Relationship between antibiotic concentration in bone and efficacy of treatment of staphylococcal osteomyelitis in rats: azithromycin compared with clindamycin and rifampin.
We examined the effect of azithromycin (CP-62,993), a new oral macrolide-like antibiotic, alone and in combination with rifampin, as treatment for experimental staphylococcal osteomyelitis. Clindamycin was used as a comparison drug. Rats (n = 10 to 15 per group) were infected by direct instillation of Staphylococcus aureus into the tibial medullary cavity. After 10 days, 21-day treatments with azithromycin (50 mg/kg of body weight, once daily, by the oral route), rifampin (20 mg/kg, once daily, subcutaneously), or clindamycin (90 mg/kg, three times daily, by the oral route) were started. The drugs were used singly or in combination (azithromycin plus rifampin or clindamycin plus rifampin). Peak azithromycin concentrations in bone were > 30 times higher than levels in serum, but the drug had little effect on final bacterial titers (5.13 +/- 0.46 log10 CFU/g of bone; for controls, 6.54 +/- 0.28 log10 CFU/g). Clindamycin was more active than azithromycin (3.26 +/- 2.14 log10 CFU/g of bone; 20% of sterilized bones), but rifampin was the most active single drug (1.5 +/- 1.92 log10 CFU/g; 53% of sterilized bones). Therapy with rifampin or clindamycin alone was associated with the emergence of resistance. Rifampin plus azithromycin (0.51 +/- 1.08 log10 CFU/g of bone; 80% of sterilized bones) and rifampin plus clindamycin (0.87 +/- 1.34 log10 CFU/g of bone; 66% of sterilized bones) were the most active regimens. Thus, azithromycin is ineffective as a single drug for the treatment of experimental staphylococcal osteomyelitis, despite high levels in bone that markedly exceeded the MIC, but it may be an attractive partner drug for rifampin.
O'Reilly
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Pharma Research, Ciba-Geigy Ltd., Basel, Switzerland.
Kunz
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Sande
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Zak
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Sande
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Täuber
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D000818:Animals; D017963:Azithromycin; D001842:Bone and Bones / Q000378:metabolism* / Q000382:microbiology; D002981:Clindamycin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004352:Drug Resistance, Microbial; D004359:Drug Therapy, Combination / Q000493:pharmacokinetics / Q000627:therapeutic use; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D010019:Osteomyelitis / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D051381:Rats; D012293:Rifampin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology
D002981:Clindamycin; D004917:Erythromycin; D017963:Azithromycin; D012293:Rifampin