Pharmacokinetics of Telavancin in Adult Patients with Cystic Fibrosis During Acute Pulmonary Exacerbation
Adults with CF frequently harbor Staphylococcus aureus , which is increasingly antibiotic-resistant. Telavancin is a once daily rapidly bactericidal antibiotic active against methicillin-, linezolid- and ceftaroline-resistant S. aureus Because CF patients experience alterations in pharmacokinetics, the optimal dose of telavancin in this population is unknown. Adult CF patients (N=18) admitted for exacerbations received 3 doses of telavancin 7.5 mg/kg (first 6 patients) or 10 mg/kg (final 12 patients) every 24 h (q24h). Population pharmacokinetic models with and without covariates were fit using the nonparametric adaptive grid algorithm in Pmetrics. The final model was used to perform 5000-patient Monte Carlo simulations for multiple telavancin doses. The best fit was a 2-compartment model describing V c as a multiple of total body weight normalized by the median observed value (Vc=Vθ*TBW/52.1) and CL as a linear function of creatinine clearance (CL = CL NR + CL θ *CRCL). Mean population parameters were: V θ , 4.92±0.76 L*kg -1 ; CL NR , 0.59±0.30 L*h -1 ; CL θ , 5.97*10 -3 ±1.24*10 -3 ; V p , 3.77±1.41 L; and Q, 4.08±2.17 L*h -1 f AUC for 7.5 and 10 mg/kg was 30±4.6 and 52±12 mg*h/L, respectively. Doses of 7.5 mg/kg and 10 mg/kg achieved 76.5% and 100% probability of target attainment (PTA) at a f AUC/MIC threshold>215, respectively, for MIC ≤0.12 mg/L. The probabilities of reaching the acute kidney injury (AKI) threshold AUC (763 mg*h*L -1 ) for these doses were 0% and 0.96%, respectively. No serious adverse events occurred. Telavancin 10 mg/kg yielded optimal PTA and minimal risk of AKI, suggesting this FDA-approved dose is appropriate to treat acute pulmonary exacerbations CF adults.