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Diagnostic Microbiology and Infectious... Jun 2024We proposed a new methodology, the microelution ATM/CZA (mATM/CZA), based on the antibiotic disc elution and the use of resazurin, for rapid (<4h) determination of in...
We proposed a new methodology, the microelution ATM/CZA (mATM/CZA), based on the antibiotic disc elution and the use of resazurin, for rapid (<4h) determination of in vitro susceptibility to aztreonam combined with ceftazidime-avibactam among Enterobacterales. The mATM/CZA presented excellent accuracy with 1.9 %, 98.1 % and 100 % of major error, specificity and sensitivity, respectively. Furthermore, we assessed synergism between aztreonam and ceftazidime-avibactam in Enterobacterales and Pseudomonas aeruginosa, which was observed in 37/55 Enterobacterales and 31/56 P. aeruginosa. As reference methodologies (checkerboard, time-kill curve) are not compatible with the routine of the clinical microbiology laboratories, mATM/CZA is an important alternative to evaluate susceptibility of the combination in a scenario where its clinical use is increasingly important.
Topics: Aztreonam; Azabicyclo Compounds; Drug Combinations; Microbial Sensitivity Tests; Anti-Bacterial Agents; Ceftazidime; Humans; Drug Synergism; Pseudomonas aeruginosa; Enterobacteriaceae; Sensitivity and Specificity; Xanthenes; Oxazines
PubMed: 38537506
DOI: 10.1016/j.diagmicrobio.2024.116236 -
Antibiotics (Basel, Switzerland) Mar 2024Since the discovery of penicillin, β-lactam antibiotics have commonly been used to treat bacterial infections. Unfortunately, at the same time, pathogens can develop... (Review)
Review
Since the discovery of penicillin, β-lactam antibiotics have commonly been used to treat bacterial infections. Unfortunately, at the same time, pathogens can develop resistance to β-lactam antibiotics such as penicillins, cephalosporins, monobactams, and carbapenems by producing β-lactamases. Therefore, a combination of β-lactam antibiotics with β-lactamase inhibitors has been a promising approach to controlling β-lactam-resistant bacteria. The discovery of novel β-lactamase inhibitors (BLIs) is essential for effectively treating antibiotic-resistant bacterial infections. Therefore, this review discusses the development of innovative inhibitors meant to enhance the activity of β-lactam antibiotics. Specifically, this review describes the classification and characteristics of different classes of β-lactamases and the synergistic mechanisms of β-lactams and BLIs. In addition, we introduce potential sources of compounds for use as novel BLIs. This provides insights into overcoming current challenges in β-lactamase-producing bacteria and designing effective treatment options in combination with BLIs.
PubMed: 38534695
DOI: 10.3390/antibiotics13030260 -
Antimicrobial Agents and Chemotherapy May 2024Carbapenemase-producing (CPEs) are one of the top priority antimicrobial-resistant pathogens. Among CPEs, those producing acquired metallo-β-lactamases (MBLs) are...
Carbapenemase-producing (CPEs) are one of the top priority antimicrobial-resistant pathogens. Among CPEs, those producing acquired metallo-β-lactamases (MBLs) are considered particularly problematic as few agents are active against them. Imipenemase (IMP) is the most frequently encountered acquired MBL in Japan, but comprehensive assessment of clinical and microbiological features of IMP-producing infection remains scarce. Here, we retrospectively evaluated 62 patients who were hospitalized at a university hospital in Japan and had IMP-producing from a clinical culture. The isolates were either complex or , and most of them were isolated from sputum. The majority of but not complex isolates, were susceptible to aztreonam. Sequence type (ST) 78 and ST517 were prevalent for complex and , respectively, and all isolates carried . Twenty-four of the patients were deemed infected with IMP-producing . Among the infected patients, therapy varied and largely consisted of conventional β-lactam agents, fluoroquinolones, or combinations. Three (13%), five (21%), and nine (38%) of them died by days 14, 30, and 90, respectively. While incremental mortality over 90 days was observed in association with underlying comorbidities, active conventional treatment options were available for most patients with IMP-producing infections, distinguishing them from more multidrug-resistant CPE infections associated with globally common MBLs, such as New Delhi metallo-β-lactamase (NDM) and Verona integron-encoded metallo-β-lactamase (VIM).
