Antibiotic resistance is a major public health concern, with fears expressed that we shortly will run out of antibiotics. In reality, the picture is more mixed, improving against some pathogens but ...worsening against others. Against methicillin-resistant Staphylococcus aureus (MRSA)—the highest profile pathogen—the range of treatment options is expanding, with daptomycin, linezolid and tigecycline all launched, and telavancin, ceftobiprole, ceftaroline and dalbavancin anticipated. There is a greater problem with enterococci, especially if, as in endocarditis, bactericidal activity is needed and the isolate has high-level aminoglycoside resistance; nevertheless, daptomycin, telavancin and razupenem all offer cidal potential. Against Enterobacteriaceae, the rapid and disturbing spread of extended-spectrum β-lactamases, AmpC enzymes and quinolone resistance is forcing increased reliance on carbapenems, with resistance to these slowly accumulating via the spread of metallo-, KPC and OXA-48 β-lactamases. Future options overcoming some of these mechanisms include various novel β-lactamase-inhibitor combinations, but none of these overcomes all the carbapenemase types now circulating. Multiresistance that includes carbapenems is much commoner in non-fermenters than in the Enterobacteriaceae, depending mostly on OXA carbapenemases in Acinetobacter baumannii and on combinations of chromosomal mutation in Pseudomonas aeruginosa. No agent in advanced development has much to offer here, though there is interest in modified, less-toxic, polymyxin derivatives and in the siderophore monobactam BAL30072, which has impressive activity against A. baumannii and members of the Burkholderia cepacia complex. 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.
Summary Klebsiella pneumoniae carbapenemases (KPCs) were originally identified in the USA in 1996. Since then, these versatile β-lactamases have spread internationally among Gram-negative bacteria, ...especially K pneumoniae , although their precise epidemiology is diverse across countries and regions. The mortality described among patients infected with organisms positive for KPC is high, perhaps as a result of the limited antibiotic options remaining (often colistin, tigecycline, or aminoglycosides). Triple drug combinations using colistin, tigecycline, and imipenem have recently been associated with improved survival among patients with bacteraemia. In this Review, we summarise the epidemiology of KPCs across continents, and discuss issues around detection, present antibiotic options and those in development, treatment outcome and mortality, and infection control. In view of the limitations of present treatments and the paucity of new drugs in the pipeline, infection control must be our primary defence for now.
In the 1980s, gram-negative pathogens appeared to have been beaten by oxyimino-cephalosporins, carbapenems, and fluoroquinolones. Yet these pathogens have fought back, aided by their membrane ...organization, which promotes the exclusion and efflux of antibiotics, and by a remarkable propensity to recruit, transfer, and modify the expression of resistance genes, including those for extended-spectrum β-lactamases (ESBLs), carbapenemases, aminoglycoside-blocking 16S rRNA methylases, and even a quinolone-modifying variant of an aminoglycoside-modifying enzyme. Gram-negative isolates--both fermenters and non-fermenters--susceptible only to colistin and, more variably, fosfomycin and tigecycline, are encountered with increasing frequency, including in Korea. Some ESBLs and carbapenemases have become associated with strains that have great epidemic potential, spreading across countries and continents; examples include Escherichia coli sequence type (ST)131 with CTX-M-15 ESBL and Klebsiella pneumoniae ST258 with KPC carbapenemases. Both of these high-risk lineages have reached Korea. In other cases, notably New Delhi Metallo carbapenemase, the relevant gene is carried by promiscuous plasmids that readily transfer among strains and species. Unless antibiotic stewardship is reinforced, microbiological diagnosis accelerated, and antibiotic development reinvigorated, there is a real prospect that the antibiotic revolution of the 20th century will crumble.
Summary Background Not all patients infected with NDM-1-positive bacteria have a history of hospital admission in India, and extended-spectrum β-lactamases are known to be circulating in the Indian ...community. We therefore measured the prevalence of the NDM-1 gene in drinking water and seepage samples in New Delhi. Methods Swabs absorbing about 100 μL of seepage water (ie, water pools in streets or rivulets) and 15 mL samples of public tap water were collected from sites within a 12 km radius of central New Delhi, with each site photographed and documented. Samples were transported to the UK and tested for the presence of the NDM-1 gene, blaNDM-1 , by PCR and DNA probing. As a control group, 100 μL sewage effluent samples were taken from the Cardiff Wastewater Treatment Works, Tremorfa, Wales. Bacteria from all samples were recovered and examined for blaNDM-1 by PCR and sequencing. We identified NDM-1-positive isolates, undertook susceptibility testing, and, where appropriate, typed the isolates. We undertook Inc typing on blaNDM-1 -positive plasmids. Transconjugants were created to assess plasmid transfer frequency and its relation to temperature. Findings From Sept 26 to Oct 10, 2010, 171 seepage samples and 50 tap water samples from New Delhi and 70 sewage effluent samples from Cardiff Wastewater Treatment Works were collected. We detected blaNDM-1 in two of 50 drinking-water samples and 51 of 171 seepage samples from New Delhi; the gene was not found in any sample from Cardiff. Bacteria with blaNDM-1 were grown from 12 of 171 seepage samples and two of 50 water samples, and included 11 species in which NDM-1 has not previously been reported, including Shigella boydii and Vibrio cholerae . Carriage by enterobacteria, aeromonads, and V cholera was stable, generally transmissible, and associated with resistance patterns typical for NDM-1; carriage by non-fermenters was unstable in many cases and not associated with typical resistance. 20 strains of bacteria were found in the samples, 12 of which carried blaNDM-1 on plasmids, which ranged in size from 140 to 400 kb. Isolates of Aeromonas caviae and V cholerae carried blaNDM-1 on chromosomes. Conjugative transfer was more common at 30°C than at 25°C or 37°C. Interpretation The presence of NDM-1 β-lactamase-producing bacteria in environmental samples in New Delhi has important implications for people living in the city who are reliant on public water and sanitation facilities. International surveillance of resistance, incorporating environmental sampling as well as examination of clinical isolates, needs to be established as a priority. Funding European Union.
