David Livermore

..015 to 0.5 microg/ml. RWJ-54428 did not select resistant mutants of MRSA or enterococci in challenge experiments and has the potential to be useful for the treatment of infections caused by gram-positive cocci...

..We tested BAL30376 and its components versus isolates and laboratory strains of Enterobacteriaceae and non-fermenters...

..For a resistance to 'succeed', it needs to have a mechanism that imposes little fitness burden, along with a biologically 'fit' host strain or strains. Once this combination arises, control is extremely difficult...

..If resistance is unlikely to be reduced significantly by changing prescription practices, how can clinicians outpace increased resistance, particularly when much of 'big pharma' is abandoning antibiotic development?..

..Irrespective of the particular enzyme, most producers are multiresistant. These changing patterns present major therapeutic and infection control challenges, with the public health intervention points unclear...

..In settings where these are unlikely or are covered by other agents, temocillin may be useful, potentially 'sparing' carbapenems and having little apparent potential to select for Clostridium difficile...

..Stabilisation or decline in penicillin resistance has occurred in Ireland despite stable or increasing oral beta-lactam sales...

..Tony Fink's work contributed greatly to our understanding of the mechanisms and active site function of beta-lactamases and this knowledge now informs the search for new beta-lactams and beta-lactamase inhibitors...

..TR-700 is the active moiety of TR-701 (DA-7157), a new oral/intravenous oxazolidinone prodrug. We examined its activity against linezolid-susceptible and -resistant staphylococci and enterococci...

..This review discusses the epidemiology and microbiology of these resistance problems, along with possible solutions...

..Unless antibacterial development is re-energised, there is a serious risk that a growing proportion of infections, especially in hospitals, will become effectively untreatable...

..There is, however, concern that this use will select for resistances to imipenem and meropenem in nosocomial pathogens, notably Pseudomonas aeruginosa, and we investigated the validity of this concern...

..MICs of CXA-101 were 2- to 16-fold below those of ceftazidime for multiresistant P. aeruginosa from CF patients, but ranged up to > 128 mg/L; values for B. cepacia from CF resembled those for ceftazidime...

..Last, there is a need to re-invigorate antimicrobial development, which has been downgraded by many major pharmaceutical houses...

..It is also likely to find a role in the treatment of infections due to multiresistant pathogens, including Acinetobacter spp. and ESBL producers, as well as MRSA and enterococci...

..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...

..This difference was significant (P=0.003), although the patients receiving nebulised drug were mostly younger, included trauma cases and were at a hospital with good outcomes...

..A final and surprising problem is Neisseria gonorrhoeae, where each good oral agent has been eroded in turn and where there is now little in reserve behind the oral oxyimino cephalosporins, to which low-level resistance is emerging...

..Combinations of clavulanate with modern anti-methicillin-resistant Staphylococcus aureus cephalosporins also deserve investigation, as these compounds remain labile to ESBLs...

..RWJ-416457 MICs for mutants with 23S rRNA mutations were 2 to 32 microg/ml, versus linezolid MICs of 8 to 64 microg/ml; actual values reflected the proportion of gene copies mutated...

..To assess ciprofloxacin resistance among Escherichia coli isolates from bacteraemia patients in England in relation to age, sex and Region...

..Nevertheless, if ertapenem is to be used widely, its effects on the resistance ecology need to be monitored carefully...

..Reflecting this importance, members of the family constitute 4 of the 12 collection groups in the British Society for Antimicrobial Chemotherapy (BSAC) Bacteraemia Surveillance Programme...

..We examined whether combinations of oxyimino-cephalosporins with NXL104, a novel non-beta-lactam beta-lactamase inhibitor, overcame these resistances...

..Studies with transconjugants and transformants confirmed the small effect of KPC enzymes against temocillin, whereas OXA-48 and NDM-1 conferred clear resistance...

..Pseudomonas spp. are collected in the British Society for Antimicrobial Chemotherapy (BSAC) bacteraemia surveillance, with Acinetobacter spp. and Stenotrophomonas maltophilia well represented in the 'other Gram-negatives' group...

..Clinical utility will depend also on a drug's ability to reach intracellular shigellae in the intestinal epithelium and this deserves exploration for clavulanic acid and faropenem...

..It seems best-and pragmatic-that the term 'ESBL' retains its broad modern usage, but that should always be accompanied by mention of the enzyme's family as, e.g., in 'TEM ESBL' or 'OXA ESBL', not as a sole moniker...

