A combined in vivo pharmacokinetic-in vitro pharmacodynamic approach to simulate target site pharmacodynamics of antibiotics in humans.

We describe a new approach to quantify in vivo anti-infective activity by simulating effect site pharmacokinetics of antibiotics in vitro. This approach is based on (i) the in vivo measurement of interstitial drug pharmacokinetics (PK) at the target site and (ii) a subsequent pharmacodynamic (PD) simulation of the time versus drug concentration profile in an in vitro setting. To demonstrate the feasibility of this approach, individual time-concentration profiles of ciprofloxacin were measured in the interstitial space fluid of eight healthy volunteers by microdialysis following iv administration of 200 mg. Thereafter, different isolates of Pseudomonas aeruginosa were exposed in vitro to the interstitial ciprofloxacin concentration profile obtained from in vivo experiments. This led to a 1- to 3-log10 decrease in the number of viable organisms after 8 h. Significant correlations were observed between the maximal bactericidal effect and several PK surrogate parameters, notably the AUC/MIC ratio (P: = 0.0005), the C:max/MIC ratio (P: = 0.006) and the time > MIC (P: = 0.02). Furthermore, the data were analysed with an integrated PK-PD model allowing a much more detailed evaluation of the data than using MIC. The model employed an E:max relationship to link unbound ciprofloxacin concentration to bacterial kill rate. In conclusion, our experiments show that therapeutic success and failure in antimicrobial therapy may be explained by pharmacokinetic variability at the target site. Therefore, the in vivo PK-in vitro PD approach presented in our study may provide valuable guidance for drug and dose selection of antimicrobial agents.

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 microg/mL and 2.1 +/-1.0 microg/mL for muscle and subcutaneous tissue, respectively; continuous infusion resulted in trough levels of 10.1 +/- 6.8 microg/mL and 10.1 +/- 4.6 microg/mL for muscle and subcutaneous tissue, respectively. This resulted in significantly longer times above the MIC with continuous infusion for Staphylococcus epidermidis and Enterobacter cloacae. Bacteria with an MIC < or =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.

Distribution and antimicrobial activity of ciprofloxacin in human soft tissues.

Interstitial ciprofloxacin concentrations in soft tissues were measured by microdialysis following intravenous administration of 200 mg to each of eight healthy volunteers. Interstitial ciprofloxacin concentrations were significantly lower than corresponding total serum drug concentrations; the interstitium-to-serum concentration ratios ranged from 0.55 to 0.73. An in vitro simulation based on interstitial pharmacokinetics showed a substantially lower antimicrobial activity than did the simulation based on serum pharmacokinetics. Thus, ciprofloxacin concentrations at the site of effect may be subinhibitory although effective concentrations are attained in serum.