Fourteen years in resistance Livermore, David M
International journal of antimicrobial agents,
04/2012, Letnik:
39, Številka:
4
Journal Article
Recenzirano
Resistance trends have changed greatly over the 14 years (1997–2011) whilst I was Director of the UK Antibiotic Resistance Monitoring and Reference Laboratory (ARMRL). Meticillin-resistant ...Staphylococcus aureus (MRSA) first rose, then fell with improved infection control, although with the decline of one major clone beginning before these improvements. Resistant pneumococci too have declined following conjugate vaccine deployment. If the situation against Gram-positive pathogens has improved, that against Gram-negatives has worsened, with the spread of (i) quinolone- and cephalosporin-resistant Enterobacteriaceae, (ii) Acinetobacter with OXA carbapenemases, (iii) Enterobacteriaceae with biochemically diverse carbapenemases and (iv) gonococci resistant to fluoroquinolones and, latterly, cefixime. Laboratory, clinical and commercial aspects have also changed. Susceptibility testing is more standardised, with pharmacodynamic breakpoints. Treatments regimens are more driven by guidelines. The industry has fewer big profitable companies and more small companies without sales income. There is good and bad here. The quality of routine susceptibility testing has improved, but its speed has not. Pharmacodynamics adds science, but over-optimism has led to poor dose selection in several trials. Guidelines discourage poor therapy but concentrate selection onto a diminishing range of antibiotics, threatening their utility. Small companies are more nimble, but less resilient. Last, more than anything, the world has changed, with the rise of India and China, which account for 33% of the world's population and increasingly provide sophisticated health care, but also have huge resistance problems. These shifts present huge challenges for the future of chemotherapy and for the edifice of modern medicine that depends upon it.
Owing to increasing resistance and the limited arsenal of new antibiotics, especially against Gram-negative pathogens, carefully designed antibiotic regimens are obligatory for febrile neutropenic ...patients, along with effective infection control. The Expert Group of the 4(th) European Conference on Infections in Leukemia has developed guidelines for initial empirical therapy in febrile neutropenic patients, based on: i) the local resistance epidemiology; and ii) the patient's risk factors for resistant bacteria and for a complicated clinical course. An 'escalation' approach, avoiding empirical carbapenems and combinations, should be employed in patients without particular risk factors. A 'de-escalation' approach, with initial broad-spectrum antibiotics or combinations, should be used only in those patients with: i) known prior colonization or infection with resistant pathogens; or ii) complicated presentation; or iii) in centers where resistant pathogens are prevalent at the onset of febrile neutropenia. In the latter case, infection control and antibiotic stewardship also need urgent review. Modification of the initial regimen at 72-96 h should be based on the patient's clinical course and the microbiological results. Discontinuation of antibiotics after 72 h or later should be considered in neutropenic patients with fever of unknown origin who are hemodynamically stable since presentation and afebrile for at least 48 h, irrespective of neutrophil count and expected duration of neutropenia. This strategy aims to minimize the collateral damage associated with antibiotic overuse, and the further selection of resistance.
Pseudomonas aeruginosa carries multiresistance plasmids less often than does Klebsiella pneumoniae, develops mutational resistance to cephalosporins less readily than Enterobacter species, and has ...less inherent resistance than Stenotrophomonas maltophilia. What nevertheless makes P. aeruginosa uniquely problematic is a combination of the following: the species' inherent resistance to many drug classes; its ability to acquire resistance, via mutations, to all relevant treatments; its high and increasing rates of resistance locally; and its frequent role in serious infections. A few isolates of P. aeruginosa are resistant to all reliable antibiotics, and this problem seems likely to grow with the emergence of integrins that carry gene cassettes encoding both carbapenemases and amikacin acetyltransferases.
