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1
Shlaes, D. M., and C. Currie-McCumber. "Mutations altering substrate specificity in OHIO-1, and SHV-1 family β-lactamase." Biochemical Journal 284, no. 2 (June 1, 1992): 411–15. http://dx.doi.org/10.1042/bj2840411.
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The OHIO-1 beta-lactamase does not normally hydrolyse oxyimino-beta-lactam substrates like cefotaxime, ceftriaxone, ceftazidime or aztreonam. We were able to select spontaneous mutants of an OHIO-1-bearing strain of Escherichia coli using the antibiotic substrates listed above by enrichment methods of frequencies of 10(-8)-10(-10) for all antibiotics except ceftazidime (frequency less than 10(-10)). Most mutants with increased resistance to the other beta-lactams were also more resistant to ceftazidime. Mutations identified by DNA sequencing included a Gly238----Ser238 substitution identical with the SHV-2 mutation previously described, cysteine and valine substitutions at the identical site, and a Gly242----Cys242 substitution. The Cys238 and Cys242 mutant enzymes had less affinity for aztreonam than had the other mutant enzymes. Hydrolysis of cefotaxime, but not cephaloridine, by the cysteine-substituted enzymes was inhibited by p-chloromercuribenzoate. The mutant enzymes had, in general, greater affinity for the mechanism-based inhibitors sulbactam, clavulanic acid and tazobactam. These results suggest two non-mutually exclusive hypotheses for the structural role of substitutions in this area of the enzyme. Either potential hydrogen-bond donors, such as serine and cysteine, interact directly with the beta-lactam molecules, or the steric bulk of these substitutions distorts the beta-pleated sheet such that the beta-lactam is held in a position favourable for stable binding and catalysis. Finally, our data raise questions about a strategy relying on oligonucleotide-probe technology to detect such mutations, because of the variety of substitutions that give rise to similar phenotypes.
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Pestana-Nobles, Roberto, Yani Aranguren-Díaz, Elwi Machado-Sierra, Juvenal Yosa, Nataly J. Galan-Freyle, Laura X. Sepulveda-Montaño, Daniel G. Kuroda, and Leonardo C. Pacheco-Londoño. "Docking and Molecular Dynamic of Microalgae Compounds as Potential Inhibitors of Beta-Lactamase." International Journal of Molecular Sciences 23, no. 3 (January 31, 2022): 1630. http://dx.doi.org/10.3390/ijms23031630.
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Bacterial resistance is responsible for a wide variety of health problems, both in children and adults. The persistence of symptoms and infections are mainly treated with β-lactam antibiotics. The increasing resistance to those antibiotics by bacterial pathogens generated the emergence of extended-spectrum β-lactamases (ESBLs), an actual public health problem. This is due to rapid mutations of bacteria when exposed to antibiotics. In this case, β-lactamases are enzymes used by bacteria to hydrolyze the beta-lactam rings present in the antibiotics. Therefore, it was necessary to explore novel molecules as potential β-lactamases inhibitors to find antibacterial compounds against infection caused by ESBLs. A computational methodology based on molecular docking and molecular dynamic simulations was used to find new microalgae metabolites inhibitors of β-lactamase. Six 3D β-lactamase proteins were selected, and the molecular docking revealed that the metabolites belonging to the same structural families, such as phenylacridine (4-Ph), quercetin (Qn), and cryptophycin (Cryp), exhibit a better binding score and binding energy than commercial clinical medicine β-lactamase inhibitors, such as clavulanic acid, sulbactam, and tazobactam. These results indicate that 4-Ph, Qn, and Cryp molecules, homologous from microalgae metabolites, could be used, likely as novel β-lactamase inhibitors or as structural templates for new in-silico pharmaceutical designs, with the possibility of combatting β-lactam resistance
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Vitus Silago. "Beta-lactam antibiotics and extended spectrum beta-lactamases." GSC Advanced Research and Reviews 9, no. 2 (November 30, 2021): 015–24. http://dx.doi.org/10.30574/gscarr.2021.9.2.0200.
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Extended spectrum beta-lactamases (ESBLs) are enzymes produced by bacteria, mostly members of the family Enterobacteriaceae commonly Escherichia coli and Klebsiella pneumoniae. ESBLs hydrolyze the beta-lactam ring of beta-lactam antibiotics making these antibiotics ineffective therefore rendering the bacteria resistance against beta-lactam antibiotics. The global upsurge of ESBLs producing bacteria causing both hospital and community acquired infections mostly urinary tract infections, pneumonia and bloodstream infections, threatens the effectiveness of infectious diseases treatment. ESBL families; TEM, SHV and CTX-M are globally disseminated and frequently detected in clinical isolates as well as colonization and contamination isolates. Various laboratory detection methods of ESBLs producing Gram negative bacteria are available. These methods; phenotypic methods, automated methods and molecular-based methods are varying in sensitivity and specificity, need of technical expertise, and rapidness. Therefore, they should be clearly understood before being employed for routine or research use for detection of ESBLs production among Enterobacteriaceae. In addition, understanding the mode of action and mechanisms of resistance to beta-lactam antibiotics, and the epidemiology of ESBLs producing bacteria is of paramount.
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Ahmadvand, Parvaneh, Johannetsy J. Avillan, Jacob A. Lewis, Douglas R. Call, and ChulHee Kang. "Characterization of Interactions between CTX-M-15 and Clavulanic Acid, Desfuroylceftiofur, Ceftiofur, Ampicillin, and Nitrocefin." International Journal of Molecular Sciences 23, no. 9 (May 7, 2022): 5229. http://dx.doi.org/10.3390/ijms23095229.
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Cefotaximase-Munich (CTX-M) extended-spectrum beta-lactamases (ESBLs) are commonly associated with Gram-negative, hospital-acquired infections worldwide. Several beta-lactamase inhibitors, such as clavulanate, are used to inhibit the activity of these enzymes. To understand the mechanism of CTX-M-15 activity, we have determined the crystal structures of CTX-M-15 in complex with two specific classes of beta-lactam compounds, desfuroylceftiofur (DFC) and ampicillin, and an inhibitor, clavulanic acid. The crystal structures revealed that Ser70 and five other residues (Lys73, Tyr105, Glu166, Ser130, and Ser237) participate in catalysis and binding of those compounds. Based on analysis of steady-state kinetics, thermodynamic data, and molecular docking to both wild-type and S70A mutant structures, we determined that CTX-M-15 has a similar affinity for all beta-lactam compounds (ceftiofur, nitrocefin, DFC, and ampicillin), but with lower affinity for clavulanic acid. A catalytic mechanism for tested β-lactams and two-step inhibition mechanism of clavulanic acid were proposed. CTX-M-15 showed a higher activity toward DFC and nitrocefin, but significantly lower activity toward ampicillin and ceftiofur. The interaction between CTX-M-15 and both ampicillin and ceftiofur displayed a higher entropic but lower enthalpic effect, compared with DFC and nitrocefin. DFC, a metabolite of ceftiofur, displayed lower entropy and higher enthalpy than ceftiofur. This finding suggests that compounds containing amine moiety (e.g., ampicillin) and the furfural moiety (e.g., ceftiofur) could hinder the hydrolytic activity of CTX-M-15.
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Anggini, Pragati Wira, Syahidah Asma Amanina, Salwa Rainha Asyura, and Romario Dion. "In silico Study of Essential Oil of Bambusa vulgaris Leaves as an Anti Beta-lactamase Compound." Molecular and Cellular Biomedical Sciences 6, no. 3 (November 2, 2022): 147. http://dx.doi.org/10.21705/mcbs.v6i3.278.
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Background: Klebsiella pneumoniae is known as an extended spectrum beta (β)-lactamases (ESBLs)-producing bacteria, which produces enzymes that cause resistance to β-lactam antibiotics by degrading β-lactam ring. A solution is needed to prevent the degradation of the β-lactam ring. In this in silico study, combining β-lactam antibiotics with secondary metabolites has the possibility to inhibit the active site of the β-lactamase enzyme. This study aimed to explore the potential of the essential oil of yellow bamboo (Bambusa vulgaris) leaves as inhibitors of β-lactamase. Materials and methods: This research was conducted by simulating molecular docking to determine the interaction of ligands with proteins, pharmacological tests of compounds based on the Lipinski’s rule of five, and ligand toxicity tests with pkCSM. Results: The free bond energy values (∆G) were in the range of -4.3 to -8.0 kcal/mol. The ligands with the best ∆G value were sulfur pentafluoride (-8.0 kcal/mol), squalene (-7.3 kcal/mol), 3-aminodibenzofuran (-7.1 kcal/mol), and 2- monolaurin (-5.5 kcal/mol). Secondary metabolites from the essential oil of B. vulgaris leaves fulfilled Lipinski’s rule of five, so that oral use can be carried out except for squalene and tridecane. Conclusion: Secondary metabolite compounds in the essential oil that have potential as oral drugs based on the Lipinski pharmacological test and the pkCSM toxicity test are dipivaloylmethane, β-ocimene, 2-monolaurin, and undecane. Keywords: β-lactamase, Bambusa vulgaris, essential oil, Klebsiella pneumoniae
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Anant, Prem Singh, and Pratima Gupta. "Application of machine learning in understanding bioactivity of beta-lactamase AmpC." Journal of Physics: Conference Series 2273, no. 1 (May 1, 2022): 012005. http://dx.doi.org/10.1088/1742-6596/2273/1/012005.
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Abstract The ability of microorganisms like bacteria to develop mechanisms against the treatment is becoming a concern globally. This topic of concern is called Antimicrobial Resistance aka AMR. In this study, with the help of machine learning algorithms we are trying to evaluate the activity of molecules that have been tested experimentally either to bind or not bind the beta lactamases. Machine learning is a technique for analysis of data which teaches the computers what naturally comes to living organisms. Beta lactamases are diverse family of microbial enzymes that hydrolyse the cyclic amide bond of susceptible to beta-lactam antibiotics. Studying the effects and functioning of beta lactamases enzymes can provide better insights into the AMR mechanism adopted by the microorganisms. AMR is one of the top 10 global public health threats facing humanity in this era. Therefore, finding potential compounds that can combat these microorganisms is very important. Here, we have considered few plant-based flavonoids and terpenoids and checked the bioactivity against these beta lactamases containing microorganisms by using machine learning algorithms. A large dataset having more than 62,000 compounds and their pPotency values against beta lactamase AmpC was obtained from ChEMBL and employed in QSAR (quantitative structure activity relationship) model in order to understand the origin of their bioactivity. Several set of fingerprint descriptors and predictive models were constructed and results are obtained.
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Krishnamoorthy, Rajapandiyan, Jegan Athinarayanan, Vaiyapuri Subbarayan Periyasamy, Mohammad A. Alshuniaber, Ghedeir Alshammari, Mohammed Jamal Hakeem, Mohammed Asif Ahmed, and Ali A. Alshatwi. "Antibacterial Mechanisms of Zinc Oxide Nanoparticle against Bacterial Food Pathogens Resistant to Beta-Lactam Antibiotics." Molecules 27, no. 8 (April 12, 2022): 2489. http://dx.doi.org/10.3390/molecules27082489.
