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      Characteristics of doripenem: a new broad-spectrum antibiotic

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          Abstract

          Doripenem (S-4661) is a new parenteral antibiotic from the carbapenem class; similarly to imipenem and meropenem, it has a broad-spectrum activity against Gram-positive, Gram-negative, and anaerobic bacteria. It is active against multiresistant Gram-negative bacilli such as extended-spectrum beta-lactamase-producing (ESBL) Gram-negative Enterobacteriaceae and nonfermentative Gram-negative bacilli including some strains of Pseudomonas aeruginosa that are resistant to other carbapenems. Doripenem’s chemical structure is similar to that of meropenem (substitution of one sulfamoxil-aminomethyl chain for the dimethyl-carboxyl chain), and has one 1-beta-methyl chain which provides resistance to dehydropeptidase-I enzyme. The clinical trials conducted so far have focused on the treatment of severe infections such as complicated intra-abdominal infections, complicated urinary tract infections and pyelonephritis, nosocomial pneumonia, and ventilator-associated pneumonia. Given its activity profile and the results from the clinical trials, this antibiotic may be used for empirical treatment of multibacterial infections produced by potentially multiresistant Gram-negative bacilli. In 2007, the US Food and Drug Administration approved the use of doripenem for the treatment of complicated intra-abdominal infections and complicated urinary tract infections. The European Medicines Agency has approved the use of doripenem for the same indications in addition to nosocomial pneumonia regardless of whether it is ventilator-associated or not.

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          Most cited references 60

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          Substrate specificities of MexAB-OprM, MexCD-OprJ, and MexXY-oprM efflux pumps in Pseudomonas aeruginosa.

          To find the exact substrate specificities of three species of tripartite efflux systems of Pseudomonas aeruginosa, MexAB-OprM, MexCD-OprJ, and MexXY-OprM, we constructed a series of isogenic mutants, each of which constitutively overproduced one of the three efflux systems and lacked the other two, and their isogenic mutants, which lacked all these systems. Comparison of the susceptibilities of the constructed mutants to 52 antimicrobial agents belonging to various groups suggested the following substrate specificities. All of the efflux systems extrude a wide variety of antimicrobial agent groups, i.e., quinolones, macrolides, tetracyclines, lincomycin, chloramphenicol, most penicillins (all but carbenicillin and sulbenicillin), most cephems (all but cefsulodin and ceftazidime), meropenem, and S-4661, but none of them extrude polymyxin B or imipenem. Extrusion of aminoglycosides is specific to MexXY-OprM, and extrusion of a group of the beta-lactams, i.e., carbenicillin, sulbenicillin, ceftazidime, moxalactam, and aztreonam, is specific to MexAB-OprM. Moreover, MexAB-OprM and MexCD-OprJ extrude novobiocin, cefsulodin, and flomoxef, while MexXY-OprM does not. These substrate specificities are distinct from those reported previously.
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            Efficacy and safety of intravenous infusion of doripenem versus imipenem in ventilator-associated pneumonia: a multicenter, randomized study.

            Doripenem is an investigational carbapenem with broad-spectrum activity against gram-negative and gram-positive pathogens, including multidrug-resistant strains, commonly responsible for ventilator-associated pneumonia (VAP). This large, phase III study compared doripenem with imipenem for the treatment of ventilator-associated pneumonia. Prospective, multicenter, parallel randomized, active-controlled, open-label study. Intensive care units. Adults (N = 531) who met clinical and radiologic criteria for ventilator-associated pneumonia. Patients were stratified by duration of mechanical ventilation ( or = 5 days), severity of illness (Acute Physiology and Chronic Health Evaluation II score 15), and geographic region and then randomly assigned to doripenem 500 mg every 8 hrs via a 4-hr intravenous infusion or imipenem 500 mg every 6 hrs or 1000 mg every 8 hrs via 30- or 60-min intravenous infusions, respectively, for 7-14 days. The primary efficacy end points were the clinical cure rates in the clinical modified intent-to-treat (cMITT) and clinically evaluable populations. Doripenem was noninferior to imipenem (lower boundary of 95% confidence interval around the difference between treatments > or = -20%). Clinical cure rates were 68.3% (doripenem) and 64.2% (imipenem) in the clinically evaluable and 59.0% (doripenem) and 57.8% (imipenem) in the cMITT populations. In patients with Pseudomonas aeruginosa, clinical cure was 80.0% (doripenem) and 42.9% (imipenem) (p not significant); microbiological cure was 65.0% (doripenem) and 37.5% (imipenem). Only 18% (5 of 28) of P. aeruginosa isolates had minimum inhibitory concentration > or = 8 microg/mL at baseline or following therapy in the doripenem arm compared with 64% (16 of 25) in the imipenem treatment group (p = .001). Clinical cure rate was higher with doripenem than imipenem at higher Acute Physiology and Chronic Health Evaluation II scores and older ages. Doripenem was generally well tolerated. In this large, phase III study of patients with ventilator-associated pneumonia, a 4-hr intravenous infusion of doripenem was clinically efficacious and therapeutically noninferior to imipenem.
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              In vitro activities of 15 antimicrobial agents against 110 toxigenic clostridium difficile clinical isolates collected from 1983 to 2004.

              The incidence and severity of Clostridium difficile-associated disease (CDAD) is increasing, and standard treatment is not always effective. Therefore, more-effective antimicrobial agents and treatment strategies are needed. We used the agar dilution method to determine the in vitro susceptibility of the following antimicrobials against 110 toxigenic clinical isolates of C. difficile from 1983 to 2004, primarily from the United States: doripenem, meropenem, gatifloxacin, levofloxacin, moxifloxacin, OPT-80, ramoplanin, rifalazil, rifaximin, nitazoxanide, tizoxanide, tigecycline, vancomycin, tinidazole, and metronidazole. Included among the isolates tested were six strains of the toxinotype III, NAP1/BI/027 group implicated in recent U.S., Canadian, and European outbreaks. The most active agents in vitro were rifaximin, rifalazil, tizoxanide, nitazoxanide, and OPT-80 with MICs at which 50% of the isolates are inhibited (MIC(50)) and MIC(90) values of 0.0075 and 0.015 microg/ml, 0.0075 and 0.03 microg/ml, 0.06 and 0.125 microg/ml, 0.06 and 0.125 microg/ml, 0.125 and 0.125 microg/ml, respectively. However, for three isolates the rifalazil and rifaximin MICs were very high (MIC of >256 microg/ml). Ramoplanin, vancomycin, doripenem, and meropenem were also very active in vitro with narrow MIC(50) and MIC(90) ranges. None of the isolates were resistant to metronidazole, the only agent for which there are breakpoints, with tinidazole showing nearly identical results. These in vitro susceptibility results are encouraging and support continued evaluation of selected antimicrobials in clinical trials of treatment for CDAD.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug design, development and therapy
                Dove Medical Press
                1177-8881
                2009
                21 September 2009
                : 3
                : 173-190
                Affiliations
                [1 ] Intensive Care Unit
                [2 ] Pharmacy Department, Hospital Del Mar, Barcelona, Spain
                Author notes
                Correspondence: Francisco Alvarez-Lerma, Intensive Care Unit, Hospital del Mar, Passeig Marítim, 25-29, 08003, Barcelona, Spain, Tel +34 93 248 3125, Fax +34 93 248 3254, Email falvarez@ 123456imas.imim.es
                Article
                dddt-3-173
                2769234
                19920933
                © 2009 Alvarez-Lerma et al, publisher and licensee Dove Medical Press Ltd.

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

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