Cefepime free minimum concentration to minimum inhibitory concentration (fC_min/MIC) ratio predicts clinical failure in patients with Gram-negative bacterial pneumonia

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 (fC_min) to MIC ratio for each patient was determined by conditioning the validated pharmacokinetic model using patient-specific creatinine clearance (CL_Cr), 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. CL_Cr and cefepime C_min in the 12 patients were 87.5 ± 21.2 mL/min and 6.2 ± 3.8 mg/L, respectively. In comparison, the C_min predicted by the pharmacokinetic model was 5.8 mg/L using a CL_Cr of 90 mL/min. MICs of organisms ranged from 0.5 mg/L to 8 mg/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 fC_min/MIC ≥ 2.1 had a significantly lower risk of clinical failure (OR = 0.11, 95% CI 0.02-0.67; P = 0.017). The fC_min/MIC ratio is a useful predictor of clinical failure in Gram-negative bacterial pneumonia. The clinical utility of fC_min/MIC in therapeutic drug monitoring should be further explored.