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

The pharmacokinetics, safety, and tolerability of doripenem in healthy subjects were evaluated in 2 studies. Study 1 was a double-blind, randomized, placebo-controlled dose-escalation study in which doripenem was administered for 7 days by infusion over 30 minutes (500 mg) or 1 hour (1000 mg). Study 2 was an open-label, randomized, 3-way crossover study in which each subject received a single dose of each of the following doripenem treatments on separate occasions: 500 mg infused over 1 hour, 500 mg infused over 4 hours, and 1000 mg infused over 4 hours. Doripenem exhibited linear pharmacokinetics with concordance between the studies for pharmacokinetic parameters. Doripenem did not accumulate with repeated dosing over 7 days. The area under the plasma concentration-time curve (AUC) for doripenem 500 mg infused over 1 hour versus 4 hours was bioequivalent, and the AUC and Cmax increased proportionally with dose for the 500- and 1000-mg doses administered over 4 hours. These results, along with the stability profile of doripenem, support its use as a prolonged infusion. All regimens of doripenem were safe and well tolerated.

In this open-label, single-center study, eight healthy men each received a single 500-mg dose of Doripenem is a new parenteral carbapenem antibiotic with broad-spectrum activity against gram-negative and gram-positive pathogens, including strains resistant to multiple antibiotic classes (1, 6, 7). It is indicated for adults in the treatment of complicated intra-abdominal infections and complicated urinary tract infections, including pyelonephritis. Doripenem exhibits in vitro activity against contemporary strains of gram-negative bacteria that are often responsible for serious, hospital-acquired infections, including Pseudomonas aeruginosa and extended-spectrum betalactamase-and AmpC beta-lactamase-producing Enterobacteriaceae (10-12, 15, 19). In addition, doripenem is less likely than meropenem or imipenem to select for carbapenem-resistant strains of Pseudomonas aeruginosa (17). Because carbapenems produce time-dependent bactericidal activity, the ability to deliver doripenem via prolonged infusion increases the time that drug concentrations are likely to remain above the MIC for the infecting pathogen (2, 5). This may be of critical importance for difficult-to-treat pathogens that are not susceptible to other carbapenems or for which the MICs are near the susceptibility limits of the drug.The present study was designed to characterize the disposition, metabolism, and excretion of doripenem in healthy men following a single 500-mg dose administered as a 1-h intravenous infusion, which is the standard doripenem dose indicated for treatment of subjects with serious bacterial infections. On the basis of clinical-trial data, the proposed dose of doripenem for treatment of moderate to severe infections is 500 mg administered by a 1-h or 4-h infusion (C. Lucasti, A. Jasovich, O. Umeh, J. Jiang, and K. Kaniga, presented at the 17th European Congress of Clinical Microbiology and Infectious Diseases, 2007; O. Malafaia, O. Umeh, and J. Jang, presented at the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, 2006; K. Naber, R. Redman, P. Kotey, L. Lorens, and K. Kaniga, presented at the 17th European Congress of Clinical Microbiology and Infectious Diseases, 2007). MATERIALS AND METHODSThe study protocol was reviewed and approved by an independent ethics committee. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and in compliance with good clinical practices and all applicable regulatory requirements. All subjects participating in the study provided written informed consent.Subjects. Eight healthy men characterized by a screening physical examination, medical history, vital signs, 12-lead electrocardiogram, laboratory testing, and normal renal function were enrolled. The study cohort had a median age of 20.5 years (range, 18 to 45 years), a median weight of 87.5 kg (range, 55 to 93 kg), and a median body mass index of 22.9 kg/m 2 (range, 19 to 28 kg/m 2 ); all were Caucasian. Eligible patients had not smoked for at least 6 months and agreed to refrain ...

‫؍‬ 5). Healthy volunteers were also assessed (n ‫؍‬ 12). Concentrations of doripenem and the primary metabolite doripenem-M-1 were measured in plasma and ultrafiltrate or ultrafiltrate/dialysate by a validated liquid chromatography-tandem mass spectrometry method. In dialysisdependent subjects, levels of systemic exposure to doripenem and doripenem-M-1 were approximately 3-and 5-fold greater, respectively, than those in healthy subjects: for doripenem, 98 g ⅐ h/ml for CVVH and 77 g ⅐ h/ml for CVVHDF versus 32 g ⅐ h/ml for healthy subjects, and for doripenem-M-1, 24 g ⅐ h/ml for CVVH and 22 g ⅐ h/ml for CVVHDF versus 4.7 g ⅐ h/ml for healthy subjects. The mean sieving coefficients and saturation coefficients were >0.67 for both doripenem and doripenem-M-1. During CVVH and CVVHDF, respectively, the percentages of administered doripenem dose removed were 38% and 29%, and clearances of doripenem were 22 and 25 ml/min. Both CVVH and CVVHDF efficiently removed doripenem and doripenem-M-1. Despite significant removal of drug by CVVH and CVVHDF, a single 1-hour, 500-mg doripenem infusion produced significantly higher plasma concentrations of doripenem, higher systemic exposure (area under the plasma concentration-time curve from time zero to 12 h after the start of infusion [AUC 0-12 ]), and longer half-life (t 1/2 ) in subjects receiving CVVH or CVVHDF than in healthy volunteers. The recovery of drug in ultrafiltrate and ultrafiltrate/dialysate and the enhanced rate of reduction of plasma concentrations indicate that CVVH and CVVHDF significantly augmented residual total body clearance of doripenem in subjects receiving CRRT. Doripenem dosage regimens for patients receiving CRRT thus need to be adjusted.

Three multicenter, randomized, controlled studies evaluated doripenem in children 3 months to <18 years of age, with complicated intra-abdominal or urinary tract infections and bacterial pneumonia.In the 66 patients treated with doripenem before early termination of the studies for nonsafety reasons, doripenem was safe and generally well tolerated. Low enrollment limited ability to assess benefits and risks of doripenem in children.