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The increase in β-lactam-resistant Gram-negative bacteria is a severe recurrent problem in the food industry for both producers and consumers. The development of nanotechnology and nanomaterial applications has transformed many features in food science. The antibacterial activity of zinc oxide nanoparticles (ZnO NPs) and their mechanism of action on β-lactam-resistant Gram-negative food pathogens, such as Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi, Serratia marcescens, Klebsiella pneumoniae, and Proteus mirabilis, are investigated in the present paper. The study results demonstrate that ZnO NPs possesses broad-spectrum action against these β-lactamase-producing strains. The minimal inhibitory and minimal bactericidal concentrations vary from 0.04 to 0.08 and 0.12 to 0.24 mg/mL, respectively. The ZnO NPs elevate the level of reactive oxygen species (ROS) and malondialdehyde in the bacterial cells as membrane lipid peroxidation. It has been confirmed from the transmission electron microscopy image of the treated bacterial cells that ZnO NPs diminish the permeable membrane, denature the intracellular proteins, cause DNA damage, and cause membrane leakage. Based on these findings, the action of ZnO NPs has been attributed to the fact that broad-spectrum antibacterial action against β-lactam-resistant Gram-negative food pathogens is mediated by Zn2+ ion-induced oxidative stress, actions via lipid peroxidation and membrane damage, subsequently resulting in depletion, leading to β-lactamase enzyme inhibition, intracellular protein inactivation, DNA damage, and eventually cell death. Based on the findings of the present study, ZnO NPs can be recommended as potent broad-spectrum antibacterial agents against β-lactam-resistant Gram-negative pathogenic strains.
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Minhas, Gurdeep S., and Simon Newstead. "Structural basis for prodrug recognition by the SLC15 family of proton-coupled peptide transporters." Proceedings of the National Academy of Sciences 116, no. 3 (January 2, 2019): 804–9. http://dx.doi.org/10.1073/pnas.1813715116.
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A major challenge in drug development is the optimization of intestinal absorption and cellular uptake. A successful strategy has been to develop prodrug molecules, which hijack solute carrier (SLC) transporters for active transport into the body. The proton-coupled oligopeptide transporters, PepT1 and PepT2, have been successfully targeted using this approach. Peptide transporters display a remarkable capacity to recognize a diverse library of di- and tripeptides, making them extremely promiscuous and major contributors to the pharmacokinetic profile of several important drug classes, including beta-lactam antibiotics and antiviral and antineoplastic agents. Of particular interest has been their ability to recognize amino acid and peptide-based prodrug molecules, thereby providing a rational approach to improving drug transport into the body. However, the structural basis for prodrug recognition has remained elusive. Here we present crystal structures of a prokaryotic homolog of the mammalian transporters in complex with the antiviral prodrug valacyclovir and the peptide-based photodynamic therapy agent, 5-aminolevulinic acid. The valacyclovir structure reveals that prodrug recognition is mediated through both the amino acid scaffold and the ester bond, which is commonly used to link drug molecules to the carrier’s physiological ligand, whereas 5-aminolevulinic acid makes far fewer interactions compared with physiological peptides. These structures provide a unique insight into how peptide transporters interact with xenobiotic molecules and provide a template for further prodrug development.
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Godijk, Noortje G., Martin C. J. Bootsma, Henri C. van Werkhoven, Valentijn A. Schweitzer, Sabine C. de Greeff, Annelot F. Schoffelen, and Marc J. M. Bonten. "Does plasmid-based beta-lactam resistance increase E. coli infections: Modelling addition and replacement mechanisms." PLOS Computational Biology 18, no. 3 (March 14, 2022): e1009875. http://dx.doi.org/10.1371/journal.pcbi.1009875.
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Infections caused by antibiotic-resistant bacteria have become more prevalent during past decades. Yet, it is unknown whether such infections occur in addition to infections with antibiotic-susceptible bacteria, thereby increasing the incidence of infections, or whether they replace such infections, leaving the total incidence unaffected. Observational longitudinal studies cannot separate both mechanisms. Using plasmid-based beta-lactam resistant E. coli as example we applied mathematical modelling to investigate whether seven biological mechanisms would lead to replacement or addition of infections. We use a mathematical neutral null model of individuals colonized with susceptible and/or resistant E. coli, with two mechanisms implying a fitness cost, i.e., increased clearance and decreased growth of resistant strains, and five mechanisms benefitting resistance, i.e., 1) increased virulence, 2) increased transmission, 3) decreased clearance of resistant strains, 4) increased rate of horizontal plasmid transfer, and 5) increased clearance of susceptible E. coli due to antibiotics. Each mechanism is modelled separately to estimate addition to or replacement of antibiotic-susceptible infections. Fitness costs cause resistant strains to die out if other strain characteristics are maintained equal. Under the assumptions tested, increased virulence is the only mechanism that increases the total number of infections. Other benefits of resistance lead to replacement of susceptible infections without changing the total number of infections. As there is no biological evidence that plasmid-based beta-lactam resistance increases virulence, these findings suggest that the burden of disease is determined by attributable effects of resistance rather than by an increase in the number of infections.
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Srivastava, Abhishikha, Neelja Singhal, Manisha Goel, Jugsharan Singh Virdi, and Manish Kumar. "Identification of Family Specific Fingerprints inβ-Lactamase Families." Scientific World Journal 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/980572.
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Beta-lactamases are a superfamily of enzymes which degrade theβ-lactam class of antibiotics. They are produced endogenously by the bacterial cells, which when exposed to theβ-lactam class of antibiotics inactivate them by cleaving theβ-lactam ring. Based on the presence or absence of metallic ligand,β-lactamases have been divided into two broad functional classes.β-Lactamases are a constitutively evolving and expanding superfamily of enzymes, which could be further subdivided on the basis of presence/absence of conserved motifs. In the present study we have used the MEME/MAST suit to identify the patterns/motifs which are specific to a particular family or subfamily ofβ-lactamases. The family specific patterns/motifs can be also useful in recognizing and assigning newly discoveredβ-lactamases to one or the other family or subfamily. Cross-validation showed that the proposed method is highly sensitive and specific. We have also designed a webserver, LactFP, for this purpose.
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Diarra, M. S., M. C. Lavoie, M. Jacques, I. Darwish, E. K. Dolence, J. A. Dolence, A. Ghosh, M. Ghosh, M. J. Miller, and F. Malouin. "Species selectivity of new siderophore-drug conjugates that use specific iron uptake for entry into bacteria." Antimicrobial Agents and Chemotherapy 40, no. 11 (November 1996): 2610–17. http://dx.doi.org/10.1128/aac.40.11.2610.
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Siderophores selectively bind ferric iron and are involved in receptor-specific iron transport into bacteria. Several types of siderophores were synthesized, and growth-promoting or inhibitory activities when they were conjugated to carbacephalosporin, erythromycylamine, or nalidixic acid were investigated. Overall, 11 types of siderophores and 21 drug conjugates were tested against seven different bacterial species: Escherichia coli, Bordetella bronchiseptica, Pasteurella multocida, Pasteurella haemolytica, Streptococcus suis, Staphylococcus aureus, and Staphylococcus epidermidis. In some species, the inhibitory activities of the drug conjugates were associated with the ability of the bacteria to use the siderophore portion of the molecules for growth promotion in disc diffusion tests (0.04 mumol of conjugate or siderophore per disc). E. coli used catechol-based siderophore portions as well as hydroxamate-based tri-delta-OH-N-OH-delta-N-acetyl-L-ornithine ferric iron ligands for growth under iron-restricted conditions achieved by supplemental ethylenediamine di (O-hydroxyphenylacetic acid) (100 micrograms/ml) and was sensitive to carbacephalosporin conjugated to these siderophore types (up to a 34-mm-diameter inhibition zone). B. bronchiseptica used desferrioxamine B and an isocyanurate-based or trihydroxamate in addition to catechol-based siderophore portions for promotion but was not inhibited by beta-lactam conjugates partly because of the presence of beta-lactamase. P. multocida and P. haemolytica did not use any of the synthetic siderophores for growth promotion, and the inhibitory activities of some conjugates seemed partly linked to their ability to withhold iron from these bacteria, since individual siderophore portions showed some antibacterial effects. Individual siderophores did not promote S. suis growth in restrictive conditions, but the type of ferric iron ligands attached to beta-lactams affected inhibitory activities. The antibacterial activities of the intracellular-acting agents erythromycylamine and nalidixic acid were reduced or lost, even against S. aureus and S. epidermidis, when the agents were conjugated to siderophores. Conjugate-resistant E. coli mutants showed the absence of some iron-regulated outer membrane proteins in gel electrophoresis profiles and in specific phage or colicin sensitivity tests, implying that the drugs used outer membrane receptors of ferric complexes to get into cells.
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Rotter, Marco J., Sabrina Zentgraf, Lilia Weizel, Denia Frank, Luisa D. Burgers, Steffen Brunst, Robert Fürst, Anna Proschak, Thomas A. Wichelhaus, and Ewgenij Proschak. "Integrating Siderophore Substructures in Thiol-Based Metallo-β-Lactamase Inhibitors." Molecules 28, no. 4 (February 20, 2023): 1984. http://dx.doi.org/10.3390/molecules28041984.
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Metallo beta lactamases (MBLs) are among the most problematic resistance mechanisms of multidrug-resistant Gram-negative pathogens due to their broad substrate spectrum and lack of approved inhibitors. In this study, we propose the integration of catechol substructures into the design of thiol-based MBL inhibitors, aiming at mimicking bacterial siderophores for the active uptake by the iron acquisition system of bacteria. We synthesised two catechol-containing MBL inhibitors, as well as their dimethoxy counterparts, and tested them for in vitro inhibitory activity against NDM-1, VIM-1, and IMP-7. We demonstrated that the most potent catechol-containing MBL inhibitor is able to bind Fe3+ ions. Finally, we could show that this compound restores the antibiotic activity of imipenem in NDM-1-expressing K. pneumoniae, while leaving HUVEC cells completely unaffected. Thus, siderophore-containing MBL inhibitors might be a valuable strategy to overcome bacterial MBL-mediated resistance to beta lactam antibiotics.
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Robledo, Iraida E., Guillermo J. Vázquez, Ellen S. Moland, Edna E. Aquino, Richard V. Goering, Kenneth S. Thomson, María I. Santé, and Nancy D. Hanson. "Dissemination and Molecular Epidemiology of KPC-Producing Klebsiella pneumoniae Collected in Puerto Rico Medical Center Hospitals during a 1-Year Period." Epidemiology Research International 2011 (December 29, 2011): 1–8. http://dx.doi.org/10.1155/2011/698705.
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During a 2003-2004 PCR-based surveillance study conducted in 6 Puerto Rico Medical Center hospitals, 27/92 multi-beta-lactam-resistant Klebsiella pneumoniae strains were identified as carbapenemase (KPC) positive in 4 hospitals. The objectives of this study were to identify the KPC variants, their genetic relatedness, and any other beta-lactamases present. Susceptibility testing, pulsed field gel electrophoresis (PFGE), isoelectric focusing, PCR, and DNA sequencing were performed. KPC variants -2, -3, -4, and -6 were identified. Additional beta-lactamases detected were TEM, DHA, OXA-9 and -30. Antimicrobial susceptibility to carbapenems varied depending on the KPC variant. Five PFGE genetically related groups were identified in 15 isolates and 12 unrelated types. PFGE profiles suggested that both clonal and horizontal transfer are contributing to the dissemination of these isolates among the various hospitals. Comparison of the 2003 and a 2009 surveillance studies showed a significant increase in the KPC-positive K. pneumoniae isolates in the latter.
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Maham Khan, Shahid Wahab, Haroon Muhammad Ali, Sadia Khan, Reema Iqbal, and Tariq Khan. "Biogenic Nanomaterials: A Way Forward in Preventing Bacterial Infections." Proceedings of the Pakistan Academy of Sciences: B. Life and Environmental Sciences 60, S (January 22, 2023): 3–23. http://dx.doi.org/10.53560/ppasb(60-sp1)814.