Abstract
Multilocus sequence typing reveals that many bacterial species have a clonal structure and that some clones are widespread. This underlying phylogeny was not revealed by pulsed-field gel ...electrophoresis, a method better suited to short-term outbreak investigation. Some global clones are multiresistant and it is easy to assume that these have disseminated from single foci. Such conclusions need caution, however, unless there is a clear epidemiological trail, as with KPC carbapenemase-positive Klebsiella pneumoniae ST258 from Greece to northwest Europe. Elsewhere, established clones may have repeatedly and independently acquired resistance. Thus, the global ST131 Escherichia coli clone most often has CTX-M-15 extended-spectrum β-lactamase (ESBL), but also occurs without ESBLs and as a host of many other ESBL types. We explore this interaction of clone and resistance for E. coli, K. pneumoniae, Acinetobacter baumannii– a species where three global lineages dominate – and Pseudomonas aeruginosa, which shows clonal diversity, but includes the relatively ‘tight’ serotype O12/Burst Group 4 cluster that has proved adept at acquiring resistances – from PSE-1 to VIM-1 β-lactamases – for over 20 years. In summary, ‘high-risk clones’ play a major role in the spread of resistance, with the risk lying in their tenacity – deriving from poorly understood survival traits – and a flexible ability to accumulate and switch resistance, rather than to constant resistance batteries.
We explore the spread of resistance in Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa, and the importance of tenacious ‘high risk clones’ with flexible abilities to accumulate and switch resistance mechanisms.
MK-7655 is a novel inhibitor of class A and C β-lactamases. We investigated its potential to protect imipenem.
Chequerboard MICs were determined by CLSI agar dilution: (i) for Enterobacteriaceae with ...carbapenemases; (ii) for Enterobacteriaceae with carbapenem resistance contingent on combinations of impermeability together with an extended-spectrum β-lactamase or AmpC enzyme; and (iii) for Pseudomonas aeruginosa and other non-fermenters.
At a concentration of 4 mg/L, MK-7655 reduced imipenem MICs for Enterobacteriaceae with KPC carbapenemases from 16-64 mg/L to 0.12-1 mg/L. Synergy also was seen for Enterobacteriaceae with impermeability-mediated carbapenem resistance, with weaker synergy seen for isolates with the OXA-48 enzyme. On the other hand, MK-7655 failed to potentiate imipenem against Enterobacteriaceae with metallo-carbapenemases. In the case of P. aeruginosa, where endogenous AmpC confers slight protection versus imipenem, 4 mg/L MK-7655 reduced the MIC of imipenem for all isolates, except those with metallo-carbapenemases: the MICs of imipenem fell from 1-2 mg/L to 0.25-0.5 mg/L for imipenem-susceptible P. aeruginosa and from 16-64 mg/L to 1-4 mg/L for OprD-deficient strains. No potentiation was seen for chryseobacteria or for Stenotrophomonas maltophilia.
MK-7655 potentiated imipenem against Enterobacteriaceae with KPC carbapenemases or combinations of β-lactamase and impermeability, but not those with metallo-carbapenemases. It augmented the activity of imipenem against P. aeruginosa in general and OprD mutants in particular.
Cefiderocol is a parenteral siderophore cephalosporin with a catechol-containing 3' substituent. We evaluated its MICs against Gram-negative bacteria, using iron-depleted Mueller-Hinton broth. The ...panel comprised 305 isolates of
, 111 of
, and 99 of
, all selected for carbapenem resistance and multidrug resistance to other agents. At 2 and 4 μg/ml, cefiderocol inhibited 78.7 and 92.1%, respectively, of all
isolates tested, with rates of 80 to 100% for isolates with all modes of carbapenem resistance except NDM enzymes (41.0% inhibited at 2 μg/ml and 72.1% at 4 μg/ml) or combinations of extended-spectrum β-lactamase (ESBL) and porin loss (61.5% inhibited at 2 μg/ml and 88.5% at 4 μg/ml). Cefiderocol also inhibited 81.1 and 86.5% of all
isolates at 2 and 4 μg/ml, respectively, with rates of 80 to 100% for isolates with VIM, IMP, GES, or VEB β-lactamases and slightly lower rates for those with NDM (45.5% at 2 μg/ml and 72.7% at 4 μg/ml) and PER (66.7% at 2 μg/ml and 73.3% at 4 μg/ml) enzymes; 63.3% of
isolates were inhibited at the FDA's 1-μg/ml breakpoint. Lastly, cefiderocol at 2 and 4 μg/ml inhibited 80.8 and 88.9% of the
isolates, respectively, with rates of >85% for isolates with OXA-51-like, -23, -24, or -58 enzymes and 50% at 2 μg/ml and 80% at 4 μg/ml for those with NDM carbapenemases. Dipicolinic acid and avibactam weakly potentiated cefiderocol against
isolates with metallo-β-lactamases (MBLs) and serine carbapenemase, respectively, indicating incomplete β-lactamase stability.
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