The CRISPR/Cas system as an antimicrobial resistance strategy in aquatic ecosystems. - Related Documents




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978601.0000The CRISPR/Cas system as an antimicrobial resistance strategy in aquatic ecosystems. With the growing population, demand for food has dramatically increased, and fisheries, including aquaculture, are expected to play an essential role in sustaining demand with adequate quantities of protein and essential vitamin supplements, employment generation, and GDP growth. Unfortunately, the incidence of emerging/re-emerging AMR pathogens annually occurs because of anthropogenic activities and the frequent use of antibiotics in aquaculture. These AMR pathogens include the WHO's top 6 prioritized ESKAPE pathogens (nosocomial pathogens: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.), extended-spectrum beta lactases (ESBLs) and carbapenemase-producing E. coli, which pose major challenges to the biomagnification of both nonnative and native antibiotic-resistant bacteria in capture and cultured fishes. Although implementing the rational use of antibiotics represents a promising mitigation measure, this approach is practically impossible due to the lack of awareness among farmers about the interplay between antimicrobial use and the emergence of antimicrobial resistance (AMR). Nevertheless, to eradicate these 'superbugs,' CRISPR/Cas (clustered regularly interspersed short palindromic repeats/CRISPR associate protein) has turned out to be a novel approach owing to its ability to perform precise site-directed targeting/knockdown/reversal of specific antimicrobial resistance genes in vitro and to distinguish AMR-resistant bacteria from a plethora of commensal aquatic bacteria. Along with highlighting the importance of virulent multidrug resistance genes in bacteria, this article aims to provide a holistic picture of CRISPR/Cas9-mediated genome editing for combating antimicrobial-resistant bacteria isolated from various aquaculture and marine systems, as well as insights into different types of CRISPR/Cas systems, delivery methods, and challenges associated with developing CRISPR/Cas9 antimicrobial agents.202438806846
978710.9999CRISPR-Cas, a Revolution in the Treatment and Study of ESKAPE Infections: Pre-Clinical Studies. One of the biggest threats we face globally is the emergence of antimicrobial-resistant (AMR) bacteria, which runs in parallel with the lack in the development of new antimicrobials. Among these AMR bacteria pathogens belonging to the ESKAPE group can be highlighted (Enterococcus spp., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) due to their profile of drug resistance and virulence. Therefore, innovative lines of treatment must be developed for these bacteria. In this review, we summarize the different strategies for the treatment and study of molecular mechanisms of AMR in the ESKAPE pathogens based on the clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) proteins' technologies: loss of plasmid or cellular viability, random mutation or gene deletion as well directed mutations that lead to a gene's loss of function.202134206474
979720.9998Evaluation of Antibiotic Resistance Mechanisms in Gram-Positive Bacteria. The prevalence of resistance in Gram-positive bacterial infections is rapidly rising, presenting a pressing global challenge for both healthcare systems and economies. The WHO categorizes these bacteria into critical, high, and medium priority groups based on the urgency for developing new antibiotics. While the first priority pathogen list was issued in 2017, the 2024 list remains largely unchanged. Despite six years having passed, the progress that has been made in developing novel treatment approaches remains insufficient, allowing antimicrobial resistance to persist and worsen on a global scale. Various strategies have been implemented to address this growing threat by targeting specific resistance mechanisms. This review evaluates antimicrobial resistance (AMR) in Gram-positive bacteria, highlighting its critical impact on global health due to the rise of multidrug-resistant pathogens. It focuses on the unique cell wall structure of Gram-positive bacteria, which influences their identification and susceptibility to antibiotics. The review explores the mechanisms of AMR, including enzymatic inactivation, modification of drug targets, limiting drug uptake, and increased drug efflux. It also examines the resistance strategies employed by high-priority Gram-positive pathogens such as Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus faecium, as identified in the WHO's 2024 priority list.202439766587