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Antibiotic resistance puts a tremendous strain on the healthcare system. Bacteria such as Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa that cause diseases like endocarditis, pneumonia, and Urinary tract infections have now become resistant to many previously used antibiotics. Antibiotic overuse must be reduced as it has become a public health threat paving the way to pandemics. Instead of creating new antibiotics, repurposing existing medicines that have faced resistance is one way forward. Plant-based antimicrobials have been explored as antibiotics to boost or augment the capability of existing antibiotics. It has been proposed that conjugates of plant-based products and antibiotics have increased activity and that the conjugated groups could help circumvent the beta-lactam antibiotic resistance mechanisms. Antibiotics have been combined with plant-based substances like Berberine, and a considerable synergy has been reported among them. Nanomaterials also promise a powerful environment-friendly strategy for weaponizing antibiotics with plant compounds. Nanoparticles could attach with many biological molecules such as DNA, enzymes, ribosomes, and lysosomes, further affecting the permeability of the cell membrane. The interaction of nanoparticles with many biological targets makes it hard for bacteria to develop resistance against them. Low molecular weight nanomaterial based on antibiotics could be very effective against multidrug-resistant gram-negative pathogens. Our study aims to analyze the progress done at the front of nanomaterials and nano-antibiotics against infectious diseases.
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Louis, Bruno, and Vijay K. Agrawal. "Quantitative structure-pharmacokinetic relationship (QSPkP) analysis of the volume of distribution values of anti-infective agents from j group of the ATC classification in humans." Acta Pharmaceutica 62, no. 3 (September 1, 2012): 305–23. http://dx.doi.org/10.2478/v10007-012-0024-z.
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In this study, a quantitative structure-pharmacokinetic relationship (QSPkR) model for the volume of distribution (Vd) values of 126 anti-infective drugs in humans was developed employing multiple linear regression (MLR), artificial neural network (ANN) and support vector regression (SVM) using theoretical molecular structural descriptors. A correlation-based feature selection (CFS) was employed to select the relevant descriptors for modeling. The model results show that the main factors governing Vd of anti-infective drugs are 3D molecular representations of atomic van der Waals volumes and Sanderson electronegativities, number of aliphatic and aromatic amino groups, number of beta-lactam rings and topological 2D shape of the molecule. Model predictivity was evaluated by external validation, using a variety of statistical tests and the SVM model demonstrated better performance compared to other models. The developed models can be used to predict the Vd values of anti-infective drugs.
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Chambers, H. F. "Methicillin resistance in staphylococci: molecular and biochemical basis and clinical implications." Clinical Microbiology Reviews 10, no. 4 (October 1997): 781–91. http://dx.doi.org/10.1128/cmr.10.4.781.
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Methicillin resistance in staphylococci is determined by mec, composed of 50 kb or more of DNA found only in methicillin-resistant strains. mec contains mecA, the gene for penicillin-binding protein 2a (PBP 2a); mecI and mecR1, regulatory genes controlling mecA expression; and numerous other elements and resistance determinants. A distinctive feature of methicillin resistance is its heterogeneous expression. Borderline resistance, a low-level type of resistance to methicillin exhibited by strains lacking mecA, is associated with modifications in native PBPs, beta-lactamase hyperproduction, or possibly a methicillinase. The resistance phenotype is influenced by numerous factors, including mec and beta-lactamase (bla) regulatory elements, fem factors, and yet to be identified chromosomal loci. The heterogeneous nature of methicillin resistance confounds susceptibility testing. Methodologies based on the detection of mecA are the most accurate. Vancomycin is the drug of choice for treatment of infection caused by methicillin-resistant strains. PBP 2a confers cross-resistance to most currently available beta-lactam antibiotics. Investigational agents that bind PBP 2a at low concentrations appear promising but have not been tested in humans. Alternatives to vancomycin are few due to the multiple drug resistances typical of methicillin-resistant staphylococci.
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Avery, Chris, Lonnie Baker, and Donald J. Jacobs. "Functional Dynamics of Substrate Recognition in TEM Beta-Lactamase." Entropy 24, no. 5 (May 20, 2022): 729. http://dx.doi.org/10.3390/e24050729.
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The beta-lactamase enzyme provides effective resistance to beta-lactam antibiotics due to substrate recognition controlled by point mutations. Recently, extended-spectrum and inhibitor-resistant mutants have become a global health problem. Here, the functional dynamics that control substrate recognition in TEM beta-lactamase are investigated using all-atom molecular dynamics simulations. Comparisons are made between wild-type TEM-1 and TEM-2 and the extended-spectrum mutants TEM-10 and TEM-52, both in apo form and in complex with four different antibiotics (ampicillin, amoxicillin, cefotaxime and ceftazidime). Dynamic allostery is predicted based on a quasi-harmonic normal mode analysis using a perturbation scan. An allosteric mechanism known to inhibit enzymatic function in TEM beta-lactamase is identified, along with other allosteric binding targets. Mechanisms for substrate recognition are elucidated using multivariate comparative analysis of molecular dynamics trajectories to identify changes in dynamics resulting from point mutations and ligand binding, and the conserved dynamics, which are functionally important, are extracted as well. The results suggest that the H10-H11 loop (residues 214-221) is a secondary anchor for larger extended spectrum ligands, while the H9-H10 loop (residues 194-202) is distal from the active site and stabilizes the protein against structural changes. These secondary non-catalytically-active loops offer attractive targets for novel noncompetitive inhibitors of TEM beta-lactamase.
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Struelens, M. J. "How Europe is facing up to antibiotic resistance." Eurosurveillance 9, no. 1 (January 1, 2004): 4. http://dx.doi.org/10.2807/esm.09.01.00439-en.
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In this issue, Witte and colleagues report on the emergence, since 2002, of cases in Germany of infection with community-acquired methicillin-resistant Staphylococcus aureus (c-MRSA) producing the Panton-Valentine leukocidin. This report adds evidence to the rapid geographical dissemination of this emerging, hyper-virulent variant of an 'old pathogen' across Europe. First reported in the early 1990s among aboriginal populations in Western Australia, outbreaks of c-MRSA infections have more recently been described in population groups such as prison inmates, injecting drug users, sports teams and schoolchildren, in the United States and Europe. Current evidence from molecular studies points to the spread in each continent of a limited number of PVL-producing MRSA clones that are genetically distinct from epidemic nosocomial strains. This represents a public health threat, because these strains are associated with severe soft tissue and pulmonary infection and the outcome of MRSA infection is worse than with infection caused by beta-lactam susceptible S. aureus, especially if inappropriately treated with beta-lactams that are usually prescribed for these infections. We must, therefore, upgrade the diagnostic work-up for this kind of infection in the outpatient setting and adapt empirical therapy accordingly. Moreover, surveillance should be intensified to monitor the incidence of MRSA and detect and control outbreaks in the community. In this respect, the report by Witte et al underscores the important early warning role that reference laboratories can play by using high resolution molecular markers based on routine typing and susceptibility data.
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Ayan, Melek, Cigdem Kuzucu, Riza Durmaz, Elif Aktas, and Zeynep Cizmeci. "Analysis of Three Outbreaks Due toKlebsiellaSpecies in a Neonatal Intensive Care Unit." Infection Control & Hospital Epidemiology 24, no. 7 (July 2003): 495–500. http://dx.doi.org/10.1086/502245.
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AbstractObjective:To investigate the clinical, microbiological, and epidemiologic features of three outbreaks caused byKlebsielladuring 3 years.Setting:Neonatal intensive care unit of a university hospital.Patients:Thirty affected neonates.Methods:Data were collected through chart reviews and conversations with physicians. Screening samples were obtained from the staff, the neonates, and the environment. Antibiogram typing and arbitrarily primed polymerase chain reaction-based fingerprinting were used to type the strains.Results:The first outbreak had 13K. pneumoniaestrains isolated. The second outbreak had 10K. oxytocastrains isolated. The third outbreak had 20K. pneumoniaestrains isolated. More than half of the patients had low birth weights, were premature, and underwent mechanical ventilation and intravenous catheterization. Approximately three-fourths of the patients died. The isolates tested were completely susceptible to meropenem, cefoxitin, and ciprofloxacin and were resistant to cephalothin. More than half of these strains were resistant to many beta-lactam antibiotics, amikacin, and trimethoprim/sul-famethoxazole. Typing procedures yielded 3 antibiotypes and 3 genotypes among the isolates of the first outbreak, 3 antibiotypes with 1 subtype and 2 genotypes with 1 subtype in the second outbreak, and 2 antibiotypes and 2 genotypes in the third outbreak.Conclusions:Klebsiellaoutbreaks mainly affected premature neonates with intravenous catheters, mechanical ventilation, or both. The high mortality rate (76.7%) was notable. Resistance to multiple antibiotics, but mainly to broad-spectrum beta-lactam antibiotics, was observed, particularly inK. pneumoniaeisolates. Molecular typing indicated that the three outbreaks were not related to one other (Infect Control Hosp Epidemiol2003;24:495-500).
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Satari, Mieke. "The molecular phenomena of the blaZ genes forming betalactamase enzymes structure in Staphylococcus aureus resistant to beta-lactam antibiotics (ampicillin)." Dental Journal (Majalah Kedokteran Gigi) 43, no. 3 (September 1, 2010): 146. http://dx.doi.org/10.20473/j.djmkg.v43.i3.p146-150.
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Background: Nowadays, infectious disease still an important problem. One of the bacteria causing infectious diseases is Staphylococcus aureus (S. aureus). In the effort to deal with infections caused by S. aureus, beta-lactam antibiotics, such as ampicillin, are used. In fact, it is unfortunately known that many of S. aureus bacteria are resistant to this group of antibiotics. Because of nucleotide base changes in the structure of the genes blaZ which encode beta-lactamase enzymes in S. aureus. Purpose: The objective of this study was to analyze the nucleotide base changes in the structure of the genes blaZ forming beta-lactamase enzymes in S. aureus resistant to ampicillin based on molecular point of view. Methods: Molecular examinations was conducted by isolating the genes, forming beta-lactamase enzyme, which length was 845bp, from 7 isolates of S. aureus resistant to ampicillin by using PCR technique. The results of blaZ amplification were then subjected to homology by using Tn 552 of S. aureus obtained from bank of genes. Results: Based on the result of the homology, it was found that there was a change in purine base TG, which was a pyrimidine base at the -37 position of the initial codon of blaZ. This change, however, did not affect the strength of the promoter since the number of A and T is still more than the number of G and C. In the structure of the blaZ gene there was even no mutation or deletion or nucleotide base substitution found, so it would not affect the effectiveness of beta-lactamase enzyme. Conclusion: It can be concluded that the resistance of S. aureus towards ampicillin was not caused by nucleotide base deletion/substation. It is suspected that there were other causes leading to the resistance, including the overproduction of beta-lactamase enzyme of the blaZ gene, causing the degradation of beta-lactam antibiotics.Latar belakang: Penyakit infeksi sampai saat ini masih merupakan masalah. Salah satu bakteri penyebab infeksi yaitu Staphylococcus aureus (S. aureus). Upaya menangani infeksi yang disebabkan S. aureus dapat menggunakan antibiotik golongan betalaktam, salah satunya ampisilin. Pada kenyataannya banyak S. aureus resisten terhadap antibiotik ini. Salah satu penyebab timbulnya resistensi ampisilin terhadap S. aureus yaitu adanya dugaan perubahan basa nukleotida dari gen struktur (blaZ) yang mengkode enzim betalaktamase. Tujuan: Untuk menganalisis perubahan basa nukleotida gen struktur pembentuk enzim betalaktamase pada S. aureus yang resisten ampisilin ditinjau secara molekuler. Metode: Pemeriksaan enzim betalaktamase secara molekuler dilakukan dengan mengisolasi gen pembentuk ensim betalaktamase (blaZ) yang memiliki panjang 845 pb terhadap 7 isolat S. aureus hasil isolasi yang berasal dari abses yang resisten terhadap ampisilin dengan mengunakan PCR . Hasil amplifikasi blaZ kemudian dilakukan homologi dengan Tn 552 S. aureus yang diperoleh dari bank gen. Hasil: Hasil homologi ditemukan adanya perubahan basa purin T G yang merupakan basa pirimidin pada posisi –37 dari kodon awal blaZ. Perubahan ini tidak mempengaruhi kekuatan promoter karena jumlah A dan T masih lebih banyak dari G dan C. Pada gen struktur blaZ ini tidak terdapat adanya mutasi ataupun delesi maupun subsitusi basa nukleotida hingga tidak akan mempengaruhi efektifitas kerja enzim betalaktamase. Kesimpulan: Terjadinya resisten S. aureus terhadap ampisilin bukan disebabkan adanya mutasi maupun delesi/ subsitusi basa nukleotida dari blaZ namun diduga adanya sebab lain yaitu produksi berlebih enzim betalaktamase hingga semua antibiotik betalaktam akan didegradasi oleh enzim betalaktamase.