Topics: Klebsiella pneumoniae; beta-Lactamases; Humans; Enterobacter cloacae; Anti-Bacterial Agents; Male; Retrospective Studies; Microbial Sensitivity Tests; Female; Middle Aged; Aged; Bacterial Proteins; Enterobacteriaceae Infections; Aztreonam; Japan; Drug Resistance, Multiple, Bacterial; Klebsiella Infections; Aged, 80 and over; Adult
PubMed: 38517188
DOI: 10.1128/aac.01672-23 -
International Journal of Antimicrobial... May 2024To analyse the impact of the most clinically relevant β-lactamases and their interplay with low outer membrane permeability on the activity of cefiderocol,...
Activity of cefiderocol and innovative β-lactam/β-lactamase inhibitor combinations against isogenic strains of Escherichia coli expressing single and double β-lactamases under high and low permeability conditions.
OBJECTIVES
To analyse the impact of the most clinically relevant β-lactamases and their interplay with low outer membrane permeability on the activity of cefiderocol, ceftazidime/avibactam, aztreonam/avibactam, cefepime/enmetazobactam, cefepime/taniborbactam, cefepime/zidebactam, imipenem/relebactam, meropenem/vaborbactam, meropenem/xeruborbactam and meropenem/nacubactam against recombinant Escherichia coli strains.
METHODS
We constructed 82 E. coli laboratory transformants expressing the main β-lactamases circulating in Enterobacterales (70 expressing single β-lactamase and 12 producing double carbapenemase) under high (E. coli TG1) and low (E. coli HB4) permeability conditions. Antimicrobial susceptibility testing was determined by reference broth microdilution.
RESULTS
Aztreonam/avibactam, cefepime/zidebactam, cefiderocol, meropenem/xeruborbactam and meropenem/nacubactam were active against all E. coli TG1 transformants. Imipenem/relebactam, meropenem/vaborbactam, cefepime/taniborbactam and cefepime/enmetazobactam were also highly active, but unstable against most of MBL-producing transformants. Combination of β-lactamases with porin deficiency (E. coli HB4) did not significantly affect the activity of aztreonam/avibactam, cefepime/zidebactam, cefiderocol or meropenem/nacubactam, but limited the effectiveness of the rest of carbapenem- and cefepime-based combinations. Double-carbapenemase production resulted in the loss of activity of most of the compounds tested, an effect particularly evident for those E. coli HB4 transformants in which MBLs were present.
CONCLUSIONS
Our findings highlight the promising activity that cefiderocol and new β-lactam/β-lactamase inhibitors have against recombinant E. coli strains expressing widespread β-lactamases, including when these are combined with low permeability or other enzymes. Aztreonam/avibactam, cefiderocol, cefepime/zidebactam and meropenem/nacubactam will help to mitigate to some extent the urgency of new compounds able to resist MBL action, although NDM enzymes represent a growing challenge against which drug development efforts are still needed.
Topics: Escherichia coli; beta-Lactamases; Cephalosporins; Microbial Sensitivity Tests; beta-Lactamase Inhibitors; Azabicyclo Compounds; Anti-Bacterial Agents; Drug Combinations; Cyclooctanes; Cefiderocol; Ceftazidime; Cefepime; Boronic Acids; Meropenem; Aztreonam; Imipenem; Bacterial Proteins; Heterocyclic Compounds, 1-Ring; Cell Membrane Permeability; Borinic Acids; Carboxylic Acids; Lactams; Triazoles
PubMed: 38513748
DOI: 10.1016/j.ijantimicag.2024.107150 -
International Journal of Antimicrobial... May 2024
Topics: Azabicyclo Compounds; Ceftazidime; Escherichia coli; beta-Lactamases; Drug Combinations; Aztreonam; Anti-Bacterial Agents; Microbial Sensitivity Tests; Humans; Escherichia coli Infections; Drug Resistance, Multiple, Bacterial
PubMed: 38484805
DOI: 10.1016/j.ijantimicag.2024.107141 -
Biological Research Mar 2024The convergence of hypervirulence and carbapenem resistance in the bacterial pathogen Klebsiella pneumoniae represents a critical global health concern. Hypervirulent K....
BACKGROUND
The convergence of hypervirulence and carbapenem resistance in the bacterial pathogen Klebsiella pneumoniae represents a critical global health concern. Hypervirulent K. pneumoniae (hvKp) strains, frequently from sequence type 23 (ST23) and having a K1 capsule, have been associated with severe community-acquired invasive infections. Although hvKp were initially restricted to Southeast Asia and primarily antibiotic-sensitive, carbapenem-resistant hvKp infections are reported worldwide. Here, within the carbapenemase production Enterobacterales surveillance system headed by the Chilean Public Health Institute, we describe the isolation in Chile of a high-risk ST23 dual-carbapenemase-producing hvKp strain, which carbapenemase genes are encoded in a single conjugative plasmid.
