Activity of ceftazidime/avibactam against problem Enterobacteriaceae and Pseudomonas aeruginosa in the UK, 2015-2016

Background: Ceftazidime/avibactam combines an established oxyimino-cephalosporin with the first diazabicyclooctane β-lactamase inhibitor to enter clinical use. We reviewed its activity against Gram-negative isolates, predominantly from the UK, referred for resistance investigation in the first year of routine testing, beginning in July 2015. Methods: Isolates were as received from referring laboratories; there is a bias to submit those with suspected carbapenem resistance. Identification was by MALDI-TOF mass spectroscopy, and susceptibility testing by BSAC agar dilution. Carbapenemase genes were sought by PCR; other resistance mechanisms were inferred using genetic data and interpretive reading. Results: Susceptibility rates to ceftazidime/avibactam exceeded 95% for: (i) Enterobacteriaceae with KPC, GES or other Class A carbapenemases; (ii) Enterobacteriaceae with OXA-48-like enzymes; and (iii) for ESBL or AmpC producers, even when these had impermeability-mediated ertapenem resistance. Almost all isolates with metallo-carbapenemases were resistant. Potentiation of ceftazidime by avibactam was seen for 87% of ceftazidime-resistant Enterobacteriaceae with ‘unassigned’ ceftazidime resistance mechanisms, including two widely referred groups of Klebsiella pneumoniae where no synergy was seen between cephalosporins and established β-lactamase inhibitors. Potentiation here may be a diazabicyclooctane/cephalosporin enhancer effect. Activity was seen against Pseudomonas aeruginosa with derepressed AmpC, but not for those with efflux-mediated resistance. Conclusions: Of the available β-lactams or inhibitor combinations, ceftazidime/avibactam has the widest activity spectrum against problem Enterobacteriaceae, covering all major types except metallo-carbapenemase producers; against P. aeruginosa it has a slightly narrower spectrum than ceftolozane/tazobactam, which also covers efflux-type resistance

Clinical isolates of salmonella enterica serovar agona producing NDM-1 metallo-beta-lactamase: first report from Pakistan

We report two cases of infantile diarrhea due to multidrug-resistant, NDM-1 metallo-beta-lactamase-producing Salmonella enterica serovar Agona from Pakistan. This study alerts toward possible risk of NDM-1 transmission to enteric fever pathogens and encourages microbiologists to consider active screening of carbapenem resistance in nontyphoidal Salmonella isolates

Carbapenemase-producing Enterobacteriaceae in hospital wastewater:a reservoir that may be unrelated to clinical isolates [star]

Summary Background: Carbapenemase-producing Enterobacteriaceae (CPE) are an emerging infection control problem in hospitals worldwide. Identifying carriers can help reduce potential spread and infections. Aim: To assess whether testing hospital wastewater for CPE can supplement patient based screening for infection prevention purposes in a hospital without a recognised endemic CPE problem. Methods: Wastewater collected from hospital pipework on 16 occasions during February-March 2014 was screened for CPE using chromID®CARBA agar and chromID®CPS agar with a 10 μg ertapenem disc and combination disc testing. MICs were determined using British Society for Antimicrobial Chemotherapy methodology and carbapenemase genes detected by PCR or wholegenome sequencing. Selected isolates were typed by PFGE. Findings: Suspected CPE were recovered from all 16 wastewater samples. Of 17 isolates sent to Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, six (four Citrobacter freundii and two Enterobacter cloacae complex) were New Delhi metallo–beta-lactamase (NDM) producers and the remaining 11 (six Klebsiella oxytoca and five Enterobacter cloacae complex), Guiana-Extended-Spectrum-5 (GES-5) producers, the first to be described in Enterobacteriaceae in the UK. The four NDM-producing C. freundii, two NDM-producing E. cloacae complex and 4/5 GES-5-producing E. cloacae complex were each indistinguishable isolates of the same three strains, whereas the six GES-5-producing K. oxytoca overall shared 79% similarity. Conclusion: CPE are readily isolated from hospital wastewater using simple culture methods. There are either undetected carriers of CPE excreting into the wastewater, or these CPE represent colonisation of the pipework. Surveillance of hospital wastewater for CPE does not appear helpful for infection control purposes

Carbapenem-resistant enterobacterales, carbapenem resistant organisms, carbapenemase-producing enterobacterales, and carbapenemase-producing organisms:Terminology past its 'sell-by-date' in an era of new antibiotics and regional carbapenemase epidemiology