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Khurana, Prerna, and Suchitra Shenoy. "Occurrence of blaTEM and blaROB in Haemophilus species Causing Respiratory Tract Infections." Infectious Disorders - Drug Targets 20, no. 3 (July 20, 2020): 385–88. http://dx.doi.org/10.2174/1871526519666190118103148.
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Background: Emergence of resistance to some antibiotics in Haemophilus influenzae, a respiratory pathogen is a cause of concern. The aim is to study the antibiotic susceptibility pattern of Haemophilus isolates from respiratory infections with reference to beta-lactam resistance. Methods: This is a laboratory based prospective study done in the department of microbiology in a tertiary care center after institutional ethics committee clearance. Haemophilus influenzae isolates from respiratory tract specimens over a period of one year were subjected to antibiotic susceptibility tests. Beta-lactamase production was detected by nitrocefin disc. hpd gene, blaTEM and blaROB genes were detected by PCR. The data was analysed using SPSS 11.5 version. Results: Of the 162 isolates, 89.5% were from sputum specimens. Ampicillin resistance was seen in 5 (3.09%) isolates. The ampicillin resistant strains were positive for beta-lactamase enzyme and blaTEM gene. BLNAR and isolates with blaROB gene were not found. Conclusion: In case of Haemophilus influenzae respiratory tract infection empirical treatment with amoxicillin clavulanate or third generation cephalosporin may be the drugs of choice in our geographic area.
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Wang, Lei, Mostafa H. Ahmed, Martin K. Safo, and Gordon L. Archer. "A Plasmid-Borne System To Assess the Excision and Integration of Staphylococcal Cassette ChromosomemecMediated by CcrA and CcrB." Journal of Bacteriology 197, no. 17 (June 8, 2015): 2754–61. http://dx.doi.org/10.1128/jb.00078-15.
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ABSTRACTResistance to methicillin and other β-lactam antibiotics in staphylococci is due tomecA, which is carried on a genomic island, staphylococcal cassette chromosomemec(SCCmec). The chromosomal excision and integration of SCCmecare mediated by the site-specific recombinase CcrAB or CcrC, encoded within this element. A plasmid-borne system was constructed to assess the activities of CcrA and CcrB in the excision and integration of SCCmecinEscherichia coliandStaphylococcus aureus. The excision frequency inE. colimediated by CcrAB from methicillin-resistantS. aureus(MRSA) strain N315 was only 9.2%, while the integration frequency was 31.4%. InS. aureusthe excision and integration frequencies were 11.0% and 18.7%, respectively. Truncated mutants identified the N-terminal domain of either CcrB or CcrA to be necessary for both integration and excision, while the C-terminal domain was important for recombination efficiency. Site-directed mutagenesis of the N-terminal domain identified S11 and R79 of CcrA and S16, R89, T149, and R151 of CcrB to be residues essential for catalytic activities, and the critical location of these residues was consistent with a model of the tertiary structure of the N terminus of CcrA and CcrB. Furthermore, CcrAB and CcrC, cloned from a panel of 6 methicillin-resistantS. aureusstrains and 2 methicillin-resistantStaphylococcus epidermidisstrains carrying SCCmectypes II, IV, and V, also catalyzed integration at rates 1.3 to 10 times higher than the rates at which they catalyzed excision, similar to the results from N315. The tendency of SCCmecintegration to be favored over excision may explain the low spontaneous excision frequency seen among MRSA strains.IMPORTANCESpontaneous excision of the genomic island (SCCmec) that encodes resistance to beta-lactam antibiotics (methicillin resistance) in staphylococci would convert a methicillin-resistant strain to a methicillin-susceptible strain, improving therapy of difficult-to-treat infections. This study characterizes a model system by which the relative frequencies of excision and integration can be compared. Using a plasmid-based model for excision and integration mediated by the recombinases CcrA and CcrB, integration occurred at a higher frequency than excision, consistent with the low baseline excision frequency seen in most strains. This model system can now be used to study conditions and drugs that may raise the SCCmecexcision frequency and generate strains that are beta-lactam susceptible.
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Hornik, Bartosz, Jakub Czarny, Justyna Staninska-Pięta, Łukasz Wolko, Paweł Cyplik, and Agnieszka Piotrowska-Cyplik. "The Raw Milk Microbiota from Semi-Subsistence Farms Characteristics by NGS Analysis Method." Molecules 26, no. 16 (August 19, 2021): 5029. http://dx.doi.org/10.3390/molecules26165029.
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The aim of this study was to analyze the microbiome of raw milk obtained from three semi-subsistence farms (A, B, and C) located in the Kuyavian-Pomeranian Voivodeship in Poland. The composition of drinking milk was assessed on the basis of 16S rRNA gene sequencing using the Ion Torrent platform. Based on the conducted research, significant changes in the composition of the milk microbiome were found depending on its place of origin. Bacteria belonging to the Bacillus (17.0%), Corynebacterium (12.0%) and Escherichia-Shigella (11.0%) genera were dominant in the milk collected from farm A. In the case of the milk from farm B, the dominant bacteria belonged to the Acinetobacter genus (21.0%), whereas in the sample from farm C, Escherichia-Shigella (24.8%) and Bacillus (10.3%) dominated the microbiome. An analysis was performed using the PICRUSt tool (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States) in order to generate a profile of genes responsible for bacterial metabolism. The conducted analysis confirmed the diversity of the profile of genes responsible for bacterial metabolism in all the tested samples. On the other hand, simultaneous analysis of six KEGG Orthologs (KO), which participated in beta-lactam resistance responsible for antibiotic resistance of bacteria, demonstrated that there is no significant relationship between the predicted occurrence of these orthologs and the place of existence of microorganisms. Therefore, it can be supposed that bacterial resistance to beta-lactam antibiotics occurs regardless of the environmental niche, and that the antibiotic resistance maintained in the population is a factor that shapes the functional structure of the microbial consortia.
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Rezai, Mohammad Sadegh, Ebrahim Salehifar, Alireza Rafiei, Taimour Langaee, Mohammadreza Rafati, Kheironesa Shafahi, and Gohar Eslami. "Characterization of Multidrug Resistant Extended-Spectrum Beta-Lactamase-ProducingEscherichia coliamong Uropathogens of Pediatrics in North of Iran." BioMed Research International 2015 (2015): 1–7. http://dx.doi.org/10.1155/2015/309478.
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Escherichia coliremains as one of the most important bacteria causing infections in pediatrics and producing extended-spectrum beta-lactamases (ESBLs) making them resistant to beta-lactam antibiotics. In this study we aimed to genotype ESBL-producingE. coliisolates from pediatric patients for ESBL genes and determine their association with antimicrobial resistance. One hundred of theE. coliisolates were initially considered ESBL producing based on their MIC results. These isolates were then tested by polymerase chain reaction (PCR) for the presence or absence ofCTX,TEM,SHV,GES, andVEBbeta-lactamase genes. About 30.5% of isolatedE. coliwas ESBL-producing strain. TheTEMgene was the most prevalent (49%) followed bySHV(44%),CTX(28%),VEB(8%), andGES(0%) genes. The ESBL-producingE. coliisolates were susceptible to carbapenems (66%) and amikacin (58%) and showed high resistance to cefixime (99%), colistin (82%), and ciprofloxacin (76%). In conclusion, carbapenems were the most effective antibiotics against ESBl-producingE. coliin urinary tract infection in North of Iran. The most prevalent gene is the TEM-type, but the other resistant genes and their antimicrobial resistance are on the rise.
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Mezoughi, Aysha B., Chiara M. Costanzo, Gregor M. Parker, Enas M. Behiry, Alan Scott, Andrew C. Wood, Sarah E. Adams, Richard B. Sessions, and E. Joel Loveridge. "The Lysozyme Inhibitor Thionine Acetate Is Also an Inhibitor of the Soluble Lytic Transglycosylase Slt35 from Escherichia coli." Molecules 26, no. 14 (July 9, 2021): 4189. http://dx.doi.org/10.3390/molecules26144189.
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Lytic transglycosylases such as Slt35 from E. coli are enzymes involved in bacterial cell wall remodelling and recycling, which represent potential targets for novel antibacterial agents. Here, we investigated a series of known glycosidase inhibitors for their ability to inhibit Slt35. While glycosidase inhibitors such as 1-deoxynojirimycin, castanospermine, thiamet G and miglitol had no effect, the phenothiazinium dye thionine acetate was found to be a weak inhibitor. IC50 values and binding constants for thionine acetate were similar for Slt35 and the hen egg white lysozyme. Molecular docking simulations suggest that thionine binds to the active site of both Slt35 and lysozyme, although it does not make direct interactions with the side-chain of the catalytic Asp and Glu residues as might be expected based on other inhibitors. Thionine acetate also increased the potency of the beta-lactam antibiotic ampicillin against a laboratory strain of E. coli.
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Sharkady, Stephen M., Brandon Bailey, and Dorothea K. Thompson. "Characterization of Two Novel AmpC Beta-Lactamases from the Emerging Opportunistic Pathogen, Cedecea neteri." Antibiotics 12, no. 2 (January 20, 2023): 219. http://dx.doi.org/10.3390/antibiotics12020219.
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The genus Cedecea (family Enterobacteriaceae) causes a wide spectrum of acute infections in immunocompromised hosts, from pneumonia and bacteremia to oral ulcers and dialysis-related peritonitis. While Cedecea infections are reported infrequently in the literature, documented clinical cases of this emerging opportunistic human pathogen have occurred worldwide. Cedecea neteri has clinical significance and exhibits antimicrobial drug resistance. However, little is known about the molecular basis underlying the resistance phenotypes in C. neteri. We previously hypothesized that the open-reading frame cnt10470 in the C. neteri SSMD04 genome encodes a chromosomal Ambler class C (AmpC) β-lactamase based on sequence homology. In this study, recombinant polyhistidine-tagged proteins were created by cloning the putative ampC genes from SSMD04 and C. neteri ATCC 33855 (a clinical isolate) into the pET-6xHN expression vector, overexpressing the proteins, and then purifying the recombinant AmpCs (rAmpCs) using immobilized metal affinity chromatography (Ni-NTA). The in vitro enzymatic analysis of the purified rAmpCs was performed to determine the Km and kcat for various β-lactam substrates. The rAmpCs are functional class C β-lactamases when assayed using the chromogenic β-lactamase substrate, nitrocefin. The presence of functional AmpCs in both C. neteri strains underscores the necessity of performing antibiotic susceptibility testing in the management of C. neteri infections.
