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Rebecca Redman - One of the best experts on this subject based on the ideXlab platform.

  • a randomized trial of 7 day doripenem versus 10 day imipenem Cilastatin for ventilator associated pneumonia
    Critical Care, 2012
    Co-Authors: Marin H Kollef, Kone Kaniga, Jean Chastre, Iolanda Cirillo, Marc Clavel, Marcos I Restrepo, Bart Michiels, Holly Kimko, Rebecca Redman
    Abstract:

    Introduction: The 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. Methods: This 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). Results: The 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). Conclusions: Among 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 Registration: ClinicalTrials.gov: NCT00589693

  • a randomized trial of 7 day doripenem versus 10 day imipenem Cilastatin for ventilator associated pneumonia
    Critical Care, 2012
    Co-Authors: Marin H Kollef, Kone Kaniga, Jean Chastre, Iolanda Cirillo, Marc Clavel, Marcos I Restrepo, Bart Michiels, Holly Kimko, Rebecca Redman
    Abstract:

    The 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. This 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). The 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). Among 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. ClinicalTrials.gov: NCT00589693

Marin H Kollef - One of the best experts on this subject based on the ideXlab platform.

  • a randomized trial of 7 day doripenem versus 10 day imipenem Cilastatin for ventilator associated pneumonia
    Critical Care, 2012
    Co-Authors: Marin H Kollef, Kone Kaniga, Jean Chastre, Iolanda Cirillo, Marc Clavel, Marcos I Restrepo, Bart Michiels, Holly Kimko, Rebecca Redman
    Abstract:

    The 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. This 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). The 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). Among 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. ClinicalTrials.gov: NCT00589693

  • a randomized trial of 7 day doripenem versus 10 day imipenem Cilastatin for ventilator associated pneumonia
    Critical Care, 2012
    Co-Authors: Marin H Kollef, Kone Kaniga, Jean Chastre, Iolanda Cirillo, Marc Clavel, Marcos I Restrepo, Bart Michiels, Holly Kimko, Rebecca Redman
    Abstract:

    Introduction: The 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. Methods: This 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). Results: The 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). Conclusions: Among 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 Registration: ClinicalTrials.gov: NCT00589693

  • levofloxacin for treatment of ventilator associated pneumonia a subgroup analysis from a randomized trial
    Clinical Infectious Diseases, 2005
    Co-Authors: Andrew F Shorr, Neringa Zadeikis, William L Jackson, Anthony S Ramage, Shuchen Wu, Alan M Tennenberg, Marin H Kollef
    Abstract:

    Ventilator-associated pneumonia (VAP) remains a significant challenge in critical care. We conducted a secondary analysis of a multicenter, prospective, randomized trial comparing levofloxacin (750 mg iv q24h) with imipenem-Cilastatin (500-1000 mg iv q6-8h) for treatment of nosocomial pneumonia and focused on the subgroup of patients with VAP. The study cohort included 222 patients, with half (111) of the patients assigned to each treatment group. The patients in both groups were similar with respect to age, severity of illness, and duration of mechanical ventilation before the onset of VAP. Among the intention-to-treat population, clinical success was achieved in 58.6% of patients receiving levofloxacin, compared with 63.1% of patients receiving imipenem-Cilastatin (P = .49; 95% confidence interval for the difference, -8.77% to 17.79%). Microbiological success and 28-day mortality rates were also comparable. Multivariate analysis demonstrated that assignment to antibiotic treatment (i.e., levofloxacin vs. imipenem-Cilastatin) was not predictive of outcomes, thus suggesting that the treatment regimens were equivalent. Both levofloxacin and imipenem-Cilastatin regimens were well tolerated and had similar adverse event profiles.

Alberto Lazaro - One of the best experts on this subject based on the ideXlab platform.

  • cisplatin induced renal inflammation is ameliorated by Cilastatin nephroprotection
    Nephrology Dialysis Transplantation, 2017
    Co-Authors: Blanca Humanes, Alberto Tejedor, Sonia Camano, Alberto Lazaro, Maria Angeles Gonzaleznicolas, Jose Manuel Lara, Venkatta Sabbisetti, Joseph V Bonventre
    Abstract:

