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International Journal of Molecular... Jul 2023Antimicrobial resistance is presently one of the greatest threats to public health. The excessive and indiscriminate use of antibiotics imposes a continuous selective...
Antimicrobial resistance is presently one of the greatest threats to public health. The excessive and indiscriminate use of antibiotics imposes a continuous selective pressure that triggers the emergence of multi-drug resistance. We performed a large-scale analysis of closed bacterial genomes to identify multi-drug resistance considering the ResFinder antimicrobial classes. We found that more than 95% of the genomes harbor genes associated with resistance to disinfectants, glycopeptides, macrolides, and tetracyclines. On average, each genome encodes resistance to more than nine different classes of antimicrobial drugs. We found higher-than-expected co-occurrences of resistance genes in both plasmids and chromosomes for several classes of antibiotic resistance, including classes categorized as critical according to the World Health Organization (WHO). As a result of antibiotic-resistant priority pathogens, higher-than-expected co-occurrences appear in plasmids, increasing the potential for resistance dissemination. For the first time, co-occurrences of antibiotic resistance have been investigated for priority pathogens as defined by the WHO. For critically important pathogens, co-occurrences appear in plasmids, not in chromosomes, suggesting that the resistances may be epidemic and probably recent. These results hint at the need for new approaches to treating infections caused by critically important bacteria.
Topics: Genome, Bacterial; Plasmids; Anti-Bacterial Agents; Computational Biology; Drug Resistance, Multiple; Drug Resistance, Multiple, Bacterial; Drug Resistance, Bacterial
PubMed: 37511196
DOI: 10.3390/ijms241411438 -
Journal of Theoretical Biology Jan 2021Combination therapies have shown remarkable success in preventing the evolution of resistance to multiple drugs, including HIV, tuberculosis, and cancer. Nevertheless,...
Combination therapies have shown remarkable success in preventing the evolution of resistance to multiple drugs, including HIV, tuberculosis, and cancer. Nevertheless, the rise in drug resistance still remains an important challenge. The capability to accurately predict the emergence of resistance, either to one or multiple drugs, may help to improve treatment options. Existing theoretical approaches often focus on exponential growth laws, which may not be realistic when scarce resources and competition limit growth. In this work, we study the emergence of single and double drug resistance in a model of combination therapy of two drugs. The model describes a sensitive strain, two types of single-resistant strains, and a double-resistant strain. We compare the probability that resistance emerges for three growth laws: exponential growth, logistic growth without competition between strains, and logistic growth with competition between strains. Using mathematical estimates and numerical simulations, we show that between-strain competition only affects the emergence of single resistance when resources are scarce. In contrast, the probability of double resistance is affected by between-strain competition over a wider space of resource availability. This indicates that competition between different resistant strains may be pertinent to identifying strategies for suppressing drug resistance, and that exponential models may overestimate the emergence of resistance to multiple drugs. A by-product of our work is an efficient strategy to evaluate probabilities of single and double resistance in models with multiple sequential mutations. This may be useful for a range of other problems in which the probability of resistance is of interest.
Topics: Combined Modality Therapy; Drug Resistance; Drug Resistance, Multiple; Humans; Probability; Tuberculosis
PubMed: 33049229
DOI: 10.1016/j.jtbi.2020.110524 -
Polish Journal of Microbiology Jun 2018Non-antibiotic medicinal products consist of drugs with diverse activity against bacteria. Many non-antibiotics demonstrate direct anti-bacterial activity against... (Review)
Review
Non-antibiotic medicinal products consist of drugs with diverse activity against bacteria. Many non-antibiotics demonstrate direct anti-bacterial activity against Gram-positive cocci. The activity observed against Gram-negative rods is much lower and non-antibiotics primarily from the following groups: non-steroidal anti-inflammatory drugs, cardiovascular and antidepressant medicinal products demonstrate this activity. It has been shown that the low activity of some non-antibiotics or the absence of activity against Gram-negative rods is related, among other things, to the extrusion of these compounds from bacterial cells by multi-drug resistance efflux pumps. Substrates for the resistance-nodulation-division efflux systems include the following non-antibiotics: salicylate, diclofenac, ibuprofen, mefenamic acid, naproxen, amitriptyline, alendronate sodium, nicergoline, and ticlopidine. In addition, interactions between non-antibiotics and multi-drug resistance efflux pumps have been observed. It has also been revealed that depending on the concentration, salicylate induces expression of multi-drug resistance efflux pumps in Escherichia coli, Salmonella enterica subsp. enterica serotype Typhimurium, and Burkholderia cenocepacia. However, salicylate does not affect the expression of the resistance-nodulation-division efflux systems in Stenotrophomonas maltophilia and Acinetobacter baumannii. Most importantly, there were no effects of medicinal products containing some non-antibiotic active substances, except salicylate, as substrates of multi-drug resistance efflux pumps, on the induction of Gram-negative rod resistance to quinolones.
Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Drug Resistance, Multiple, Bacterial; Escherichia coli; Gram-Negative Bacteria; Membrane Transport Proteins; Microbial Sensitivity Tests; Naproxen; Pseudomonas aeruginosa; Salicylates
PubMed: 30015451
DOI: 10.21307/pjm-2018-017 -
Current Drug Metabolism 2023Cancer drug resistance remains a difficult barrier to effective treatment, necessitating a thorough understanding of its multi-layered mechanism. (Review)
Review
BACKGROUND
Cancer drug resistance remains a difficult barrier to effective treatment, necessitating a thorough understanding of its multi-layered mechanism.
OBJECTIVE
This study aims to comprehensively explore the diverse mechanisms of cancer drug resistance, assess the evolution of resistance detection methods, and identify strategies for overcoming this challenge. The evolution of resistance detection methods and identification strategies for overcoming the challenge.
METHODS
A comprehensive literature review was conducted to analyze intrinsic and acquired drug resistance mechanisms, including altered drug efflux, reduced uptake, inactivation, target mutations, signaling pathway changes, apoptotic defects, and cellular plasticity. The evolution of mutation detection techniques, encompassing clinical predictions, experimental approaches, and computational methods, was investigated. Strategies to enhance drug efficacy, modify pharmacokinetics, optimizoptimizee binding modes, and explore alternate protein folding states were examined.
RESULTS
The study comprehensively overviews the intricate mechanisms contributing to cancer drug resistance. It outlines the progression of mutation detection methods and underscores the importance of interdisciplinary approaches. Strategies to overcome drug resistance challenges, such as modulating ATP-binding cassette transporters and developing multidrug resistance inhibitors, are discussed. The study underscores the critical need for continued research to enhance cancer treatment efficacy.
CONCLUSION
This study provides valuable insights into the complexity of cancer drug resistance mechanisms, highlights evolving detection methods, and offers potential strategies to enhance treatment outcomes.
Topics: Humans; Drug Resistance, Multiple; Drug Resistance, Neoplasm; ATP-Binding Cassette Transporters; Neoplasms; Biological Transport; Antineoplastic Agents
PubMed: 38141188
DOI: 10.2174/0113892002266408231207150547 -
Journal of Infection in Developing... Dec 2022Multi-Drug Resistance (MDR) is common in hospitalized geriatric patients. The study aims to investigate the pattern of antibiotic use and determine its association with... (Review)
Review
INTRODUCTION
Multi-Drug Resistance (MDR) is common in hospitalized geriatric patients. The study aims to investigate the pattern of antibiotic use and determine its association with MDR in hospitalized geriatric patients.
METHODOLOGY
A retrospective cohort study including 193 geriatric patients admitted to a Geriatric Intensive Care Unit (GICU) in a tertiary care Geriatrics hospital in Egypt, throughout a consecutive 6 months duration. A review of medical records was done to extract clinical, socio-demographic, and prescribing data on antibiotics throughout admission. The presence of MDR organisms (MDROs) was determined by reviewing culture and sensitivity reports. Descriptive statistics and logistic regression analysis were performed.
RESULTS
181 (93.8%) patients received at least 1 antibiotic. Cephalosporins were the most commonly consumed antibiotics (24%). MDROs were significantly associated with receiving ≥ 3 antibiotics. Longer hospital stay was a predictor of multiple antibiotics use (Odds Ratio of 1.075). MDROs were prevalent in 110 (57.0 %) patients. Klebsiella species were the most frequent MDROs (26%) with the highest susceptibility to amikacin.