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Zalas-Więcek, Patrycja, Katarzyna Płachta, and Eugenia Gospodarek-Komkowska. "Cefiderocol against Multi-Drug and Extensively Drug-Resistant Escherichia coli: An In Vitro Study in Poland." Pathogens 11, no. 12 (December 9, 2022): 1508. http://dx.doi.org/10.3390/pathogens11121508.
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Cefiderocol (CFDC) is a novel, broad-spectrum siderophore cephalosporin with potential activity against multi-drug (MDR) and extensively drug-resistant (XDR) Enterobacterales, including carbapenem-resistant strains. We assessed the in vitro susceptibility to CFDC of MDR, and XDR E. coli isolates derived from clinical samples of hospitalized patients. Disk diffusion (DD) and MIC (minimum inhibitory concentration) test strip (MTS) methods were used. The results were interpreted based on EUCAST (version 12.0 2022) recommendations. Among all E. coli isolates, 98 (94.2%) and 99 (95.2%) were susceptible to CFDC when the DD and MTS methods were used, respectively (MIC range: <0.016–4 µg/mL, MIC50: 0.19 µg/mL, MIC90: 0.75 µg/mL). With the DD and MTS methods, all (MIC range: 0.016–2 µg/mL, MIC50: 0.19 µg/mL, MIC90: 0.75 µg/mL) but three (96.6%) ESBL-positive isolates were susceptible to CFDC. Out of all the metallo-beta-lactamase-positive E. coli isolates (MIC range: 0.016–4 µg/mL, MIC50: 0.5 µg/mL, MIC90: 1.5 µg/mL), 16.7% were resistant to CFDC with the DD method, while 11.1% were resistant to CFDC when the MTS method was used. CFDC is a novel therapeutic option against MDR and XDR E. coli isolates and is promising in the treatment of carbapenem-resistant E. coli strains, also for those carrying Verona integron-encoded metallo-beta-lactamases, when new beta-lactam-beta-lactamase inhibitors cannot be used.
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Zahraa A Sahan and Saad L Hamed. "Molecular Detection of Extended-Spectrum β-Lactamases- Producer Serratia marcescens Causing Neonatal Sepsis in Iraq." International Journal of Research in Pharmaceutical Sciences 11, no. 4 (September 29, 2020): 5803–8. http://dx.doi.org/10.26452/ijrps.v11i4.3229.
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Serratia marcescens is an important nosocomial pathogen that causes a variety of infections, especially urinary tract and bloodstream infections. The emergence and spread of multidrug-resistant Serratia marcescens producing extended-spectrum beta-lactamases is a threat to public health worldwide at present. Extended-spectrum β-lactamases (ESβLs) including TEM, SHV, and CTX-M are the predominant types that confer resistance to beta-lactam group of antibiotics. Many reports have been investigated ESBL-producing isolates of Enterobacteriaceae in Iraq. However, there are few studies concerned about ESβL-producing Serratia marcescens particularly, detection of ESBLs encoding genes. Therefore this study aimed to identify ESβLs encoding genes in Serratia marcescens isolates from a neonatal intensive care unit. Fifty isolates were identified phenotypically using the VITEK® 2 compact system. For confirming the identification of bacterial strains, molecular detection of housekeeping LuxS gene was done using species-specific designed primers. Antibiogram was performed using the VITEK® 2 compact system. A phenotypic confirmatory test for ESβLs producers was performed using a combination disc method. The ESβLs encoding genes, including blaTEM, blaSHV, and blaCTX-M, were amplified using a PCR-based technique; the amplified products of some selected isolates were sequenced. Molecular detection of isolates using PCR-based amplification of the LuxS gene showed that all isolates possessed this gene. The patterns of antimicrobial resistance for isolates under study showed very high resistance to cephalosporins, while they were susceptible to carbapenem drugs and tigecycline. Findings based on the PCR technique showed that the prevalence of ESβLs encoding genes of isolates was 13 (26%), 31 (62%), and 46 (92%) for blaTEM, blaSHV, and blaCTX-M respectively. In the present study, it was concluded that blaCTX-M gene was the most prevalent ESβLs-encoding gene among ESβLs producing Serratia marcescens isolates.
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Masumi, Motahareh, Fatemeh Noormohammadi, Fatemeh Kianisaba, Fatemeh Nouri, Mohammad Taheri, and Amir Taherkhani. "Methicillin-Resistant Staphylococcus aureus: Docking-Based Virtual Screening and Molecular Dynamics Simulations to Identify Potential Penicillin-Binding Protein 2a Inhibitors from Natural Flavonoids." International Journal of Microbiology 2022 (May 4, 2022): 1–14. http://dx.doi.org/10.1155/2022/9130700.
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Staphylococcus aureus (S. aureus) is responsible for several disorders including skin and soft tissue infections, bacteremia, pulmonary infections, septic arthritis, osteomyelitis, meningitis, gastroenteritis, toxic-shock syndrome, and urinary tract infections. Methicillin-resistant S. aureus (MRSA) contains penicillin-binding protein 2a (SauPBP2a) responsible for catalyzing the peptidoglycan production within the bacterial cell wall. The binding affinity of SauPBP2a to beta-lactam antibiotics is low, and thus, it is necessary to discover new effective SauPBP2a inhibitors to combat mortality and morbidity in patients affected by MRSA. The binding affinity of 46 natural flavonoids to the SauPBP2a active site was examined via molecular docking analysis. The stability of docked poses associated with the top-ranked flavonoids was tested by performing molecular dynamics (MD) in 10 nanoseconds (ns) computer simulations. Kaempferol 3-rutinoside-7-sophoroside and rutin demonstrated a considerable binding affinity to the SauPBP2a active site (Δ G binding < − 11 kcal/mol). Their docked poses were found to be stable for 10 ns MD simulations. Kaempferol 3-rutinoside-7-sophoroside and rutin also exhibited salient binding affinity to the enzyme’s allosteric site. This study suggests that kaempferol 3-rutinoside-7-sophoroside and rutin may be considered as drug candidates for therapeutic aims in several human infections associated with MRSA. Nevertheless, in vitro and in vivo confirmations are warranted.
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Doshi, Dhruvi M., Bharat B. Bhanderi, Rafiyuddin A. Mathakiya, Vipul R. Nimavat, and Mayurdwaj K. Jhala. "Isolation, Characterization, Antibiogram and Molecular Detection of Antibiotic Resistance Genes from Bacteria Isolated from Otitis Externa in Dogs." Indian Journal of Veterinary Sciences and Biotechnology 17, no. 02 (July 15, 2007): 42–47. http://dx.doi.org/10.21887/ijvsbt.17.2.8.
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Otitis externa is one of the most common diseases of the canines, defined as an acute or chronic inflammation of the external ear canal. In the present study, 124 samples were collected, out of which 94 samples were from 75 dogs suffering from otitis externa and 30 from 15 healthy dogs from the regions of Anand and Vadodara districts of Gujarat. Total 129 bacteria comprised of Staphylococcus spp. (58.40%), Pseudomonas spp. (10.62%), Proteus spp. (10.62%), Streptococcus spp. (7.08%), Corynebacterium spp. (6.19%), E. coli (4.42%), Klebsiella spp. (1.77%) and Enterobacter spp. (0.88%) were isolated from otitic and healthy ears of dogs based upon colonial, microscopic, and biochemical characteristics. The bacterial isolates showed least resistance towards tobramycin (1.51%) followed by enrofloxacin (5.52%), ofloxacin (11.98%), amikacin (15.20), gentamicin (17.07), and amoxycillin clavulanic acid (17.53%), while they showed the highest resistance towards ampicillin (63.90%). The multidrug resistance was detected in 29.46% (34/129) of the total bacterial isolates. Beta-lactam resistance genes were detected in E. coli, Klebsiella spp., Enterobacter spp. and Pseudomonas spp.; quinolone resistance genes were detected in E. coli, and aminoglycoside resistance genes were detected in E. coli, Proteus spp. and Staphylococcus spp.
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Albekairi, Thamer H., Abdulrahman Alshammari, Metab Alharbi, Amal F. Alshammary, Muhammad Tahir ul Qamar, Asad Ullah, Muhammad Irfan, and Sajjad Ahmad. "Designing of a Novel Multi-Antigenic Epitope-Based Vaccine against E. hormaechei: An Intergraded Reverse Vaccinology and Immunoinformatics Approach." Vaccines 10, no. 5 (April 22, 2022): 665. http://dx.doi.org/10.3390/vaccines10050665.
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Enterobacter hormaechei is involved in multiple hospital-associated infections and is resistant to beta-lactam and tetracycline antibiotics. Due to emerging antibiotics resistance in E. hormaechei and lack of licensed vaccine availability, efforts are required to overcome the antibiotics crisis. In the current research study, a multi-epitope-based vaccine against E. hormaechei was designed using reverse vaccinology and immunoinformatic approaches. A total number of 50 strains were analyzed from which the core proteome was extracted. One extracellular (curlin minor subunit CsgB) and two periplasmic membrane proteins (flagellar basal-body rod protein (FlgF) and flagellar basal body P-ring protein (FlgI) were prioritized for B and T-cell epitope prediction. Only three filtered TPGKMDYTS, GADMTPGKM and RLSAESQAT epitopes were used when designing the vaccine construct. The epitopes were linked via GPGPG linkers and EAAAK linker-linked cholera toxin B-subunit adjuvant was used to enhance the immune stimulation efficacy of the vaccine. Docking studies of the vaccine construct with immune cell receptors revealed better interactions, vital for generating proper immune reactions. Docked complexes of vaccine with MHC-I, MHC-II and Tool-like receptor 4 (TLR-4) reported the lowest binding energy of −594.1 kcal/mol, −706.7 kcal/mol, −787.2 kcal/mol, respectively, and were further subjected to molecular dynamic simulations. Net binding free energy calculations also confirmed that the designed vaccine has a strong binding affinity for immune receptors and thus could be a good vaccine candidate for future experimental investigations.
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Kachalov, Viacheslav N., Huyen Nguyen, Suraj Balakrishna, Luisa Salazar-Vizcaya, Rami Sommerstein, Stefan P. Kuster, Anthony Hauser, Pia Abel zur Wiesch, Eili Klein, and Roger D. Kouyos. "Identifying the drivers of multidrug-resistant Klebsiella pneumoniae at a European level." PLOS Computational Biology 17, no. 1 (January 29, 2021): e1008446. http://dx.doi.org/10.1371/journal.pcbi.1008446.
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Beta-lactam- and in particular carbapenem-resistant Enterobacteriaceae represent a major public health threat. Despite strong variation of resistance across geographical settings, there is limited understanding of the underlying drivers. To assess these drivers, we developed a transmission model of cephalosporin- and carbapenem-resistant Klebsiella pneumoniae. The model is parameterized using antibiotic consumption and demographic data from eleven European countries and fitted to the resistance rates for Klebsiella pneumoniae for these settings. The impact of potential drivers of resistance is then assessed in counterfactual analyses. Based on reported consumption data, the model could simultaneously fit the prevalence of extended-spectrum beta-lactamase-producing and carbapenem-resistant Klebsiella pneumoniae (ESBL and CRK) across eleven European countries over eleven years. The fit could explain the large between-country variability of resistance in terms of consumption patterns and fitted differences in hospital transmission rates. Based on this fit, a counterfactual analysis found that reducing nosocomial transmission and antibiotic consumption in the hospital had the strongest impact on ESBL and CRK prevalence. Antibiotic consumption in the community also affected ESBL prevalence but its relative impact was weaker than inpatient consumption. Finally, we used the model to estimate a moderate fitness cost of CRK and ESBL at the population level. This work highlights the disproportionate role of antibiotic consumption in the hospital and of nosocomial transmission for resistance in gram-negative bacteria at a European level. This indicates that infection control and antibiotic stewardship measures should play a major role in limiting resistance even at the national or regional level.
