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 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.

The role of tazobactam‐based combinations for the management of infections due to extended‐spectrum β‐lactamase‐producing Enterobacterales: Insights from the Society of Infectious Diseases Pharmacists

Extended‐spectrum β‐lactamase (ESBL)‐producing Enterobacterales are a global threat to public health due to their antimicrobial resistance profile and, consequently, their limited available treatment options. Tazobactam is a sulfone β‐lactamase inhibitor with in vitro inhibitory activity against common ESBLs in Enterobacterales, including CTX‐M. However, the role of tazobactam‐based combinations in treating infections caused by ESBL‐producing Enterobacterales remains unclear. In the United States, two tazobactam‐based combinations are available, piperacillin‐tazobactam and ceftolozane‐tazobactam. We evaluated and compared the roles of tazobactam‐based combinations against ESBL‐producing organisms with emphasis on pharmacokinetic/pharmacodynamic exposures in relation to MIC distributions and established breakpoints, clinical outcomes data specific to infection site, and considerations for downstream effects with these agents regarding antimicrobial resistance development. While limited data with ceftolozane‐tazobactam are encouraging for its potential role in infections due to ESBL‐producing Enterobacterales, further evidence is needed to determine its place in therapy. Conversely, currently available microbiologic, pharmacokinetic, pharmacodynamic, and clinical data do not suggest a role for piperacillin‐tazobactam, and we caution clinicians against its usage for these infections.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/170903/1/phar2623.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/170903/2/phar2623_am.pd

Nafcillin versus cefazolin for the treatment of methicillin-susceptible Staphylococcus aureus bacteremia

Background: Anti-staphylococcal penicillins have long been the first-line treatment option for methicillin-susceptible Staphylococcus aureus (MSSA) infections. Recent retrospective data comparing nafcillin and cefazolin report similar clinical efficacy despite concerns about high inoculum MSSA infections. Methods: This was a retrospective, non-inferiority, cohort study comparing treatment failure rates between nafcillin and cefazolin in patients with MSSA bacteremia from any source, other than meningitis. Multiple logistic regression was used to adjust for confounding variables. Results: A total of 142 patients were included in the study. The overall treatment failure rate among patients receiving cefazolin was non-inferior to nafcillin (11.3% versus 8.5%; 90% confidence interval −5.2% to 10.8%). Rates of adverse drug events were significantly higher in the nafcillin arm (19.7% versus 7%; p = 0.046). After adjustment for confounding variables, no difference between treatment groups was found in treatment failure (adjusted odds ratio (OR) = 1.2; 95% CI, 0.3–4.5), but nafcillin was associated with significantly higher nephrotoxicity (adjusted odds ratio (OR) = 5.4; 95% CI, 1.1–26.8). Conclusion: Cefazolin was associated with lower nephrotoxicity and similar treatment failure rates compared to nafcillin suggesting that cefazolin is an appealing first line agent for most MSSA bloodstream infections. Keywords: Nafcillin, Cefazolin, Methicillin-susceptible Staphylococcus aureus, MSSA, Bacteremi

Population Pharmacokinetics and Safety of Ceftolozane-Tazobactam in Adult Cystic Fibrosis Patients Admitted with Acute Pulmonary Exacerbation

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 (V(c)) were lower than those for adults without CF (ceftolozane CF V(c), 7.51 ± 2.05 liters; tazobactam CF V(c), 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.