CONCLUSIONS
The study provides a detailed description of both antibiotics use and MDR among hospitalized geriatric patients in Egypt. It gives a novel insight into the ongoing drug-pathogen combinations in acute healthcare settings of the aged. This data has a potential role in applying antimicrobial stewardship programs for hospitalized geriatric patients to mitigate antimicrobial resistance in similar settings.
Topics: Humans; Aged; Anti-Bacterial Agents; Retrospective Studies; Egypt; Tertiary Healthcare; Drug Resistance, Multiple, Bacterial; Geriatrics; Hospitals; Tertiary Care Centers
PubMed: 36753654
DOI: 10.3855/jidc.17257 -
Ocular Immunology and Inflammation May 2022To present a case of necrotizing sclerokeratitis in a patient with multidrug-resistant tuberculosis and study the challenges in diagnosis and management of anterior... (Review)
Review
PURPOSE
To present a case of necrotizing sclerokeratitis in a patient with multidrug-resistant tuberculosis and study the challenges in diagnosis and management of anterior tuberculous scleritis.
METHODS
Retrospective observational case report and review of anterior tuberculous scleritis.
RESULTS
A 28-year-old woman, previously diagnosed as presumed tubercular panuveitis, presented with necrotizing sclerokeratitis and progressed to develop panophthalmitis. Laboratory investigations revealed multidrug-resistant as the etiological agent. We reviewed cases of anterior tuberculous scleritis published in the literature, with regards to clinical features, microbiological investigations, treatment, and outcomes. Treatment includes standard antitubercular therapy, with or without systemic corticosteroids. Poor response to treatment is seen either due to delayed diagnosis or drug resistance, and the significance of the same is highlighted in our case.
CONCLUSION
Diagnosis of tuberculous scleritis is a challenge. Therapeutic failure must alert the clinician for drug resistance which is diagnosed early, can prevent the devastating outcomes.
Topics: Adult; Antitubercular Agents; Drug Resistance, Multiple; Female; Humans; Keratitis; Retrospective Studies; Scleritis; Tuberculosis; Tuberculosis, Ocular
PubMed: 33416427
DOI: 10.1080/09273948.2020.1853176 -
Biochemical Pharmacology Jun 2017Hospitals are breeding grounds for many life-threatening bacteria worldwide. Clinically associated gram-positive bacteria such as Staphylococcus... (Review)
Review
Hospitals are breeding grounds for many life-threatening bacteria worldwide. Clinically associated gram-positive bacteria such as Staphylococcus aureus/methicillin-resistant S. aureus and many others increase the risk of severe mortality and morbidity. The failure of antibiotics to kill various pathogens due to bacterial resistance highlights the urgent need to develop novel, potent, and less toxic agents from natural sources against various infectious agents. Currently, several promising classes of natural molecules from snake (terrestrial and sea), scorpion, spider, honey bee and wasp venoms hold promise as rich sources of chemotherapeutics against infectious pathogens. Interestingly, snake venom-derived synthetic peptide/snake cathelicidin not only has potent antimicrobial and wound-repair activity but is highly stable and safe. Such molecules are promising candidates for novel venom-based drugs against S. aureus infections. The structure of animal venom proteins/peptides (cysteine rich) consists of hydrophobic α-helices or β-sheets that produce lethal pores and membrane-damaging effects on bacteria. All these antimicrobial peptides are under early experimental or pre-clinical stages of development. It is therefore important to employ novel tools for the design and the development of new antibiotics from the untapped animal venoms of snake, scorpion, and spider for treating resistant pathogens. To date, snail venom toxins have shown little antibiotic potency against human pathogens.
