Case Report Provides New Insights on Dosing of Novel Drug for Patients with Cystic Fibrosis

Ceftolozane/tazobactam is safe, effective, and well-tolerated in the treatment of multidrug-resistant Pseudomonas aeruginosa infection (MDR-PSA)—even in a post-lung transplant patient with pulmonary exacerbation complicated by comorbid cystic fibrosis, malnutrition, and chronic kidney disease.

At least this was the conclusion of a case report published online recently in the journal Respiratory Medicine Case Reports. The report, which also offers insights into the pharmacokinetics-pharmacodynamics of the novel second-generation β-lactam/β-lactamase inhibitor while also recommending a framework for dosing, will be published in the print edition of the journal in 2018.

According to data provided by the authors, nearly 10% of all adult cystic fibrosis patients are infected with MDR-PSA. Ceftolozane/tazobactam has been approved by the US Food and Drug Administration for the treatment of complicated intra-abdominal and urinary tract infections.

The 35-year-old female described in the case report originally presented to the authors, who work in the Division of Pulmonary and Critical Care Medicine at Maine Medical Center in Portland, with cystic fibrosis (homozygous for the F508del mutation) and chronic MDR-PSA infection. She also had undergone a living-donor lung transplant 17 years earlier, had cystic fibrosis-related diabetes and calcineurin-associated chronic kidney disease (estimated creatinine clearance of 40 to 50 mL/min), and had been diagnosed with hypertension. Her MDR-PSA infection was treated previously with ciprofloxacin/piperacillin-tazobactam and with meropenem, to limited effect. At the time of presentation, her Akron pulmonary exacerbation score was 13 (up from 9) and her 6-min walk distance was 1020 feet (down from 1400 feet). Her serum C-reactive protein was 62 mg/L.

Following their initial evaluation, the authors administered ceftolozane/tazobactam at a dose of 2000 mg/1000 mg intravenous (IV) q12h, adopting the initial dose from a clinical trial in which the drug was used to treat nosocomial pneumonia in mechanically ventilated patients. In subsequent blood samples from the patient, they found that steady state 1-h post-infusion peak concentration was 174.1 μg/mL for ceftolozane, while ceftolozane steady-state volume of distribution, half-life, and minimum concentration were 11.5 liters, 2.3 hours, and 9.2 μg/mL, respectively; tazobactam half-life was 2.1 hours.

In subsequent susceptibility testing performed on 2 PSA isolates from a sputum sample collected prior to treatment initiation, minimum inhibitory concentrations were 2.00/4.00 μg/mL and 0.5/0.25 μg/mL for ceftolozane and tazobactam, respectively, while trough tissue concentrations were estimated at 5.4 and 0.8 μg/mL, respectively. The patient remained on the novel regimen without any significant side effects or complications, and she reported: “significant improvement” in sputum production as well as reduced fatigue and dyspnea. Her C-reactive protein fell to <1.0 mg/L.

The authors did not respond to requests for comment. However, in their concluding remarks, they noted, “To our knowledge, this is… the first [report] to describe the pharmacokinetics of [ceftolozane/tazobactam] in a [cystic fibrosis] patient with renal insufficiency. Published pharmacokinetic-pharmacodynamic data are currently sparse, and it was unclear how this limited information would apply to a patient with… chronic kidney disease, and concomitant use of immunosuppressive medications… The serum concentrations of ceftolozane obtained from our patient may provide a basis for estimating appropriate dosing regimens for [cystic fibrosis] patients with similar characteristics.”

Brian P. Dunleavy is a medical writer and editor based in New York. His work has appeared in numerous healthcare-related publications. He is the former editor of Infectious Disease Special Edition.