Efficacy of High Doses of Daptomycin versus Alternative Therapies against Experimental Foreign-Body Infection by Methicillin-Resistant Staphylococcus aureus

Abstract

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.Daptomycin is a lipopeptide drug with bactericidal activity toward methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) in a concentration-dependent manner (27,32). It is currently approved for use at 4 mg/kg of body weight/day for skin and soft-tissue infections (1) and at 6 mg/kg/day for bacteremia and right-side endocarditis (12,14).In recent years, reports of clinical failures and the emergence of resistant strains following daptomycin treatment have raised great concern (6, 18, 31). As a result, higher doses of daptomycin are being proposed as an alternative for some difficult-to-treat infections such as complicated bacteremia and endocarditis. Recently, doses of 10 mg/kg/day were studied using an in vitro model of staphylococcal endocarditis, with the results being promising in terms of efficacy and resistance prevention (25, 26). To date, clinical experience with the activity of the drug at doses higher than 6 mg/kg/day is limited (15, 28), whereas good safety and tolerance profiles for daptomycin at up to 12 mg/kg/day in volunteers have been reported (4).Foreign-body infections are difficult to treat because of the presence of bacterial biofilm and tolerance to antibiotics (10,39). MRSA is commonly involved in such infections, and daptomycin may be a pro...

Biofilm-Related Infections: Bridging the Gap between Clinical Management and Fundamental Aspects of Recalcitrance toward Antibiotics

“…Nevertheless, these 2 antibiotic combinations were more efficient than the previously recommended vancomycin-rifampin and linezolid-rifampin combinations (229). Using a similar methodology, another group demonstrated that daptomycin or rifampin as a single agent against MRSA was more effective than vancomycin or linezolid (221). Daptomycin has also been proposed for the treatment of catheter-related infections, and an in vivo study demonstrated that vancomycin and daptomycin were equally efficient at eradicating methicillin-resistant S. epidermidis (MRSE) catheter-related infections (230).…”

“…Furthermore, fosfomycin and daptomycin are currently being investigated and might be promising candidates in the fight against foreign-body-related infections (219)(220)(221). In the case of prosthetic joint-related infection (PJI), in vivo models led to the demonstration that fluoroquinolones exhibited more penetration into the site of infection (222).…”

In vitro Activity of Daptomycin, Linezolid and Rifampicin on Staphylococcus epidermidis Biofilms

“…Cells were harvested by centrifugation (for 10 min at 9,5009g and 4°C), resuspended in TSB, and the suspension was adjusted to an optical density (640 nm) equivalent to 1 9 10 9 cells ml -1 before being used in the subsequent assays. Each stock solution of daptomycin (with calcium supplementation at 50 mg l -1 ) [15,16] and rifampicin was prepared in methanol. It was confirmed that methanol, at the concentration used, had no effect on the growth of the S. epidermidis strains studied.…”

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

“…We have recently reported an 86% rate of success at 3 to 5 years in a cohort of 29 patients with osteomyelitis or infected total joint prostheses, most of whom had failed conventional therapy, usually with vancomycin (7). Previous in vitro synergy studies with daptomycin and rifampin have demonstrated an additive effect in laboratory MRSA strains (4,7). This combination in our study was synergistic or indifferent in all of our strains in the checkerboard assay, while no synergy was found in the majority of the strains with the time-kill technique.…”

“…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.…”