Doripenem for treating nosocomial pneumonia and ventilator-associated pneumonia – Authors' reply

TY - JOUR

T1 - Doripenem for treating nosocomial pneumonia and ventilator-associated pneumonia – Authors' reply

AU - Kollef, Marin H.

AU - Réa-Neto, Álvaro

AU - Wunderink, Richard G.

AU - Bruno, Christopher J.

AU - Rhee, Elizabeth G.

N1 - Funding Information: Marin H Kollef a Álvaro Réa-Neto b Richard G Wunderink c Christopher J Bruno d Elizabeth G Rhee d [email protected] a Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St Louis, MO, USA Division of Pulmonary and Critical Care Medicine Washington University School of Medicine St Louis MO USA Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St Louis, MO, USA b Departamento de Clínica Médica, Universidade Federal do Paraná, Curitiba, Brazil Departamento de Clínica Médica Universidade Federal do Paraná Curitiba Brazil Departamento de Clínica Médica, Universidade Federal do Paraná, Curitiba, Brazil c Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Feinberg School of Medicine Northwestern University Chicago IL USA Feinberg School of Medicine, Northwestern University, Chicago, IL, USA d Merck & Co, Rahway, NJ 07065, USA Merck & Co, Rahway NJ 07065 USA Merck & Co, Rahway, NJ 07065, USA We thank Hung-Jen Tang and Chih-Cheng Lai for their interest in our Article. 1 Contemporary non-inferiority clinical trials of hospital-acquired pneumonia and ventilator-associated pneumonia assess two main efficacy endpoints: 28 day all-cause mortality and clinical response after the end of therapy. Although regulatory agencies differ in their preferred primary endpoint, it is crucial that results for all-cause mortality and clinical response are supportive of each other when evaluating new therapies for hospital-acquired and ventilator-associated pneumonia. The two initial trials of doripenem for hospital-acquired pneumonia and ventilator-associated pneumonia cited by Tang and Lai showed non-inferiority of doripenem compared with piperacillin–tazobactam and imipenem based on clinical response. 2,3 However, post-hoc analyses done as part of a regulatory review suggested potential mortality imbalances, favouring piperacillin–tazobactam and imipenem. 4 This finding led to a third clinical trial with doripenem in patients with confirmed ventilator-associated pneumonia; however, the trial was stopped early because of higher mortality and lower clinical response in the doripenem group. 5 Mortality was predominantly driven by pseudomonas infections, and outcomes were worse in patients with augmented renal clearance. As a result, doripenem was not approved for hospital-acquired pneumonia or ventilator-associated pneumonia in several countries (including the USA), whereas in others (including the European Economic Area) it was approved only for hospital-acquired pneumonia. Mechanically ventilated patients are generally critically ill, and thus might have augmented renal clearance or other factors affecting antimicrobial pharmacokinetics. 6 This can lead to insufficient drug concentrations at the infection site, compounded by the greater prevalence of pathogens with higher minimum inhibitory concentrations in the intensive-care unit. 6,7 Under-dosing, especially in ventilated patients, has been suggested as a contributing factor in several trials unable to show non-inferiority of novel drugs compared with established therapies for hospital-acquired pneumonia and ventilator-associated pneumonia. 6–8 Unlike most other trials in patients with hospital-acquired or ventilator-associated pneumonia, ASPECT-NP exclusively enrolled patients who were mechanically ventilated and at a high risk of death and other adverse outcomes. On the basis of previous pharmacokinetic and pharmacodynamic data, ASPECT-NP evaluated a dose of ceftolozane–tazobactam that was twice that approved for other indications to ensure sufficient pulmonary target concentrations in all patients. This approach was successful: non-inferiority of ceftolozane–tazobactam over meropenem was shown for both all-cause mortality and clinical response, with outcomes similar between treatments across clinically relevant subpopulations. As Tang and Lai state, treatment duration (doripenem 7 days and imipenem 10 days) might have contributed to the worse outcomes seen in the third doripenem trial. 5 ASPECT-NP permitted treatment durations of up to 14 days, the recommended duration for Pseudomonas aeruginosa infection. The benefit of treatment durations longer than 7 days for P aeruginosa and other difficult-to-treat pathogens remains controversial and ultimately can only be definitively determined by a randomised controlled trial comparing different regimen durations of the same antibiotic. MHK reports advisory board and speaker's bureau fees from Merck & Co, outside the submitted work, and has received institutional research funding from Merck & Co. ÁR-N has received institutional research funding from Merck & Co. RGW reports grants and personal fees from Merck & Co, during the conduct of the study; grants and personal fees from Shionogi, Polyphor, Melinta, The Medicines Company, and Arsanis; personal fees from Microbiotix, KBP Biosciences, and Meiji-Seiko, outside the submitted work; and receiving institutional research funding from Merck & Co. CJB and EGR are employees of Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA, and hold stock and stock options in the company.

PY - 2020/1

Y1 - 2020/1

UR - http://www.scopus.com/inward/record.url?scp=85076705940&partnerID=8YFLogxK

U2 - 10.1016/S1473-3099(19)30717-0

DO - 10.1016/S1473-3099(19)30717-0

M3 - Letter

C2 - 31876489

AN - SCOPUS:85076705940

SN - 1473-3099

VL - 20

SP - 20

EP - 21

JO - The Lancet Infectious Diseases

JF - The Lancet Infectious Diseases

IS - 1

ER -