title: Population Pharmacokinetics and Safety of Ceftolozane-Tazobactam in Adult Cystic Fibrosis Patients Admitted with Acute Pulmonary Exacerbation.
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.affiliation: Center for Anti-Infective Research & Development, Hartford Hospital, Hartford, Connecticut, USA.
authors.forename: Marguerite L
authors.initials: ML
authors.lastname: Monogue
authors.affiliation: Riley Hospital for Children, Indianapolis, Indiana, USA.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Pettit
authors.affiliation: University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Marianne
authors.initials: M
authors.lastname: Muhlebach
authors.affiliation: St. Christopher's Hospital for Children, Philadelphia, Pennsylvania, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Cies
authors.affiliation: Center for Anti-Infective Research & Development, Hartford Hospital, Hartford, Connecticut, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
authors.affiliation: Center for Anti-Infective Research & Development, Hartford Hospital, Hartford, Connecticut, USA joseph.kuti@hhchealth.org.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Kuti
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics*; D002511:Cephalosporins / Q000097:blood / Q000493:pharmacokinetics*; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000382:microbiology; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008168:Lung / Q000187:drug effects / Q000382:microbiology; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009010:Monte Carlo Method; D061214:Patient Safety; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D018410:Pneumonia, Bacterial / Q000188:drug therapy* / Q000382:microbiology; D011446:Prospective Studies; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000254:growth & development; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D000078142:Tazobactam
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; C000594038:ceftolozane, tazobactam drug combination; D010397:Penicillanic Acid; D000078142:Tazobactam