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Antimicrobial Agents and Chemotherapy, October 2009, p. 4252-4257, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00208-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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

O. Murillo,1* C. Garrigós,1 M. E. Pachón,1 G. Euba,1 R. Verdaguer,2 C. Cabellos,1 J. Cabo,3 F. Gudiol,1 and J. Ariza1

Laboratory of Experimental Infection, Infectious Diseases Service,1 Departments of Microbiology,2 Orthopaedic Surgery, IDIBELL, Hospital Universitari de Bellvitge (Feixa Llarga s/n, 08907 Barcelona-Spain), Barcelona, Spain3

Received 16 February 2009/ Returned for modification 24 June 2009/ Accepted 13 July 2009

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.

* Corresponding author. Mailing address: Infectious Diseases Service, Hospital Universitari de Bellvitge, Feixa Llarga s/n, 08907 L'Hospitalet de Llobregat, Barcelona, Spain. Phone: 34.93.260 7625. Fax: 34.93.260 7637. E-mail: 32186omr{at}comb.es

{triangledown} Published ahead of print on 27 July 2009.

Antimicrobial Agents and Chemotherapy, October 2009, p. 4252-4257, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00208-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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