Levofloxacin Dosing Regimen in Severely Morbidly Obese Patients (BMI ≥40 kg/m2) Should Be Guided by Creatinine Clearance Estimates Based on Ideal Body Weight and Optimized by Therapeutic Drug Monitoring

Abstract

Levofloxacin is a commonly prescribed antimicrobial where recommendations exist to reduce doses for renal impairment but not to increase doses for augmented renal function. Morbidly obese patients are increasing in prevalence, and represent a population that can have augmented renal function requiring higher-than-standard doses. The current investigation was performed to characterize the pharmacokinetics (PK) and evaluate the influence of alternate body size descriptors and renal function as predictors of levofloxacin clearance (CL) and the area under the curve over 24h (AUC24). A database of patients undergoing levofloxacin therapeutic drug monitoring (TDM) were queried to identify patients ≥18years of age with a body mass index ≥40kg/m(2). A maximum a posteriori probability Bayesian approach using a two-compartment linear PK model was used to estimate individual PK parameters and AUC24. A total of 394 concentration-time data points (peaks and trough) from 68 patients between 98 and 250kg were evaluated. The median (5th, 95th percentile) daily dose and AUC24 was 1,000 (250, 1,500) mg and 90.7 (44.4, 228) mg·h/L, respectively. Levofloxacin CL was significantly (p<0.05) related to height but not weight. As a result, levofloxacin CL was best related (R (2)=0.57) to creatinine CL (CLcr) estimated by the Cockcroft-Gault (CG) equation and ideal body weight (IBW) because IBW is a height transformation. An empiric four-category daily-dose regimen (500, 750, 1,000, 1,250mg) stratified by CLcr (CG-IBW) is expected to have >90% probability of achieving an AUC24 of 50-150mg·h/L in morbidly obese patients. Subsequent application of TDM and integration with pathogen-specific information could then be applied to tailor the levofloxacin regimen. The proposed approach serves as a relevant alternative to the current fixed-dosing paradigm of levofloxacin in the morbidly obese.