432930.9998Bacterial resistance: new threats, new challenges. Bacterial resistance remains a major concern. Recently, genetic transfers from saprophytic, non-pathogenic, species to pathogenic S. pneumoniae and N. meningitidis have introduced multiple changes in the penicillin target molecules, leading to rapidly growing penicillin resistance. In enterobacteriaceae, a succession of minute mutations has generated new beta-lactamases with increasingly expanded spectrum, now covering practically all available beta-lactam antibiotics. Resistance emerges in the hospital environment but also, and increasingly, in the community bacteria. Widespread resistance is probably associated with antibiotic use, abuse and misuse but direct causality links are difficult to establish. In some countries as in some hospitals, unusual resistance profiles seem to correspond to unusual antibiotic practices. For meeting the resistance challenge, no simple solutions are available, but combined efforts may help. For improving the situation, the following methods can be proposed. At the world level, a better definition of appropriate antibiotic policies should be sought, together with strong education programmes on the use of antibiotics and the control of cross-infections, plus controls on the strategies used by pharmaceutical companies for promoting antibiotics. At various local levels, accurate guidelines should be adapted to each institution and there should be regularly updated formularies using scientific, and not only economic, criteria; molecular technologies for detecting subtle epidemic variations and emergence of new genes should be developed and regular information on the resistance profiles should be available to all physicians involved in the prevention and therapy of infections.19938149138
955940.9998CRISPR-Cas Systems in the Fight Against Antimicrobial Resistance: Current Status, Potentials, and Future Directions. BACKGROUND: Antimicrobial resistance (AMR) is a critical global health concern that threatens the efficacy of existing antibiotics and poses significant challenges to public health and the economy worldwide. This review explores the potential of CRISPR-Cas systems as a novel approach to combating AMR and examines current applications, limitations, and prospects. METHODS: A comprehensive literature search was conducted across multiple databases, including PubMed, Google Scholar, Scopus, and Web of Science, covering publications published from 2014 to August 2024. This review focuses on CRISPR-Cas technologies and their applications in AMR. RESULTS: CRISPR-Cas systems have demonstrated efficacy in combating antimicrobial resistance by targeting and eliminating antibiotic-resistance genes. For example, studies have shown that CRISPR-Cas9 can effectively target and eliminate colistin resistance genes in MCR-1 plasmids, restoring susceptibility to carbapenems in bacteria such as E. coli and Klebsiella pneumoniae. Further molecular findings highlight the impact of CRISPR-Cas systems on various bacterial species, such as Enterococcus faecalis, in which CRISPR systems play a crucial role in preventing the acquisition of resistance genes. The effectiveness of CRISPR-Cas in targeting these genes varies due to differences in CRISPR locus formation among bacterial species. For instance, variations in CRISPR loci influence the targeting of resistance genes in E. faecalis, and CRISPR-Cas9 successfully reduces resistance by targeting genes such as tetM and ermB. CONCLUSION: CRISPR-Cas systems are promising for fighting AMR by targeting and eliminating antibiotic-resistant genes, as demonstrated by the effective targeting of colistin resistance genes on MCR-1 plasmids and their similar activities. However, the effectiveness of CRISPR-Cas is affected by variations in the CRISPR loci among bacterial species. Challenges persist, such as optimizing delivery methods and addressing off-target effects to ensure the safety and precision of CRISPR-Cas systems in clinical settings.202439619730
488750.9998Mechanisms of Bacterial Drug Resistance with Special Emphasis on Phenotypic and Molecular Characterization of Extended Spectrum Beta-lactamase. Antibiotics are designed to effectively treat bacterial infections while minimizing harm to the human body. They work by targeting specific components of bacteria or by disrupting essential processes such as cell wall synthesis, membrane function, protein production, and metabolic pathways. However, the misuse and overuse of antibiotics have led to the emergence of drug resistance in humans, animals, and agriculture, contributing to the global spread of this problem. Drug resistance can be either innate or acquired, with acquired resistance involving changes in the bacterial chromosomes or transferable elements. Bacterial species employ various mechanisms of drug resistance, including modifying the antibiotic targets, inactivating the drug, reducing uptake or increasing efflux, overexpressing the target, utilizing alternative pathways, and forming biofilms. One significant concern in the realm of drug resistance revolves around the emergence and proliferation of extended-spectrum beta-lactamases (ESBLs), a gene that is found in most gram-negative bacteria, primarily carried by Escherichia coli and Klebsiella pneumoniae in healthcare settings. ESBL-mediated resistance poses challenges for diagnosis, treatment, infection control, and antibiotic stewardship. Accurate detection of ESBL genes is crucial, and phenotypic methods are commonly used for initial screening. However, these