Clinical Pharmacokinetics

, Volume 42, Issue 6, pp 589–598

Pharmacokinetics and Pharmacodynamics of Intravenous Levofloxacin in Patients with Early-Onset Ventilator-Associated Pneumonia

  • Federico Pea
  • Elena Di Qual
  • Aldo Cusenza
  • Loris Brollo
  • Marco Baldassarre
  • Mario Furlanut
Original Research Article

Abstract

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.

Design

Prospective non-blinded pharmacokinetic-pharmacodynamic study.

Participants

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 (AUCτ) 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 Cmax/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 methicillinsensitive Staphylococcus aureus and Haemophilus influenzile. 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 β-lactams or aminoglycosides in the empirical treatment of early-onset VAP. However, further larger studies are warranted to investigate its efficacy.

References

  1. 1.
    Barcenilla F, Gasco E, Rello J, et al. Antibacterial treatment of invasive mechanical ventilation-associated pneumonia. Drags Aging 2001; 18(3): 189–200CrossRefGoogle Scholar
  2. 2.
    Luna CM, Vujacich P, Niederman MS, et al. Impact of BAL data on the therapy and outcome of ventilator-associated pneumonia. Chest 1997; 111(3): 676–85PubMedCrossRefGoogle Scholar
  3. 3.
    Alvarez-Lerma F. Modification of empiric antibiotic treatment in patients with pneumonia acquired in the intensive care unit. ICU-Acquired Pneumonia Study Group. Intensive Care Med 1996; 22(5): 387–94PubMedCrossRefGoogle Scholar
  4. 4.
    Kirton OC, DeHaven B, Morgan J, et al. A prospective, randomized comparison of an in-line heat moisture exchange filter and heated wire humidifiers: rates of ventilator-associated early-onset (community-acquired) or late-onset (hospital-acquired) pneumonia and incidence of endotracheal tube occlusion. Chest 1997; 112(4): 1055–9PubMedCrossRefGoogle Scholar
  5. 5.
    Rello J, Ausina V, Ricart M, et al. Impact of previous antimicrobial therapy on the etiology and outcome of ventilator-associated pneumonia. Chest 1993; 104(4): 1230–5PubMedCrossRefGoogle Scholar
  6. 6.
    Rello J, Torres A, Ricart M, et al. Ventilator-associated pneumonia by Staphylococcus aureus: comparison of methicillin-resistant and methicillin-sensitive episodes. Am J Respir Crit Care Med 1994; 150(6 Pt 1): 1545–9PubMedGoogle Scholar
  7. 7.
    Ewig S, Torres A, El-Ebiary M, et al. Bacterial colonization patterns in mechanically ventilated patients with traumatic and medical head injury: incidence, risk factors, and association with ventilator-associated pneumonia. Am J Respir Crit Care Med 1999; 159(1): 188–98PubMedGoogle Scholar
  8. 8.
    American Thoracic Society. Hospital-acquired pneumonia in adults: diagnosis, assessment of severity, initial antimicrobial therapy, and preventive strategies: a consensus statement, American Thoracic Society, 1995 Nov. Am J Respir Crit Care Med 1996; 153(5): 1711–25Google Scholar
  9. 9.
    Langtry HD, Lamb HM. Levofloxacin. Its use in infections of the respiratory tract, skin, soft tissues and urinary tract. Drags 1998; 56(3): 487–515CrossRefGoogle Scholar
  10. 10.
    Pea F, Furlanut M. Pharmacokinetic aspects of treating infections in the intensive care unit: focus on drag interactions. Clin Pharmacokinet 2001; 40(11): 833–68PubMedCrossRefGoogle Scholar
  11. 11.
    Pugin J, Auckenthaler R, Mili N, et al. Diagnosis of ventilator-associated pneumonia by bacteriologic analysis of bronchoscopic and nonbronchoscopic ‘blind’ bronchoalveolar lavage fluid. Am Rev Respir Dis 1991; 143(5 Pt 1): 1121–9PubMedGoogle Scholar
  12. 12.
    Acar JF, Goldstein FW. Disk susceptibility test. In: Lorian V, editor. Antibiotics in laboratory medicine. Baltimore: Williams & Wilkins, 1996: 1–51Google Scholar
  13. 13.
    Comaglia G, Ligozzi M, Mazzariol A, et al. Rapid increase of resistance to erythromycin and clindamycin in Streptococcus pyogenes in Italy, 1993-1995. The Italian Surveillance Group for Antimicrobial Resistance. Emerg Infect Dis 1996; 2(4): 339–42CrossRefGoogle Scholar
  14. 14.
    Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16(1): 31–41PubMedCrossRefGoogle Scholar
  15. 15.
    Wong FA, Juzwin SJ, Flor SC. Rapid stereospecific high-performance liquid Chromatographie determination of levofloxacin in human plasma and urine. J Pharm Biomed Anal 1997; 15(6): 765–71PubMedCrossRefGoogle Scholar
  16. 16.
    Mack G. Improved high-performance liquid chromatographic determination of ciprofloxacin and its metabolites in human specimens. J Chromatogr 1992; 582(1–2): 263–7PubMedGoogle Scholar
  17. 17.
