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Population Pharmacokinetics and Safety of Ceftolozane-Tazobactam in Adult Cystic Fibrosis Patients Admitted with Acute Pulmonary Exacerbation.
Antimicrob Agents Chemother. 2016 11; 60(11):6578-6584.AA

Abstract

Ceftolozane-tazobactam has potent activity against Pseudomonas aeruginosa, a pathogen associated with cystic fibrosis (CF) acute pulmonary exacerbations (APE). Due to the rapid elimination of many antibiotics, CF patients frequently have altered pharmacokinetics. In this multicenter, open-label study, we described the population pharmacokinetics and safety of ceftolozane-tazobactam at 3 g every 8 h (q8h) in 20 adult CF patients admitted with APE. Population pharmacokinetics were determined using the nonparametric adaptive grid program in Pmetrics for R. A 5,000-patient Monte Carlo simulation was performed to determine the probability of target attainment (PTA) for the ceftolozane component at 1.5 g and 3 g of ceftolozane-tazobactam q8h across a range of MICs using a primary threshold exposure of 60% free time above the MIC (fT>MIC). In these 20 adult CF patients, ceftolozane and tazobactam concentration data were best described by 2-compartment models, and ceftolozane clearance (CL) was significantly correlated with creatinine clearance (r = 0.71, P < 0.001). These data suggest that ceftolozane and tazobactam clearance estimates in CF patients are similar to those in adults without CF (ceftolozane CF CL, 4.76 ± 1.13 liter/h; tazobactam CF CL, 20.51 ± 4.41 liter/h). However, estimates of the volume of the central compartment (Vc) were lower than those for adults without CF (ceftolozane CF Vc, 7.51 ± 2.05 liters; tazobactam CF Vc, 7.85 ± 2.66 liters). Using a threshold of 60% fT>MIC, ceftolozane-tazobactam regimens of 1.5 g and 3 g q8h should achieve PTAs of ≥90% at MICs up to 4 and 8 μg/ml, respectively. Ceftolozane-tazobactam at 3 g q8h was well tolerated. These observations support additional studies of ceftolozane-tazobactam for Pseudomonas aeruginosa APE in CF patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02421120.).

Authors+Show Affiliations

Center for Anti-Infective Research & Development, Hartford Hospital, Hartford, Connecticut, USA.Riley Hospital for Children, Indianapolis, Indiana, USA.University of North Carolina, Chapel Hill, North Carolina, USA.St. Christopher's Hospital for Children, Philadelphia, Pennsylvania, USA.Center for Anti-Infective Research & Development, Hartford Hospital, Hartford, Connecticut, USA.Center for Anti-Infective Research & Development, Hartford Hospital, Hartford, Connecticut, USA joseph.kuti@hhchealth.org.

Pub Type(s)

Clinical Trial
Journal Article
Multicenter Study

Language

eng

PubMed ID

27550351

Citation

Monogue, Marguerite L., et al. "Population Pharmacokinetics and Safety of Ceftolozane-Tazobactam in Adult Cystic Fibrosis Patients Admitted With Acute Pulmonary Exacerbation." Antimicrobial Agents and Chemotherapy, vol. 60, no. 11, 2016, pp. 6578-6584.
Monogue ML, Pettit RS, Muhlebach M, et al. Population Pharmacokinetics and Safety of Ceftolozane-Tazobactam in Adult Cystic Fibrosis Patients Admitted with Acute Pulmonary Exacerbation. Antimicrob Agents Chemother. 2016;60(11):6578-6584.
Monogue, M. L., Pettit, R. S., Muhlebach, M., Cies, J. J., Nicolau, D. P., & Kuti, J. L. (2016). Population Pharmacokinetics and Safety of Ceftolozane-Tazobactam in Adult Cystic Fibrosis Patients Admitted with Acute Pulmonary Exacerbation. Antimicrobial Agents and Chemotherapy, 60(11), 6578-6584. https://doi.org/10.1128/AAC.01566-16
Monogue ML, et al. Population Pharmacokinetics and Safety of Ceftolozane-Tazobactam in Adult Cystic Fibrosis Patients Admitted With Acute Pulmonary Exacerbation. Antimicrob Agents Chemother. 2016;60(11):6578-6584. PubMed PMID: 27550351.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Population Pharmacokinetics and Safety of Ceftolozane-Tazobactam in Adult Cystic Fibrosis Patients Admitted with Acute Pulmonary Exacerbation. AU - Monogue,Marguerite L, AU - Pettit,Rebecca S, AU - Muhlebach,Marianne, AU - Cies,Jeffrey J, AU - Nicolau,David P, AU - Kuti,Joseph L, Y1 - 2016/10/21/ PY - 2016/07/18/received PY - 2016/08/13/accepted PY - 2016/8/24/pubmed PY - 2017/8/18/medline PY - 2016/8/24/entrez SP - 6578 EP - 6584 JF - Antimicrobial agents and chemotherapy JO - Antimicrob Agents Chemother VL - 60 IS - 11 N2 - Ceftolozane-tazobactam has potent activity against Pseudomonas aeruginosa, a pathogen associated with cystic fibrosis (CF) acute pulmonary exacerbations (APE). Due to the rapid elimination of many antibiotics, CF patients frequently have altered pharmacokinetics. In this multicenter, open-label study, we described the population pharmacokinetics and safety of ceftolozane-tazobactam at 3 g every 8 h (q8h) in 20 adult CF patients admitted with APE. Population pharmacokinetics were determined using the nonparametric adaptive grid program in Pmetrics for R. A 5,000-patient Monte Carlo simulation was performed to determine the probability of target attainment (PTA) for the ceftolozane component at 1.5 g and 3 g of ceftolozane-tazobactam q8h across a range of MICs using a primary threshold exposure of 60% free time above the MIC (fT>MIC). In these 20 adult CF patients, ceftolozane and tazobactam concentration data were best described by 2-compartment models, and ceftolozane clearance (CL) was significantly correlated with creatinine clearance (r = 0.71, P < 0.001). These data suggest that ceftolozane and tazobactam clearance estimates in CF patients are similar to those in adults without CF (ceftolozane CF CL, 4.76 ± 1.13 liter/h; tazobactam CF CL, 20.51 ± 4.41 liter/h). However, estimates of the volume of the central compartment (Vc) were lower than those for adults without CF (ceftolozane CF Vc, 7.51 ± 2.05 liters; tazobactam CF Vc, 7.85 ± 2.66 liters). Using a threshold of 60% fT>MIC, ceftolozane-tazobactam regimens of 1.5 g and 3 g q8h should achieve PTAs of ≥90% at MICs up to 4 and 8 μg/ml, respectively. Ceftolozane-tazobactam at 3 g q8h was well tolerated. These observations support additional studies of ceftolozane-tazobactam for Pseudomonas aeruginosa APE in CF patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02421120.). SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/27550351/Population_Pharmacokinetics_and_Safety_of_Ceftolozane_Tazobactam_in_Adult_Cystic_Fibrosis_Patients_Admitted_with_Acute_Pulmonary_Exacerbation_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&amp;pmid=27550351 DB - PRIME DP - Unbound Medicine ER -