methods have limitations, and confirmatory molecular techniques such as PCR and DNA sequencing are employed to accurately identify ESBL genes. Despite the significant global concerns surrounding ESBLs, they have spread worldwide, mainly facilitated by healthcare settings, inappropriate antimicrobial use, and host susceptibility. Addressing this issue requires implementing comprehensive measures, including enhanced surveillance, strict infection control practices, antibiotic stewardship programs, rapid diagnostic methods, alternative therapies, public education initiatives, and research focused on developing new drugs. Furthermore, collaboration among the healthcare, public health, and research sectors is pivotal in effectively combating the escalating threat posed by ESBL-mediated resistance. Antibiotics have revolutionized medical care by effectively treating bacterial infections. However, the emergence of ESBL gene resistance poses a global challenge that requires an integrated approach to prevent a threatening future.202438700878
433060.9998Decolonization of asymptomatic carriage of multi-drug resistant bacteria by bacteriophages? Antimicrobial resistance is a major threat to human and animal health and accounted for up to 4.5 million deaths worldwide in 2019. Asymptomatic colonization of the digestive tract by multidrug resistant (multi-resistant) bacteria such as extended-spectrum beta-lactamase-, or carbapenemase- producing Enterobacterales is (i) a risk factor for infection by these multi-resistant bacteria, (ii) a risk factor of dissemination of these multi-resistant bacteria among patients and in the community, and (iii) allows the exchange of resistance genes between bacteria. Hence, decolonization or reduction of the gastrointestinal tract colonization of these multi-resistant bacteria needs to be urgently explored. Developing new non-antibiotic strategies to limit or eradicate multi-resistant bacteria carriage without globally disrupting the microbiota is considered a priority to fight against antibiotic resistance. Probiotics or Fecal Microbiota Transplantation are alternative strategies to antibiotics that have been considered to decolonize intestinal tract from MDR bacteria but there is currently no evidence demonstrating their efficacy. Lytic bacteriophages are viruses that kill bacteria and therefore could be considered as a promising strategy to combat antibiotic resistance. Successful decolonization by bacteriophages has already been observed clinically. Here, we discuss the current alternative strategies considered to decolonize the digestive tract of multidrug resistant bacteria, briefly describing probiotics and fecal microbiota transplantation approaches, and then detail the in vivo and in vitro studies using bacteriophages, while discussing their limits regarding the animal models used, the characteristics of phages used and their activity in regards of the gut anatomy.202338075897
980970.9998The gut microbiome: an emerging epicenter of antimicrobial resistance? The human gut is one of the most densely populated microbial environments, home to trillions of microorganisms that live in harmony with the body. These microbes help with digestion and play key roles in maintaining a balanced immune system and protecting us from harmful pathogens. However, the crowded nature of this ecosystem makes it easier for harmful bacteria to acquire antimicrobial resistance (AMR) genes, which can lead to multidrug-resistant (MDR) infections. The rise of MDR infections makes treatments harder, leading to more extended hospital stays, relapses, and worse outcomes for patients, ultimately increasing healthcare costs and environmental strain. Since many MDR infections are challenging to treat, nosocomial infection control protocols and infection prevention programmes are frequently the only measures in our hands to stop the spread of these bacteria. New approaches are therefore urgently required to prevent the colonization of MDR infections. This review aims to explore the current understanding of antimicrobial resistance pathways, focusing on how the gut microbiota contributes to AMR. We have also emphasized the potential strategies to prevent the spread and colonization of MDR infections.202540463440
661380.9998Approaches for characterizing and tracking hospital-associated multidrug-resistant bacteria. Hospital-associated infections are a major concern for global public health. Infections with antibiotic-resistant pathogens can cause empiric treatment failure, and for infections with multidrug-resistant bacteria which can overcome antibiotics of "last resort" there exists no alternative treatments. Despite extensive sanitization protocols, the hospital environment is a potent reservoir and vector of antibiotic-resistant organisms. Pathogens can persist on hospital surfaces and plumbing for months to years, acquire new antibiotic resistance genes by horizontal gene transfer, and initiate outbreaks of hospital-associated infections by spreading to patients via healthcare workers and visitors. Advancements in next-generation sequencing of bacterial genomes and metagenomes have expanded our ability to (1) identify species and track distinct strains, (2) comprehensively profile antibiotic resistance genes, and (3) resolve the mobile elements that facilitate intra- and intercellular gene transfer. This information can, in turn, be used to characterize the population dynamics of hospital-associated microbiota, track outbreaks to their environmental reservoirs, and inform future interventions. This review provides a detailed overview of the approaches and bioinformatic tools available to study isolates and metagenomes of hospital-associated bacteria, and their multi-layered networks of transmission.202133582841
