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

      review-article
      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.

          Most cited references20

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          Doripenem versus Pseudomonas aeruginosa in vitro: activity against characterized isolates, mutants, and transconjugants and resistance selection potential.

          Doripenem is a broad-spectrum parenteral carbapenem under clinical development in Japan and North America. Its activities against (i) Pseudomonas aeruginosa isolates with graded levels of intrinsic efflux-type resistance, (ii) mutants with various combinations of AmpC and OprD expression, (iii) PU21 transconjugants with class A and D beta-lactamases, and (iv) P. aeruginosa isolates with metallo-beta-lactamases were tested by the agar dilution method of the National Committee for Clinical Laboratory Standards. Selection of resistant P. aeruginosa mutants was investigated in single- and multistep procedures. Doripenem MICs for isolates without acquired resistance mostly were 0.12 to 0.5 microg/ml, whereas meropenem MICs were 0.25 to 0.5 microg/ml and imipenem MICs were 1 to 2 microg/ml. The MICs of doripenem, meropenem, ertapenem, and noncarbapenems for isolates with increased efflux-type resistance were elevated, whereas the MICs of imipenem were less affected. The MICs of doripenem were increased by the loss of OprD but not by derepression of AmpC; nevertheless, and as with other carbapenems, the impermeability-determined resistance caused by the loss of OprD corequired AmpC activity and was lost in OprD- mutants also lacking AmpC. The TEM, PSE, PER, and OXA enzymes did not significantly protect P. aeruginosa PU21 against the activity of doripenem, whereas MICs of > or =16 microg/ml were seen for clinical isolates with VIM and IMP metallo-beta-lactamases. Resistant mutants seemed to be harder to select with doripenem than with other carbapenems (or noncarbapenems), and the fold increases in the MICs were smaller for the resistant mutants. Single-step doripenem mutants were mostly resistant only to carbapenems and had lost OprD; multistep mutants had broader resistance, implying the presence of additional mechanisms, putatively including up-regulated efflux. Most mutants selected with aminoglycosides and quinolones had little or no cross-resistance to carbapenems, including doripenem.
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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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                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
                0d105b6e-46d3-4a6d-9ffe-e2997e8b24ef
                © 2007 Dove Medical Press Limited. All rights reserved
                History
                Categories
                Review

                Medicine
                mbc,pharmacokinetics,mutant,pharmacodynamics,mic
                Medicine
                mbc, pharmacokinetics, mutant, pharmacodynamics, mic

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