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 +/- 643ml / 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 +/- 93.3mg/L at 0-2h, 2-4h, 4-8h and 8-12h, respectively, with urinary AUC0-tau of 3171.4 +/- 1192.1mg/L x 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, 500mg 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 (CU/MIC of >12.2 and/or AUC24h U /MIC of >125h), 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.

Pharmacodynamic Evaluation of Fosfomycin against Escherichia coli and Klebsiella spp. from Urinary Tract Infections and the Influence of pH on Fosfomycin Activities

“…Fosfomycin is excreted in the active form in the urine via the kidneys and might achieve in vivo concentrations above the usual MIC against common uropathogens (9,10). The same studies demonstrated that serum susceptibility data overestimated the resistance of urinary isolates in the presence of high urine antibiotic levels (10,(31)(32)(33). Even though only the higher doses may be required to achieve the PTA for an MIC of 64 g/ml, fosfomycin becomes highly concentrated in the urine.…”

Pharmacokinetics of ciprofloxacin XR (1000mg) versus levofloxacin (500mg) in plasma and urine of male and female healthy volunteers receiving a single oral dose

“…Even in complicated UTI the two dosages studied should be at the lower border. It has even been shown that a dosage regimen of levofloxacin 500 mg bid may ensure optimal exposure for the treatment of catheter-related and severe lower UTIs in intensive care patients [25].…”

Optimal management of urosepsis from the urological perspective

“…In patients with early-onset ventilator-associated pneumonia Pea et al [36] found a reduced area under the concentration-time curve (AUC) over the 12-hour dosage interval after the administration of parenteral levofloxacin 500 mg twice daily. The authors explained the reduction by a greater clearance of levofloxacin leading to a shorter elimination half-life.…”