title: In-vitro activity of biapenem, compared with imipenem and meropenem, against Pseudomonas aeruginosa strains and mutants with known resistance mechanisms.
abstract: The activity of biapenem (L-627, LJC-10627), a new carbapenem, was investigated against Pseudomonas aeruginosa strains, mutants and isolates with known resistance mechanisms to other beta-lactams. The behaviour of biapenem closely resembled that of imipenem, although it showed minor differences compared with meropenem, Inducible (i.e. normal) or derepressed chromosomal beta-lactamase expression gave slight protection against biapenem and imipenem, but insufficient to raise the MICs above clinically significant limits. This behaviour correlated with the slight lability of these compounds to the purified enzyme and with their strong capacity to induce beta-lactamase synthesis. Inducible or derepressed enzyme gave no protection against meropenem, possibly reflecting this compound's particular ability to deactivate the enzyme. Biapenem also has some ability to reversibly deactivate the enzyme. None of several plasmid-mediated beta-lactamases (TEM-2, PSE-1, -3 or -4; OXA-3,-6,-10,-11; NPS-1 or LCR-1) introduced into a P. aeruginosa PU21 recipient strain reduced susceptibility to biapenem or other carbapenems. Amongst permeability mutants, those lacking the D2 'carbapenem-specific' porin had reduced susceptibility to biapenem as well as to imipenem and meropenem. Biapenem and imipenem insusceptibility in these D2 porin-deficient mutants required continued expression of the chromosomal beta-lactamase, although this did not apply to meropenem. P. aeruginosa isolates and mutants with broad-spectrum insusceptibility ('intrinsic resistance') to penicillins, cephalosporins and unrelated drugs remained fully susceptible to biapenem and imipenem, whilst showing slightly reduced susceptibility to meropenem. Overall, these findings suggest that biapenem, like the earlier carbapenems, should prove to be a useful antipseudomonal agent, overcoming the mechanisms that commonly confer resistance to other classes of antipseudomonal beta-lactams.
authors.affiliation: Department of Medical Microbiology, London Hospital Medical College, UK.
authors.forename: H Y
authors.initials: HY
authors.lastname: Chen
authors.forename: D M
authors.initials: DM
authors.lastname: Livermore
mesh_terms: D002228:Carbenicillin / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D006868:Hydrolysis; D015378:Imipenem / Q000494:pharmacology*; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010403:Penicillin Resistance / Q000235:genetics; D018272:Porins / Q000096:biosynthesis; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D013845:Thienamycins / Q000494:pharmacology*; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D018272:Porins; D013845:Thienamycins; D065093:beta-Lactamase Inhibitors; D015378:Imipenem; D001618:beta-Lactamases; D000077731:Meropenem; D002228:Carbenicillin; C065257:biapenem