979290.9998Emergence of antibiotic resistance Pseudomonas aeruginosa in intensive care unit; a critical review. The emergence of antibiotic resistant bacteria in the healthcare is a serious concern. In the Healthcare premises precisely intensive care unit are major sources of microbial diversity. Recent findings have demonstrated not only microbial diversity but also drug resistant microbes largely habitat in ICU. Pseudomonas aeruginosa found as a part of normal intestinal flora and a significant pathogen responsible for wide range of ICU acquired infection in critically ill patients. Nosocomial infection associated with this organism including gastrointestinal infection, urinary tract infections and blood stream infection. Infection caused by this organism are difficult to treat because of the presence of its innate resistance to many antibiotics (β-lactam and penem group of antibiotics), and its ability to acquire further resistance mechanism to multiple class of antibiotics, including Beta-lactams, aminoglycosides and fluoroquinolones. In the molecular evolution microbes adopted several mechanism to maintain genomic plasticity. The tool microbe use for its survival is mainly biofilm formation, quorum sensing, and horizontal gene transfer and enzyme promiscuity. Such genomic plasticity provide an ideal habitat to grow and survive in hearse environment mainly antibiotics pressure. This review focus on infection caused by Pseudomonas aeruginosa, its mechanisms of resistance and available treatment options. The present study provides a systemic review on major source of Pseudomonas aeruginosa in ICU. Further, study also emphasizes virulence gene/s associated with Pseudomonas aeruginosa genome for extended drug resistance. Study gives detailed overview of antibiotic drug resistance mechanism.201931194018
9806100.9998Resistance of Gram-Positive Bacteria to Current Antibacterial Agents and Overcoming Approaches. The discovery of antibiotics has created a turning point in medical interventions to pathogenic infections, but unfortunately, each discovery was consistently followed by the emergence of resistance. The rise of multidrug-resistant bacteria has generated a great challenge to treat infections caused by bacteria with the available antibiotics. Today, research is active in finding new treatments for multidrug-resistant pathogens. In a step to guide the efforts, the WHO has published a list of the most dangerous bacteria that are resistant to current treatments and requires the development of new antibiotics for combating the resistance. Among the list are various Gram-positive bacteria that are responsible for serious healthcare and community-associated infections. Methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and drug-resistant Streptococcus pneumoniae are of particular concern. The resistance of bacteria is an evolving phenomenon that arises from genetic mutations and/or acquired genomes. Thus, antimicrobial resistance demands continuous efforts to create strategies to combat this problem and optimize the use of antibiotics. This article aims to provide a review of the most critical resistant Gram-positive bacterial pathogens, their mechanisms of resistance, and the new treatments and approaches reported to circumvent this problem.202032586045
4292110.9997The impact of different antibiotic regimens on the emergence of antimicrobial-resistant bacteria. BACKGROUND: The emergence and ongoing spread of antimicrobial-resistant bacteria is a major public health threat. Infections caused by antimicrobial-resistant bacteria are associated with substantially higher rates of morbidity and mortality compared to infections caused by antimicrobial-susceptible bacteria. The emergence and spread of these bacteria is complex and requires incorporating numerous interrelated factors which clinical studies cannot adequately address. METHODS/PRINCIPAL FINDINGS: A model is created which incorporates several key factors contributing to the emergence and spread of resistant bacteria including the effects of the immune system, acquisition of resistance genes and antimicrobial exposure. The model identifies key strategies which would limit the emergence of antimicrobial-resistant bacterial strains. Specifically, the simulations show that early initiation of antimicrobial therapy and combination therapy with two antibiotics prevents the emergence of resistant bacteria, whereas shorter courses of therapy and sequential administration of antibiotics promote the emergence of resistant strains. CONCLUSIONS/SIGNIFICANCE: The principal findings suggest that (i) shorter lengths of antibiotic therapy and early interruption of antibiotic therapy provide an advantage for the resistant strains, (ii) combination therapy with two antibiotics prevents the emergence of resistance strains in contrast to sequential antibiotic therapy, and (iii) early initiation of antibiotics is among the most important factors preventing the emergence of resistant strains. These findings provide new insights into strategies aimed at optimizing the administration of antimicrobials for the treatment of infections and the prevention of the emergence of antimicrobial resistance.200819112501
