infections caused by methicillin-resistant Staphylococcus aureus (MRSA) continues to be a challenge for the clinician. The aim of this study was to evaluate the efficacies of daptomycin at usual and high doses (equivalent to 6 and 10 mg/kg of body weight/day, respectively, in humans) and in combination with rifampin and to compare the activities to those of conventional anti-MRSA therapies. We used MRSA strain HUSA 304, with the following MICs and minimal bactericidal concentrations (MBCs), respectively: daptomycin, 1 µg/ml and 4 µg/ml; vancomycin, 2 µg/ml and 4 µg/ml; linezolid, 2 µg/ml and >32 µg/ml; and rifampin, 0.03 µg/ml and 0.5 µg/ml. In time-kill curves, only daptomycin and its combinations with rifampin achieved a bactericidal effect in log and stationary phases. For in vivo studies, we used a rat foreign-body infection model. Therapy was administered for 7 days with daptomycin at 100 mg/kg/day and 45/mg/kg/day, vancomycin at 50 mg/kg/12 h, rifampin at 25 mg/kg/12 h, and linezolid at 35 mg/kg/12 h, and each antibiotic was also combined with rifampin. Among monotherapies, daptomycin at 100 mg/kg/day and rifampin performed better than vancomycin and linezolid. In combination with rifampin, both dosages of daptomycin were significantly better than all other combinations, but daptomycin at 100 mg/kg/day plus rifampin achieved better cure rates at day 11 (P < 0.05) than daptomycin at 45 mg/kg/day plus rifampin. Resistant strains were found in monotherapies with rifampin and daptomycin at 45 mg/kg/day. In conclusion, daptomycin at high doses was the most effective monotherapy and also improved the efficacy of the combination with rifampin against foreign-body infections by MRSA. Clinical studies should confirm whether this combination may be considered the first-line treatment for foreign-body infections by MRSA in humans.

Efficacy of high doses of daptomycin versus alternative therapies against experimental foreign-body infection by methicillin-resistant Staphylococcus aureus.

Since the currently approved dose of daptomycin (6 mg/kg of body weight/day) has been associated with clinical failures and resistance development, higher doses for some difficult-to-treat infections are being proposed. We studied the efficacy of daptomycin at high doses (equivalent to 10 mg/kg/day in humans) and compared it to that of reference and alternative treatments in a model of foreign-body infection with methicillin (meticillin)-resistant Staphylococcus aureus. In vitro studies were conducted with bacteria in the log and stationary phases. For the in vivo model, therapy with daptomycin at 100 mg/kg/day, vancomycin at 50 mg/kg/12 h, rifampin (rifampicin) at 25 mg/kg/12 h, or linezolid at 35 mg/kg/12 h was administered for 7 days. Antibiotic efficacy was evaluated using either bacteria from tissue cage fluids or those attached to coverslips. We screened for the emergence of linezolid- and rifampin-resistant strains and analyzed the surviving population from the daptomycin-treated group. Only daptomycin was bactericidal in both the log- and stationary-phase studies. Daptomycin (decrease in the log number of CFU per milliliter of tissue cage fluid, 2.57) and rifampin (decrease, 2.6 log CFU/ml) were better (P < 0.05) than vancomycin (decrease, 1.1 log CFU/ml) and linezolid (decrease, 0.9 log CFU/ml) in the animal model. Rifampin-resistant strains appeared in 60% of cases, whereas no linezolid resistance emerged. No daptomycin-resistant subpopulations were detected at frequencies of 10(-7) or higher. In conclusion, daptomycin at high doses proved to be as effective as rifampin, and the two were the most active therapies for this experimental foreign-body infection. These high doses ensured a profile of safety from the development of resistance.