Target site concentrations after continuous infusion and bolus injection of cefpirome to healthy volunteers

Background: Recent data indicate a higher level of effectivity of beta-lactam antibiotics if serum concentrations are kept above the minimal inhibitory concentration (MIC) of the pathogen. This concept would favor continuous infusion over bolus dosing. However, it is usually not the serum concentration but the free interstitial concentration in the target tissue that determines antibiotic activity. We therefore set out to measure effective drug concentrations in the interstitial space of muscle and subcutaneous adipose tissue and to compare trough levels and times above the MIC after bolus versus continuous infusion of cefpirome. Methods: Twelve healthy volunteers received a single dose of 2 g cefpirome as an intravenous bolus or as a continuous infusion over 8 hours in a crossover design, and the resulting free interstitial tissue concentrations were measured with use of microdialysis. Results: After bolus injection, mean interstitial trough concentrations were 3.0 +/- 1.9 mu g/mL and 2.1 +/- 1.0 mu g/mL for muscle and subcutaneous tissue, respectively; continuous infusion resulted in trough levels of 10.1 +/- 6.8 mu g/mL and 10.1 +/- 4.6 mu g/mL for muscle and subcutaneous tissue, respectively. This resulted in significantly longer times above the MIC with continuous infusion for Straphylococcus epidermidis and Enterobacter cloacae. Bacteria with an MIC less than or equal to 1 would be covered by either method, whereas higher doses seem to be necessary for Pseudomonas aeruginosa. Conclusion: Although susceptible organisms will usually be covered sufficiently with standard dosing regimens, soft tissue infections with bacteria that have MIC values of 2 to 8 may profit from continuous application. Coverage of P aeruginosa, however, would be inadequate with conventional daily doses of 4 g cefpirome regardless of the method of application.