Carbapenem resistance in Gram-negative bacteria is a public health concern. Consequently, numerous government and agency reports discuss carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant organisms (CROs). Unfortunately, these terms are fuzzy. Do they include (1) Proteeae with inherent imipenem resistance; (2) porin-deficient Enterobacterales resistant to ertapenem but not other carbapenems; (3) Enterobacterales with OXA-48-like enzymes that remain "carbapenem susceptible" at breakpoint; and (4) Pseudomonas aeruginosa that merely lack porin OprD? Counting CPE or CPOs is better but still insufficient, because different carbapenemases have differing treatment implications, particularly for new β-lactam/β-lactamase inhibitor combinations. At the least, it is essential for authors, journals, and regulatory agencies to specify the carbapenemases meant. The future may demand even greater precision, for mutations can alter hydrolytic activity, and the ability to confer resistance, within carbapenemase families

OXA-48-like carbapenemases in the UK: an analysis of isolates and cases from 2007 to 2014

Objectives: OXA-48-like carbapenemases have spread worldwide since 2001. We analysed patient and microbiological data for UK isolates with these enzymes as confirmed by the national reference laboratory from November 2007 - December 2014.  Methods: MICs were determined using BSAC agar dilution. Isolates with reduced susceptibility or resistance to at least one carbapenem and high-level resistance to both piperacillin/tazobactam (MIC ≥ 64 mg/L) and temocillin (MICs ≥ 128 mg/L) were screened by PCR for blaOXA-48-like genes. The genomes of around half of the isolates were sequenced, with MLST types, resistance genes and plasmid replicon types inferred. Patient data provided by sending laboratories were reviewed.  Results: Isolates (n=741) with OXA-48-like carbapenemases were submitted from 111 UK laboratories, representing 536 patients. Almost all (99%; 736/741) were Enterobacteriaceae, predominantly Klebsiella pneumoniae (55%; 408), and most (80%; 595) were from inpatients. WGS of 351 non-duplicate isolates identified blaOXA-48 as the most common variant, found in two-thirds (235/351) of isolates, followed by blaOXA-181 (68), blaOXA-232 (32), blaOXA-244 (10), blaOXA-484 (5) and blaOXA-245 (1). Among K. pneumoniae (163/351), E.coli (114/351), and E. cloacae (42/351), 119 STs were identified. Mapping analyses revealed that 63% (222/351) of isolates harboured plasmids that shared >99% identity to one of four known plasmids; pOXA-48a (44%; 154/351), pOXA-232 (10%; 34/351), pOXA181 (9%; 30/351), and pKP3-A (1%; 4/351); the remaining 37% of isolates harboured blaOXA-48-like in unknown environments.  Conclusions: OXA-48-like carbapenemases are an increasing problem in the UK. This study highlights both the role of successful plasmids and polyclonal nature of their dissemination

OXA-1 β-lactamase and non-susceptibility to penicillin/β-lactamase inhibitor combinations among ESBL-producing Escherichia coli

Background ESBL-producing Escherichia coli have expanded globally since the turn of the century and present a major public health issue. Their in vitro susceptibility to penicillin/inhibitor combinations is variable, and clinical use of these combinations against ESBL producers remains controversial. We hypothesized that this variability related to co-production of OXA-1 penicillinase. Methods During a national study we collected 293 ESBL-producing E. coli from bacteraemias, determined MICs by BSAC agar dilution, and undertook genomic sequencing with Illumina methodology. Results The collection was dominated by ST131 (n = 188 isolates, 64.2%) and bla CTX-M-15 (present in 229 isolates, 78.2%); over half the isolates (159/293, 54.3%) were ST131 with bla CTX-M-15. bla OXA-1 was found in 149 ESBL producers (50.9%) and bla TEM-1/191 in 137 (46.8%). Irrespective of whether all isolates were considered, or ST131 alone, there were strong associations (P < 0.001) between co-carriage of bla OXA-1 and reduced susceptibility to penicillin/inhibitor combinations, whereas there was no significant association with co-carriage of bla TEM-1/191. For piperacillin/tazobactam the modal MIC rose from 2 mg/L in the absence of bla OXA-1 to 8 or 16 mg/L in its presence; for co-amoxiclav the shift was smaller, from 4 or 8 to 16 mg/L, but crossed the breakpoint. bla OXA-1 was strongly associated with co-carriage also of aac(6′)-Ib-cr, which compromises amikacin and tobramycin. Conclusions Co-carriage of OXA-1, a penicillinase with weak affinity for inhibitors, is a major correlate of resistance to piperacillin/tazobactam and co-amoxiclav in E. coli and is commonly associated with co-carriage of aac(6′)-Ib-cr, which narrows aminoglycoside options