Journal
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Volume 53, Issue 10, Pages 4172-4177Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.00051-09
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Funding
- Cubist Pharmaceuticals, Inc., Lexington, MA
- Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III Madrid (Spain)
- Spanish Network for the Research in Infectious Diseases [REIPI RD06/0008]
- CIBER [CB 06/06/2008]
- Fondo de Investigaciones Sanitarias (FIS) ( Madrid, Spain)
- Fundacion Maximo Soriano Jimenez (Barcelona, Spain)
- Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona (Spain)
- [FIS 00/0475]
- [FIS 02/0322]
- [FIS 05/0170]
- [FIS 08/0268]
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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 1 x and 2 x the MIC yielded synergy, while the addition of rifampin at 2 to 4 mu g/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] log(10) 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] log(10) 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 mu g/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.
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