Urinary Pharmacokinetics and Theoretical Pharmacodynamics of Intravenous Levofloxacin in Intensive Care Unit Patients Treated with 500 mg b.i.d. for Ventilator-Associated Pneumonia

Abstract

This study assessed the urinary pharmacokinetics and theoretical pharmacodynamics of levofloxacin in ICU patients treated with 500 mg b.i.d. i.v. for ventilator associated pneumonia to evaluate if this high dosage regimen might ensure appropriate exposure in the treatment of severe UTIs in ICU patients. Nineteen patients (11M, 8F; age, 52 ± 21 years; weight, 75 ± 16 kg) presenting with normal renal function (estimated creatinine clearance, 1.83 ± 0.61 ml/min/kg; diuresis, 1709 ± 643 ml/24h) were assessed. In steady-state conditions, urine samples were collected at 0-2h, 2-4h, 4-8h and 8-12h during a dosing interval, and urinary concentrations of levofloxacin were assayed by HPLC. Mean (± SD) levofloxacin urinary concentrations were 329.1 ± 159.9, 388.6 ± 143.5, 266.0 ± 102.8 and 168.1 ± 93.3 mg/L at 0-2h, 2-4h, 4-8h and 8-12h, respectively, with urinary AUC0- of 3171.4 ± 1192.1 mg/L·h. Mean (± SD) levofloxacin excretion rates were 44.1 ± 20.7, 42.8 ± 8.2, 31.7 ± 5.8 and 19.8 ± 4.2 mg/h during the 0-2h, 2-4, 4-8h and 8-12h interval, respectively. Our findings suggest that, consistently with levofloxacin showing high renal excretion as unmodified drug, 500 mg b.i.d. i.v. of levofloxacin ensure and maintain urinary concentrations at least 50-fold higher than the MIC⁹⁰ of most sensitive uropathogens during the overall dosing interval in ICU patients with normal renal function. Considering the major pharmacodynamic determinants for the concentration-dependent bactericidal activity of levofloxacin as applicable at the urinary level (C_U/MIC of >12.2 and/or AUC_{24h U}/MIC of >125 h), this high dosage regimen may ensure optimal exposure for the treatment of catheter-related and severe lower UTIs not only against sensitive microorganisms, but probably also whenever microorganisms usually considered as intermediate susceptible or resistant to levofloxacin may be involved.