Extended-spectrum β-lactamases (ESBLs) are a rapidly evolving group of β-lactamases which share the ability to hydrolyze third-generation cephalosporins and aztreonam yet are inhibited by clavulanic acid. Typically, they derive from genes for TEM-1, TEM-2, or SHV-1 by mutations that alter the amino acid configuration around the active site of these β-lactamases. This extends the spectrum of β-lactam antibiotics susceptible to hydrolysis by these enzymes. An increasing number of ESBLs not of TEM or SHV lineage have recently been described. The presence of ESBLs carries tremendous clinical significance. The ESBLs are frequently plasmid encoded. Plasmids responsible for ESBL production frequently carry genes encoding resistance to other drug classes (for example, aminoglycosides). Therefore, antibiotic options in the treatment of ESBL-producing organisms are extremely limited. Carbapenems are the treatment of choice for serious infections due to ESBL-producing organisms, yet carbapenem-resistant isolates have recently been reported. ESBL-producing organisms may appear susceptible to some extended-spectrum cephalosporins. However, treatment with such antibiotics has been associated with high failure rates. There is substantial debate as to the optimal method to prevent this occurrence. It has been proposed that cephalosporin breakpoints for the Enterobacteriaceae should be altered so that the need for ESBL detection would be obviated. At present, however, organizations such as the Clinical and Laboratory Standards Institute (formerly the National Committee for Clinical Laboratory Standards) provide guidelines for the detection of ESBLs in klebsiellae and Escherichia coli. In common to all ESBL detection methods is the general principle that the activity of extended-spectrum cephalosporins against ESBL-producing organisms will be enhanced by the presence of clavulanic acid. ESBLs represent an impressive example of the ability of gram-negative bacteria to develop new antibiotic resistance mechanisms in the face of the introduction of new antimicrobial agents.

Extended-spectrum beta-lactamases: a clinical update.

A classification scheme for b-lactamases based on functional characteristics is presented. Three major groups of enzymes are defined by their substrate and inhibitor profiles: group 1 cephalosporinases that are not well inhibited by clavulanic acid; group 2 penicillinases, cephalosporinases, and broadspectrum b-lactamases that are generally inhibited by active site-directed b-lactamase inhibitors; and the group 3 metallob-lactamases that hydrolyze penicillins, cephalosporins, and carbapenems and that are poorly inhibited by almost all b-lactam-containing molecules. Functional characteristics have been correlated with molecular structure in a dendrogram for those enzymes with known amino acid sequences. b-Lactamases (EC 3.5.2.6) have been designated by the Nomenclature Committee of the International Union of Biochemistry as ‘‘enzymes hydrolysing amides, amidines and other CON bonds . . . separated on the basis of the substrate: . . . cyclic amides’’ (323). These enzymes are the major cause of bacterial resistance to b-lactam antibiotics and have been the subject of extensive microbiological, biochemical, and genetic investigations. Investigators have described more than 190 unique bacterial proteins with the ability to interact with the variety of b-lactam-containing molecules that can serve as sub-

A functional classification scheme for beta-lactamases and its correlation with molecular structure.

Carbapenemases are β-lactamases with versatile hydrolytic capacities. They have the ability to hydrolyze penicillins, cephalosporins, monobactams, and carbapenems. Bacteria producing these β-lactamases may cause serious infections in which the carbapenemase activity renders many β-lactams ineffective. Carbapenemases are members of the molecular class A, B, and D β-lactamases. Class A and D enzymes have a serine-based hydrolytic mechanism, while class B enzymes are metallo-β-lactamases that contain zinc in the active site. The class A carbapenemase group includes members of the SME, IMI, NMC, GES, and KPC families. Of these, the KPC carbapenemases are the most prevalent, found mostly on plasmids in Klebsiella pneumoniae. The class D carbapenemases consist of OXA-type β-lactamases frequently detected in Acinetobacter baumannii. The metallo-β-lactamases belong to the IMP, VIM, SPM, GIM, and SIM families and have been detected primarily in Pseudomonas aeruginosa; however, there are increasing numbers of reports worldwide of this group of β-lactamases in the Enterobacteriaceae. This review updates the characteristics, epidemiology, and detection of the carbapenemases found in pathogenic bacteria.

https://www.sld.cu/galerias/pdf/sitios/apua-cuba/r11-carbapenemases._the_versatile_%DF-lactamases.pdf

Carbapenemases: the versatile beta-lactamases.

