David M Livermore1, Shazad Mushtaq, Marina Warner. 1. Antibiotic Resistance Monitoring & Reference Laboratory, Health Protection Agency Centre for Infections, 61 Colindale Avenue, London, NW9 5EQ, UK. david.livermore@hpa.org.uk
Abstract
BACKGROUND: Razupenem (previously known as PTZ601, PZ-601, SMP-601 or SM-216601) is a novel carbapenem, active against Enterobacteriaceae as well as Gram-positive bacteria including methicillin-resistant staphylococci and enterococci. METHODS: We examined the effect of extended-spectrum beta-lactamases (ESBLs) and AmpC beta-lactamases on the activity of razupenem, using the CLSI agar dilution method to measure MICs for mutants, transconjugants and isolates with and without these enzymes. RESULTS: ESBLs had no effect on the activity of razupenem against Escherichia coli and Klebsiella spp., and only a small effect when coupled with outer membrane impermeability. Inducible or, more especially, derepressed AmpC enzymes gave some protection, with most AmpC-derepressed Enterobacter and Citrobacter spp. requiring MICs of approximately 8 mg/L. This relative resistance was further increased when porins were lost, restricting drug uptake. Metallo- and class A-carbapenemases conferred resistance, with MICs > or =16 mg/L. CONCLUSIONS: Razupenem has good activity against ESBL producers, but is affected by AmpC enzymes, especially when derepressed and coupled with outer membrane impermeability; its activity is also compromised by carbapenemases.
BACKGROUND:Razupenem (previously known as PTZ601, PZ-601, SMP-601 or SM-216601) is a novel carbapenem, active against Enterobacteriaceae as well as Gram-positive bacteria including methicillin-resistant staphylococci and enterococci. METHODS: We examined the effect of extended-spectrum beta-lactamases (ESBLs) and AmpC beta-lactamases on the activity of razupenem, using the CLSI agar dilution method to measure MICs for mutants, transconjugants and isolates with and without these enzymes. RESULTS: ESBLs had no effect on the activity of razupenem against Escherichia coli and Klebsiella spp., and only a small effect when coupled with outer membrane impermeability. Inducible or, more especially, derepressed AmpC enzymes gave some protection, with most AmpC-derepressed Enterobacter and Citrobacter spp. requiring MICs of approximately 8 mg/L. This relative resistance was further increased when porins were lost, restricting drug uptake. Metallo- and class A-carbapenemases conferred resistance, with MICs > or =16 mg/L. CONCLUSIONS:Razupenem has good activity against ESBL producers, but is affected by AmpC enzymes, especially when derepressed and coupled with outer membrane impermeability; its activity is also compromised by carbapenemases.