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Campanón Toro, María del Valle, Esther Moreno Rodilla, Alicia Gallardo Higueras, Elena Laffond Yges, Francisco J. Muñoz Bellido, María Teresa Gracia Bara, Cristina Martin García, et al. "Changes in Sensitization Patterns in the Last 25 Years in 619 Patients with Confirmed Diagnoses of Immediate Hypersensitivity Reactions to Beta-Lactams." Biomedicines 10, no. 7 (June 28, 2022): 1535. http://dx.doi.org/10.3390/biomedicines10071535.
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Beta-lactam (BL) drugs are the antibiotics most prescribed worldwide due to their broad spectrum of action. They are also the most frequently implied in hypersensitivity reactions with a known specific immunological mechanism. Since the commercialization of benzylpenicillin, allergic reactions have been described; over the years, other new BL drugs provided alternative treatments to penicillin, and amoxicillin is now the most prescribed BL in Europe. Diagnosis of BL allergy is mainly based on skin tests and drug provocation tests, defining different sensitization patterns or phenotypes. In this study, we evaluated 619 patients with a confirmed diagnosis of BL-immediate allergy during the last 25 years, using the same diagnostic procedures with minor adaptations to the successive guidelines. The initial eliciting drug was benzylpenicillin, which changed to amoxicillin with or without clavulanic acid and cephalosporins in recent years. In skin tests, we found a decrease in sensitivity to major and minor penicillin determinants and an increase in sensitivity to amoxicillin and others; this might reflect that the changes in prescription could have influenced the sensitization patterns, thus increasing the incidence of specific reactions to side-chain selective reactions.
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Hussain, Arif, Christa Ewers, Nishant Nandanwar, Sebastian Guenther, Savita Jadhav, Lothar H. Wieler, and Niyaz Ahmed. "Multiresistant Uropathogenic Escherichia coli from a Region in India Where Urinary Tract Infections Are Endemic: Genotypic and Phenotypic Characteristics of Sequence Type 131 Isolates of the CTX-M-15 Extended-Spectrum-β-Lactamase-Producing Lineage." Antimicrobial Agents and Chemotherapy 56, no. 12 (October 8, 2012): 6358–65. http://dx.doi.org/10.1128/aac.01099-12.
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ABSTRACTEscherichia colisequence type 131 (O25b:H4), associated with the CTX-M-15 extended-spectrum beta-lactamases (ESBLs) and linked predominantly to the community-onset antimicrobial-resistant infections, has globally emerged as a public health concern. However, scant attention is given to the understanding of the molecular epidemiology of these strains in high-burden countries such as India. Of the 100 clinicalE. coliisolates obtained by us from a setting where urinary tract infections are endemic, 16 ST131E. coliisolates were identified by multilocus sequence typing (MLST). Further, genotyping and phenotyping methods were employed to characterize their virulence and drug resistance patterns. All the 16 ST131 isolates harbored the CTX-M-15 gene, and half of them also carried TEM-1; 11 of these were positive forblaOXAgroups 1 and 12 foraac(6′)-Ib-cr. At least 12 isolates were refractory to four non-beta-lactam antibiotics: ciprofloxacin, gentamicin, sulfamethoxazole-trimethoprim, and tetracycline. Nine isolates carried the class 1 integron. Plasmid analysis indicated a large pool of up to six plasmids per strain with a mean of approximately three plasmids. Conjugation and PCR-based replicon typing (PBRT) revealed that the spread of resistance was associated with the FIA incompatibility group of plasmids. Pulsed-field gel electrophoresis (PFGE) and genotyping of the virulence genes showed a low level of diversity among these strains. The association of ESBL-encoding plasmid with virulence was demonstrated in transconjugants by serum assay. None of the 16 ST131 ESBL-producingE. colistrains were known to synthesize carbapenemase enzymes. In conclusion, our study reports a snapshot of the highly virulent/multiresistant clone ST131 of uropathogenicE. colifrom India. This study suggests that the ST131 genotypes from this region are clonally evolved and are strongly associated with the CTX-M-15 enzyme, carry a high antibiotic resistance background, and have emerged as an important cause of community-acquired urinary tract infections.
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Javed, Naima, Sajjad Ahmad, Saad Raza, and Syed Sikander Azam. "Subtractive Proteomics Supported with Rational Drug Design Approach Revealed ZINC23121280 as a Potent Lead Inhibitory Molecule for Multi-drug Resistant Francisella tularensis." Proceedings of the Pakistan Academy of Sciences: B. Life and Environmental Sciences 58, no. 1 (September 6, 2021): 1–42. http://dx.doi.org/10.53560/ppasb(58-1)349.
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Francisella tularensis is a Gram-negative bacterium and is the etiological agent of taluremia. The prolonged use of antibiotics is the reason for pathogen resistance to antibiotics such as beta-lactams and macrolides. This leads to the search to explore novel drug targets for F. tularensis to inhibit its growth. Subtractive proteomics revealed Glucose-1-phosphate thymidylyltransferase (G1PTT) as the most promising protein as a drug target. A pharmacophore model was generated for virtual screening of a druglike library comprised of 1,000,000 drug molecules. Based on a pharmacophore-based search, a set of 152 compounds was predicted as the most potent inhibitors against this enzyme. The screened hits were docked with the target enzyme; which unveiled ZINC23121280 as the best-docked inhibitor having Autdock Vina binding energy of -7.2 kcal/mol and the GOLD score of 64.06. Moreover, the timedependent dynamic behavior of the complex was analyzed using Molecular Dynamics (MD) simulation studies that revealed a stable system with a Root Mean Square Deviation (RMSD) average value of 2.25 Å and Root Mean SquareFluctuations (RMSF) of 1.16 Å. Radial Distribution Function (RDF) predicted strong hydrogen interactions between the ligand and Trp221 from the enzyme active pocket. The higher affinity of the antagonist for the enzyme was further supported by Molecular Mechanics Energies combined with the Poisson–Boltzmann and Surface Area (MMPBSA) and or Generalized Born and Surface Area (MMGBSA) with the estimated binding free energy of −1.07 kcal/mol and −29.59 kcal/mol, respectively. Findings from this present computational framework may provide the foundation for future drug discovery against F. tularensis.
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Kugelman, Gayle, John W. Tapsall, Namraj Goire, Melanie W. Syrmis, Athena Limnios, Stephen B. Lambert, Michael D. Nissen, Theo P. Sloots, and David M. Whiley. "Simple, Rapid, and Inexpensive Detection of Neisseria gonorrhoeae Resistance Mechanisms Using Heat-Denatured Isolates and SYBR Green-Based Real-Time PCR." Antimicrobial Agents and Chemotherapy 53, no. 10 (June 15, 2009): 4211–16. http://dx.doi.org/10.1128/aac.00385-09.
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ABSTRACT Neisseria gonorrhoeae has developed resistance to multiple classes of antimicrobials. There is now growing concern that without the availability of appropriate public health strategies to combat this problem, gonorrhea could become untreatable. For this reason, surveillance for gonococcal antimicrobial resistance must be optimal both in terms of obtaining a representative sample of gonococcal isolates and in terms of having the appropriate tools to identify resistance. To aid with this surveillance, molecular tools are increasingly being used. In the present study, we investigated the use of a simple heat denaturation protocol for isolate DNA preparation combined with SYBR green-based real-time PCR for the identification of mutations associated with N. gonorrhoeae antimicrobial resistance. A total of 109 clinical gonococcal isolates were tested by high-resolution melting (HRM) curve analysis for chromosomal mutations associated with gonococcal resistance to beta-lactam antibiotics: a penA 345A insertion, ponA L421P, mtrR G45D, substitutions at positions 120 and 121 in porB1b, and an adenine deletion in the mtrR promoter. An allele-specific PCR assay was also investigated for its ability to detect the adenine deletion in the mtrR promoter. The results were compared to those obtained by DNA sequencing. Our HRM assays provided the accurate discrimination of heat-treated isolates in which the sequence types differed in GC content, including isolates with the penA 345A insertion and the ponA L421P and mtrR G45D mutations. The allele-specific PCR assay accurately identified isolates with the adenine deletion in the mtrR promoter. Heat-denatured DNA combined with SYBR green-based real-time PCR offers a simple, rapid, and inexpensive means of detecting gonococcal resistance mechanisms. These methods may have broader application in the detection of polymorphisms associated with phenotypes of interest.
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Dahlhausen, Katherine E., Guillaume Jospin, David A. Coil, Jonathan A. Eisen, and Laetitia G. E. Wilkins. "Isolation and sequence-based characterization of a koala symbiont: Lonepinella koalarum." PeerJ 8 (October 20, 2020): e10177. http://dx.doi.org/10.7717/peerj.10177.
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Koalas (Phascolarctos cinereus) are highly specialized herbivorous marsupials that feed almost exclusively on Eucalyptus leaves, which are known to contain varying concentrations of many different toxic chemical compounds. The literature suggests that Lonepinella koalarum, a bacterium in the Pasteurellaceae family, can break down some of these toxic chemical compounds. Furthermore, in a previous study, we identified L. koalarum as the most predictive taxon of koala survival during antibiotic treatment. Therefore, we believe that this bacterium may be important for koala health. Here, we isolated a strain of L. koalarum from a healthy koala female and sequenced its genome using a combination of short-read and long-read sequencing. We placed the genome assembly into a phylogenetic tree based on 120 genome markers using the Genome Taxonomy Database (GTDB), which currently does not include any L. koalarum assemblies. Our genome assembly fell in the middle of a group of Haemophilus, Pasteurella and Basfia species. According to average nucleotide identity and a 16S rRNA gene tree, the closest relative of our isolate is L. koalarum strain Y17189. Then, we annotated the gene sequences and compared them to 55 closely related, publicly available genomes. Several genes that are known to be involved in carbohydrate metabolism could exclusively be found in L. koalarum relative to the other taxa in the pangenome, including glycoside hydrolase families GH2, GH31, GH32, GH43 and GH77. Among the predicted genes of L. koalarum were 79 candidates putatively involved in the degradation of plant secondary metabolites. Additionally, several genes coding for amino acid variants were found that had been shown to confer antibiotic resistance in other bacterial species against pulvomycin, beta-lactam antibiotics and the antibiotic efflux pump KpnH. In summary, this genetic characterization allows us to build hypotheses to explore the potentially beneficial role that L. koalarum might play in the koala intestinal microbiome. Characterizing and understanding beneficial symbionts at the whole genome level is important for the development of anti- and probiotic treatments for koalas, a highly threatened species due to habitat loss, wildfires, and high prevalence of Chlamydia infections.
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Qi, Yanjiao, Mingyang Wang, Bo Zhang, Yue Liu, Jiaqin Fan, Zifan Wang, Li Song, Peer Mohamed Abdul, and Hong Zhang. "Effects of Natural Rheum tanguticum on the Cell Wall Integrity of Resistant Phytopathogenic Pectobacterium carotovorum subsp. Carotovorum." Molecules 27, no. 16 (August 19, 2022): 5291. http://dx.doi.org/10.3390/molecules27165291.
