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Antimicrobial Agents and Chemotherapy, October 2009, p. 4172-4177, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00051-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Addition of Gentamicin or Rifampin Does Not Enhance the Effectiveness of Daptomycin in Treatment of Experimental Endocarditis Due to Methicillin-Resistant Staphylococcus aureus{triangledown}

J. M. Miró,1* C. García-de-la-Mària,2 Y. Armero,2 D. Soy,3 A. Moreno,1 A. del Río,1 M. Almela,2 M. Sarasa,3 C. A. Mestres,4 J. M. Gatell,1 M. T. Jiménez de Anta,2 F. Marco,2 and the Hospital Clinic Experimental Endocarditis Study Group {dagger}

Infectious Diseases Service, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona School of Medicine, Barcelona, Catalunya, Spain,1 Microbiology Service, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona School of Medicine, Barcelona, Catalunya, Spain,2 Pharmacy Service, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona School of Medicine, Barcelona, Catalunya, Spain,3 Cardiovascular Institute, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona School of Medicine, Barcelona, Catalunya, Spain4

Received 14 April 2009/ Returned for modification 19 April 2009/ Accepted 9 July 2009

This study evaluated the activity of daptomycin combined with either gentamicin or rifampin against three methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates in vitro and one isolate in vivo against a representative strain (MRSA-572). Time-kill experiments showed that daptomycin was bactericidal against these strains at concentrations over the MIC. Daptomycin at sub-MIC concentrations plus gentamicin at 1x and 2x the MIC yielded synergy, while the addition of rifampin at 2 to 4 µg/ml resulted in indifference (two strains) or antagonism (one strain). The in vivo activity of daptomycin (6 mg/kg of body weight once a day) was evaluated ± gentamicin (1 mg/kg intravenously [i.v.] every 8 h [q8h]) or rifampin (300 mg i.v. q8h) in a rabbit model of infective endocarditis by simulating human pharmacokinetics. Daptomycin plus gentamicin (median, 0 [interquartile range, 0 to 2] log10 CFU/g vegetation) was as effective as daptomycin alone (0 [0 to 2] log10 CFU/g vegetation) in reducing the density of bacteria in valve vegetations (P = 0.83), and both were more effective than daptomycin plus rifampin (3 [2 to 3.5] log10 CFU/g vegetation; P < 0.05) for the strain studied. In addition, daptomycin sterilized a ratio of vegetations that was similar to that of daptomycin plus gentamicin (10/15 [67%] versus 9/15 [60%]; P = 0.7), and both regimens did so more than daptomycin plus rifampin (3/15 [20%]; P = 0.01 and P = 0.02, respectively). No statistical difference was noted between daptomycin plus gentamicin and daptomycin alone for MRSA treatment. In the combination arm, all isolates from vegetations remained susceptible to daptomycin, gentamicin, and rifampin. Sixty-one percent of the isolates (8/13) acquired resistance to rifampin during monotherapy. In the daptomycin arm, resistance was detected in only one case, in which the daptomycin MIC rose to 2 µg/ml among the recovered bacteria. In conclusion, the addition of gentamicin or rifampin does not enhance the effectiveness of daptomycin in the treatment of experimental endocarditis due to MRSA.

* Corresponding author. Mailing address: Infectious Diseases Service, Hospital Clínic Universitari, Villarroel 170, 08036 Barcelona, Spain. Phone: 34-93-2275586. Fax: 34-93-4514438. E-mail: jmmiro{at}ub.edu

{triangledown} Published ahead of print on 20 July 2009.

{dagger} Members of the Hospital Clínic Endocarditis Study Group, Hospital Clínic-IDIBAPS, University of Barcelona School of Medicine, Barcelona, Spain, include the following: from the Infectious Diseases Service, J. M. Miró, A. Moreno, A. del Río, C. Cervera, X. Castañeda, and J. M. Gatell; from the Microbiology Service, F. Marco, C. García-de-la-Mària, Y. Armero, M. Almela, and M. T. Jiménez de Anta; from the Cardiovascular Institute, C. A. Mestres, J. C. Paré, C. Falces, R. Cartañá, S. Ninot, M. Azqueta, M. Sitges, M. Heras, and J. L. Pomar; from the Pathology Department, J. Ramírez, and T. Ribalta; from the Toxicology Service, M. Brunet; from the Pharmacy Service, D. Soy; and from UASP, E. de Lazzari.

Antimicrobial Agents and Chemotherapy, October 2009, p. 4172-4177, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00051-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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