The discovery, commercialization, and routine administration of antimicrobial compounds to treat infections revolutionized modern medicine and changed the therapeutic paradigm. Indeed, antibiotics have become one of the most important medical interventions needed for the development of complex medical approaches such as cutting-edge surgical procedures, solid organ transplantation, and management of patients with cancer, among others. Unfortunately, the marked increase in antimicrobial resistance among common bacterial pathogens is now threatening this therapeutic accomplishment, jeopardizing the successful outcomes of critically ill patients. In fact, the World Health Organization has named antibiotic resistance as one of the three most important public health threats of the 21st century (
1
).

Mechanisms of Antibiotic Resistance

beta-Lactamases are the commonest single cause of bacterial resistance to beta-lactam antibiotics. Numerous chromosomal and plasmid-mediated types are known and may be classified by their sequences or phenotypic properties. The ability of a beta-lactamase to cause resistance varies with its activity, quantity, and cellular location and, for gram-negative organisms, the permeability of the producer strain. beta-Lactamases sometimes cause obvious resistance to substrate drugs in routine tests; often, however, these enzymes reduce susceptibility without causing resistance at current, pharmacologically chosen breakpoints. This review considers the ability of the prevalent beta-lactamases to cause resistance to widely used beta-lactams, whether resistance is accurately reflected in routine tests, and the extent to which the antibiogram for an organism can be used to predict the type of beta-lactamase that it produces.

https://courses.washington.edu/pharm522/Week9/0139.pdf

beta-Lactamases in laboratory and clinical resistance.

Tea tree oil has recently emerged as an effective topical antimicrobial agent active against a wide range of organisms. Tea tree oil may have a clinical application in both the hospital and community, especially for clearance of methicillin-resistant Staphylococcus aureus (MRSA) carriage or as a hand disinfectant to prevent cross-infection with Gram-positive and Gramnegative epidemic organisms. Our study, based on the time-kill approach, determined the kill rate of tea tree oil against several multidrug-resistant organisms, including MRSA, glycopeptide-resistant enterococci, aminoglycoside-resistant klebsiellae, Pseudomonas aeruginosa and Stenotrophomonas maltophilia, and also against sensitive microorganisms. The study was performed with two chemically different tea tree oils. One was a standard oil and the other was Clone 88 extracted from a specially bred tree, which has been selected and bred for increased activity and decreased skin irritation. Our results confirm that the cloned oil had increased antimicrobial activity when compared with the standard oil. Most results indicated that the susceptibility pattern and Gram reaction of the organism did not influence the kill rate. A rapid killing time (less than 60 min) was achieved with both tea tree oils with most isolates, but MRSA was killed more slowly than other organisms.

/pdf/time-kill-studies-of-tea-tree-oils-on-clinical-isolates-1fvinqcqtm.pdf

Time-kill studies of tea tree oils on clinical isolates

Treatment failures with vancomycin prompted us to investigate the phenomenon of tolerance to glycopeptides in recent clinical isolates of Staphylococcus aureus. We used both MBC/MIC determinations and time-kill measurements to study tolerance to vancomycin and teicoplanin in 35 blood or heart valve isolates of S. aureus from patients with endocarditis or bacteraemia. There was generally good agreement between vancomycin tolerance indicated by an MBC:MIC ratio of > or =32 and by < or =90% kill after 6 h incubation in the presence of 20 mg/L vancomycin. However, two isolates were tolerant according to their MBC:MIC ratios but non-tolerant as judged by time-kill measurements. Seven of 15 methicillin-resistant S. aureus (MRSA) isolates but only two of 20 methicillin-susceptible ones were tolerant as judged by time-kill experiments (chi2 = 4.27 with Yates' correction, P = 0.04). Seven of the 16 isolates from patients with endocarditis were tolerant, compared with only two of the 19 isolates from patients with other conditions (chi2 = 3.43 with Yates' correction, P = 0.06). Within the endocarditis and non-endocarditis subgroups, tolerance was associated more frequently with methicillin resistance than with susceptibility, but the numbers were too small for the differences to be statistically significant. Most of the vancomycin-tolerant isolates were also tolerant to teicoplanin. We conclude that glycopeptide tolerance is a real phenomenon in S. aureus, particularly amongst MRSA isolates, and can be reliably determined by our method of time-kill analysis. Tolerance may compromise glycopeptide therapy of serious S. aureus infection and should be taken into account when deciding treatment.

