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.
Modern medicine is threatened by the global rise of antibiotic resistance, especially among Gram-negative bacteria. Metallo-β-lactamase (MBL) enzymes are a particular concern and are increasingly ...disseminated worldwide, though particularly in Asia. Many MBL producers have multiple further drug resistances, leaving few obvious treatment options. Nonetheless, and more encouragingly, MBLs may be less effective agents of carbapenem resistance
, under zinc limitation, than
Owing to their unique structure and function and their diversity, MBLs pose a particular challenge for drug development. They evade all recently licensed β-lactam-β-lactamase inhibitor combinations, although several stable agents and inhibitor combinations are at various stages in the development pipeline. These potential therapies, along with the epidemiology of producers and current treatment options, are the focus of this review.
Diazabicyclooctanes (DBOs) inhibit class A, class C and some class D β-lactamases. A few also bind PBP2, conferring direct antibacterial activity and a β-lactamase-independent 'enhancer' effect, ...potentiating β-lactams targeting PBP3. We tested a novel DBO, zidebactam, combined with cefepime.
CLSI agar dilution MICs were determined with cefepime/zidebactam in a chequerboard format. Bactericidal activity was also measured.
Zidebactam MICs were ≤2 mg/L (mostly 0.12-0.5 mg/L) for most Escherichia coli , Klebsiella , Citrobacter and Enterobacter spp., but were >32 mg/L for Proteeae, most Serratia and a few E. coli , Klebsiella and Enterobacter/Citrobacter . The antibacterial activity of zidebactam dominated chequerboard studies for Enterobacteriaceae, but potentiation of cefepime was apparent for zidebactam-resistant isolates with class A and C enzymes, illustrating β-lactamase inhibition. Overall, cefepime/zidebactam inhibited almost all Enterobacteriaceae with AmpC, ESBL, K1, KPC and OXA-48-like β-lactamases at 1 + 1 mg/L and also 29 of 35 isolates with metallo-carbapenemases, including several resistant to zidebactam alone. Zidebactam MICs for 36 of 50 Pseudomonas aeruginosa were 4-16 mg/L, and the majority of AmpC, metallo-β-lactamase-producing and cystic fibrosis isolates were susceptible to cefepime/zidebactam at 8 + 8 mg/L. Zidebactam MICs for Acinetobacter baumannii and Stenotrophomonas maltophilia were >32 mg/L; potentiation of cefepime was frequent for S. maltophilia , but minimal for A. baumannii . Kill curve results largely supported MICs.
Zidebactam represents a second triple-action DBO following RG6080, with lower MICs for Enterobacteriaceae and P. aeruginosa . Clinical evaluation of cefepime/zidebactam must critically evaluate the reliance that can be placed on this direct antibacterial activity and on the enhancer effect as well as β-lactamase inhibition.
The emerging NDM carbapenemases Nordmann, Patrice; Poirel, Laurent; Walsh, Timothy R ...
Trends in microbiology (Regular ed.),
12/2011, Letnik:
19, Številka:
12
Journal Article
Recenzirano
Carbapenems were the last β-lactams retaining near-universal anti-Gram-negative activity, but carbapenemases are spreading, conferring resistance. New Delhi metallo-β-lactamase (NDM) enzymes are the ...latest carbapenemases to be recognized and since 2008 have been reported worldwide, mostly in bacteria from patients epidemiologically linked to the Indian subcontinent, where they occur widely in hospital and community infections, and also in contaminated urban water. The main type is NDM-1, but minor variants occur. NDM enzymes are present largely in Enterobacteriaceae, but also in non-fermenters and Vibrionaceae. Dissemination predominantly involves transfer of the blaNDM-1 gene among promiscuous plasmids and clonal outbreaks. Bacteria with NDM-1 are typically resistant to nearly all antibiotics, and reliable detection and surveillance are crucial.
The need for governments to encourage antibiotic development is widely agreed, with 'market entry rewards' being suggested. Unless these are to be spread widely-which is unlikely given the $1 billion ...sums proposed-we should be wary, for this approach is likely to evolve into one of picking, or commissioning, a few 'winners' based on extrapolation of current resistance trends. The hazard to this is that whilst the evolution of resistance has predictable components, notably mutation, it also has completely unpredictable ones, contingent upon 'Black Swan' events. These include the escape of 'new' resistance genes from environmental bacteria and the recruitment of these genes by promiscuous mobile elements and epidemic strains. Such events can change the resistance landscape rapidly and unexpectedly, as with the rise of Escherichia coli ST131 with CTX-M ESBLs and the emergence of 'impossible' VRE. Given such unpredictability, we simply cannot say with any certainty, for example, which of the four current approaches to combating MBLs offers the best prospect of sustainable prizeworthy success. Only time will tell, though it is encouraging that multiple potential approaches to overcoming these problematic enzymes are being pursued. Rather than seeking to pick winners, governments should aim to reduce development barriers, as with recent relaxation of trial regulations. In particular, once β-lactamase inhibitors have been successfully trialled with one partner drug, there is scope to facilitate licensing them for partnering with other established β-lactams, thereby insuring against new emerging resistance.