RESULTS
Phenotypic and molecular tests of this strain revealed an extensive resistance to at least 15 antibiotic classes and the production of KPC-2 and VIM-1 carbapenemases. Unexpectedly, this isolate lacked hypermucoviscosity, challenging this commonly used hvKp identification criteria. Complete genome sequencing and analysis confirmed the K1 capsular type, the KpVP-1 virulence plasmid, and the GIE492 and ICEKp10 genomic islands carrying virulence factors strongly associated with hvKp. Although this isolate belonged to the globally disseminated hvKp clonal group CG23-I, it is unique, as it formed a clade apart from a previously reported Chilean ST23 hvKp isolate and acquired an IncN KPC-2 plasmid highly disseminated in South America (absent in other hvKp genomes), but now including a class-I integron carrying bla and other resistance genes. Notably, this isolate was able to conjugate the double carbapenemase plasmid to an E. coli recipient, conferring resistance to 1st -5th generation cephalosporins (including combinations with beta-lactamase inhibitors), penicillins, monobactams, and carbapenems.
CONCLUSIONS
We reported the isolation in Chile of high-risk carbapenem-resistant hvKp carrying a highly transmissible conjugative plasmid encoding KPC-2 and VIM-1 carbapenemases, conferring resistance to most beta-lactams. Furthermore, the lack of hypermucoviscosity argues against this trait as a reliable hvKp marker. These findings highlight the rapid evolution towards multi-drug resistance of hvKp in Chile and globally, as well as the importance of conjugative plasmids and other mobile genetic elements in this convergence. In this regard, genomic approaches provide valuable support to monitor and obtain essential information on these priority pathogens and mobile elements.
Topics: Humans; Klebsiella pneumoniae; Chile; Escherichia coli; Klebsiella Infections; Plasmids; Anti-Bacterial Agents; Carbapenems; Bacterial Proteins; beta-Lactamases
PubMed: 38475927
DOI: 10.1186/s40659-024-00485-2 -
Molecular Genetics and Genomics : MGG Mar 2024Pseudomonas aeruginosa (PA) is an important opportunistic pathogen that causes different infections on immunocompromised patients. Within PA accessory genome,...
Comparative genomic analysis of Pseudomonas aeruginosa strains susceptible and resistant to carbapenems and aztreonam isolated from patients with healthcare-associated infections in a Mexican hospital.
Pseudomonas aeruginosa (PA) is an important opportunistic pathogen that causes different infections on immunocompromised patients. Within PA accessory genome, differences in virulence, antibiotic resistance and biofilm formation have been described between strains, leading to the emergence of multidrug-resistant strains. The genome sequences of 17 strains isolated from patients with healthcare-associated infections in a Mexican hospital were genomically and phylogenetically analyzed and antibiotic resistance genes, virulence genes, and biofilm formation genes were detected. Fifteen of the 17 strains were resistant to at least two of the carbapenems meropenem, imipenem, and the monobactam aztreonam. The antibiotic resistance (mexA, mexB, and oprM) and the biofilm formation (pslA and pslD) genes were detected in all strains. Differences were found between strains in accessory genome size. The strains had different sequence types, and seven strains had sequence types associated with global high risk epidemic PA clones. All strains were represented in two groups among PA global strains. In the 17 strains, horizontally acquired resistance genes to aminoglycosides and beta-lactams were found, mainly, and between 230 and 240 genes that encode virulence factors. The strains under study were variable in terms of their accessory genome, antibiotic resistance, and virulence genes. With these characteristics, we provide information about the genomic diversity of clinically relevant PA strains.
Topics: Humans; Carbapenems; Aztreonam; Pseudomonas aeruginosa; Anti-Bacterial Agents; Pseudomonas Infections; Hospitals; Genomics; Delivery of Health Care; Microbial Sensitivity Tests
PubMed: 38472486
DOI: 10.1007/s00438-024-02122-9 -
BMC Microbiology Mar 2024Chryseobacterium arthrosphaerae strain FS91703 was isolated from Rana nigromaculata in our previous study. To investigate the genomic characteristics,...
