title: Population Pharmacokinetics and Pharmacodynamics of Levofloxacin in Acutely Hospitalized Older Patients with Various Degrees of Renal Function.
abstract: A retrospective study was conducted in a large sample of acutely hospitalized older patients who underwent therapeutic drug monitoring during levofloxacin treatment. The aim was to assess the population pharmacokinetics (popPK) and pharmacodynamics of levofloxacin among older patients. PopPK and Monte Carlo simulation were performed to define the permissible doses in older patients according to various degrees of renal function. Classification and regression tree (CART) analysis was used to detect the cutoff 24-hour area under the concentration-time curve (AUC24)/MIC ratio that best correlated with the clinical outcome. The probability of target attainment (PTA) of this value was calculated against different pathogens. A total of 168 patients were included, and 330 trough and 239 peak concentrations were used for the popPK analysis. Creatinine clearance (CrCL) was the only covariate that improved the model fit (levofloxacin CL = 0.399 + 0.051 × CrCLCKD-EPI[creatinine clearance estimated by means of the chronic kidney disease epidemiology]). Drug doses ranged between 500 mg every 48 h and 500 mg every 12 h in relation to different renal functions. The identified cutoff AUC24/MIC ratio (≥95.7) was the only covariate that correlated with a favorable clinical outcome in multivariate regression analysis (odds ratio [OR], 20.85; 95% confidence interval [CI], 1.56 to 186.73). PTAs were optimal (>80%) againstEscherichia coliandHaemophilus influenzae, borderline againstStaphylococcus aureus, and suboptimal againstPseudomonas aeruginosaThe levofloxacin doses defined in our study may be effective for the treatment of infections due to bacterial pathogens, with an MIC of ≤0.5 mg/liter in older patients with various degrees of renal function, while minimizing the toxicity risk. Conversely, the addition of another active antimicrobial should be considered whenever treating infections caused by less susceptible pathogens.
authors.affiliation: Institute of Clinical Pharmacology, Santa Maria della Misericordia University Hospital of Udine, Udine, Italy.|Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy.
authors.forename: Pier Giorgio
authors.initials: PG
authors.lastname: Cojutti
authors.affiliation: Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Virginia
authors.initials: V
authors.lastname: Ramos-Martin
authors.affiliation: First Division of Internal Medicine Santa Maria della Misericordia University Hospital of Udine, Udine, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Schiavon
authors.affiliation: First Division of Internal Medicine Santa Maria della Misericordia University Hospital of Udine, Udine, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Rossi
authors.affiliation: Institute of Clinical Pharmacology, Santa Maria della Misericordia University Hospital of Udine, Udine, Italy.|Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Baraldo
authors.affiliation: Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: William
authors.initials: W
authors.lastname: Hope
authors.affiliation: Institute of Clinical Pharmacology, Santa Maria della Misericordia University Hospital of Udine, Udine, Italy federico.pea@asuiud.sanita.fvg.it.|Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Pea
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001424:Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D001682:Biological Availability; D015992:Body Mass Index; D003404:Creatinine / Q000097:blood; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D016903:Drug Monitoring; D004926:Escherichia coli / Q000187:drug effects* / Q000254:growth & development; D005260:Female; D006193:Haemophilus influenzae / Q000187:drug effects* / Q000254:growth & development; D006760:Hospitalization; D006801:Humans; D007677:Kidney Function Tests; D064704:Levofloxacin / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008826:Microbial Sensitivity Tests; D015233:Models, Statistical; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000254:growth & development; D012189:Retrospective Studies; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development
chemical_list: D000900:Anti-Bacterial Agents; D064704:Levofloxacin; D003404:Creatinine
keywords: efficacy; fluoroquinolones; personalized therapy; population pharmacokinetics; safety