Introduction:~The treatment of resistant pathogens is becoming more difficult, and only a few novel antimicrobial agents are currently in development with activity against highly resistant Gram negative bacteria. Doripenem is a carbapenem antibacterial agent with a broad spectrum of activity against Gram-negative and Gram-positive bacteria. This agent is often used as the last line of therapy for highly resistant Gram negative bacilli nosocomial pathogens. In common with other beta-lactam, the main pharmacokinetic/pharmacodynamic (PK/PD) index that correlates with the therapeutic efficacy is the time that concentrations in the tissue and serum are above the MIC (t>MIC). However, in tropical countries the stability of carbapenem antibiotics is an important consideration when considering continuous infusion. Therefore, prolonged infusion may be a useful route of administration to maximize bactericidal activity. In addition, pharmacokinetic changes have been found for several antimicrobial agents in critically ill patients, including ventilator-associated pneumonia. However, until now we have had no data to reveal the PK/PD index of doripenem in these critically ill patients.~Objectives:~To assess the pharmacodynamics (t>MIC) of 0.5 g every 8 h of doripenem in patients with VAP following administration by a 4 h infusion or 1 h infusion.~Clinical and laboratory data: Age,Sex, Body weight, Electrolyte, Vital signs, APACHE II score, BUN, Cr, Blood culture~Drug preparation and administration:~Doripenem will be reconstituted with saline solution according to the manufacturer's guidelines and then administered to the patients by 2 regimens:~1.0.5 g in 100 ml of normal saline solution and administered via an infusion pump at a constant flow rate over 4 h every 8 h.~2.0.5 g in 100 ml of normal saline solution and administered via an infusion pump at a constant flow rate over 1 h every 8 h.~Study design:~The study is planned as a prospective and randomized in patients with VAP. Each patients will receive doripenem in 2 regimens at room temperature (37°C) consecutively: (i) infusion of 0.5 g of doripenem for 4 h via an infusion pump at a constant flow rate every 8 h; (ii) infusion of 0.5 g of doripenem for 1 h via an infusion pump at a constant flow rate every 8 h.~Twelve patients will be enrolled in this study. After completion of the doripenem therapy for 3 days in this study, all patients will receive other sensitive antibiotics to eradicate their bacterial infections.~Sample collections:~Doripenem pharmacokinetic study will be carried out during the doripenem therapy.~Blood samples (approximately 2 ml) in group  0.5 g of doripenem with 4 h infusion every 8 h regimen will be obtained by direct venepuncture at the following time: 0, 0.5, 1, 2, 3, 4, 4.5, 5, 6, 7 and 8 h after 7th dose of doripenem.~Blood samples (approximately 2 ml) in group  0.5 g of doripenem with 1 h infusion every 8 h regimen will be obtained by direct venepuncture at the following time: 1, 1.5, 2, 4, 5, 6, 7 and 8 h after 7th dose of doripenem.~All blood samples will be allowed to clot and then cebtrifuged at 2,000g.~The serum obtained will be stored at-80°C until analysis.~Doripenem assay:~The doripenem assays by method of Ikeda K et al. (J Chromatogr B, 2008) will be performed at Department of Medicine, Faculty of Medicine.~Clinical data and pathogens collection:~Initial patient demographic data (age, sex, weight, diagnosis, APACHE II scores) will be collected upon enrollment in the study.~The Gram negative bacilli isolated from sputum in 12 patients will be collected and the MIC of the doripenem for pathogens will be determined by E tests upon enrollment in the study.~Duration of study:~Patients will receive doripenem for 3 days~Pharmacokinetic and pharmacodynamic analysis:~Concentration of doripenem in plasma will be simulated in Monte Carlo technique (Computer model) to get PK/PD index (40%T>MIC) and reported to % PTA (Probability Target Attainment) and %CFR (Cumulative Faction Response)~Sample Size: Twelve patients with VAP will be enrolled in this study.
This is prospective and randomized study to assess the pharmacodynamics (t>MIC) of 0.5 g every 8 h of doripenem in patients with VAP following administration by a 4 h infusion or 1 h infusion.~Clinical and laboratory data such as Age,Sex, Body weight, Electrolyte, Vital signs, APACHE II score, BUN, Cr, Blood culture will be collected.~Twelve patients will be enrolled in this study. After completion of the doripenem therapy for 3 days in this study, all patients will receive other sensitive antibiotics to eradicate their bacterial infections.~Doripenem pharmacokinetic study will be carried out during the doripenem therapy. Blood samples (approximately 2 ml) in group  0.5 g of doripenem with 4 h infusion every 8 h regimen will be obtained by direct venepuncture at the following time: 0, 0.5, 1, 2, 3, 4, 4.5, 5, 6, 7 and 8 h after 7th dose of doripenem.~Blood samples (approximately 2 ml) in group  0.5 g of doripenem with 1 h infusion every 8 h regimen will be obtained by direct venepuncture at the following time: 1, 1.5, 2, 4, 5, 6, 7 and 8 h after 7th dose of doripenem.~The doripenem assays by method of Ikeda K et al. (J Chromatogr B, 2008) will be performed.~Concentration of doripenem in plasma will be simulated in Monte Carlo technique (Computer model) to get PK/PD index (40%T>MIC) and reported to % PTA (Probability Target Attainment) and %CFR (Cumulative Faction Response)