..Chromogenic tests might usefully shorten this delay, and we investigated the Cica-beta-Test for this purpose...

..They included 53 Klebsiella spp., 19 Enterobacter spp., 6 Escherichia coli and 4 others; most were multiresistant. Genes were identified by PCR and sequencing; MICs were measured by CLSI agar dilution...

..One that does have increased anti-Gram-negative activity, compared with earlier analogues, is tigecycline, a glycylcycline derivative of minocycline...

..There is presently a paradox whereby vancomycin is agreed to be less than ideal, with outcomes impaired against MRSA with modestly raised MICs, but where new agents have yet to demonstrate unequivocal superiority...

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..Disturbingly, there is a near-total lack of developmental antibiotics active against gram-negative pathogens...

..A phase II trial in skin and skin structure infection recorded cures by ceftobiprole in 4/4 MRSA infections, and results of the phase III trials are awaited with great interest...

..Thus, if disc tests suggest that an isolate is marginally resistant to piperacillin/tazobactam and the drug is sought as therapy, it is recommended that MIC be determined with, e.g., an Etest...

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..with the KPC enzyme, but metallo-?-lactamase producers were resistant. Aztreonam-NXL104 was active against all carbapenemase producers at 4 and 4 ?g/ml, including those with metallo-?-lactamases...

..The aim of this study was to investigate the presence of VEB enzymes among Pseudomonas spp. referred to the UK's national reference laboratory and with phenotypic evidence of extended-spectrum beta-lactamase (ESBL) production...

..Ceftaroline (PPI-0903M, T-91825) is a novel cephalosporin, administered as an N-phosphono prodrug. We investigated its in vitro activity and resistance selection potential...

..and against laboratory P. aeruginosa strains with defined resistance mechanisms...

..Overexpressed mexA or ampC and reduced oprD were associated with beta-lactam resistance. A specific combination of mexR, nalC, and nalD mutations occurred in 11 Liverpool strain isolates, including 7 with upregulated mexA...

..baumannii clones. The role of AdeABC in the emergence of tigecycline resistance during therapy was also investigated for two representatives of the prevalent UK lineage, OXA-23 clone 1...

..5 microg/ml) of E. coli derivatives with cloned IMP-1 and NMC-A beta-lactamases suggested that carbapenem resistance might require other factors besides the enzymes...

..2% and 35.4%, respectively). We sought to determine the proportions of these strains before and after the general decline in MRSA bacteraemia that began around 2004...

..To describe the current patterns and trends in antimicrobial susceptibility in enterococci and streptococci (excepting pneumococci) from bacteraemia in the UK and Ireland from 2001 to 2006...

..Most mutants selected with aminoglycosides and quinolones had little or no cross-resistance to carbapenems, including doripenem...

..AZD2563 was equally active against the surveillance isolates and those that had been selected for their multiresistance to other agents. The MICs of AZD2563 were either the same as those of linezolid or two-fold lower...

..Further work is needed to characterize these two 'epidemic' E. faecalis strains and to investigate the presence of virulence genes...

..For now, the best pharmaceutical strategy seems to lie in the development of novel antimicrobial classes with anti-Gram-negative activity, rather than in overcoming carbapenemases directly...

..1% in 1990 to 10.5% in 1996 and 10.9% in 1999. For both Klebsiella and Enterobacter spp., most resistance was localized in a few centers. Resistance was infrequent and scattered in P. mirabilis, but reached a prevalence of 3.3% in 1999...

..In conclusion, carbapenems, colistin and minocycline retained greatest activity against the Acinetobacter isolates collected. Tigecycline was less active than minocycline, but both agents overcame most tetracycline resistance...

..Both assays detected isolates heterozygous at this position. Recognition of isolates with what is presently the most frequent oxazolidinone resistance mutation may aid surveillance and individual case management...

..We investigated the tazobactam concentrations needed to potentiate this cephalosporin against strains with these mechanisms...

..Their spread is forcing the use of unorthodox therapies, principally colistin and tigecycline, although the optimal regimens remain uncertain...

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..Overall, the best that can reasonably be anticipated is an improved balance between the accumulation of resistance and new antibacterial development...

..We therefore evaluated faropenem, a penem in Phase III development, against recently collected oxyimino-cephalosporin-resistant bacteria...

..Most isolates (28 of 30) also had bla(OXA-51). We conclude that bla(OXA-58) is geographically widespread and has occurred in Acinetobacter spp. for over 10 years...

