Levofloxacin pharmacokinetics in adult cystic fibrosis.
BACKGROUND
Cystic fibrosis (CF) patients have enhanced renal clearance of aminoglycosides and several beta-lactams and require higher dosages. Levofloxacin is a fluoroquinolone with extensive renal elimination and enhanced penetration into lungs and Pseudomonas aeruginosa (PA) biofilms. We studied the preliminary pharmacokinetic and pharmacodynamic (PK/PD) relationship of levofloxacin in CF.


METHODS
Twelve patients at least 18 years old with a mild-to-moderate pulmonary exacerbation and fluoroquinolone-sensitive PA colonization received oral levofloxacin, 500 mg qd, for 14 days. Steady-state serum concentrations were collected after 3 to 7 days, and sputum samples for PA densities were collected before and after levofloxacin. PK/PD relationships for reducing PA sputum densities were evaluated.


RESULTS
When compared to published data on non-CF patients, CF patients had similar area under the curve for 24 h (AUC(24)), total clearance, volume of distribution, maximum serum concentration (Cpmax), and elimination half-life: mean, 7.33 microg x h/mL/kg (SD, 1.70); 2.43 mL/min/kg (SD, 0.74); 1.33 L/kg (SD, 0.37); 7.06 microg/mL (SD, 2.35); and 6.44 h (SD, 1.1), respectively. Time to reach maximum serum concentration (Tmax) in CF was longer: mean, 2.20 h (SD, 0.99) vs 1.1 h (SD, 0.4) [p < 0.01]. Preliminary PK/PD analysis failed to demonstrate trends for decreasing PA sputum densities with increasing Cpmax/minimum inhibitory concentration (MIC) ratio and AUC(24)/MIC ratio.


CONCLUSIONS
CF levofloxacin pharmacokinetics corrected for body weight are similar to non-CF, except for Tmax. Standard levofloxacin dosing (especially monotherapy) is unlikely to produce maximum therapeutic effectiveness. Additional levofloxacin studies in CF are necessary to evaluate its sputum concentrations; the benefits of higher daily dosages (>/= 750 mg); and establish PK/PD targets for managing PA pulmonary infections.
Lee
Carlton K K
CKK
Departments of Pediatrics, Johns Hopkins University. Electronic address: cleea@jhmi.edu.
Boyle
Michael P
MP
Medicine, Johns Hopkins University.
Diener-West
Marie
M
Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD.
Brass-Ernst
Lois
L
Departments of Pediatrics, Johns Hopkins University.
Noschese
Michelle
M
Medicine, Johns Hopkins University.
Zeitlin
Pamela L
PL
Departments of Pediatrics, Johns Hopkins University.
D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003550:Cystic Fibrosis / Q000097:blood* / Q000188:drug therapy; D005260:Female; D006801:Humans; D007677:Kidney Function Tests; D064704:Levofloxacin; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D015242:Ofloxacin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018410:Pneumonia, Bacterial / Q000097:blood* / Q000188:drug therapy; D011552:Pseudomonas Infections / Q000097:blood* / Q000188:drug therapy; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013183:Sputum / Q000382:microbiology
D000900:Anti-Bacterial Agents; D064704:Levofloxacin; D015242:Ofloxacin