/pdf/glycopeptide-tolerance-in-staphylococcus-aureus-36plh3kwh5.pdf

Glycopeptide tolerance in Staphylococcus aureus.

Among Escherichia coli organisms isolated at St. Thomas's Hospital during the years 1990 to 1994, the frequency of resistance to amoxicillin-clavulanic acid (tested by disk diffusion in a ratio of 2:1) remained constant at about 5% of patient isolates (10 to 15% of the 41 to 45% that were amoxicillin resistant). Mechanisms of increased resistance were determined for 72 consecutively collected such amoxicillin-clavulanic acid-resistant isolates. MICs of the combination were 16-8 micrograms/ml for 51 (71%) of these and > or = 32-16 micrograms/ml for the remainder. The predominant mechanism was hyperproduction of enzymes isoelectrically cofocusing with TEM-1 (beta-lactamase activities, > 200 nmol of nitrocefin hydrolyzed per min per mg of protein) which was found in 44 isolates (61%); two isolates produced smaller amounts (approximately 150 nmol/min/mg) of such enzymes, and two isolates hyperproduced enzymes cofocusing with TEM-2. Eleven isolates produced enzymes cofocusing with OXA-1 beta-lactamase, which has previously been associated with resistance to amoxicillin-clavulanic acid. Ten isolates produced increased amounts of chromosomal beta-lactamase, and four of these additionally produced TEM-1 or TEM-2. Three isolates produced inhibitor-resistant TEM-group enzymes. In one of the enzymes (pI, 5.4), the amino acid sequence change was Met-67-->Val, and thus the enzyme is identical to TEM-34. Another (pI, 5.4) had the substitution Met-67-->Ile and is identical to IRT-I67, which we propose now be given the designation TEM-40. The third (pI, 5.2) had the substitution Arg-241-->Thr; this enzyme has not been reported previously and should be called TEM-41. The rarity and diversity of inhibitor-resistant TEM-group enzymes suggest that they are the result of spontaneous mutations that have not yet spread.

Incidence and mechanisms of resistance to the combination of amoxicillin and clavulanic acid in Escherichia coli.

Objective: We compared the in vitro activity of telavancin with that of vancomycin, teicoplanin, linezolid, quInupristin/dalfopristin, moxifloxacin and ampicillin, penicillin or oxacillin as appropriate, by the NCCLS/ EUCAST and BSAC methods. Methods: The organisms (n = 401) included in the study were patient isolates from St Thomas' Hospital and were selected to include representatives of the clinically important Gram-positive aerobic species. Susceptibility testing was performed by agar dilution methods on Mueller-Hinton agar according to the NCCLS/ EUCAST guidelines, in comparison with Iso-Sensitest agar according to the BSAC guidelines. Results: Telavancin was active against all the Gram-positive species tested and nearly 90% of isolates included in the study had telavancin MICs 64 mglL had telavancin MIC ranges of 0.5-8 and 2-16 mglL, respectively. There was no evidence of cross-resistance with other comparator drugs. The results for telavancin for the two susceptibility testing methods were mostly either the same or within one doubling dilution. Conclusion: The susceptibility breakpoints for telavancin have yet to be established, but it would appear that telavancin has superior potency to the other tested glycopeptides, and on a weight-for-weight basis displays activity that is comparable to, or better than, that of the other agents tested.

Comparative in vitro activity of telavancin (TD-6424), a rapidly bactericidal, concentration-dependent anti-infective with multiple mechanisms of action against Gram-positive bacteria

The in vitro antibacterial activity of cefamandole, a new cephalosporin antibiotic, was compared with that of cephaloridine, cephalothin, and cephalexin against 1,213 strains of gram-positive and gram-negative bacteria recently isolated from clinical sources. The decreasing order of activity of the four agents against gram-positive cocci was cephaloridine, cephalothin, cefamandole, and cephalexin. However, cefamandole was the most active of the four against Haemophilus species and gram-negative bacilli susceptible to cephalosporins. It was also active against many strains resistant to the other cephalosporins, such as Enterobacter species and indole-positive Proteus species, but there was a marked inoculum effect with all of these organisms, and minimal bactericidal concentrations were usually considerably higher than minimal inhibitory concentrations. Cefamandole, like other cephalosporins, had no useful activity against Pseudomonas species.

Antibacterial Activity of Cefamandole, a New Cephalosporin Antibiotic, Compared with that of Cephaloridine, Cephalothin, and Cephalexin

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Anna King

Author Tools

Chat about Author