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The abuse of agricultural antibiotics has led to the emergence of drug-resistant phytopathogens. Rifampicin and streptomycin and streptomycin resistance Pectobacterium carotovorum subsp. carotovorum (PccS1) was obtained from pathological plants in a previous experiment. Rheum tanguticum, derived from the Chinese plateau area, exhibits excellent antibacterial activity against PccS1, yet the action mode has not been fully understood. In present text, the cell wall integrity of the PccS1 was tested by the variation of the cellular proteins, SDS polyacrylamide gel electrophoresis (SDS-PAGE), scanning electron microscopy (SEM) and Fourier transform infrared spectrophotometer (FTIR) characteristics. Label-free quantitative proteomics was further used to identify the DEPs in the pathogen response to treatment with Rheum tanguticum Maxim. ex Balf. extract (abbreviated as RTMBE). Based on the bioinformatics analysis of these different expressed proteins (DEPs), RTMBE mainly inhibited some key protein expressions of beta-Lactam resistance, a two-component system and phosphotransferase system. Most of these membrane proteins were extraordinarily suppressed, which was also consistent with the morphological tests. In addition, from the downregulated flagellar motility related proteins, it was also speculated that RTMBE played an essential antibacterial role by affecting the swimming motility of the cells. The results indicated that Rheum tanguticum can be used to attenuate the virulence of the drug-resistant phytopathogenic bacteria.
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Yasir, Muhammad, Abdullah Mohammad Subahi, Hani A. Shukri, Fehmida Bibi, Sayed Sartaj Sohrab, Maha Alawi, Anees A. Sindi, Asif A. Jiman-Fatani, and Esam I. Azhar. "Bacterial Community and Genomic Analysis of Carbapenem-Resistant Acinetobacter baumannii Isolates from the Environment of a Health Care Facility in the Western Region of Saudi Arabia." Pharmaceuticals 15, no. 5 (May 16, 2022): 611. http://dx.doi.org/10.3390/ph15050611.
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The escalating transmission of hospital-acquired infections, especially those due to antimicrobial-resistant bacteria, is a major health challenge worldwide. In this study, a culturomic analysis of bacterial community in a tertiary care hospital in the western region of Saudi Arabia is performed using environmental samples. The genome sequencing of four Acinetobacter baumannii was performed on isolates recovered from an intensive care unit (ICU) environment and clinical samples. A total of 361 bacterial isolates from surface and air samples were identified by MALDI-TOF technique or 16S rRNA gene sequencing. The isolates were classified into 70 distinct species, including ESKAPE pathogens. Resistance in Gram-positive isolates was mainly found to be against benzylpenicillin, azithromycin, ampicillin, and trimethoprim/sulfamethoxazole. Carbapenem- and multidrug-resistant isolates of A. baumannii and Klebsiella pneumonia were found on the ICU surfaces. Genome sequencing revealed that the carbapenem-resistant A. baumannii isolate from ICU environment was linked with those of clinical origin. The isolate Ab133-HEnv was classified as a novel sequence type (ST2528) based on a new allele of Oxf_gdhB-286. Three beta-lactam-antibiotic-resistance genes, blaADC-25, blaOXA-23, and blaOXA-66, were found in most of the analyzed genomes. Collectively, the results of this study highlight the spread of antimicrobial-resistant nosocomial pathogens in a health care facility in Saudi Arabia.
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Janse, Ingmar, Rick Beeloo, Arno Swart, Michael Visser, Leo Schouls, Engeline van Duijkeren, and Mark W. J. van Passel. "The extent of carbapenemase-encoding genes in public genome sequences." PeerJ 9 (March 9, 2021): e11000. http://dx.doi.org/10.7717/peerj.11000.
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Genome sequences provide information on the genetic elements present in an organism, and currently there are databases containing hundreds of thousands of bacterial genome sequences. These repositories allow for mining patterns concerning antibiotic resistance gene occurrence in both pathogenic and non-pathogenic bacteria in e.g. natural or animal environments, and link these to relevant metadata such as bacterial host species, country and year of isolation, and co-occurrence with other resistance genes. In addition, the advances in the prediction of mobile genetic elements, and discerning chromosomal from plasmid DNA, broadens our view on the mechanism mediating dissemination. In this study we utilize the vast amount of data in the public database PATRIC to investigate the dissemination of carbapenemase-encoding genes (CEGs), the emergence and spread of which is considered a grave public health concern. Based on publicly available genome sequences from PATRIC and manually curated CEG sequences from the beta lactam database, we found 7,964 bacterial genomes, belonging to at least 70 distinct species, that carry in total 9,892 CEGs, amongst which blaNDM, blaOXA, blaVIM, blaIMP and blaKPC. We were able to distinguish between chromosomally located resistance genes (4,137; 42%) and plasmid-located resistance genes (5,753; 58%). We found that a large proportion of the identified CEGs were identical, i.e. displayed 100% nucleotide similarity in multiple bacterial species (8,361 out of 9,892 genes; 85%). For example, the New Delhi metallo-beta-lactamase NDM-1 was found in 42 distinct bacterial species, and present in seven different environments. Our data show the extent of carbapenem-resistance far beyond the canonical species Acetinobacter baumannii, Klebsiella pneumoniae or Pseudomonas aeruginosa. These types of data complement previous systematic reviews, in which carbapenem-resistant Enterobacteriaceae were found in wildlife, livestock and companion animals. Considering the widespread distribution of CEGs, we see a need for comprehensive surveillance and transmission studies covering more host species and environments, akin to previous extensive surveys that focused on extended spectrum beta-lactamases. This may help to fully appreciate the spread of CEGs and improve the understanding of mechanisms underlying transmission, which could lead to interventions minimizing transmission to humans.
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Haji, Sayran Hamad, Safaa Toma Hanna Aka, and Fattma A. Ali. "Prevalence and characterisation of carbapenemase encoding genes in multidrug-resistant Gram-negative bacilli." PLOS ONE 16, no. 11 (November 1, 2021): e0259005. http://dx.doi.org/10.1371/journal.pone.0259005.
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Background Emerging worldwide in the past decade, there has been a significant increase in multidrug-resistant bacteria from serious nosocomial infections, especially carbapenemase-producing Gram-negative bacilli that have emerged worldwide. The objective of this study is to investigate carbapenem resistance in Gram-negative bacilli bacteria using phenotypic detection, antimicrobial resistance profiles and genotypic characterisation methods. Methods 200 Gram-negative bacilli isolates were collected from different clinical specimens. All clinical samples were exposed to isolation and identification of significant pathogens applying bacteriological examination and an automated Vitek-2 system. The isolates were subjected to susceptibility tests by the Vitek-2 automated system and those isolates that were resistant to beta-lactam drugs, including carbapenems, third-generation cephalosporines or cefoxitin, were selected for phenotyping using Carba plus disc system assay for detection of carbapenemase-producing isolates. These isolates were further confirmed by molecular detection. PCR was used for the detection carbapenem-resistant genes (OXA-48, IMP, NDM, VIM, and KPC). Results 110 (55%) of 200 Gram-negative bacilli were identified as beta-lactam-resistant isolates. The frequency of carbapenem-resistant isolates was calculated to be 30.9% (n = 34/110). A collection totalling 65/110 (59%) isolates were identified as carbapenemase producers by phenotypic method. Moreover, among the 65 carbapenemase-producing Gram-negative isolates with a positive phenotype-based result, 30 (46%), 20 (30%) and 18 (27%) isolates were positive for OXA-48, KPC and MBL enzymes, respectively, as well as the production of 27% of AmpC with porin loss. Tigecycline was the most effective antibiotic that affected 70% of MDR isolates, but high rates of resistance were detected to other tested antimicrobials. Of interest, a high incidence of MDR, XDR and PDR profiles were observed among all carbapenemase-producing isolates. 36% (24/65) of the tested isolates were MDR to 3 to 5 antimicrobial classes. 29% (17/65) of the recovered isolates were XDR to 6 to 7 antimicrobial classes. Alarmingly, 24% (16/65) of isolates displayed PDR to all the tested 8 antimicrobial classes. Genotype assay, including 53 phenotypically confirmed carbapenemase-producing isolates of Gram-negative bacilli, found 51(96%) isolates were harbouring one or more genes. The most common carbapenemase gene was bla NDM 83% (44/53) followed by bla OXA-48 75% (40/53), bla VIM 49% (26/53) and bla IMP 43% (23/53), while the gene bla KPC was least frequent 7% (4/53). 92% (46/51) of isolates were involved in the production of more than one carbapenemase gene. Conclusion This study demonstrated the emergence of carbapenemase-producing Gram-negative pathogens implicated in healthcare-related infections. Accurate identification of carbapenem-resistant bacterial pathogens is essential for patient treatment, as well as the development of appropriate contamination control measures to limit the rapid spread of pathogens. Tigecycline exhibited potent antimicrobial activity against MDR, XDR and PDR-producing strains that establish a threatening alert which indicates the complex therapy of infections caused by these pathogens.
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Muleta, Daniel, Cullen Adre, and Benji-Byrd Warner. "839. Epidemiology of Extended-Spectrum Beta-lactamase (ESBL) Producing Enterobacteriaceae in the South East Tennessee, October-December 2017." Open Forum Infectious Diseases 7, Supplement_1 (October 1, 2020): S460—S461. http://dx.doi.org/10.1093/ofid/ofaa439.1028.
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Abstract Background The increasing spread of drug resistant gram-negative organisms is one of the major public health challenges. ESBL-producing Enterobacteriaceae has become the most common multi drug resistant pathogen in the last three decades. These organisms confer resistance to most beta-lactam antibiotics, including penicillins, third generation cephalosporins, monobactams and tazobactam. Methods The Tennessee Health Department (TDH) collaborated with CDC to pilot population based surveillance of ESBL producing organisms in Maury, Wayne, Lewis and Marshall Counties during October to December 2017. A case was defined as isolation of Escherichia coli, Klebsiella pneumoniae, or Klebsiella oxytoca resistant to at least one extended-spectrum cephalosporin (ceftazidime, cefotaxime or ceftriaxone) and non-resistant to all carbapenem antibiotics from urine or normally sterile body sites from a resident of the surveillance catchment area. A line list of ESBL-producing organisms was received from the labs that serve the catchment population. Case report forms were completed for the first ESBL culture collected from a single patient in a 30 day-period. Results A total of 154 cases were identified during the study period. E.coli constitutes 92.2% of the ESBL producing organisms followed by Klebsiella pneumonia (5.2%) and K. oxytoca (2.6%). The estimated annual incidence rate was 400.7 per 100,000 population which is more than twice of the average rates of other sites that conducted similar studies. The most common isolate source was urine (97%), and 81.2% of all cases were female. Patient ages ranged from 3-99 years, with average of 67 years. Thirty-two isolates underwent additional sequence typing and 76.7% (23) of the isolates were ST 131. 21 (91.3%) of ST-131 isolates were resistant to ciprofloxacin. Conclusion The study revealed that the incidence of ESBL producing organisms is very high in the Tennessee study area compared to other sites. The most common ESBL-producing pathogen was found to be ST 131 and most of these were resistant to ciprofloxacin suggesting that resistance to fluoroquinolone may be co-transmitted in ESBL producing pathogens through plasmids. Continued surveillance of molecular epidemiology is important to guide the prevention of the spread of drug resistant pathogens. Disclosures All Authors: No reported disclosures
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Nguyen, Trung Thanh, Hoa Vinh Le, Ha Vu Thi Hai, Thanh Nguyen Tuan, Huong Minh Nguyen, Da Pham Xuan, Huyen Tran Thi Thanh, and Hao Hong Le Thi. "Whole-Genome Analysis of Antimicrobial-Resistant Salmonella enterica Isolated from Duck Carcasses in Hanoi, Vietnam." Current Issues in Molecular Biology 45, no. 3 (March 8, 2023): 2213–29. http://dx.doi.org/10.3390/cimb45030143.
