Potentiation of beta-lactams against Pseudomonas aeruginosa strains by Ro 48-1256, a bridged monobactam inhibitor of AmpC beta-lactamases

Ro 48-1256 is a bridged monobactam inhibitor of Class C beta-lactamases, without significant antibacterial activity of its own. It was tested in combination with imipenem, meropenem, piperacillin and ceftazidime against Pseudomonas aeruginosa isolates, mutants and transconjugants. Imipenem was potentiated against all strains where the AmpC enzyme was inducible or derepressed, with its MICs being reduced from 1-2 mg/L to 0.25-0.5 mg/L for most isolates and from 8-16 mg/L to 1-2 mg/L for those lacking OprD (D2 porin). Ro 48-1256 also abolished in-vitro selection of OprD-deficient mutants by imipenem. Ceftazidime and piperacillin were potentiated against strains derepressed for AmpC enzyme, but not against those where the enzyme remained inducible. For over 90% of AmpC-derepressed organisms, the MICs of ceftazidime were reduced to < or = 8 mg/L by Ro 48-1256 (4 mg/L) and those of piperacillin were reduced to < or = 16 mg/L. Meropenem, which is very stable to AmpC, was not potentiated. Ro 48-1256 did not potentiate piperacillin, ceftazidime or carbapenems when resistance was mediated by Class A, B or D enzymes. Tazobactam, tested as control, had opposite behaviour to Ro 48-1256, potentiating beta-lactams when resistance was due to Class A beta-lactamases but failing to reverse resistance mediated by AmpC. Ro 48-1256 could be used with imipenem to overcome resistance mediated by loss of OprD, or with ceftazidime or piperacillin to overcome derepression of AmpC.