Efficacy of daptomycin in implant-associated infection due to methicillin-resistant Staphylococcus aureus: importance of combination with rifampin.
Limited treatment options are available for implant-associated infections caused by methicillin (meticillin)-resistant Staphylococcus aureus (MRSA). We compared the activity of daptomycin (alone and with rifampin [rifampicin]) with the activities of other antimicrobial regimens against MRSA ATCC 43300 in the guinea pig foreign-body infection model. The daptomycin MIC and the minimum bactericidal concentration in logarithmic phase and stationary growth phase of MRSA were 0.625, 0.625, and 20 microg/ml, respectively. In time-kill studies, daptomycin showed rapid and concentration-dependent killing of MRSA in stationary growth phase. At concentrations above 20 microg/ml, daptomycin reduced the counts by >3 log(10) CFU/ml in 2 to 4 h. In sterile cage fluid, daptomycin peak concentrations of 23.1, 46.3, and 53.7 microg/ml were reached 4 to 6 h after the administration of single intraperitoneal doses of 20, 30, and 40 mg/kg of body weight, respectively. In treatment studies, daptomycin alone reduced the planktonic MRSA counts by 0.3 log(10) CFU/ml, whereas in combination with rifampin, a reduction in the counts of >6 log(10) CFU/ml was observed. Vancomycin and daptomycin (at both doses) were unable to cure any cage-associated infection when they were given as monotherapy, whereas rifampin alone cured the infections in 33% of the cages. In combination with rifampin, daptomycin showed cure rates of 25% (at 20 mg/kg) and 67% (at 30 mg/kg), vancomycin showed a cure rate of 8%, linezolid showed a cure rate of 0%, and levofloxacin showed a cure rate of 58%. In addition, daptomycin at a high dose (30 mg/kg) completely prevented the emergence of rifampin resistance in planktonic and adherent MRSA cells. Daptomycin at a high dose, corresponding to 6 mg/kg in humans, in combination with rifampin showed the highest activity against planktonic and adherent MRSA. Daptomycin plus rifampin is a promising treatment option for implant-associated MRSA infections.
John
Anne-Kathrin
AK
Infectious Diseases Service, Department of Internal Medicine, University Hospital and University of Lausanne, Rue du Bugnon 46, Lausanne, Switzerland.
Baldoni
Daniela
D
Haschke
Manuel
M
Rentsch
Katharina
K
Schaerli
Patrick
P
Zimmerli
Werner
W
Trampuz
Andrej
A
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003428:Cross Infection / Q000188:drug therapy* / Q000382:microbiology*; D017576:Daptomycin / Q000627:therapeutic use*; D004343:Drug Implants / Q000009:adverse effects*; D004359:Drug Therapy, Combination; D006168:Guinea Pigs; D008297:Male; D013058:Mass Spectrometry; D055624:Methicillin-Resistant Staphylococcus aureus / Q000502:physiology*; D008826:Microbial Sensitivity Tests; D012293:Rifampin / Q000627:therapeutic use*; D013203:Staphylococcal Infections / Q000188:drug therapy*
D004343:Drug Implants; D017576:Daptomycin; D012293:Rifampin