    Background Cisplatin is a potent chemotherapeutic drug whose nephrotoxic effect is a major complication and a dose-limiting factor for antitumoral therapy. There is much evidence that inflammation contributes to the pathogenesis of cisplatin-induced nephrotoxicity. We found that Cilastatin, a renal dehydropeptidase-I inhibitor, has protective effects in vitro and in vivo against cisplatin-induced renal damage by inhibiting apoptosis and oxidation. Here, we investigated the potential use of Cilastatin to protect against cisplatin-induced kidney injury and inflammation in rats. Methods Male Wistar rats were divided into four groups: control, Cilastatin-control, cisplatin and Cilastatin-cisplatin. Nephrotoxicity was assessed 5 days after administration of cisplatin based on blood urea nitrogen, creatinine, glomerular filtration rate (GFR), kidney injury molecule (KIM)-1 and renal morphology. Inflammation was measured using the electrophoretic mobility shift assay, immunohistochemical studies and evaluation of inflammatory mediators. Results Compared with the control rats, cisplatin-administered rats were affected by significant proximal tubule damage, decreased GFR, increased production of inflammatory mediators and elevations in urea, creatinine and tissue KIM-1 levels. Cilastatin prevented these changes in renal function and ameliorated histological damage in cisplatin-administered animals. Cilastatin also reduced pro-inflammatory cytokine levels, activation of nuclear factor-κB and CD68-positive cell concentrations. Conclusions Cilastatin reduces cisplatin-induced nephrotoxicity, which is associated with decreased inflammation in vivo. Although the exact role of decreased inflammation in nephroprotection has not been fully elucidated, treatment with Cilastatin could be a novel strategy for the prevention of cisplatin-induced acute kidney injury.

  • protective effects of Cilastatin against vancomycin induced nephrotoxicity
    BioMed Research International, 2015
    Co-Authors: Blanca Humanes, Ana Torres, Alberto Tejedor, Sonia Camano, Juan Carlos Jado, Emilia Cercenado, Virginia Lopezparra, Luis A Alvarezsala, Alberto Lazaro
    Abstract:

    Vancomycin is a very effective antibiotic for treatment of severe infections. However, its use in clinical practice is limited by nephrotoxicity. Cilastatin is a dehydropeptidase I inhibitor that acts on the brush border membrane of the proximal tubule to prevent accumulation of imipenem and toxicity. The aim of this study was to investigate the potential protective effect of Cilastatin on vancomycin-induced apoptosis and toxicity in cultured renal proximal tubular epithelial cells (RPTECs). Porcine RPTECs were cultured in the presence of vancomycin with and without Cilastatin. Vancomycin induced dose-dependent apoptosis in cultured RPTECs, with DNA fragmentation, cell detachment, and a significant decrease in mitochondrial activity. Cilastatin prevented apoptotic events and diminished the antiproliferative effect and severe morphological changes induced by vancomycin. Cilastatin also improved the long-term recovery and survival of RPTECs exposed to vancomycin and partially attenuated vancomycin uptake by RPTECs. On the other hand, Cilastatin had no effects on vancomycin-induced necrosis or the bactericidal effect of the antibiotic. This study indicates that Cilastatin protects against vancomycin-induced proximal tubule apoptosis and increases cell viability, without compromising the antimicrobial effect of vancomycin. The beneficial effect could be attributed, at least in part, to decreased accumulation of vancomycin in RPTECs.

  • Cilastatin protects against cisplatin induced nephrotoxicity without compromising its anticancer efficiency in rats
    Kidney International, 2012
    Co-Authors: Blanca Humanes, Jose A. Lazaro, Sonia Camano, Alberto Lazaro, Estefania Morenogordaliza, Jose Manuel Lara, Montserrat Blancocodesido, Alberto Ortiz, Maria M Gomezgomez, Pablo Martinvasallo
    Abstract:

    Cisplatin is an anticancer agent marred by nephrotoxicity; however, limiting this adverse effect may allow the use of higher doses to improve its efficacy. Cilastatin, a small molecule inhibitor of renal dehydropeptidase I, prevents proximal tubular cells from undergoing cisplatin-induced apoptosis in vitro. Here, we explored the in vivo relevance of these findings and the specificity of protection for kidney cells in cisplatin-treated rats. Cisplatin increased serum blood urea nitrogen and creatinine levels, and the fractional excretion of sodium. Cisplatin decreased the glomerular filtration rate, promoted histological renal injury and the expression of many pro-apoptotic proteins in the renal cortex, increased the Bax/Bcl2 ratio, and oxidative stress in kidney tissue and urine. All these features were decreased by Cilastatin, which preserved renal function but did not modify the pharmacokinetics of cisplatin area under the curve. The cisplatin-induced death of cervical, colon, breast, and bladder-derived cancer cell lines was not prevented by Cilastatin. Thus, Cilastatin has the potential to prevent cisplatin nephrotoxicity without compromising its anticancer efficacy.

