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Войти в исследования The Journal of antimicrobial chemotherapy · 2013
Activity of biapenem (RPX2003) combined with the boronate β-lactamase inhibitor RPX7009 against carbapenem-resistant Enterobacteriaceae.
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Livermore David M, Mushtaq Shazad
Аннотация
OBJECTIVES: The proliferation of carbapenemases in Enterobacteriaceae demands new therapies, with current interest centred on β-lactamase inhibitor combinations. RPX7009 is a new boron-based inhibitor of several class A and C β-lactamases and is being developed in combination with biapenem (RPX2003). We investigated the in vitro activity of the combination.
METHODS: Three hundred Enterobacteriaceae isolates, representing major carbapenemase types, were tested. MICs were determined by CLSI agar dilution with RPX7009 at 2, 4 and 8 mg/L or in a chequerboard format with RPX7009 in doubling dilutions from 0.25 to 32 mg/L.
RESULTS: RPX7009 lacked direct antibacterial activity but achieved a dose-dependent potentiation of biapenem against Enterobacteriaceae possessing KPC, SME or IMI/NMC-A carbapenemases: concentrations as low as 2 mg/L reduced the MICs of biapenem to ≤1 mg/L for over 90% of isolates. RPX7009 also gave a weak potentiation of biapenem against Enterobacteriaceae with combinations of AmpC or extended-spectrum β-lactamase activity and impermeability, although any practical gain against such strains will depend on the breakpoints assigned. RPX7009 had no effect on the MICs of biapenem for isolates with metallo- (IMP, NDM or VIM) or OXA-48 β-lactamases; however, most isolates with these enzymes were less resistant to biapenem than to imipenem or, especially, ertapenem.
CONCLUSIONS: Biapenem/RPX7009 (Carbavance) overcame most resistance due to KPC and other class A carbapenemases. Class B and D carbapenemases were not inhibited but conferred less consistent resistance to biapenem than to other carbapenems.
METHODS: Three hundred Enterobacteriaceae isolates, representing major carbapenemase types, were tested. MICs were determined by CLSI agar dilution with RPX7009 at 2, 4 and 8 mg/L or in a chequerboard format with RPX7009 in doubling dilutions from 0.25 to 32 mg/L.
RESULTS: RPX7009 lacked direct antibacterial activity but achieved a dose-dependent potentiation of biapenem against Enterobacteriaceae possessing KPC, SME or IMI/NMC-A carbapenemases: concentrations as low as 2 mg/L reduced the MICs of biapenem to ≤1 mg/L for over 90% of isolates. RPX7009 also gave a weak potentiation of biapenem against Enterobacteriaceae with combinations of AmpC or extended-spectrum β-lactamase activity and impermeability, although any practical gain against such strains will depend on the breakpoints assigned. RPX7009 had no effect on the MICs of biapenem for isolates with metallo- (IMP, NDM or VIM) or OXA-48 β-lactamases; however, most isolates with these enzymes were less resistant to biapenem than to imipenem or, especially, ertapenem.
CONCLUSIONS: Biapenem/RPX7009 (Carbavance) overcame most resistance due to KPC and other class A carbapenemases. Class B and D carbapenemases were not inhibited but conferred less consistent resistance to biapenem than to other carbapenems.