Distribution of metronidazole in muscle tissue of patients with septic shock and its efficacy against Bacteroides fragilis in vitro

Objectives: Studies investigating the target site concentration of antibiotics, such as \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \({\beta}\) \end{document}-lactams and fluoroquinolones, have demonstrated differences between the drug concentrations in healthy volunteers and septic patients. The aims of this study were (i) to evaluate the muscle tissue concentration of metronidazole in patients with septic shock and (ii) to test the efficacy of metronidazole in an in vitro pharmacodynamic model at different single doses. Materials and methods: Six patients admitted to the ICU of Tartu University Clinics with a diagnosis of septic shock were studied. Patients receiving metronidazole treatment within 48 h before the study or with a BMI > 35 were excluded. Metronidazole muscle tissue concentration was assessed by a microdialysis technique. Based on the microdialysis data, similar kinetics were simulated in in vitro experiments using Bacillus fragilis strains with MIC90s of 0.125 mg/L (BF125) and 1.0 mg/L (BF1). Results: Metronidazole concentrations in plasma achieved a mean (s.d.) value of 11.4±2.0 mg/L at 30 min after administration of a single 500 mg intravenous dose, while in the muscle tissue, maximum concentrations of 8.2±4.5 mg/L were achieved at 140±92.3 min after the dose. When this metronidazole time course was simulated in vitro, the time to 99.9% kill ranged from 1.0 to 1.4 h for BF125 and from 1.8 to 3.5 h for BF1, while the eradication time ranged from 1.7 to 2.5 h and from 3.4 to 6.5 h, respectively. No regrowth was detected. Conclusion: Pharmacokinetic–pharmacodynamic simulation of metronidazole interstitial concentrations shows a high efficacy of the drug in septic patients.