  • Cilastatin attenuates cisplatin induced proximal tubular cell damage
    Journal of Pharmacology and Experimental Therapeutics, 2010
    Co-Authors: Sonia Camano, Ana Torres, Jose A. Lazaro, Alberto Lazaro, Estefania Morenogordaliza, Carmen De Lucas, Blanca Humanes, Milagros M Gomezgomez, Lisardo Bosca, Alberto Tejedor
    Abstract:

    A major area in cancer therapy is the search for protective strategies against cisplatin-induced nephrotoxicity. We investigated the protective effect of Cilastatin on cisplatin-induced injury to renal proximal tubular cells. Cilastatin is a specific inhibitor of renal dehydrodipeptidase I (DHP-I), which prevents hydrolysis of imipenem and its accumulation in the proximal tubule. Primary cultures of proximal cells were treated with cisplatin (1-30 microM) in the presence or absence of Cilastatin (200 microg/ml). Apoptosis and mitochondrial injury were assessed by different techniques. Cisplatin uptake and DNA binding were measured by inductively coupled plasma spectrometry. HeLa cells were used to control the effect of Cilastatin on the tumoricidal activity of cisplatin. Cisplatin increased cell death, apoptotic-like morphology, caspase activation, and mitochondrial injury in proximal tubular cells in a dose- and time-dependent way. Concomitant treatment with Cilastatin reduced cisplatin-induced changes. Cilastatin also reduced the DNA-bound platinum but did not modify cisplatin-dependent up-regulation of death receptors (Fas) or ligands (tumor necrosis factor alpha, Fas ligand). In contrast, Cilastatin did not show any effects on cisplatin-treated HeLa cells. Renal DHP-I was virtually absent in HeLa cells. Cilastatin attenuates cisplatin-induced cell death in proximal tubular cells without reducing the cytotoxic activity of cisplatin in tumor cells. Our findings suggest that the affinity of Cilastatin for renal dipeptidase makes this effect specific for proximal tubular cells and may be related to a reduction in intracellular drug accumulation. Therefore, Cilastatin administration might represent a novel strategy in the prevention of cisplatin-induced acute renal injury.

Bart Michiels - One of the best experts on this subject based on the ideXlab platform.

  • a randomized trial of 7 day doripenem versus 10 day imipenem Cilastatin for ventilator associated pneumonia
    Critical Care, 2012
    Co-Authors: Marin H Kollef, Kone Kaniga, Jean Chastre, Iolanda Cirillo, Marc Clavel, Marcos I Restrepo, Bart Michiels, Holly Kimko, Rebecca Redman
    Abstract:

    Introduction: The 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. Methods: This 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). Results: The 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). Conclusions: Among 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 Registration: ClinicalTrials.gov: NCT00589693

  • a randomized trial of 7 day doripenem versus 10 day imipenem Cilastatin for ventilator associated pneumonia
    Critical Care, 2012
    Co-Authors: Marin H Kollef, Kone Kaniga, Jean Chastre, Iolanda Cirillo, Marc Clavel, Marcos I Restrepo, Bart Michiels, Holly Kimko, Rebecca Redman
    Abstract:

    The 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. This 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). The 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). Among 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. ClinicalTrials.gov: NCT00589693

Iolanda Cirillo - One of the best experts on this subject based on the ideXlab platform.

  • a randomized trial of 7 day doripenem versus 10 day imipenem Cilastatin for ventilator associated pneumonia
    Critical Care, 2012
    Co-Authors: Marin H Kollef, Kone Kaniga, Jean Chastre, Iolanda Cirillo, Marc Clavel, Marcos I Restrepo, Bart Michiels, Holly Kimko, Rebecca Redman
    Abstract:

    Introduction: The 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. Methods: This 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). Results: The 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). Conclusions: Among 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 Registration: ClinicalTrials.gov: NCT00589693

  • a randomized trial of 7 day doripenem versus 10 day imipenem Cilastatin for ventilator associated pneumonia
    Critical Care, 2012
    Co-Authors: Marin H Kollef, Kone Kaniga, Jean Chastre, Iolanda Cirillo, Marc Clavel, Marcos I Restrepo, Bart Michiels, Holly Kimko, Rebecca Redman
    Abstract:

    The 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. This 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). The 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). Among 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. ClinicalTrials.gov: NCT00589693