Chryseobacterium arthrosphaerae strain FS91703 was isolated from Rana nigromaculata in our previous study. To investigate the genomic characteristics, pathogenicity-related genes, antimicrobial resistance, and phylogenetic relationship of this strain, PacBio RS II and Illumina HiSeq 2000 platforms were used for the whole genome sequencing. The genome size of strain FS91703 was 5,435,691 bp and GC content was 37.78%. A total of 4,951 coding genes were predicted; 99 potential virulence factors homologs were identified. Analysis of antibiotic resistance genes revealed that strain FS91703 harbored 10 antibiotic resistance genes in 6 categories and 2 multidrug-resistant efflux pump genes, including adeG and farA. Strain FS91703 was sensitive to β-lactam combination drugs, cephem, monobactam and carbapenems, intermediately resistant to phenicol, and resistant to penicillin, aminoglycosides, tetracycline, fluoroquinolones, and folate pathway inhibitors. Phylogenetic analysis revealed that strain FS91703 and C. arthrosphaerae CC-VM-7 were on the same branch of the phylogenetic tree based on 16 S rRNA; the ANI value between them was 96.99%; and the DDH values were 80.2, 72.2 and 81.6% by three default calculation formulae. These results suggested that strain FS91703 was a species of C. arthrosphaerae. Pan-genome analysis showed FS91703 had 566 unique genes compared with 13 other C. arthrosphaerae strains, and had a distant phylogenetic relationship with the other C. arthrosphaerae strains of the same branch in phylogenetic tree based on orthologous genes. The results of this study suggest that strain FS91703 is a multidrug-resistant and highly virulent bacterium, that differs from other C. arthrosphaerae strains at the genomic level. The knowledge about the genomic characteristics and antimicrobial resistance of strain FS91703 provides valuable insights into this rare species, as well as guidance for the treatment of the disease caused by FS91703 in Rana nigromaculata.
Topics: Animals; DNA, Bacterial; Phylogeny; Whole Genome Sequencing; Chryseobacterium; Anti-Bacterial Agents; Ranidae; Genome, Bacterial
PubMed: 38459435
DOI: 10.1186/s12866-024-03223-6 -
Journal of Clinical Microbiology Apr 2024Traditionally, cephalothin susceptibility results were used to predict the susceptibility of additional cephalosporins; however, in 2013-2014, the Clinical and... (Review)
Review
Traditionally, cephalothin susceptibility results were used to predict the susceptibility of additional cephalosporins; however, in 2013-2014, the Clinical and Laboratory Standards Institute (CLSI) revisited this practice and determined that cefazolin is a more accurate proxy than cephalothin for uncomplicated urinary tract infections (uUTIs). Therefore, a cefazolin surrogacy breakpoint was established to predict the susceptibility of seven oral cephalosporins for , , and in the context of uUTIs. Clinical microbiology laboratories face several operational challenges when implementing the cefazolin surrogacy breakpoint, which may lead to confusion for the best path forward. Here, we review the historical context and data behind the surrogacy breakpoints, review PK/PD profiles for oral cephalosporins, discuss challenges in deploying the breakpoint, and highlight the limited clinical outcome data in this space.
Topics: Humans; Cefazolin; Cephalosporins; Cephalothin; Anti-Bacterial Agents; Microbial Sensitivity Tests; Urinary Tract Infections; Escherichia coli; Monobactams
PubMed: 38457194
DOI: 10.1128/jcm.00788-21 -
European Journal of Medicinal Chemistry Mar 2024Global public health is facing a serious problem as a result of the rise in antibiotic resistance and the decline in the discovery of new antibiotics. In this study, two...
Global public health is facing a serious problem as a result of the rise in antibiotic resistance and the decline in the discovery of new antibiotics. In this study, two series of amphiphilic-cephalosporins were designed and synthesized, several of which showed good antibacterial activity against both Gram-positive and Gram-negative bacteria. Structure-activity relationships indicated that the length of the hydrophobic alkyl chain significantly affects the antibacterial activity against Gram-negative bacteria. The best compound 2d showed high activity against drug-susceptible Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA) with MICs of 0.5 and 2-4 μg/mL, respectively. Furthermore, 2d remained active in complex mammalian body fluids and had a longer post-antibiotic effect (PAE) than vancomycin. Mechanism studies indicated that compound 2d lacks membrane-damaging properties and can target penicillin-binding proteins to disrupt bacterial cell wall structure, inhibit the metabolic activity and induce the accumulation of reactive oxygen species (ROS) in bacteria. Compound 2d showed minimal drug resistance and was nontoxic to HUVEC and HBZY-1 cells with CC > 128 μg/mL. These findings suggest that 2d is a promising drug candidate for treating bacterial infections.
Topics: Animals; Anti-Bacterial Agents; Cephalosporins; Methicillin-Resistant Staphylococcus aureus; Gram-Positive Bacteria; Gram-Negative Bacteria; Staphylococcal Infections; Monobactams; Microbial Sensitivity Tests; Mammals
PubMed: 38447461
DOI: 10.1016/j.ejmech.2024.116293