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Revista Espanola de Quimioterapia :... Nov 2023In recent years, new antimicrobials have been introduced in therapeutics, including new beta-lactam-beta-lactamase inhibitor combinations and cefiderocol in response to... (Review)
Review
In recent years, new antimicrobials have been introduced in therapeutics, including new beta-lactam-beta-lactamase inhibitor combinations and cefiderocol in response to therapeutic needs in the face of increasing resistance. There are also different treatment guidelines for infections caused by these microorganisms that have been approved by different professional societies, including those of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), the Infectious Disease Society of America (IDSA) and the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC). All of them are based on scientific evidence, but with differences in the weight of expert opinion in their recommendations. Both ESCMID and IDSA include recommendations for the treatment of extended-spectrum beta-lactamase-producing microorganisms. The IDSA is the only one including AmpC producers, all address the treatment of infections caused by carbapenem-resistant Enterobacterales and Acinetobacter baumannii and multidrug-resistant or difficult-to-treat Pseudomonas aeruginosa, and the IDSA and SEIMC include recommendations on the treatment of Stenotrophomonas maltophilia. Future guidelines should integrate new antimicrobials and new innovative management options not covered by current guidelines.
Topics: Humans; Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Cephalosporins; Carbapenems; beta-Lactamase Inhibitors; Communicable Diseases; Gram-Negative Bacteria; Microbial Sensitivity Tests
PubMed: 37997871
DOI: 10.37201/req/s01.11.2023 -
Nature Reviews. Cancer Nov 2023Cancer cells frequently display intrinsic or acquired resistance to chemically diverse anticancer drugs, limiting therapeutic success. Among the main mechanisms of this... (Review)
Review
Cancer cells frequently display intrinsic or acquired resistance to chemically diverse anticancer drugs, limiting therapeutic success. Among the main mechanisms of this multidrug resistance is the overexpression of ATP-binding cassette (ABC) transporters that mediate drug efflux, and, specifically, ABCB1, ABCG2 and ABCC1 are known to cause cancer chemoresistance. High-resolution structures, biophysical and in silico studies have led to tremendous progress in understanding the mechanism of drug transport by these ABC transporters, and several promising therapies, including irradiation-based immune and thermal therapies, and nanomedicine have been used to overcome ABC transporter-mediated cancer chemoresistance. In this Review, we highlight the progress achieved in the past 5 years on the three transporters, ABCB1, ABCG2 and ABCC1, that are known to be of clinical importance. We address the molecular basis of their broad substrate specificity gleaned from structural information and discuss novel approaches to block the function of ABC transporters. Furthermore, genetic modification of ABC transporters by CRISPR-Cas9 and approaches to re-engineer amino acid sequences to change the direction of transport from efflux to import are briefly discussed. We suggest that current information regarding the structure, mechanism and regulation of ABC transporters should be used in clinical trials to improve the efficiency of chemotherapeutics for patients with cancer.
Topics: Humans; ATP-Binding Cassette Transporters; Drug Resistance, Neoplasm; Drug Resistance, Multiple; Antineoplastic Agents
PubMed: 37714963
DOI: 10.1038/s41568-023-00612-3 -
Nature Chemical Biology Nov 2023Acinetobacter baumannii is a nosocomial Gram-negative pathogen that often displays multidrug resistance. Discovering new antibiotics against A. baumannii has proven...
Acinetobacter baumannii is a nosocomial Gram-negative pathogen that often displays multidrug resistance. Discovering new antibiotics against A. baumannii has proven challenging through conventional screening approaches. Fortunately, machine learning methods allow for the rapid exploration of chemical space, increasing the probability of discovering new antibacterial molecules. Here we screened ~7,500 molecules for those that inhibited the growth of A. baumannii in vitro. We trained a neural network with this growth inhibition dataset and performed in silico predictions for structurally new molecules with activity against A. baumannii. Through this approach, we discovered abaucin, an antibacterial compound with narrow-spectrum activity against A. baumannii. Further investigations revealed that abaucin perturbs lipoprotein trafficking through a mechanism involving LolE. Moreover, abaucin could control an A. baumannii infection in a mouse wound model. This work highlights the utility of machine learning in antibiotic discovery and describes a promising lead with targeted activity against a challenging Gram-negative pathogen.
