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International Journal of Antimicrobial... Jun 2024Carbapenem-resistant Klebsiella pneumoniae (CRKP) poses immense threats to the health of infected patients worldwide, especially children. This study reports the...
Carbapenem-resistant Klebsiella pneumoniae (CRKP) poses immense threats to the health of infected patients worldwide, especially children. This study reports the infection caused by CRKP in a paediatric intensive care unit (PICU) child and its drug-resistant mutation during the treatment. Twelve Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae strains were isolated from the child. Broth microdilution method, plasmid transformation assay, and whole genome sequencing (WGS) were performed to investigate the antimicrobial susceptibility, resistance mechanisms, and genetic structural features of CRKPs. The results showed that 12 strains were highly resistant to most available antimicrobial agents. Among them, K. pneumoniae FD11 and K. pneumoniae FD12 were resistant to ceftazidime-avibactam (CZA, MIC >64 mg/L) and restored the carbapenem susceptibility (Imipenem, MIC =0.25 mg/L; Meropenem, MIC =2 mg/L). The patient improved after treatment with CZA in combination with aztreonam. Plasmid transformation assay demonstrated that the bla-positive transformant increased MICs of CZA by at least 33-fold and 8-fold compared with the recipient Escherichia coli DH5α and bla-positive transformants. WGS analysis revealed that all strains belonged to the ST11-KL64 type and showed highly homologous (3-26 single nucleotide polymorphisms [SNPs]). A single base mutation (G532T) of bla resulted in a tyrosine to aspartic acid substitution at Ambler amino acid position 179 (D179Y), which conferred CZA resistance in K. pneumoniae. This is the first report of a drug-resistant mutation evolving into bla during the treatment of bla-positive CRKP in paediatric-infected patients. It advises clinicians that routine sequential antimicrobial susceptibility testing and KPC genotyping are critical during CZA therapy in children infected with CRKP.
Topics: Humans; Klebsiella pneumoniae; Azabicyclo Compounds; Drug Combinations; Ceftazidime; Klebsiella Infections; Microbial Sensitivity Tests; beta-Lactamases; Anti-Bacterial Agents; Bacterial Proteins; Whole Genome Sequencing; Drug Resistance, Multiple, Bacterial; Child; Plasmids; Carbapenem-Resistant Enterobacteriaceae; Male; Aztreonam
PubMed: 38570018
DOI: 10.1016/j.ijantimicag.2024.107163 -
Microbiology Spectrum Aug 2023Plasmid-mediated quinolone resistance (PMQR) determinants, such as genes, have been widely reported in spp. while other types of PMQR genes were rarely reported in...
Plasmid-mediated quinolone resistance (PMQR) determinants, such as genes, have been widely reported in spp. while other types of PMQR genes were rarely reported in these bacteria. This study characterized the phenotypic and genotypic features of foodborne spp. carrying , a key PMQR gene in . Among a total of 1,811 foodborne isolates tested, 34 (1.88%) were found to harbor the gene. The allele was the most prevalent, but coexistence with other alleles was common. Missense mutations in the quinolone resistance-determining region (QRDR) of the and genes were only found in 11 of the 34 -bearing isolates. Antimicrobial susceptibility tests showed that all 34 -bearing isolates were resistant to ampicillin and that a high percentage also exhibited resistance to cefotaxime, ceftriaxone, and trimethoprim-sulfamethoxazole. Genetic analysis showed that these phenotypes were attributed to a diverse range of resistance elements that the -bearing isolates harbored. The gene could be found in both the chromosome and plasmids; the plasmid-borne genes could be found on both conjugative and nonconjugative plasmids. pAQU-type -bearing conjugative plasmids were able to mediate expression of phenotypic resistance to both ciprofloxacin and cephalosporins. Transmission of this plasmid among spp. would speed up the emergence of multidrug-resistant (MDR) pathogens that are resistant to the most important antibiotics used in treatment of infections, suggesting that close monitoring of emergence and dissemination of MDR spp. in both food samples and clinical settings is necessary. spp. used to be very susceptible to antibiotics. However, resistance to clinically important antibiotics, such as cephalosporins and fluoroquinolones, among clinically isolated strains is increasingly common. In this study, we found that plasmid-mediated quinolone resistance (PMQR) genes, such as , that have not been previously reported in spp. can now be detected in food isolates. The gene alone could mediate expression of ciprofloxacin resistance in spp.; importantly, this gene could be found in both the chromosome and plasmids. The plasmids that harbor the gene could be both conjugative and nonconjugative, among which the pAQU-type -bearing conjugative plasmids were able to mediate expression of resistance to both ciprofloxacin and cephalosporins. Transmission of this plasmid among spp. would accelerate the emergence of multidrug-resistant pathogens.
