In Vitro and In Vivo Evaluation of BO-2727 against Imipenem- and/or Meropenem-resistant Pseudomonas aeruginosa.

Abstract

The in vitro and in vivo activity of BO-2727,a carbapenem antibiotic, against resistant clinical isolates of Pseudomonasaeruginosa was studied. The geometric meanMICsagainst three groups of clinical isolates resistant to imipenem, meropenem and both carbapenems were 4.28, 4.08 and 5.44 /zg/ml, respectively. BO-2727 also inhibited multiply antibiotic resistant isolates and laboratory mutants including a nalB-typQ mutant, which showed resistance to antibiotics such as imipenem, meropenem, ceftazidime, and/or ciprofloxacin, at less than 1.56 /ig/ml. Overall, BO-2727 was 4-fold more active than biapenem, meropenem, panipenem and imipenem with an MIC90of less than 6.25/Lig/mlThe presence of basic amino acids in minimal mediumless affected the antipseudomonal activity to a minimal extent, suggesting that BO-2727has diverse penetration routes through the outer membraneother than OprDchannel, which facilitates the diffusion of basic amino acids and carbapenems. The in vitro activity of BO-2727reflected well in its therapeutic efficacy in experimental systemic infection in mice. These results suggest a possibility for the development of antipseudomonal carbapenems having activity against imipenem-and/or meropenem-resistant P. aeruginosa as well as a broad spectrum encompassing Gram-positive and -negative bacteria.Since the discovery of thienamycin1^carbapenem antibiotics are knownto have a broad spectrum encompassing both Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa. However, the recent problems are the emergenceof carbapenem-resistant P. aeruginosa, in which the mechanismsof resistance are a) deficiency or decreased amount of OprDof the outer membrane, which facilitates the diffusion of carbapenem and basic amino acids2~5), b) nalB mutation responsible for multiple resistance to cephems, quinolones, tetracyclines as well as meropenem5) and c) the evolution of a class B metallo-/Mactamase capable of hydrolyzing carbapenems6).