title: Cefepime free minimum concentration to minimum inhibitory concentration (fCmin/MIC) ratio predicts clinical failure in patients with Gram-negative bacterial pneumonia.
abstract: Cefepime is an antibiotic commonly used in nosocomial infections. The objective of this study was to elucidate the relationship between cefepime exposure and clinical outcome in patients with Gram-negative bacterial pneumonia. A previously published population pharmacokinetic model of cefepime was validated in 12 adult patients with normal renal function by measuring plasma concentrations at steady-state. Additionally, clinical outcomes for 33 patients with Gram-negative bacterial pneumonia who received cefepime monotherapy were determined. The free minimum concentration (fCmin) to MIC ratio for each patient was determined by conditioning the validated pharmacokinetic model using patient-specific creatinine clearance (CLCr), dosing regimen and cefepime MIC of the organism isolated, and was subsequently correlated with clinical failure. Classification and regression tree (CART) analysis was used to determine the most significant drug exposure breakpoint. Mean±S.D. CLCr and cefepime Cmin in the 12 patients were 87.5±21.2mL/min and 6.2±3.8mg/L, respectively. In comparison, the Cmin predicted by the pharmacokinetic model was 5.8mg/L using a CLCr of 90mL/min. MICs of organisms ranged from 0.5mg/L to 8mg/L. Percent time free drug above MIC of 100% was achieved in 32/33 patients, but 12 patients experienced clinical failure. CART analysis determined patients with an fCmin/MIC≥2.1 had a significantly lower risk of clinical failure (OR=0.11, 95% CI 0.02-0.67; P=0.017). The fCmin/MIC ratio is a useful predictor of clinical failure in Gram-negative bacterial pneumonia. The clinical utility of fCmin/MIC in therapeutic drug monitoring should be further explored.
authors: Department of Clinical Sciences and Administration, University of Houston College of Pharmacy, 1441 Moursund Street, Houston, TX 77030, USA.
authors: Samuel L
authors: SL
authors: Aitken
authors: Department of Pharmacy, Memorial Hermann-Texas Medical Center, 6411 Fannin Street, Houston, TX 77030, USA.
authors: Jerry
authors: J
authors: Altshuler
authors: Department of Pharmacy, Memorial Hermann-Texas Medical Center, 6411 Fannin Street, Houston, TX 77030, USA.
authors: David J
authors: DJ
authors: Guervil
authors: Department of Clinical Sciences and Administration, University of Houston College of Pharmacy, 1441 Moursund Street, Houston, TX 77030, USA.
authors: Elizabeth B
authors: EB
authors: Hirsch
authors: Division of Infectious Diseases, Memorial Hermann-Texas Medical Center, 6411 Fannin Street, Houston, TX 77030, USA; Division of Infectious Diseases, University of Texas Health Science Center at Houston, 7000 Fannin Street, Houston, TX 77030, USA.
authors: Luis L
authors: LL
authors: Ostrosky-Zeichner
authors: Division of Infectious Diseases, Memorial Hermann-Texas Medical Center, 6411 Fannin Street, Houston, TX 77030, USA; Division of Infectious Diseases, University of Texas Health Science Center at Houston, 7000 Fannin Street, Houston, TX 77030, USA.
authors: Charles D
authors: CD
authors: Ericsson
authors: Department of Clinical Sciences and Administration, University of Houston College of Pharmacy, 1441 Moursund Street, Houston, TX 77030, USA. Electronic address: vtam@uh.edu.
authors: Vincent H
authors: VH
authors: Tam
mesh_terms: D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D000077723:Cefepime; D002511:Cephalosporins / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D003404:Creatinine / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry*; D018410:Pneumonia, Bacterial / Q000188:drug therapy* / Q000382:microbiology; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D000077723:Cefepime; D003404:Creatinine
keywords: Acinetobacter; Clinical outcomes; Pharmacodynamics; Pharmacokinetics; Pseudomonas