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      Doripenem: A new carbapenem antibiotic a review of comparative antimicrobial and bactericidal activities

      Therapeutics and Clinical Risk Management

      Dove Medical Press

      MIC, mutant, MBC, pharmacokinetics, pharmacodynamics

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          Abstract

          Doripenem is a new parental 1-β-methyl carbapenem which, unlike imipenem, does not require the addition of cilastatin on administration because of the protection afforded to doripenem by the 1-β-methyl component. It combines the in vitro activities of imipenem and ertapenem against gram-positive bacteria with the in vitro activity of meropenem against gram-negative bacteria. It has excellent bactericidal activity against Streptococcus neumoniae. Carbapenem resistant mutants were selected with less frequency and lower minimum inhibitory concentrations (MICs) after exposure to doripenem than to imipenem or meropenem. High concentration levels of doripenem may be achieved in plasma. The half life of doripenem is higher than imipenem or meropenem. This new antibiotic has excellent in vitro activity and pharmacological properties. but how it may best be utilized still needs to be determined.

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          Most cited references 20

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          Use of pharmacokinetic-pharmacodynamic target attainment analyses to support phase 2 and 3 dosing strategies for doripenem.

          A doripenem population pharmacokinetic model and Monte Carlo simulations were utilized for dose regimen decision support for future clinical development. Simulation results predict that 500 mg of doripenem administered over 1 h every 8 h would be effective against bacterial strains with MICs less than 2 microg/ml and that less susceptible strains could be treated with prolonged infusions.
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            Doripenem (S-4661), a novel carbapenem: comparative activity against contemporary pathogens including bactericidal action and preliminary in vitro methods evaluations.

            To investigate the potency of doripenem, a broad-spectrum carbapenem characterized by a wider spectrum of activity combining antimicrobial and bactericidal features of imipenem and meropenem. This parenteral compound was studied against recent clinical isolates (2001-2002) from a worldwide organism collection. A total of 902 strains were susceptibility tested by reference methods against doripenem and six to 28 comparators including ertapenem, imipenem and meropenem. The organisms tested included: Enterobacteriaceae (281 strains), Acinetobacter spp. (33), Pseudomonas aeruginosa (35), Stenotrophomonas maltophilia (36), other non-fermenters (22), Haemophilus influenzae (61), Moraxella catarrhalis (33), oxacillin-susceptible staphylococci (39), enterococci (84), streptococci (163), various anaerobes (98), and other Gram-positive species such as Corynebacterium and Bacillus spp. (17). Against Enterobacteriaceae, the average doripenem MIC90 was 0.03 mg/L (range, 32 mg/L) and Enterococcus faecium (MIC90, >32 mg/L) among the enterococcal species. Time-dependent bactericidal action was observed for doripenem and broth MIC results were slightly greater when compared to agar MIC results. In pilot testing, the optimal doripenem disc concentration was 10 microg, identical to standardized reagents for other clinically available carbapenems. Doripenem appears to be a potent carbapenem with a spectrum resembling currently marketed antipseudomonal carbapenems, but with greater activity when tested against some non-fermentative bacillary strains. Continued evaluation of doripenem against isolates resistant to other beta-lactams appears to be warranted.
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              Antimicrobial activity of doripenem (S-4661): a global surveillance report (2003).

              The spectrum of activity and potency of doripenem, a broad-spectrum parenteral carbapenem currently in clinical development, was evaluated using 16 008 clinical bacterial isolates collected as part of an international surveillance project during 2003. Using reference broth microdilution methods, doripenem was found to be highly active against oxacillin-susceptible Staphylococcus aureus and coagulase-negative staphylococci (2705 and 297 isolates, respectively; MIC90s 0.06 mg/L), with a potency greater than that of other carbapenem antibiotics. Against enterococci (1474 isolates), with the exception of Enterococcus faecium, doripenem displayed modest activity (MIC50 4). Doripenem was among the most potent agents tested against Streptococcus pneumoniae, viridans group streptococci and beta-haemolytic streptococci (885, 140 and 397 isolates; MIC(90)s 0.5, 0.5 and 0.03 mg/L, respectively). For Enterobacteriaceae (> 6200 isolates), doripenem was four- to 32-fold more active than imipenem against wild-type isolates (MIC90s 0.03-0.5 mg/L). MIC90s for confirmed extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae (121 and 155 isolates; 0.06 and 0.12 mg/L, respectively) were two-fold higher than for wild-type isolates. Doripenem was also active against Citrobacter spp., Enterobacter spp. and Serratia spp. (MIC90s 0.06-0.25 mg/L), including ceftazidime-resistant isolates. Doripenem and meropenem were the most active agents among all beta-lactams against Pseudomonas aeruginosa (829 isolates; MIC50/90s 0.5/8 and 0.5/16 mg/L, respectively), whereas doripenem and imipenem were the most active agents against Acinetobacter spp. (155 isolates; MIC50/90s 0.5/4 and
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                October 2007
                October 2007
                : 3
                : 5
                : 789-794
                Affiliations
                Department of Clinical Microbiology, Trinity College Dublin Dublin, Ireland
                Author notes
                Correspondence: Fiona Walsh Department of Clinical Microbiology, Trinity College Dublin, Dublin 8, Ireland Tel +35 1896 3620 Email walshf1@ 123456tcd.ie
                Article
                2376073
                18473003
                © 2007 Dove Medical Press Limited. All rights reserved
                Categories
                Review

                Medicine

                mic, pharmacodynamics, mutant, pharmacokinetics, mbc

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