Topics: Ciprofloxacin; Cephalosporins; Drug Resistance, Bacterial; Anti-Bacterial Agents; Quinolones; Plasmids; Monobactams; Vibrio; Microbial Sensitivity Tests
PubMed: 37395663
DOI: 10.1128/spectrum.01032-23 -
Scientific Reports Apr 2024Bacterial resistance surveillance is one of the main outputs of microbiological laboratories and its results are important part of antimicrobial stewardship (AMS). In...
Bacterial resistance surveillance is one of the main outputs of microbiological laboratories and its results are important part of antimicrobial stewardship (AMS). In this study, the susceptibility of specific bacteria to selected antimicrobial agents was tested. The susceptibility of 90 unique isolates of pathogens of critical priority obtained from clinically valid samples of ICU patients in 2017-2021 was tested. 50% of these fulfilled difficult-to-treat resistance (DTR) criteria and 50% were susceptible to all antibiotics included in the definition. 10 Enterobacterales strains met DTR criteria, and 2 (20%) were resistant to colistin (COL), 2 (20%) to cefiderocol (FCR), 7 (70%) to imipenem/cilastatin/relebactam (I/R), 3 (30%) to ceftazidime/avibactam (CAT) and 5 (50%) to fosfomycin (FOS). For Enterobacterales we also tested aztreonam/avibactam (AZA) for which there are no breakpoints yet. The highest MIC of AZA observed was 1 mg/l, MIC range in the susceptible cohort was 0.032-0.064 mg/l and in the DTR cohort (incl. class B beta-lactamase producers) it was 0.064-1 mg/l. Two (13.3%) isolates of Pseudomonas aeruginosa (15 DTR strains) were resistant to COL, 1 (6.7%) to FCR, 13 (86.7%) to I/R, 5 (33.3%) to CAT, and 5 (33.3%) to ceftolozane/tazobactam. All isolates of Acinetobacter baumannii with DTR were susceptible to COL and FCR, and at the same time resistant to I/R and ampicillin/sulbactam. New antimicrobial agents are not 100% effective against DTR. Therefore, it is necessary to perform susceptibility testing of these antibiotics, use the data for surveillance (including local surveillance) and conform to AMS standards.
Topics: Humans; Anti-Bacterial Agents; Retrospective Studies; Cephalosporins; Aztreonam; Cefiderocol; Gram-Negative Bacteria; Colistin; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Azabicyclo Compounds
PubMed: 38594467
DOI: 10.1038/s41598-024-59036-0 -
Molecules (Basel, Switzerland) Oct 2023is a common human pathogen. Methicillin-resistant (MRSA) infections pose significant and challenging therapeutic difficulties. MRSA often acquires the non-native gene... (Review)
Review
is a common human pathogen. Methicillin-resistant (MRSA) infections pose significant and challenging therapeutic difficulties. MRSA often acquires the non-native gene PBP2a, which results in reduced susceptibility to β-lactam antibiotics, thus conferring resistance. PBP2a has a lower affinity for methicillin, allowing bacteria to maintain peptidoglycan biosynthesis, a core component of the bacterial cell wall. Consequently, even in the presence of methicillin or other antibiotics, bacteria can develop resistance. Due to genes responsible for resistance, becomes MRSA. The fundamental premise of this resistance mechanism is well-understood. Given the therapeutic concerns posed by resistant microorganisms, there is a legitimate demand for novel antibiotics. This review primarily focuses on PBP2a scaffolds and the various screening approaches used to identify PBP2a inhibitors. The following classes of compounds and their biological activities are discussed: Penicillin, Cephalosporins, Pyrazole-Benzimidazole-based derivatives, Oxadiazole-containing derivatives, non-β-lactam allosteric inhibitors, 4-(3)-Quinazolinones, Pyrrolylated chalcone, Bis-2-Oxoazetidinyl macrocycles (β-lactam antibiotics with 1,3-Bridges), Macrocycle-embedded β-lactams as novel inhibitors, Pyridine-Coupled Pyrimidinones, novel Naphthalimide corbelled aminothiazoximes, non-covalent inhibitors, Investigational-β-lactam antibiotics, Carbapenem, novel Benzoxazole derivatives, Pyrazolylpyridine analogues, and other miscellaneous classes of scaffolds for PBP2a. Additionally, we discuss the penicillin-binding protein, a crucial target in the MRSA cell wall. Various aspects of PBP2a, bacterial cell walls, peptidoglycans, different crystal structures of PBP2a, synthetic routes for PBP2a inhibitors, and future perspectives on MRSA inhibitors are also explored.
