Variation in postantibiotic effect of clindamycin against clinical isolates of Staphylococcus aureus and implications for dosing of patients with osteomyelitis.
Initial measurements of postantibiotic effect (PAE) were made by a standard laboratory method (exposure to 1 mg of clindamycin per liter for 1 h). The range of PAE for 21 strains of Staphylococcus aureus isolated from osteomyelitis patients was 0.4 to 3.9 h, which markedly exceeded the coefficient of variation for the method (6 to 19%). Exposure of S. aureus to three doses of clindamycin at 8-h intervals had no consistent effect on either PAE or MIC. The PAE was dependent on both concentration and duration of exposure to clindamycin: for example, the PAEs for one strain were 1.7 h after exposure to 1 mg/liter for 1 h, 2.4 h after exposure to 4 mg/liter for 1 h, and 5.9 h after exposure to 4 mg/liter for 3 h. Pharmacokinetic simulations showed that the dose required to maintain free serum clindamycin concentrations above the MIC was 300 mg 6 hourly after oral administration (95% confidence interval, 243 to 301 mg) and 1.2 g 6 hourly (95% confidence interval, 305 to 1,145 mg) after intravenous (i.v.) administration. The duration of PAE would have to be at least 2.4 h to allow an increase in the oral dose interval to 8 h or to allow i.v. administration of 300 mg 6 hourly. Additional PAE experiments were performed with the three strains for which PAEs are the shortest after exposure to 1 mg/liter for 1 h (0.4 to 1.2 h). The PAE for these three strains increased markedly to 4.4 to 6.7 h following exposure to 2 mg/liter for 6 h (to mimic the area under the concentration-time curve from 0 to 6 h after a 300-mg dose). These data suggest that oral clindamycin could be administered at 300 mg 8 hourly in the treatment of S. aureus infection, whereas the i.v. dose interval should be 6 h. These suggestions should be confirmed by performing clinical trials.
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Department of Clinical Pharmacology, Ninewells Hospital and Medical School, Dundee, United Kingdom.
Davey
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Phillips
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D000284:Administration, Oral; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002981:Clindamycin / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007275:Injections, Intravenous; D008826:Microbial Sensitivity Tests; D010019:Osteomyelitis / Q000188:drug therapy*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000302:isolation & purification; D013997:Time Factors
D000900:Anti-Bacterial Agents; D002981:Clindamycin