4889120.9997The Challenge of Overcoming Antibiotic Resistance in Carbapenem-Resistant Gram-Negative Bacteria: "Attack on Titan". The global burden of bacterial resistance remains one of the most serious public health concerns. Infections caused by multidrug-resistant (MDR) bacteria in critically ill patients require immediate empirical treatment, which may not only be ineffective due to the resistance of MDR bacteria to multiple classes of antibiotics, but may also contribute to the selection and spread of antimicrobial resistance. Both the WHO and the ECDC consider carbapenem-resistant Enterobacteriaceae (CRE), carbapenem-resistant Pseudomonas aeruginosa (CRPA), and carbapenem-resistant Acinetobacter baumannii (CRAB) to be the highest priority. The ability to form biofilm and the acquisition of multiple drug resistance genes, in particular to carbapenems, have made these pathogens particularly difficult to treat. They are a growing cause of healthcare-associated infections and a significant threat to public health, associated with a high mortality rate. Moreover, co-colonization with these pathogens in critically ill patients was found to be a significant predictor for in-hospital mortality. Importantly, they have the potential to spread resistance using mobile genetic elements. Given the current situation, it is clear that finding new ways to combat antimicrobial resistance can no longer be delayed. The aim of this review was to evaluate the literature on how these pathogens contribute to the global burden of AMR. The review also highlights the importance of the rational use of antibiotics and the need to implement antimicrobial stewardship principles to prevent the transmission of drug-resistant organisms in healthcare settings. Finally, the review discusses the advantages and limitations of alternative therapies for the treatment of infections caused by these "titans" of antibiotic resistance.202337630472
4886130.9997Molecular diagnostics for genotypic detection of antibiotic resistance: current landscape and future directions. Antimicrobial resistance (AMR) among bacteria is an escalating public health emergency that has worsened during the COVID-19 pandemic. When making antibiotic treatment decisions, clinicians rely heavily on determination of antibiotic susceptibility or resistance by the microbiology laboratory, but conventional methods often take several days to identify AMR. There are now several commercially available molecular methods that detect antibiotic resistance genes within hours rather than days. While these methods have limitations, they offer promise for optimizing treatment and patient outcomes, and reducing further emergence of AMR. This review provides an overview of commercially available genotypic assays that detect individual resistance genes and/or resistance-associated mutations in a variety of specimen types and discusses how clinical outcomes studies may be used to demonstrate clinical utility of such diagnostics.202336816746
6610140.9997The Gut Microbiome and Colistin Resistance: A Hidden Driver of Antimicrobial Failure. Colistin, a polymyxin antibiotic reintroduced as a last-resort therapy against multidrug-resistant Gram-negative bacteria, is increasingly being compromised by the emergence of plasmid-mediated colistin resistance genes (mcr-1 to mcr-10). The human gut microbiota serves as a major reservoir and transmission hub for these resistance determinants, even among individuals without prior colistin exposure. This review explores the mechanisms, dissemination, and clinical implications of mcr-mediated colistin resistance within the gut microbiota, highlighting its role in horizontal gene transfer, colonization, and environmental persistence. A comprehensive synthesis of the recent literature was conducted, focusing on epidemiological studies, molecular mechanisms, neonatal implications and decolonization strategies. The intestinal tract supports the enrichment and exchange of mcr genes among commensal and pathogenic bacteria, especially under antibiotic pressure. Colistin use in agriculture has amplified gut colonization with resistant strains in both animals and humans. Surveillance gaps remain, particularly in neonatal populations, where colonization may occur early and persist silently. Promising interventions, such as fecal microbiota transplantation and phage therapies, are under investigation but lack large-scale clinical validation. The gut microbiome plays a central role in the global spread of colistin resistance. Mitigating this threat requires integrated One Health responses, improved diagnostics for gut colonization, and investment in microbiome-based therapies. A proactive, multisectoral approach is essential to safeguard colistin efficacy and address the expanding threat of mcr-mediated resistance.202541009471
