Pharmacokinetics and pharmacodynamics of intravenous levofloxacin in patients with early-onset ventilator-associated pneumonia.
OBJECTIVE
To investigate the pharmacokinetics of levofloxacin and the pharmacokinetic-pharmacodynamic appropriateness of its total body exposure in patients in the intensive care unit (ICU) treated for early-onset ventilator-associated pneumonia (VAP) with intravenous levofloxacin 500mg twice daily.


METHODS
Prospective non-blinded pharmacokinetic-pharmacodynamic study.


METHODS
Ten critically ill adult patients with normal renal function.


METHODS
Blood and urine samples were collected at appropriate times during a 12-hour administration interval at steady state. Levofloxacin concentrations were determined by high-performance liquid chromatography. Clinical and microbiological outcomes were assessed.


RESULTS
Levofloxacin pharmacokinetics were only partially comparable with those obtained from literature data for healthy volunteers. Area under the concentration-time curve (AUC(tau)) over the 12-hour dosage interval was about 30-40% lower than in healthy volunteers (33.90 vs 49.60 mg. h/L). The reduced exposure may be due to a greater clearance of levofloxacin (0.204 vs 0.145 L/h/kg [3.40 vs 2.42 mL/min/kg]), leading to a shorter elimination half-life (5.2 vs 7.6 hours). Cumulative urinary excretion during the 12-hour dosage interval confirmed the greater excretion of unchanged drug in these patients compared with healthy subjects (76% vs 68%). Coadministered drugs used to treat underlying diseases (dopamine, furosemide, mannitol) may at least partially account for this enhanced elimination in critically ill patients. Intravenous levofloxacin 500mg twice daily ensured a median C(max)/MIC (maximum plasma concentration/minimum inhibitory concentration) ratio of 102 and a median 24-hour AUC/MIC ratio of 930 SIT(-1). h (inverse serum inhibitory titre integrated over time) against methicillin-sensitive Staphylococcus aureus and Haemophilus influenzae. The overall success rate of the assessable cases was 75% (6/8). Bacterial eradication was obtained in all of the assessable cases (8/8), but a superinfection (Acinetobacter anitratus,Pseudomonas aeruginosa) occurred in three cases.


CONCLUSIONS
The findings support the suitability of intravenous levofloxacin 500mg twice daily in the treatment of early-onset VAP in ICU patients with normal renal function. Levofloxacin may represent a valid alternative to non-pseudomonal beta-lactams or aminoglycosides in the empirical treatment of early-onset VAP. However, further larger studies are warranted to investigate its efficacy.
Pea
Federico
F
Department of Experimental and Clinical Pathology and Medicine, Medical School, Institute of Clinical Pharmacology and Toxicology, University of Udine, Udine, Italy. federico.pea@med.uniud.it
Di Qual
Elena
E
Cusenza
Aldo
A
Brollo
Loris
L
Baldassarre
Marco
M
Furlanut
Mario
M
D000368:Aged; D000890:Anti-Infective Agents / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D016638:Critical Illness / Q000628:therapy; D003428:Cross Infection / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007362:Intensive Care Units; D064704:Levofloxacin; D008297:Male; D008875:Middle Aged; D015242:Ofloxacin / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D018410:Pneumonia, Bacterial / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D013997:Time Factors; D012122:Ventilators, Mechanical / Q000009:adverse effects
D000890:Anti-Infective Agents; D064704:Levofloxacin; D015242:Ofloxacin