..coli belonging to the international uropathogenic ST131 clone...

..coli...

..The emergence of antibiotic resistance is inevitable, but we must seek to decrease its impact and prolong the effectiveness of the agents available to us...

..To describe the emergence of linezolid-resistant methicillin-resistant Staphylococcus aureus (MRSA) of sequence type (ST)36 lineage in two paediatric patients with cystic fibrosis, after long-term low-dose linezolid treatment...

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..coli O25b:H4 ST131 clone that commonly produces this enzyme. We describe rapid real-time polymerase chain reaction (PCR) assays able to detect E. coli belonging to the ST131 clone and to identify bla(CTX-M-15)-like...

..Treatment with ciprofloxacin, a substrate of AcrAB in E. cloacae, possibly selected for cross-resistance to tigecycline as a result of RamA-mediated AcrAB upregulation...

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..KPC-type carbapenemases are increasingly prevalent in parts of the USA and Israel and are an emerging concern in South America, Europe and China. We investigated the UK's first two KPC-producing Klebsiella pneumoniae isolates...

..Mutants of one E. faecalis isolate had a G2576-->U 23S rRNA mutation; mutants derived from the second E. faecalis isolate lacked this mutation...

..8%, 5.4% and 13% of the isolates, respectively. These results show that the large majority of pneumococci were susceptible to moxifloxacin in 2003, the year when it was licensed for clinical use in the UK...

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..Genes encoding OXA-58 were detected (with bla(OXA-51-like)) in a cluster of related isolates from a single hospital. This simple assay will assist in monitoring the mechanisms responsible for carbapenem resistance in Acinetobacter spp...

..To investigate the molecular epidemiology of Enterobacteriaceae producing extended-spectrum beta-lactamases (ESBLs) in London and South-East England...

..Hypermutability among natural E. coli populations might facilitate the emergence of resistance to fosfomycin. We therefore examined the prevalence of mutators amongst urinary isolates of E. coli producing CTX-M beta-lactamases...

..To determine the distribution of acquired AmpC beta-lactamases in 173 isolates of Escherichia coli and Klebsiella spp. submitted to the UK's national reference laboratory for antibiotic resistance...

..These findings suggest that national and local treatment guidelines need to be reviewed urgently...

..or an AmpC enzyme in Enterobacter spp. - plus impermeability and/or increased efflux. Imipenem and meropenem often remain moderately active against isolates with low-level ertapenem resistance...

..Of these, 58 isolates belonged to UK strain A, a variant of the international ST131 clone. Here we investigated the remaining 60 ESBL producers...

..These results suggest that ISAba1 is providing the promoter for blaOXA-51-like and, probably, for blaOXA-23-like...

..They produced a novel integron-associated metallo-beta-lactamase, designated IMP-7, with 91% identity to IMP-1. bla(IMP-7) was not detected with standard bla(IMP)-specific primers, owing to mismatches in the forward primer...

..Both isolates also had group 1 CTX-M-type ESBLs and had lost major outer membrane proteins. OXA-48-like carbapenemases appear to be scattered in Turkey and surveillance to determine their prevalence is warranted...

..Treatment options were limited, although the isolates were susceptible to polymyxin B in vitro. The strain contributed to the deaths of five patients...

..Elevated resistance to piperacillin + tazobactam was not associated with porin change in any ESBL producer examined, but has been found by others...

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..The two mechanisms of resistance, mediated by sul2 and modified folP, were detected in isolates from both the United Kingdom and Kenya...

..Strict measures are required in order to control a further spread of resistance...

..The pI 8.4 activity was an AmpC-type enzyme. Determinants of the pI 5.6 and 7.6 activities were not identified...

..pneumoniae at this Korean hospital was largely co-mediated by production of plasmid-mediated AmpC beta-lactamases along with lack or greatly diminished expression of OmpK35 and OmpK36 porins...

..All 4 isolates belonged to the same strain and produced a group 1 CTX-M enzyme; additionally, the resistant isolates had lost a porin...

..When choosing antibiotic therapy, the risk of development of resistance to cephalosporins should be considered in infections caused by M. morganii and other Gram-negative organisms with inducible AmpC beta-lactamases...

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..It is associated with various beta-lactamases, including PER-1 and VIM metalloenzymes. This work further demonstrates the value of MLST of P. aeruginosa...

..To test this hypothesis, we examined the fitness impact of four naturally occurring sul2-coding plasmids upon their hosts...