9675150.9997CRISPR-Cas inhibits plasmid transfer and immunizes bacteria against antibiotic resistance acquisition in manure. The horizontal transfer of antibiotic resistance genes among bacteria is a pressing global issue. The bacterial defense system clustered regularly interspaced short palindromic repeats (CRISPR)-Cas acts as a barrier to the spread of antibiotic resistance plasmids, and CRISPR-Cas-based antimicrobials can be effective to selectively deplete antibiotic-resistant bacteria. While significant surveillance efforts monitor the spread of antibiotic-resistant bacteria in the clinical context, a major, often overlooked aspect of the issue is resistance emergence in agriculture. Farm animals are commonly treated with antibiotics, and antibiotic resistance in agriculture is on the rise. Yet, CRISPR-Cas efficacy has not been investigated in this setting. Here, we evaluate the prevalence of CRISPR-Cas in agricultural Enterococcus faecalis strains and its antiplasmid efficacy in an agricultural niche: manure. Analyzing 1,986 E. faecalis genomes from human and animal hosts, we show that the prevalence of CRISPR-Cas subtypes is similar between clinical and agricultural E. faecalis strains. Using plasmid conjugation assays, we found that CRISPR-Cas is a significant barrier against resistance plasmid transfer in manure. Finally, we used a CRISPR-based antimicrobial approach to cure resistant E. faecalis of erythromycin resistance, but this was limited by delivery efficiency of the CRISPR antimicrobial in manure. However, immunization of bacteria against resistance gene acquisition in manure was highly effective. Together, our results show that E. faecalis CRISPR-Cas is prevalent and effective in an agricultural setting and has the potential to be utilized for depleting antibiotic-resistant populations. Our work has broad implications for tackling antibiotic resistance in the increasingly relevant agricultural setting, in line with a One Health approach.IMPORTANCEAntibiotic resistance is a growing global health crisis in human and veterinary medicine. Previous work has shown technologies based on CRISPR-Cas-a bacterial defense system-to be effective in tackling antibiotic resistance. Here we test if CRISPR-Cas is present and effective in agricultural niches, specifically in the ubiquitously present bacterium, Enterococcus faecalis. We show that CRISPR-Cas is both prevalent and functional in manure and has the potential to be used to specifically kill bacteria carrying antibiotic resistance genes. This study demonstrates the utility of CRISPR-Cas-based strategies for control of antibiotic resistance in agricultural settings.202439158272
9573160.9997Bacteriophage Infections of Biofilms of Health Care-Associated Pathogens: Klebsiella pneumoniae. Members of the family Enterobacteriaceae, such as Klebsiella pneumoniae, are considered both serious and urgent public health threats. Biofilms formed by these health care-associated pathogens can lead to negative and costly health outcomes. The global spread of antibiotic resistance, coupled with increased tolerance to antimicrobial treatments in biofilm-associated bacteria, highlights the need for novel strategies to overcome treatment hurdles. Bacteriophages (phages), or viruses that infect bacteria, have reemerged as one such potential strategy. Virulent phages are capable of infecting and killing their bacterial hosts, in some cases producing depolymerases that are able to hydrolyze biofilms. Phage therapy does have its limitations, however, including potential narrow host ranges, development of bacterial resistance to infection, and the potential spread of phage-encoded virulence genes. That being said, advances in phage isolation, screening, and genome sequencing tools provide an upside in overcoming some of these limitations and open up the possibilities of using phages as effective biofilm control agents.202033118486
9788170.9997Global antibacterial resistance: The never-ending story. Bacterial resistance is undoubtedly recognised as a major medical challenge in most healthcare systems. Resistance-determining genes, mostly in combination, and multidrug-resistant (MDR) pathogens are spreading with unprecedented speed. Well known resistance carriers with high clinical impact include the Gram-positive organisms Staphylococcus aureus and Enterococcus spp. In contrast to these organisms that are usually still treatable with newer alternative antibacterial drugs, some Gram-negative bacteria, especially Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter spp., have developed resistance to most or all available antibiotics. Such strains are already a reality in some Mediterranean and Asian countries. According to their resistance epidemiology (based on major drivers favouring resistance), three regions are pinpointed as high-impact resistance hot spots. Despite the clear medical need for novel antibiotics without cross-resistance issues, antibacterial research and development pipelines are nearly dry, thus failing to provide the flow of novel antibiotics required to match the fast emergence and spread of MDR bacteria. In a globalised world, only concerted global actions can mitigate a future with untreatable infectious diseases.201327873580
