A randomized trial of 7-day doripenem versus 10-day imipenem-cilastatin for ventilator-associated pneumonia

Abstract

IntroductionThe aim of this study was to compare a 7-day course of doripenem to a 10-day course of imipenem-cilastatin for ventilator-associated pneumonia (VAP) due to Gram-negative bacteria.MethodsThis was a prospective, double-blinded, randomized trial comparing a fixed 7-day course of doripenem one gram as a four-hour infusion every eight hours with a fixed 10-day course of imipenem-cilastatin one gram as a one-hour infusion every eight hours (April 2008 through June 2011).ResultsThe study was stopped prematurely at the recommendation of the Independent Data Monitoring Committee that was blinded to treatment arm assignment and performed a scheduled review of data which showed signals that were close to the pre-specified stopping limits. The final analyses included 274 randomized patients. The clinical cure rate at the end of therapy (EOT) in the microbiological intent-to-treat (MITT) population was numerically lower for patients in the doripenem arm compared to the imipenem-cilastatin arm (45.6% versus 56.8%; 95% CI, -26.3% to 3.8%). Similarly, the clinical cure rate at EOT was numerically lower for patients with Pseudomonas aeruginosa VAP, the most common Gram-negative pathogen, in the doripenem arm compared to the imipenem-cilastatin arm (41.2% versus 60.0%; 95% CI, -57.2 to 19.5). All cause 28-day mortality in the MITT group was numerically greater for patients in the doripenem arm compared to the imipenem-cilastatin arm (21.5% versus 14.8%; 95% CI, -5.0 to 18.5) and for patients with P. aeruginosa VAP (35.3% versus 0.0%; 95% CI, 12.6 to 58.0).ConclusionsAmong patients with microbiologically confirmed late-onset VAP, a fixed 7-day course of doripenem was found to have non-significant higher rates of clinical failure and mortality compared to a fixed 10-day course of imipenem-cilastatin. Consideration should be given to treating patients with VAP for more than seven days to optimize clinical outcome.Trial RegistrationClinicalTrials.gov: NCT00589693

Pseudomonas aeruginosaNosocomial Pneumonia: Impact of Pneumonia Classification

“…[6][7][8][9][10] Mortality associated with P. aeruginosa NP (Pa-NP) is among the highest of any bacteria owing to both the virulence of P. aeruginosa as well as the administration of inappropriate initial antibiotic therapy (IIAT) in MDR isolates. [11][12][13][14][15] The escalating prevalence of antibiotic resistance in P. aeruginosa, along with the development and availability of novel antimicrobial therapies, requires a precise understanding of how the various categories of Pa-NP influence outcome. A comparison of mortality of Pa-NP, as well as risk factors for mortality, according to pneumonia classification has not previously been performed.…”

Optimizing Antibiotic Pharmacodynamics for Clinical Practice

“…Finally, a doubleblind, randomized controlled study of doripenem 500 mg q8h as a 4 hour prolonged infusion versus standard infusion imipenem-cilastatin in patients with ventilator-associated pneumonia demonstrated noninferiority between dosing regimens; however, clinical success against the small population of patients infected with P. aeruginosa was numerically in favor of the prolonged infusion regimen [80% (16/20) vs. 43% (6/14)] [63]. Unfortunately, these results could not be replicated in a randomized controlled trial evaluating shorter courses of a higher dose prolonged infusion doripenem [64].…”

Modern Antibacterial Therapy in Hospital-Acquired Pneumonia

“…В 2012 г. было прекращено постмаркетинговое рандо-мизированное сравнительное исследование эффектив-ности лечения НПивл дорипенемом (7 суток лечения) и имипенемом/циластатином (10 суток лечения) [8]. Его результаты указывали на недостоверную статистически низкую клиническую эффективность и достоверно более высокую 28-суточную летальность в группе пациентов, получавших дорипенем по сравнению с группой полу-чавших имипенем/циластатин.…”

“…Позже в рамках метаанализа всех рандомизирован-ных клинических исследований дорипенема была отдель-но проанализирована группа из 3 исследований, специ-ально посвященных применению дорипенема у пациен-тов с нозокомиальной пневмонией и НПивл, целью кото-рого была оценка эффективности и безопасности именно для этой группы пациентов [4,8,10,11]. Препаратами сравнения в этих исследованиях были те, которые на момент исследования имелись в протоколах лечения нозокомиальной пневмонии или НПивл (пиперациллин/ тазобактам и имипенем/циластатин).…”

“…Однако высокая активностью дорипенема in vitro и желание максимально сократить продолжительность лечения, вероятно, послужили основанием для организа-ции клинического исследования высокого уровня для сравнения 7-суточного применения дорипенема и 10-суточного применения имипенема/циластатина для лечения пациентов с «поздней» НПивл [8]. С учетом пред-шествующих данных [13] продолжительность лечения НПивл менее 8 суток является малоизученным объектом и требует дальнейшего изучения.…”