Topics: Animals; Mice; Anti-Bacterial Agents; Acinetobacter baumannii; Deep Learning; Drug Resistance, Multiple, Bacterial; Microbial Sensitivity Tests
PubMed: 37231267
DOI: 10.1038/s41589-023-01349-8 -
Emerging Microbes & Infections Dec 2024The escalation of antibiotic resistance and the diminishing antimicrobial pipeline have emerged as significant threats to public health. The ESKAPE pathogens -... (Review)
Review
The escalation of antibiotic resistance and the diminishing antimicrobial pipeline have emerged as significant threats to public health. The ESKAPE pathogens - Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp. - were initially identified as critical multidrug-resistant bacteria, demanding urgently effective therapies. Despite the introduction of various new antibiotics and antibiotic adjuvants, such as innovative β-lactamase inhibitors, these organisms continue to pose substantial therapeutic challenges. People's Republic of China, as a country facing a severe bacterial resistance situation, has undergone a series of changes and findings in recent years in terms of the prevalence, transmission characteristics and resistance mechanisms of antibiotic resistant bacteria. The increasing levels of population mobility have not only shaped the unique characteristics of antibiotic resistance prevalence and transmission within People's Republic of China but have also indirectly reflected global patterns of antibiotic-resistant dissemination. What's more, as a vast nation, People's Republic of China exhibits significant variations in the levels of antibiotic resistance and the prevalence characteristics of antibiotic resistant bacteria across different provinces and regions. In this review, we examine the current epidemiology and characteristics of this important group of bacterial pathogens, delving into relevant mechanisms of resistance to recently introduced antibiotics that impact their clinical utility in China.
Topics: Humans; Anti-Bacterial Agents; Bacterial Infections; Klebsiella pneumoniae; Drug Resistance, Multiple, Bacterial; Enterococcus faecium
PubMed: 38356197
DOI: 10.1080/22221751.2024.2317915 -
Proceedings of the National Academy of... Aug 2023Microbes evolve rapidly by modifying their genomes through mutations or through the horizontal acquisition of mobile genetic elements (MGEs) linked with fitness traits...
Microbes evolve rapidly by modifying their genomes through mutations or through the horizontal acquisition of mobile genetic elements (MGEs) linked with fitness traits such as antimicrobial resistance (AMR), virulence, and metabolic functions. We conducted a multicentric study in India and collected different clinical samples for decoding the genome sequences of bacterial pathogens associated with sepsis, urinary tract infections, and respiratory infections to understand the functional potency associated with AMR and its dynamics. Genomic analysis identified several acquired AMR genes (ARGs) that have a pathogen-specific signature. We observed that , , , and (2) were prevalent in , and , , , , and were dominant in . In contrast, and harbored , , 3'), , , (3') variants, and , respectively. Regardless of the type of ARG, the MGEs linked with ARGs were also pathogen-specific. The sequence type of these pathogens was identified as high-risk international clones, with only a few lineages being predominant and region-specific. Whole-cell proteome analysis of extensively drug-resistant , and strains revealed differential abundances of resistance-associated proteins in the presence and absence of different classes of antibiotics. The pathogen-specific resistance signatures and differential abundance of AMR-associated proteins identified in this study should add value to AMR diagnostics and the choice of appropriate drug combinations for successful antimicrobial therapy.