Optical properties of compressed fluid hydrogen in the region where dissociation and metallization is observed are computed by ab initio methods and compared with recent experimental results. We ...confirm that at T > 3,000 K, both processes are continuous, while at T < 1,500 K, the first-order phase transition is accompanied by a discontinuity of the dc conductivity and the thermal conductivity, while both the reflectivity and absorption coefficient vary rapidly but continuously. Our results support the recent analysis of National Ignition Facility (NIF) experiments Celliers PM, et al. (2018) Science 361:677–682, which assigned the inception of metallization to pressures where the reflectivity is ∼0.3. Our results also support the conclusion that the temperature plateau seen in laser-heated diamond-anvil cell (DAC) experiments at temperatures higher than 1,500 K corresponds to the onset of optical absorption, not to the phase transition.
Abstract
Background
Diazabicyclooctanes (DBOs) are promising β-lactamase inhibitors. Some, including nacubactam (OP0595/RG6080), also bind PBP2 and have an enhancer effect, allowing activity against ...Enterobacteriaceae with MBLs, which DBOs do not inhibit. We tested the activity of nacubactam/β-lactam combinations against MBL-producing Enterobacteriaceae.
Methods
Test panels comprised (i) 210 consecutive Enterobacteriaceae with NDM or VIM MBLs, as referred by UK diagnostic laboratories, and (ii) 99 supplementary MBL-producing Enterobacteriaceae, representing less prevalent phenotypes, species and enzymes. MICs were determined by CLSI agar dilution.
Results
MICs of nacubactam alone were bimodal, clustering at 1–8 mg/L or >32 mg/L; >85% of values for Escherichia coli and Enterobacter spp. fell into the low MIC cluster, whereas Proteeae were universally resistant and the Klebsiella spp. were divided between the two groups. Depending on the prospective breakpoint (4 + 4 or 8 + 4 mg/L), and on whether all isolates were considered or solely the Consecutive Collection, meropenem/nacubactam and cefepime/nacubactam inhibited 80.3%–93.3% of MBL producers, with substantial gains over nacubactam alone. Against the most resistant isolates (comprising 57 organisms with MICs of nacubactam >32 mg/L, cefepime ≥128 mg/L and meropenem ≥128 mg/L), cefepime/nacubactam at 8 + 4 mg/L inhibited 63.2% and meropenem/nacubactam at 8 + 4 mg/L inhibited 43.9%. Aztreonam/nacubactam, incorporating an MBL-stable β-lactam partner, was almost universally active against the MBL producers and, unlike aztreonam/avibactam, had an enhancer effect.
Conclusions
Nacubactam combinations, including those using MBL-labile β-lactams, e.g. meropenem and cefepime, can overcome most MBL-mediated resistance. This behaviour reflects nacubactam’s direct antibacterial and enhancer activity.
...the need for increased education and awareness about antimicrobial resistance among the public, National Health Service managers, and health-care professionals. ...the need to develop and improve ...surveillance systems for antimicrobial resistance and infectious diseases in general, particularly through improved linkage of data.
Summary Infections caused by multidrug-resistant Gram-positive bacteria represent a major public health burden, not just in terms of morbidity and mortality, but also in terms of increased ...expenditure on patient management and implementation of infection control measures. Staphylococcus aureus and Enterococcus spp. are established pathogens in the hospital environment, and their frequent multidrug resistance complicates therapy. The archetypal hospital “superbug”, methicillin-resistant S. aureus (MRSA), regularly attracts mass-media interest and, in many countries, there is political pressure to reduce MRSA infection rates, with some progress now being made in the United Kingdom and the United States. To compound these established problems, we have witnessed the emergence and spread of virulent clones of MRSA in the community, and of Clostridium difficile in hospitals. Multidrug-resistant Streptococcus pneumoniae clones are major community pathogens in many parts of the world, but are now being challenged by new conjugate vaccines. Using combinations of molecular epidemiological tools, which characterize the resistant isolates and their resistance determinants, scientists can track highly successful bacterial strains at local, national, and international levels. These methods have provided new insights into the evolution of key pathogens, and this information may aid the design of control strategies and vaccines. In addition, the development of new antimicrobials including oxazolidinones, lipopeptides, glycylcyclines, ketolides, and new generations of fluoroquinolones, antistaphylococcal b-lactams, and glycopeptides must remain a high priority for the continued effective treatment of infections caused by resistant strains. So far, resistance to these newer agents is identified rarely in surveillance programs, but occasional reports of resistance causing therapeutic failure (e.g., with linezolid, daptomycin, telithromycin, or newer fluoroquinolones) give cause for concern. 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.
The phase diagram of high-pressure hydrogen is of great interest for fundamental research, planetary physics, and energy applications. A first-order phase transition in the fluid phase between a ...molecular insulating fluid and a monoatomic metallic fluid has been predicted. The existence and precise location of the transition line is relevant for planetary models. Recent experiments reported contrasting results about the location of the transition. Theoretical results based on density functional theory are also very scattered. We report highly accurate coupled electron–ion Monte Carlo calculations of this transition, finding results that lie between the two experimental predictions, close to that measured in diamond anvil cell experiments but at 25–30 GPa higher pressure. The transition along an isotherm is signaled by a discontinuity in the specific volume, a sudden dissociation of the molecules, a jump in electrical conductivity, and loss of electron localization.
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