Topics: Animals; Anti-Infective Agents; Drug Resistance, Multiple, Bacterial; Humans; Microbial Sensitivity Tests; Venoms; Wound Healing
PubMed: 28288817
DOI: 10.1016/j.bcp.2017.03.005 -
Current Topics in Medicinal Chemistry 2023Multi-drug resistance and its transmission is a ubiquitous health issue worldwide. The beta-lactamase AmpC resistance is a major concern among all health settings like... (Review)
Review
Multi-drug resistance and its transmission is a ubiquitous health issue worldwide. The beta-lactamase AmpC resistance is a major concern among all health settings like hospitals and child care centers, . The clinical pipeline of the new antibiotics remains dry due to the production of AmpC beta-lactamases by the bacteria to develop resistance against antibiotics. According to the global antimicrobial resistance and use surveillance system, the rate of resistance to ciprofloxacin an antibiotic commonly used to treat urinary tract infections, varied from 8.4% to 92.9% for and from 4.1% to 79.4% for in different countries. The lack of comprehensiveness within the data makes a choice problematic for the selection of appropriate β-lactam antibiotic for the treatment of resistant microorganisms. Most experts agree it is prudent to avoid expanded-spectrum ( third-generation) cephalosporins for the treatment of organisms posing the greatest risk of AmpC induction. Nonetheless, the development of specific inhibitors for the AmpC enzyme, either naturally or synthetically, is only unfolding. To date, there is no single and clinically active drug available that inhibits the AmpC enzyme and combats multidrug resistance and its transmission in individuals. The deficit of the enzyme inhibitor focused the researchers to work in the area. This present review will emphasize on the chemistry, and structure of clinically important and potent inhibitors against AmpC enzymes.
Topics: Humans; Anti-Bacterial Agents; beta-Lactamases; Bacterial Proteins; Escherichia coli; Cephalosporins; Drug Resistance, Multiple; Enzyme Inhibitors; Microbial Sensitivity Tests
PubMed: 37150991
DOI: 10.2174/1568026623666230504095005 -
Microbial Drug Resistance (Larchmont,... Jan 2020Tuberculosis (TB) is a major issue in global health and affects millions of people each year. Multidrug-resistant tuberculosis (MDR-TB) annually causes many deaths... (Review)
Review
Tuberculosis (TB) is a major issue in global health and affects millions of people each year. Multidrug-resistant tuberculosis (MDR-TB) annually causes many deaths worldwide. Development of a way to diagnose and treat patients with MDR-TB can potentially reduce the incidence of the disease. The current study reviews the risk factors, pattern of progression, mechanism of resistance, and interaction between bacteria and the host immune system, which disrupts the immune response. It also targets the components of (Mtb) and diagnosis and treatment options that could be available for clinical use in the near future. Mutations play an important role in development of MDR-TB and the selection of appropriate mutations can help to understand the type of resistance in patients to anti-TB drugs. In this way, they can be initially treated with proper and effective therapeutic choices, which can accelerate the course of treatment and improve patient health. Targeting the components and enzymes of Mtb is necessary for understanding bacterial survival and finding a way to destroy the pathogen and allow patients to recover faster and prevent the spread of disease, especially resistant strains.
Topics: Animals; Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Global Health; Humans; Mutation; Mycobacterium tuberculosis; Risk Factors; Tuberculosis, Multidrug-Resistant
PubMed: 31517569
DOI: 10.1089/mdr.2018.0353 -
Toxins May 2023is a spore-forming, Gram-positive anaerobic pathogen that causes several disorders in humans and animals. A multidrug-resistant strain was isolated from the fecal...
is a spore-forming, Gram-positive anaerobic pathogen that causes several disorders in humans and animals. A multidrug-resistant strain was isolated from the fecal sample of a patient who was clinically suspected of gastrointestinal infection and had a recent history of antibiotic exposure and diarrhea. The strain was identified by 16s rRNA sequencing as . The strain's pathogenesis was analyzed through its complete genome, specifically antimicrobial resistance-related genes. The IRMC2505A genome contains 19 (, , , , , , , , , , , , , , , , , and ) antibiotic-susceptible genetic species according to the k-mer-based detection of antimicrobial resistance genes. Genome mapping using CARD and VFDB databases revealed significant (-value = 1 × 10) genes with aligned reads against antibiotic-resistant genes or virulence factors, including phospholipase C, perfringolysin O, collagenase, hyaluronidase, alpha-clostripain, exo-alpha-sialidase, and sialidase activity. In conclusion, this is the first report on from Saudi Arabia that conducted whole genome sequencing of IRMC2505A and confirmed the strain as an MDR bacterium with several virulence factors. Developing control strategies requires a detailed understanding of the epidemiology of , its virulence factors, and regional antimicrobial resistance patterns.
Topics: Animals; Humans; Clostridium perfringens; Virulence Factors; RNA, Ribosomal, 16S; Genomics; Anti-Bacterial Agents; Drug Resistance, Multiple; Clostridium Infections
PubMed: 37368661
DOI: 10.3390/toxins15060359