Topics: Anti-Bacterial Agents; Escherichia coli; beta-Lactamases; Proteomics; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Klebsiella pneumoniae; Microbial Sensitivity Tests
PubMed: 37549252
DOI: 10.1073/pnas.2305465120 -
Nature Reviews. Microbiology Jan 2024Antimicrobial resistance (AMR) poses a substantial threat to human health. The widespread prevalence of AMR is, in part, due to the horizontal transfer of antibiotic... (Review)
Review
Antimicrobial resistance (AMR) poses a substantial threat to human health. The widespread prevalence of AMR is, in part, due to the horizontal transfer of antibiotic resistance genes (ARGs), typically mediated by plasmids. Many of the plasmid-mediated resistance genes in pathogens originate from environmental, animal or human habitats. Despite evidence that plasmids mobilize ARGs between these habitats, we have a limited understanding of the ecological and evolutionary trajectories that facilitate the emergence of multidrug resistance (MDR) plasmids in clinical pathogens. One Health, a holistic framework, enables exploration of these knowledge gaps. In this Review, we provide an overview of how plasmids drive local and global AMR spread and link different habitats. We explore some of the emerging studies integrating an eco-evolutionary perspective, opening up a discussion about the factors that affect the ecology and evolution of plasmids in complex microbial communities. Specifically, we discuss how the emergence and persistence of MDR plasmids can be affected by varying selective conditions, spatial structure, environmental heterogeneity, temporal variation and coexistence with other members of the microbiome. These factors, along with others yet to be investigated, collectively determine the emergence and transfer of plasmid-mediated AMR within and between habitats at the local and global scale.
Topics: Animals; Humans; Anti-Bacterial Agents; Drug Resistance, Bacterial; One Health; Drug Resistance, Multiple; Plasmids
PubMed: 37430173
DOI: 10.1038/s41579-023-00926-x -
Current Opinion in Infectious Diseases Dec 2023To update the management of severe Acinetobacter baumannii infections (ABI), particularly those caused by multi-resistant isolates. (Review)
Review
PURPOSE OF REVIEW
To update the management of severe Acinetobacter baumannii infections (ABI), particularly those caused by multi-resistant isolates.
RECENT FINDINGS
The in vitro activity of the various antimicrobial agents potentially helpful in treating ABI is highly variable and has progressively decreased for many of them, limiting current therapeutic options. The combination of more than one drug is still advisable in most circumstances. Ideally, two active first-line drugs should be used. Alternatively, a first-line and a second-line drug and, if this is not possible, two or more second-line drugs in combination. The emergence of new agents such as Cefiderocol, the combination of Sulbactam and Durlobactam, and the new Tetracyclines offer therapeutic options that need to be supported by clinical evidence.
SUMMARY
The apparent limitations in treating infections caused by this bacterium, the rapid development of resistance, and the serious underlying situation in most cases invite the search for alternatives to antibiotic treatment, the most promising of which seems to be bacteriophage therapy.
Topics: Humans; Acinetobacter baumannii; Acinetobacter Infections; Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Microbial Sensitivity Tests; Sulbactam
PubMed: 37930071
DOI: 10.1097/QCO.0000000000000974 -
Clinical Microbiology and Infection :... Oct 2023Mycobacterium abscessus complex is responsible for 2.6-13.0% of all non-tuberculous mycobacterial pulmonary infections and these are notoriously difficult to treat due...
OBJECTIVES
Mycobacterium abscessus complex is responsible for 2.6-13.0% of all non-tuberculous mycobacterial pulmonary infections and these are notoriously difficult to treat due to the complex regimens required, drug resistance and adverse effects. Hence, bacteriophages have been considered in clinical practice as an additional treatment option. Here, we evaluated antibiotic and phage susceptibility profiles of M. abscessus clinical isolates. Whole-genome sequencing (WGS) revealed the phylogenetic relationships, dominant circulating clones (DCCs), the likelihood of patient-to-patient transmission and the presence of prophages.
METHODS
Antibiotic susceptibility testing was performed using CLSI breakpoints (n = 95), and plaque assays were used for phage susceptibility testing (subset of n = 88, 35 rough and 53 smooth morphology). WGS was completed using the Illumina platform and analysed using Snippy/snp-dists and Discovery and Extraction of Phages Tool (DEPhT).