    Scotton PG, Pea F, Giobbia M, et al. Cerebrospinal fluid penetration of levofloxacin in patients with spontaneous acute bacterial meningitis. Clin Infect Dis 2001; 33(9): e109–11PubMedCrossRefGoogle Scholar
  18. 18.
    Fish DN, Chow AT. The clinical pharmacokinetics of levofloxacin. Clin Pharmacokinet 1997; 32(2): 101–19PubMedCrossRefGoogle Scholar
  19. 19.
    Aminimanizani A, Beringer P, Jelliffe R. Comparative pharmacokinetics and pharmacodynamics of the newer fluoroquinolone antibacterials. Clin Pharmacokinet 2001; 40(3): 169–87PubMedCrossRefGoogle Scholar
  20. 20.
    Blaser J, Stone BB, Groner MC, et al. Comparative study with enoxacin and netilmicin in a pharmacodynamic model to determine importance of ratio of antibiotic peak concentration to MIC for bactericidal activity and emergence of resistance. Antimicrob Agents Chemother 1987; 31(7): 1054–60PubMedCrossRefGoogle Scholar
  21. 21.
    Forrest A, Nix DE, Ballow CH, et al. Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. Antimicrob Agents Chemother 1993; 37(5): 1073–81PubMedCrossRefGoogle Scholar
  22. 22.
    Preston SL, Drusano GL, Berman AL, et al. Pharmacodynamics of levofloxacin: a new paradigm for early clinical trials. JAMA 1998; 279(2): 125–9PubMedCrossRefGoogle Scholar
  23. 23.
    Chien SC, Rogge MC, Gisclon LG, et al. Pharmacokinetic profile of levofloxacin following once-daily 500-milligram oral or intravenous doses. Antimicrob Agents Chemother 1997; 41(10): 2256–60PubMedGoogle Scholar
  24. 24.
    Chien SC, Wong FA, Fowler CL, et al. Double-blind evaluation of the safety and pharmacokinetics of multiple oral once-daily 750-milligram and 1-gram doses of levofloxacin in healthy volunteers. Antimicrob Agents Chemother 1998; 42(4): 885–8PubMedGoogle Scholar
  25. 25.
    Robert S, Zarowitz BJ, Peterson EL, et al. Predictability of creatinine clearance estimates in critically ill patients. Crit Care Med 1993; 21(10): 1487–95PubMedCrossRefGoogle Scholar
  26. 26.
    Benmalek F, Behforouz N, Benoist JF, et al. Renal effects of low-dose dopamine during vasopressor therapy for posttraumatic intracranial hypertension. Intensive Care Med 1999; 25(4): 399–405PubMedCrossRefGoogle Scholar
  27. 27.
    Pea F, Porreca L, Baraldo M, et al. High vancomycin dosage regimens required by intensive care unit patients cotreated with drugs to improve haemodynamics following cardiac surgical procedures. J Antimicrob Chemother 2000; 45(3): 329–35PubMedCrossRefGoogle Scholar
  28. 28.
    Lang F. Osmotic diuresis. Ren Physiol 1987; 10(3–4): 160–73PubMedGoogle Scholar
  29. 29.
    Koren G, Klein J, Bentur Y, et al. The effects of mannitol diuresis on digoxin and phenobarbital handling by the kidney: implications for tubular reabsorption and secretion of the cardiac glycoside. Clin Invest Med 1989; 12(5): 279–84PubMedGoogle Scholar
  30. 30.
    Preston SL, Drusano GL, Berman AL, et al. Levofloxacin population pharmacokinetics and creation of a demographic model for prediction of individual drug clearance in patients with serious community-acquired infection. Antimicrob Agents Chemother 1998; 42(5): 1098–104PubMedGoogle Scholar
  31. 31.
    Turnidge J. Pharmacokinetics and pharmacodynamics of fluoroquinolones. Drugs 1999; 58 Suppl. 2: 29–36PubMedCrossRefGoogle Scholar
  32. 32.
    Lister PD, Sanders CC. Pharmacodynamics of levofloxacin and ciprofloxacin against Streptococcus pneumoniae. J Antimicrob Chemother 1999; 43(1): 79–86PubMedCrossRefGoogle Scholar
  33. 33.
    Lister PD, Sanders CC. Pharmacodynamics of trovafloxacin, ofloxacin, and ciprofloxacin against Streptococcus pneumoniae in an in vitro pharmacokinetic model. Antimicrob Agents Chemother 1999; 43(5): 1118–23PubMedGoogle Scholar
  34. 34.
    Hershberger E, Rybak MJ. Activities of trovafloxacin, gatifloxacin, clinafloxacin, sparfloxacin, levofloxacin, and ciprofloxacin against penicillin-resistant Streptococcus pneumoniae in an in vitro infection model. Antimicrob Agents Chemother 2000; 44(3): 598–601PubMedCrossRefGoogle Scholar
  35. 35.
    Wright DH, Brown GH, Peterson ML, et al. Application of fluoroquinolone pharmacodynamics. J Antimicrob Chemother 2000; 46(5): 669–83PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2003

Authors and Affiliations

  • Federico Pea
    • 1
  • Elena Di Qual
    • 1
  • Aldo Cusenza
    • 2
  • Loris Brollo
    • 1
  • Marco Baldassarre
    • 2
  • Mario Furlanut
    • 1
  1. 1.Department of Experimental and Clinical Pathology and Medicine, Medical School, Institute of Clinical Pharmacology and ToxicologyUniversity of UdineUdineItaly
  2. 2.First Department of Anaesthesia and Intensive Care UnitS. M. Misericordia HospitalUdineItaly

Personalised recommendations