Daptomycin plus fosfomycin, a synergistic combination in experimental implant-associated osteomyelitis due to methicillin-resistant Staphylococcus aureus in rats.
The aim of this study was to evaluate the combination of daptomycin and fosfomycin in experimental chronic implant-associated osteomyelitis due to methicillin-resistant Staphylococcus aureus (MRSA). Infection was induced in the tibiae of rats by the insertion of a bacterial inoculum (1 to 5×10(8) CFU/ml) of a clinical MRSA isolate and a titanium wire. Four weeks after infection, each animal was assigned to a treatment group: daptomycin monotherapy at 60 mg/kg of body weight once daily (n=10), fosfomycin monotherapy at 40 mg/kg once daily (n=10), or daptomycin and fosfomycin combined at 60 mg/kg and 40 mg/kg, respectively, once daily (n=9). Ten animals were left untreated. After a 3-week treatment period, the animals were euthanized, and the infected tibiae and implants were processed for quantitative bacterial cultures. The bacterial cultures from bones were positive for MRSA in all animals in the untreated group, the daptomycin group, and the fosfomycin group, with median bacterial counts of 2.34×10(6) CFU/g bone, 1.57×10(6) CFU/g bone, and 3.48×10(2) CFU/g bone, respectively. In the daptomycin-fosfomycin group, 6 out of 9 animals were positive for MRSA, with a median count of 7.92 CFU/g bone. Bacterial cultures derived from the titanium wires were negative in the fosfomycin- and daptomycin-fosfomycin-treated groups. Based on bacterial counts in bones, treatment with daptomycin-fosfomycin was statistically significantly superior to all that of the other groups (P≤0.003). Fosfomycin was superior to daptomycin and no treatment (P<0.0001). No development of resistance was observed in any treatment arm. The combination of daptomycin and fosfomycin demonstrated synergism against MRSA in experimental implant-associated osteomyelitis.
Department of Internal Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria.
Tilman
T
Lingscheid
Department of Internal Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria.
Wolfgang
W
Poeppl
Department of Internal Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria.
Dominik
D
Bernitzky
Department of Internal Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria.
Luzia
L
Veletzky
Department of Internal Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria.
Manuel
M
Kussmann
Division for Biomedical Research, Medical University of Vienna, Vienna, Austria.
Roberto
R
Plasenzotti
Department of Internal Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria heinz.burgmann@meduniwien.ac.at.
Heinz
H
Burgmann
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D017576:Daptomycin / Q000627:therapeutic use*; D005578:Fosfomycin / Q000627:therapeutic use*; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000472:pathogenicity*; D010019:Osteomyelitis / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000900:Anti-Bacterial Agents; D005578:Fosfomycin; D017576:Daptomycin