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Salmonella enterica is one of the most dangerous foodborne pathogens listed by the World Health Organization. In this study, whole-duck samples were collected at wet markets in five districts in Hanoi, Vietnam, in October 2019 to assess their Salmonella infection rates and evaluate the susceptibility of the isolated strains to antibiotics currently used in the prophylaxis and treatment of Salmonella infection. Based on the antibiotic resistance profiles, eight multidrug resistance strains were whole-genome-sequenced, and their antibiotic resistance genes, genotypes, multi-locus sequence-based typing (MLST), virulence factors, and plasmids were analyzed. The results of the antibiotic susceptibility test indicate that phenotypic resistance to tetracycline and cefazolin was the most common (82.4%, 28/34 samples). However, all isolates were susceptible to cefoxitin and meropenem. Among the eight sequenced strains, we identified 43 genes associated with resistance to multiple classes of antibiotics such as aminoglycoside, beta-lactam, chloramphenicol, lincosamide, quinolone, and tetracycline. Notably, all strains carried the blaCTX-M-55 gene, which confers resistance to third-generation antibiotics including cefotaxime, cefoperazone, ceftizoxime, and ceftazidime, as well as resistance genes of other broad-spectrum antibiotics used in clinical treatment such as gentamicin, tetracycline, chloramphenicol, and ampicillin. Forty-three different antibiotic resistance genes were predicted to be present in the isolated Salmonella strains’ genomes. In addition, three plasmids were predicted in two strains, 43_S11 and 60_S17. The sequenced genomes also indicated that all strains carried SPI-1, SPI-2, and SPI-3. These SPIs are composed of antimicrobial resistance gene clusters and thus represent a potential threat to public health management. Taken together, this study highlights the extent of multidrug-resistant Salmonella contamination in duck meat in Vietnam.
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Aricò, Melodie O., Enrico Valletta, and Désirée Caselli. "Appropriate Use of Antibiotic and Principles of Antimicrobial Stewardship in Children." Children 10, no. 4 (April 17, 2023): 740. http://dx.doi.org/10.3390/children10040740.
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Antibiotics account for over 10% of the overall drug expense of the National Health System in Italy in 2021. Their use in children is of particular interest on one side, because acute infections are very common in children, while they build their immunologic library of competence; on the other side, although many acute infections are expected and turn out to be of viral origin, caregivers will often ask the family doctor or primary care attending to reassure them by prescribing antibiotic treatment, although it may often be unnecessary. The inappropriate prescription of antibiotics in children may likely be a source not only of undue economic burden for the public health system but also of increasing development of antimicrobial resistance (AMR). Based on those issues, the inappropriate use of antibiotics in children should be avoided to reduce the risks of unnecessary toxicity, increase in health costs, lifelong effects, and selection of resistant organisms causing undue deaths. Antimicrobial stewardship (AMS) describes a coherent set of actions that ensure an optimal use of antimicrobials to improve patient outcomes while limiting the risk of adverse events including AMR. The aim of this paper is to spread some concept of good use of antibiotics for pediatricians or every other physician involved in the choice to prescribe, or not, antibiotics in children. Several actions could be of help in this process, including the following: (1) identify patients with high probability of bacterial infection; (2) collect samples for culture study before starting antibiotic treatment if invasive bacterial infection is suspected; (3) select the appropriate antibiotic molecule based on local resistance and narrow spectrum for the suspected pathogen(s); avoid multi-antibiotic association; prescribe correct dosage; (4) choose the best route of administration (oral vs. parenteral) and the best schedule of administration for every prescription (i.e., multiple administration for beta lactam); (5) schedule clinical and laboratory re-evaluation with the aim to consider therapeutic de-escalation; (6) stop antibiotic administration as soon as possible, avoiding the application of “antibiotic course”.
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Tuveri, Gian Marco, Matteo Ceccarelli, Alessandro Pira, and Igor V. Bodrenko. "The Optimal Permeation of Cyclic Boronates to Cross the Outer Membrane via the Porin Pathway." Antibiotics 11, no. 7 (June 23, 2022): 840. http://dx.doi.org/10.3390/antibiotics11070840.
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We investigated the diffusion of three cyclic boronates formulated as beta-lactamase inhibitors through the porin OmpF to evaluate their potential to cross OM via the porin pathway. The three nonbeta-lactam molecules diffuse through the porin eyelet region with the same mechanism observed for beta-lactam molecules and diazobicyclooctan derivatives, with the electric dipole moment aligned with the transversal electric field. In particular, the BOH group can interact with both the basic ladder and the acidic loop L3, which is characteristic of the size-constricted region of this class of porins. On one hand, we confirm that the transport of small molecules through enterobacter porins has a common general mechanism; on the other, the class of cyclic boronate molecules does not seem to have particular difficulties in diffusing through enterobacter porins, thus representing a good scaffold for new anti-infectives targeting Gram-negative bacteria research.
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Bush, K. "Beta-lactamase inhibitors from laboratory to clinic." Clinical Microbiology Reviews 1, no. 1 (January 1988): 109–23. http://dx.doi.org/10.1128/cmr.1.1.109.
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beta-Lactamases constitute the major defense mechanism of pathogenic bacteria against beta-lactam antibiotics. When the beta-lactam ring of this antibiotic class is hydrolyzed, antimicrobial activity is destroyed. Although beta-lactamases have been identified with clinical failures for over 40 years, enzymes with various abilities to hydrolyze specific penicillins or cephalosporins are appearing more frequently in clinical isolates. One approach to counteracting this resistance mechanism has been through the development of beta-lactamase inactivators. beta-Lactamase inhibitors include clavulanic acid and sulbactam, molecules with minimal antibiotic activity. However, when combined with safe and efficacious penicillins or cephalosporins, these inhibitors can serve to protect the familiar beta-lactam antibiotics from hydrolysis by penicillinases or broad-spectrum beta-lactamases. Both of these molecules eventually inactivate the target enzymes permanently. Although clavulanic acid exhibits more potent inhibitory activity than sulbactam, especially against the TEM-type broad-spectrum beta-lactamases, the spectrum of inhibitory activities are very similar. Neither of these inhibitors acts as a good inhibitor of the cephalosporinases. Clavulanic acid has been most frequently combined with amoxicillin in the orally active Augmentin and with ticarcillin in the parenteral beta-lactam combination Timentin. Sulbactam has been used primarily to protect ampicillin from enzymatic hydrolysis. Sulbactam has been used either in the orally absorbed prodrug form as sultamicillin or as the injectable combination ampicillin-sulbactam. Synergy has been demonstrated for these combinations for most members of the Enterobacteriaceae, although those organisms that produce cephalosporinases are not well inhibited. Synergy has also been observed for Neisseria gonorrhoeae, Haemophilus influenzae, penicillinase-producing Staphylococcus aureus, and anaerobic organisms. These antibiotic combinations have been used clinically to treat urinary tract infections, bone and soft-tissue infections, gonorrhea, respiratory infections, and otitis media. Gastrointestinal side effects have been reported for Augmentin and sultamicillin; most side effects with these agents have been mild. Although combination therapy with beta-lactamase inactivators has been used successfully, the problem of resistance development to two agents must be considered. Induction of cephalosporinases can occur with clavulanic acid. Permeability mutants could arise, especially with added pressure from a second beta-lactam.(ABSTRACT TRUNCATED AT 250 WORDS)
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Stover, Kayla R., Katie E. Barber, and Jamie L. Wagner. "Allergic Reactions and Cross-Reactivity Potential with Beta-Lactamase Inhibitors." Pharmacy 7, no. 3 (June 28, 2019): 77. http://dx.doi.org/10.3390/pharmacy7030077.
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Although beta-lactam allergies are an emerging focus of stewardship programs and interventions, less is publicly released regarding allergies to beta-lactamase inhibitors. This review presents and evaluates the data regarding allergic reactions with beta-lactamase inhibitors. Clavulanate, sulbactam, and tazobactam are beta-lactam-based beta-lactamase inhibitors that are combined with several penicillins or cephalosporins in order to preserve antimicrobial activity in the presence of beta-lactamases. Avibactam, relebactam, and vaborbactam are non-beta-lactam beta-lactamase inhibitors that are combined with cephalosporins or carbapenems in order to expand the antimicrobial activity against broader-spectrum beta-lactamases. Case reports document hypersensitivity reactions to clavulanate, sulbactam, and tazobactam, but not to avibactam, relebactam, or vaborbactam. Based on these reports and considering the chemical structures, cross-allergenicity with beta-lactams is likely with sulbactam and tazobactam. Considering the slightly altered beta-lactam structure, cross-allergenicity is less likely with clavulanate, but still possible. It appears that cross-allergenicity between beta-lactam antimicrobials and the newer, non-beta-lactam beta-lactamase inhibitors is unlikely. It is important for clinicians to perform allergy testing to both the beta-lactam and the beta-lactamase inhibitor in order to confirm the specific allergy and reaction type.
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Abraham, Ochoa-Aguilar, Ventura-Martinez Rosa, Sotomayor-Sobrino Marco Antonio, Gómez Claudia, and Morales-Espinosa María del Rosario. "Review of Antibiotic and Non-Antibiotic Properties of Beta-lactam Molecules." Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry 15, no. 1 (September 30, 2016): 3–14. http://dx.doi.org/10.2174/1871523015666160517114027.
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Al-Salloum, Jumana, Syed Wasif Gillani, Rana Kamran Mahmood, and Shabaz Mohiuddin Gulam. "Comparative efficacy of azithromycin versus clarithromycin in combination with beta-lactams to treat community-acquired pneumonia in hospitalized patients: a systematic review." Journal of International Medical Research 49, no. 10 (October 2021): 030006052110499. http://dx.doi.org/10.1177/03000605211049943.
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Objective The objective was to compare the efficacy of azithromycin and clarithromycin in combination with beta-lactams to treat community-acquired pneumonia among hospitalized adults. Methods Five databases (PubMed, Google Scholar, Trip, Medline, and Clinical Key) were searched to identify randomized clinical trials with patients exposed to azithromycin or clarithromycin in combination with a beta-lactam. All articles were critically reviewed for inclusion in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results Seven clinical trials were included. The treatment success rate for azithromycin–beta-lactam after 10 to 14 days was 87.55% and that for clarithromycin–beta-lactam after 5 to 7 days of therapy was 75.42%. Streptococcus pneumoniae was commonly found in macrolide groups, with 130 and 80 isolates in the clarithromycin-based and azithromycin-based groups, respectively. The length of hospital stay was an average of 8.45 days for patients receiving a beta-lactam–azithromycin combination and 7.25 days with a beta-lactam–clarithromycin combination. Conclusion Macrolide inter-class differences were noted, with a higher clinical success rate for azithromycin-based combinations. However, a shorter length of hospital stay was achieved with a clarithromycin–beta-lactam regimen. Thus, a macrolide combined with a beta-lactam should be chosen using susceptibility data from the treating facility.
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Kóczián, Kristóf, Zoltán Szakács, József Kökösi, and Béla Noszál. "Site-specific protonation microequilibria of penicillin and cephalosporin beta-lactam core molecules." European Journal of Pharmaceutical Sciences 32, no. 1 (September 2007): 1–7. http://dx.doi.org/10.1016/j.ejps.2007.05.001.
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