Efficacy and safety of doripenem versus piperacillin/tazobactam in nosocomial pneumonia: a randomized, open-label, multicenter study^*

ABSTRACT

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).

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 µg/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.

Trial registration: ClinicalTrials.gov identifier: NCT00211003.

Key words: :

• Carbapenem
• Klebsiella pneumoniae
• Pseudomonas aeruginosa
• Ventilator-associated pneumonia

Acknowledgments

Declaration of interest: This study was funded by Johnson & Johnson Pharmaceutical, Raritan, NJ, USA. ML, KK, PP, and IF were employees of Johnson & Johnson during the term of this study. AR-N, SML, and ES were lead investigators in this study. MN served as a consultant for this study. The authors have no financial interests to declare.

The authors acknowledge the contribution of Matthew Wickler to the original study design. Medical writing and editorial assistance were contributed by William B. Gough, PhD, of Phase Five Communications Inc, New York, NY.

Investigators:

In addition to the authors, study investigators included:

Argentina: G. Ambasch, Córdoba; H.A. Ariza, Buenos Aires; J.A. Corral, Buenos Aires; O. Fariña, Buenos Aires; C.R. Fuentes, Buenos Aires; G.I.S.L. Hara, Buenos Aires; G.D. Lopardo, Buenos Aires; M.J.L. Furst, Buenos Aires; C. Lovesio, Rosario; D.M. Maurizi, Buenos Aires; Á.R. Minguez, Provincia de Córdoba; M.E. Oliva, Entre Rios; C.G. Rodriguez, Buenos Aires; G.I. Vidal, Capitol Federal. Belarus: A. Karpuk, Minsk; K. Makarenko, Minsk; S. Pimanov, Vitebsk; N. Soroka, Minsk. Brazil: A.P. Cardoso, Rio de Janeiro; J.C. Correa, Rio de Janeiro; J.C. Fiterman, Porto Alegre; F.R. Machado, São Paulo; O.H.C. Messeder, Salavador. Canada: J. Embil, Winnepeg, Manitoba; D. Grimard, Chicoutimi, Quebec; G. Poirier, Greenfield Park, Quebec. Chile: L.V.B. Fernández, Viña del Mar; M.I.E.C. Barker, Santiago. Georgia: M. Makhviladze, Tbilisi. Russia: A. Bezlepko, Moscow; O.B. Ershova, Yaroslavl; S. Fitilev, Moscow; I. Fomina, Moscow; N.I. Glotova, Novosibirsk; A.I. Kuzin, Chelyabinsk; V. Novozhenov, Moscow; V. Popova, St. Petersburg; G. Reshedko, Smolensk; L. Shpagina, Novosibirsk; V. Simanenkov, St. Petersburg; S. Yakovlev, Moscow; V. Zadionchenko, Moscow; M. Zamyatin, Moscow; E.V. Zonova, Novosibirsk. South Africa: M.M.de V. Basson, Bellville; F.C.J. Bester, Bloemfontaine; L. Jamjam, Port Elizabeth; J.G. Kilian, Pretoria; T.G. Mothabeng, Gauteng; M. Mukansi, Johannesburg; I.H. Vermooten, Krugersdorp; R.P. von Rahden, Soweto; N. Welkovics, Pretoria. Ukraine: I. Bereznyakov, Kharkov; V. Boyko, Kharkov; O. Dzyublyk, Kiev; I. Krayz, Kharkov; V. Lebednyets, Kharkov; Y. Rudyk, Kharkov. USA: A. Agrawal, Anaheim, CA; R.M. Aris, Chapel Hill, NC; R.H. Bartlett, Ann Arbor, MI; J.M. Bernstein, Dayton, OH; J. Boghossian, Belleville, NJ; L. Bush, Atlantis, FL; K. Chaudhuri, El Paso, TX; B. DiGiovine, Detroit, MI; M.W. Farra, Southfield, MI; T.J. Ferro, Richmond, VA; P. Fornos, San Antonio, TX; G. Fulda, Newark, DE; D.R. Graham, Springfield, IL; A.A. Haidar, Picayune, MS; J.W. Hawkins, Birmingham, AL; D.W. Hecht, Maywood, IL; G.A. Hicklin, Des Moines, IA; M. Horattas, Akron, OH; S. John, Knoxville, TN; K. Kalassian, Atlanta, GA; D.C. Kaufman, Rochester, NY; G.T. Kinasewitz, Oklahoma City, OK; T. Lo, Loma Linda, CA; L. Lottenberg, Gainesville, FL; A. Malas, Charleston, WV; M.C. Meadors, Winston-Salem, NC; J.E. Michaelson, Decatur, GA; A.M. Mohr, Newark, NJ; M. Nelson, Shawnee Mission, KS; R. Pearl, Stanford, CA; J.L. Pearle, Fullerton, CA; D.M. Perlman, Denver, CO; D. Phillips, Pensacola, FL; J. Pullman, Butte, MT; A.A. Quartin, Miami, FL; I.I. Raad, Houston, TX; S.G. Rosenberg, Denver, CO; D.J. Schuerer, St. Louis, MO; A. Seibert, Mobile, AL; J. Slim, Newark, NJ; H.C. Standiford, Baltimore, MD; J. Suen, Vero Beach, FL; W.P. Tillis, Peoria, IL; J.A. Vazquez, Detroit, MI.