Pneumonia Patients on Ventilators May Benefit from New Ceftolozane/Tazobactam Antibiotics Interview with:

Dr. Elizabeth Rhee MD Director, Infectious Disease Clinical Research at Merck

Dr. Rhee

Dr. Elizabeth Rhee MD
Director, Infectious Disease Clinical Research Merck What is the background for this study? What are the main findings?

Response: High-risk patients, such as the critically ill, with suspected bacterial infections require prompt treatment with appropriate empiric therapy to improve survival. Given the high prevalence of multidrug-resistant (MDR) Pseudomonas aeruginosa in the ICU setting, new safe and broadly effective treatment options are needed for critically ill patients requiring antipseudomonal agents.

Ceftolozane/tazobactam (C/T) is an antipseudomonal cephalosporin/beta-lactamase inhibitor combination with broad in vitro activity against Gram-negative pathogens, including MDR P. aeruginosa and many extended-spectrum beta-lactamase (ESBL) producers. It is FDA approved for complicated intra-abdominal and urinary tract infections in adults at 1.5g (1g/0.5g) q8h. C/T is currently being studied at 3g (2g/1g) q8h, for the treatment of ventilated nosocomial pneumonia, in the ASPECT-NP Phase 3 trial.

This Phase 1 pharmacokinetic (PK) study investigated the penetration of a 3g dose of C/T in the epithelial lining fluid (ELF) of ventilated patients with proven or suspected pneumonia. This is the dose and patient population being evaluated in ASPECT-NP. ELF lines the alveoli, and investigators took samples in a group of 26 patients to see what amount of C/T was in the lung and what was circulating in the plasma during the dosing intervals.

In mechanically ventilated critically ill patients, the 3g dose of C/T achieved ≥50% lung penetration (relative to free plasma) and sustained levels in ELF above the target concentrations for the entire dosing interval. These findings support the 3g dose that is included in the ASPECT-NP Phase 3 trial. What should readers take away from your report?

Response: Critically ill patients often exhibit pathophysiological changes that can substantially affect antimicrobial pharmacokinetics and pharmacodynamics. Since efficacy depends on drug exposure at the infection site, it is imperative to determine the optimum dosing of new antibacterials in this high-risk patient population. Good intrapulmonary penetration in healthy volunteers has already been demonstrated with C/T; however, it was important to confirm this finding in critically ill patients with bacterial pneumonia.

This study is unusual in that it involved very ill patients. Typically, studies like this are done in healthy volunteers; this trial evaluated a patient population that is similar to the target patient population who will conceivably benefit from C/T treatment. What recommendations do you have for future research as a result of this work? 

Response: These results indicate that the 3g C/T regimen provides adequate plasma and ELF exposure from the initiation of therapy in ventilated patients with pneumonia and support use of this regimen in the ongoing ASPECT-NP nosocomial pneumonia trial ( NCT02070757). Is there anything else you would like to add? 

Response: Pseudomonas aeruginosa is one of a handful of bacterial strains that accounts for the majority of HABP/VABP infections – which can be serious and, in some cases, life-threatening. It is important to continue researching new treatments and optimal doses to give critically-ill patients the best chance of survival. 

Disclosures: Dr. Rhee is an employee of Merck & Co., Inc.


Lung Penetration and PK/PD Attainment in Pulmonary Epithelial Lining Fluid (ELF) Following 3g Administration of Ceftolozane/Tazobactam (C/T) to Ventilated, Critically-Ill Patients

Presented at the 28th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) in Madrid, April 21-24.

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Last Updated on May 10, 2018 by Marie Benz MD FAAD