RESULTS
Amikacin and Tigecycline were the most active drugs (with 2 strains resistant to amikacin, and one strain with Tigecycline MIC of 4 μg/mL). Most strains were resistant to all other drugs tested, with Linezolid and Imipenem showing the least resistance, at 38% (36/95) and 55% (52/95), respectively. Rough colony morphotype strains were more phage-susceptible than smooth strains (77%-27/35 versus 48%-25/53 in the plaque assays, but smooth strains are not killed efficiently by those phages in liquid infection assay). We have also identified 100 resident prophages, some of which were propagated lytically. DCC1 (20%-18/90) and DCC4 (22%-20/90) were observed to be the major clones and WGS identified 6 events of possible patient-to-patient transmission.
DISCUSSION
Many strains of M. abscessus complex are intrinsically resistant to available antibiotics and bacteriophages represent an alternative therapeutic option, but only for strains with rough morphology. Further studies are needed to elucidate the role of hospital-borne M. abscessus transmission.
Topics: Humans; Mycobacterium abscessus; Amikacin; Tigecycline; Bacteriophages; Phylogeny; Mycobacterium Infections, Nontuberculous; Anti-Bacterial Agents; Drug Resistance, Multiple; Delivery of Health Care; Microbial Sensitivity Tests
PubMed: 37364635
DOI: 10.1016/j.cmi.2023.06.026 -
Trends in Microbiology Dec 2023Acinetobacter baumannii is a Gram-negative opportunistic bacterium responsible for nosocomial and community-acquired infections. This pathogen is globally disseminated... (Review)
Review
Acinetobacter baumannii is a Gram-negative opportunistic bacterium responsible for nosocomial and community-acquired infections. This pathogen is globally disseminated and associated with high levels of antibiotic resistance, which makes it an important threat to human health. Recently, new evidence showed that several A. baumannii isolates can survive and proliferate within eukaryotic professional and/or nonprofessional phagocytic cells, with in vivo consequences. This review provides updated information and describes the tools that A. baumannii possesses to adhere, colonize, and replicate in host cells. Additionally, we emphasize the high genetic and phenotypic heterogeneity detected amongst A. baumannii isolates and its impact on the bacterial intracellular features. We also discuss the need for standardized methods to characterize this pathogen robustly and consequently consider some strains as facultative intracellular bacteria.
Topics: Humans; Drug Resistance, Multiple, Bacterial; Acinetobacter baumannii; Acinetobacter Infections; Anti-Bacterial Agents; Microbial Sensitivity Tests
PubMed: 37487768
DOI: 10.1016/j.tim.2023.06.007 -
Drugs Jun 2024Cefepime/enmetazobactam (EXBLIFEP), an intravenous (IV) antibacterial fixed-dose combination of a 4th generation cephalosporin and an extended-spectrum β-lactamase... (Review)
Review
Cefepime/enmetazobactam (EXBLIFEP), an intravenous (IV) antibacterial fixed-dose combination of a 4th generation cephalosporin and an extended-spectrum β-lactamase (ESBL) inhibitor, is being developed by Allecra Therapeutics and ADVANZ PHARMA for the treatment of infections caused by multi-drug-resistant (MDR) Gram-negative bacteria. In February 2024, cefepime/enmetazobactam was approved in the USA for use in adults with complicated urinary tract infections (cUTI) including pyelonephritis, caused by susceptible strains of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis, and Enterobacter cloacae complex. In March 2024, cefepime/enmetazobactam was approved in the EU for use in adults for the treatment of cUTI, including pyelonephritis, and hospital-acquired pneumonia, including ventilator associated pneumonia, and the treatment of patients with bacteraemia occurring in association with or suspected to be associated with any of these infections. This article summarizes the milestones in the development of cefepime/enmetazobactam leading to this first approval for the treatment of adults with infections caused by MDR Gram-negative bacteria.
Topics: Humans; Cefepime; Anti-Bacterial Agents; Urinary Tract Infections; Drug Approval; Gram-Negative Bacterial Infections; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Cephalosporins; beta-Lactamase Inhibitors; United States; Drug Combinations; Pyelonephritis
PubMed: 38761353
DOI: 10.1007/s40265-024-02035-2