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Antimicrobial Agents and Chemotherapy, November 2003, p. 3548-3553, Vol. 47, No. 11
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.11.3548-3553.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Relevance of Soft-Tissue Penetration by Levofloxacin for Target Site Bacterial Killing in Patients with Sepsis

Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics,¹ Department of Internal Medicine II, Cardiac Intensive Care Unit,² Department of Internal Medicine I, Division of Infectious Diseases and Chemotherapy,³ Institute of Pharmacology, University of Vienna Medical School, Vienna, Austria⁴

Received 26 February 2003/ Returned for modification 29 May 2003/ Accepted 20 August 2003

Antimicrobial therapy of soft tissue infections in patients with sepsis sometimes lacks efficiency, despite the documented susceptibility of the causative pathogen to the administered antibiotic. In this context, impaired equilibration between the antibiotic concentrations in plasma and those in tissues in critically ill patients has been discussed. To characterize the impact of tissue penetration of anti-infective agents on antimicrobial killing, we used microdialysis to measure the concentration-versus-time profiles of levofloxacin in the interstitial space fluid of skeletal muscle in patients with sepsis. Subsequently, we applied an established dynamic in vivo pharmacokinetic-in vitro pharmacodynamic approach to simulate bacterial killing at the site of infection. The population mean areas under the concentration-time curves (AUCs) for levofloxacin showed that levofloxacin excellently penetrates soft tissues, as indicated by the ratio of the AUC from time zero to 8 h (AUC_0-8) for muscle tissue (AUC_{0-8 muscle}) to the AUC_0-8 for free drug in plasma (AUC_{0-8 plasma free}) (AUC_{0-8 muscle}/AUC_{0-8 plasma free} ratio) of 0.85. The individual values of tissue penetration and maximum concentration (C_max) in muscle tissue were highly variable. No difference in bacterial killing of a select Staphylococcus aureus strain for which the MIC was 0.5 µg/ml was found between individuals after exposure to dynamically changing concentrations of levofloxacin in plasma and tissue in vitro. In contrast, the decrease in the bacterial counts of Pseudomonas aeruginosa (MIC = 2 µg/ml) varied extensively when the bacteria were exposed to levofloxacin at the concentrations determined from the individual concentration-versus-time profiles obtained in skeletal muscle. The extent of bacterial killing could be predicted by calculating individual C_max/MIC and AUC_{0-8 muscle}/AUC_{0-8 plasma free} ratios (R = 0.96 and 0.93, respectively). We have therefore shown in the present study that individual differences in the tissue penetration of levofloxacin may markedly affect target site killing of bacteria for which MICs are close to 2 µg/ml.

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