6678180.9997Bacteriophage Therapy to Combat Microbial Infections and Antimicrobial Resistance. Antimicrobial resistance (AMR) is a global issue; however, in lower resource settings, uncontrolled measures and uncontrolled use of antibiotics in human, animal, and agricultural practices have increased their prevalence in developing countries. Various mechanisms have been implicated to explain the AMR, like the circulation of the plasmid carrying antibiotic resistance genes (ARG), mutation in target genes (intrinsic and plasmid), overexpression of efflux pumps, underexpression of porins, etc. Various therapeutic strategies used to combat AMR exist, such as nonantibiotic approaches (vaccinations or immunotherapy, nano-derived treatments, and bacteriophage therapy), Anti-plasmid and plasmid curing approaches, combinatorial approaches (combination of antibiotics as well as a combination of two different approaches), and plant-based therapeutics. In this focused review, we have discussed the potential use of bacteriophage-based therapy to combat AMR and biofilm formation through multifaceted ways, including lysis of the drug-resistant bacteria, targeting the pili of AMR plasmids conjugation systems, and use of phage-derived lytic proteins. Phages can also be used to decontaminate surfaces in healthcare settings, prevent bacterial contamination in food (meat and dairy), and control bacterial populations in environmental settings, such as water and soil. Therefore, the bacteriophages-based approach served as a dual sword and could not only prevent the spread of infectious diseases but also manage the AMR.202540757460
9790190.9997Emerging antibiotic resistance: carbapenemase-producing enterobacteria. Bad new bugs, still no new drugs. Antimicrobial resistance (AMR) is a global health security threat requiring actions across government sectors and society. Many factors are involved in this phenomenon, being overuse of antibiotics, incorrect antibiotic prophylaxis, and use of antibiotics for zootechnic reasons the main causes of the increasing rate of multi-drug resistant (MDR) bacteria. The impact of resistance to antimicrobials is an important threat due also to the emergence of MDR Gram-negative bacteria resistant to carbapenems, and the lack of the research for new active molecules. The production of extended spectrum beta-lactamase enzymes has been the first threatening mechanism for Gram-negative resistance to antibiotics, which prompted the development of new classes of antibiotics such as carbapenems. Unfortunately, resistance to carbapenems developed because of multiple mechanisms including efflux pumps, porin mutations and enzyme production, being the latter particularly relevant in terms of diffusion due to the genes located within plasmids that drive their horizontal diffusion. In this scenario, antimicrobial stewardship programs (ASP) are a mandatory resource in fighting the resistance spread. The reduction of total amount of antibiotics administration in the hospital setting and guiding prescribers in the correct administration of antibiotics for the smallest period possible, at the correct dosage, can be defined as the first goals of an ASP. Anyway, in an efficacious ASP, apart from antibiotic administration, efforts must been made in ensuring the lowest probability of spreading of MDR by efficacious measures of isolation of carriers, and by offering tools for a rapid diagnosis of viral infections avoiding the administration of unnecessary antibiotics. A continuous audit of the ASP programs and a correct assessment of the allergy to drugs such as penicillin have to complete the program. Currently, only a few options are available for patients with an infection sustained by Gram-negative MDR bacteria. All the options actually available are based on the administration of colystin, an old drug whose real efficacy is reduced due to its relevant toxicity, or on the administration of recently proposed drugs such as ceftolozane-tazobactam, ceftazidime-avibactam and meropenem-vaborbactam. All these new drugs do not have a novel mechanism of action and have limited spectrum in term of activity against MDR bacteria. In conclusion, antimicrobial resistance is a global emergence and AMP is the most powerful tool actually available. Few limited options are available to treat infections due to Carbapenem Resistant Enterobacteria. Antimicrobial molecules with true novel mechanism of action are needed to win the fight against antimicrobial resistance.201931846984