title: 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 Pseudomonas aeruginosa was studied. The geometric mean MICs against three groups of clinical isolates resistant to imipenem, meropenem and both carbapenems were 4.28, 4.08 and 5.44 micrograms/ml, respectively. BO-2727 also inhibited multiply antibiotic resistant isolates and laboratory mutants including a nalB-type mutant, which showed resistance to antibiotics such as imipenem, meropenem, ceftazidime, and/or ciprofloxacin, at less than 1.56 micrograms/ml. Overall, BO-2727 was 4-fold more active than biapenem, meropenem, panipenem and imipenem with an MIC90 of less than 6.25 micrograms/ml. The presence of basic amino acids in minimal medium less affected the antipseudomonal activity to a minimal extent, suggesting that BO-2727 has diverse penetration routes through the outer membrane other than OprD channel, which facilitates the diffusion of basic amino acids and carbapenems. The in vitro activity of BO-2727 reflected 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.
authors.affiliation: Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Japan.
authors.forename: K
authors.initials: K
authors.lastname: Shibata
authors.forename: Y
authors.initials: Y
authors.lastname: Adachi
authors.forename: E
authors.initials: E
authors.lastname: Kato
authors.forename: R
authors.initials: R
authors.lastname: Nagano
authors.forename: A
authors.initials: A
authors.lastname: Fuse
authors.forename: T
authors.initials: T
authors.lastname: Hashizume
authors.forename: N
authors.initials: N
authors.lastname: Ohtake
authors.forename: O
authors.initials: O
authors.lastname: Okamoto
authors.forename: S
authors.initials: S
authors.lastname: Nakagawa
mesh_terms: D000818:Animals; D015780:Carbapenems / Q000494:pharmacology*; D002442:Ceftazidime / Q000494:pharmacology; D002511:Cephalosporins / Q000494:pharmacology; D003470:Culture Media / Q000737:chemistry; D004352:Drug Resistance, Microbial / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics; D006801:Humans; D015378:Imipenem / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D000077731:Meropenem; D051379:Mice; D009154:Mutation; D011552:Pseudomonas Infections / Q000188:drug therapy; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D013845:Thienamycins / Q000494:pharmacology*
chemical_list: D015780:Carbapenems; D002511:Cephalosporins; D003470:Culture Media; D013845:Thienamycins; C085890:BO 2727; D015378:Imipenem; D002442:Ceftazidime; D000077731:Meropenem