Efficacy and safety of doripenem versus piperacillin/tazobactam in nosocomial pneumonia: a randomized, open-label, multicenter study.
OBJECTIVE
Doripenem is a new carbapenem that has broad-spectrum activity against bacterial pathogens commonly responsible for nosocomial pneumonia (NP). It has several advantages over currently available carbapenems and other classes of drugs used in this indication. This prospective, randomized, open-label, multicenter study was designed to establish whether doripenem was noninferior to piperacillin/tazobactam in NP.


METHODS
Adults (n=448) with signs and symptoms of NP, including non-ventilated patients and those ventilated for <5 days, were stratified by ventilation mode, illness severity (Acute Physiology and Chronic Health Evaluation II score), and geographic region and then randomly allocated to treatment with doripenem 500 mg every 8 h by a 1-h intravenous (IV) infusion or piperacillin/tazobactam 4.5 g every 6 h by 30-min IV infusion. After receiving IV study drug for at least 72 h, eligible patients could be switched to oral levofloxacin 750 mg once daily. Antibiotic therapy was continued for a total of 7-14 days. The primary endpoint was the clinical cure rate, assessed 7-14 days after treatment completion, in clinically evaluable patients and in the clinical modified intent-to-treat population (cMITT).


BACKGROUND
ClinicalTrials.gov, NCT00211003.


RESULTS
Doripenem was noninferior to piperacillin/tazobactam. Clinical cure rates in clinically evaluable patients (n=253) were 81.3% in the doripenem arm and 79.8% in the piperacillin/tazobactam arm (between-treatment difference: 1.5%; 95% confidence interval [CI], -9.1 to 12.1%) and in the cMITT population 69.5% and 64.1%, respectively, (between-treatment difference: 5.4%; 95% CI, -4.1 to 14.8%). Baseline resistance of Klebsiella pneumoniae and Pseudomonas aeruginosa to piperacillin/tazobactam was 44% and 26.9%, respectively; a doripenem minimum inhibitory concentration (MIC) >8 mug/mL occurred in 0% and 7.7%, respectively. Favorable microbiological outcome rates against Gram-negative pathogens were numerically higher with doripenem than with piperacillin/tazobactam, but the difference was not statistically significant. Both study drugs were generally well tolerated, as only 16.1% and 17.6% of patients receiving doripenem and piperacillin/tazobactam, respectively, had a drug-related adverse event. Study limitations included the open-label design, the low rate of monotherapy (adjunctive use of aminoglycoside was required when P. aeruginosa was suspected), and the exclusion of the most critically ill and immunocompromized patients.


CONCLUSIONS
Doripenem was clinically and microbiologically effective in patents with NP, including those with early-onset ventilator-associated pneumonia, and was therapeutically noninferior to piperacillin/tazobactam.
Hospital de Clínicas da Universidade Federal do Paraná, Rua General Carneiro, Curitiba, Brasil. rea-neto@uol.com.br
Alvaro
A
Réa-Neto
Michael
M
Niederman
Suzana Margareth
SM
Lobo
Eric
E
Schroeder
Michael
M
Lee
Koné
K
Kaniga
Nzeera
N
Ketter
Philippe
P
Prokocimer
Ian
I
Friedland
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001419:Bacteria / Q000187:drug effects / Q000302:isolation & purification; D015780:Carbapenems / Q000627:therapeutic use*; D003428:Cross Infection / Q000188:drug therapy* / Q000382:microbiology; D000077726:Doripenem; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010878:Piperacillin / Q000627:therapeutic use*; D018410:Pneumonia, Bacterial / Q000188:drug therapy*; D011446:Prospective Studies; D000078142:Tazobactam; D016896:Treatment Outcome
D000900:Anti-Bacterial Agents; D015780:Carbapenems; D010397:Penicillanic Acid; D000077726:Doripenem; D000078142:Tazobactam; D010878:Piperacillin