title: What remains against carbapenem-resistant Enterobacteriaceae? Evaluation of chloramphenicol, ciprofloxacin, colistin, fosfomycin, minocycline, nitrofurantoin, temocillin and tigecycline.
abstract: Carbapenem-resistant Enterobacteriaceae present an increasing and diverse problem, including strains of multiple species with metallo-β-lactamases (IMP, NDM or VIM) and non-metallo (KPC and OXA-48) enzymes as well as those combining an extended-spectrum β-lactamase (ESBL) or AmpC enzyme with porin loss. Most strains, except those with OXA-48 alone, are broadly resistant to β-lactams and have multiple aminoglycoside-modifying enzymes; those with NDM-1 carbapenemase typically also have 16S rRNA methylases, conferring complete aminoglycoside resistance. In this study, the activity of chloramphenicol, ciprofloxacin, colistin, fosfomycin, minocycline, nitrofurantoin, temocillin and tigecycline was evaluated against 81 carbapenem-resistant Enterobacteriaceae isolates from the UK. Testing was performed by the Clinical and Laboratory Standards Institute (CLSI) agar dilution method. Chloramphenicol, ciprofloxacin and nitrofurantoin inhibited <25% of the isolates at the breakpoint, whereas colistin was active against 75/81 isolates (92.6%), the exceptions being four Klebsiella pneumoniae and Enterobacter cloacae isolates along with members of inherently resistant genera. Fosfomycin was active against 49/81 isolates (60.5%), including 7/7 Escherichia coli, 16/20 Enterobacter and Citrobacter spp., but only 25/52 Klebsiella spp. Tigecycline was active against 38/81 isolates (46.9%) and was intermediate against another 27 (33.3%), with resistance scattered amongst K. pneumoniae and Enterobacter spp. The activity of colistin, fosfomycin and tigecycline was unrelated to the isolates' carbapenem resistance mechanisms. Temocillin was fully active [minimum inhibitory concentration (MIC) ≤8 mg/L] against only 4/81 isolates (4.9%), but inhibited a further 22 isolates (27.2%) at the British Society for Antimicrobial Chemotherapy (BSAC) urinary breakpoint (32 mg/L), predominantly comprising those isolates with combinations of impermeability and an ESBL or AmpC enzyme, along with 6/11 isolates producing KPC carbapenemases. Studies with transconjugants and transformants confirmed the small effect of KPC enzymes against temocillin, whereas OXA-48 and NDM-1 conferred clear resistance.
authors.affiliation: Antibiotic Resistance Monitoring & Reference Laboratory, Health Protection Agency Microbiology Services-Colindale, 61 Colindale Avenue, London NW9 5EQ, UK. david.livermore@hpa.org.uk
authors.forename: David M
authors.initials: DM
authors.lastname: Livermore
authors.forename: Marina
authors.initials: M
authors.lastname: Warner
authors.forename: Shazad
authors.initials: S
authors.lastname: Mushtaq
authors.forename: Michel
authors.initials: M
authors.lastname: Doumith
authors.forename: Jiancheng
authors.initials: J
authors.lastname: Zhang
authors.forename: Neil
authors.initials: N
authors.lastname: Woodford
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000096:biosynthesis*; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000201:enzymology / Q000302:isolation & purification; D004756:Enterobacteriaceae Infections / Q000382:microbiology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D006113:United Kingdom; D018440:beta-Lactam Resistance; D001618:beta-Lactamases / Q000096:biosynthesis*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001618:beta-Lactamases; C063912:carbapenemase