Topics: Humans; Penicillin-Binding Proteins; Methicillin-Resistant Staphylococcus aureus; Methicillin; Staphylococcus aureus; Anti-Bacterial Agents; Monobactams; Bacterial Proteins; Microbial Sensitivity Tests
PubMed: 37894491
DOI: 10.3390/molecules28207008 -
Antimicrobial Agents and Chemotherapy Oct 2023Novel antibacterial agents and strategies are urgently needed to fight against the ongoing global antibiotic resistance problem. While natural products remain the main...
Novel antibacterial agents and strategies are urgently needed to fight against the ongoing global antibiotic resistance problem. While natural products remain the main source in antibiotic discovery, synthetic antibacterials provide an attractive alternative and may evade the ancient antibiotic resistance. Herein, we report a small molecule that re-sensitizes methicillin-resistant to β-lactam antibiotics with extremely low potential for resistance development. It belongs to a new class of broad-spectrum antibacterials, trypyricins, which share similar structural characteristics and mechanism of action to the cationic antimicrobial peptides. Mechanistic studies indicated that trypyricins fluidize and disrupt bacterial cytoplasmic membrane. These results suggested that trypyricins represent a promising new class of antibacterials and may be further developed as antibiotic adjuvants to fight against resistant bacteria in the clinic.
Topics: Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Anti-Bacterial Agents; Monobactams; Drug Resistance, Microbial
PubMed: 37681969
DOI: 10.1128/aac.00051-23 -
ACS Infectious Diseases Aug 2023Addressing antibacterial resistance is a major concern of the modern world. The development of new approaches to meet this deadly threat is a critical priority. In this...
Addressing antibacterial resistance is a major concern of the modern world. The development of new approaches to meet this deadly threat is a critical priority. In this article, we investigate a new approach to negate bacterial resistance: exploit the β-lactam bond cleavage by β-lactamases to selectively trigger antibacterial prodrugs into the bacterial periplasm. Indeed, multidrug-resistant Gram-negative pathogens commonly produce several β-lactamases that are able to inactivate β-lactam antibiotics, our most reliable and widely used therapeutic option. The chemical structure of these prodrugs is based on a monobactam promoiety, covalently attached to the active antibacterial substance, zidovudine (AZT). We describe the synthesis of 10 prodrug analogues () in four to nine steps and their biological activity. Selective enzymatic activation by a panel of β-lactamases is demonstrated, and subsequent structure-activity relationships are discussed. The best compounds are further evaluated for their activity on both laboratory strains and clinical isolates, preliminary stability, and toxicity.
Topics: beta-Lactams; beta-Lactamases; Zidovudine; Prodrugs; Anti-Bacterial Agents; Gram-Negative Bacteria
PubMed: 37439673
DOI: 10.1021/acsinfecdis.3c00110 -
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 -
Clinical Infectious Diseases : An... Jul 2023The spread of extended-spectrum cephalosporin-resistant Enterobacterales (ESCrE) and carbapenem-resistant Enterobacterales (CRE) represents a significant global public...
Risk Factors for Colonization With Extended-Spectrum Cephalosporin-Resistant and Carbapenem-Resistant Enterobacterales Among Hospitalized Patients in Kenya: An Antibiotic Resistance in Communities and Hospitals (ARCH) Study.
BACKGROUND
The spread of extended-spectrum cephalosporin-resistant Enterobacterales (ESCrE) and carbapenem-resistant Enterobacterales (CRE) represents a significant global public health threat. We identified putative risk factors for ESCrE and CRE colonization among patients in 1 urban and 3 rural hospitals in Kenya.
METHODS
During a January 2019 and March 2020 cross-sectional study, stool samples were collected from randomized inpatients and tested for ESCrE and CRE. The Vitek2 instrument was used for isolate confirmation and antibiotic susceptibility testing, and least absolute shrinkage and selection operator (LASSO) regression models were used to identify colonization risk factors while varying antibiotic use measures.
RESULTS
Most (76%) of the 840 enrolled participants received ≥1 antibiotic in the 14 days preceding their enrollment, primarily ceftriaxone (46%), metronidazole (28%), or benzylpenicillin-gentamycin (23%). For LASSO models that included ceftriaxone administration, ESCrE colonization odds were higher among patients hospitalized for ≥3 days (odds ratio, 2.32 [95% confidence interval, 1.6-3.37]; P < .001), intubated patients (1.73 [1.03-2.91]; P = .009), and persons living with human immunodeficiency virus (1.70 [1.03-2.8]; P = .029). CRE colonization odds were higher among patients receiving ceftriaxone (odds ratio, 2.23 [95% confidence interval, 1.14-4.38]; P = .025) and for every additional day of antibiotic use (1.08 [1.03-1.13]; P = .002).
CONCLUSIONS
While CRE colonization was strongly associated with ceftriaxone use and duration of antibiotic use, the odds of ESCrE colonization increased with exposure to the hospital setting and invasive medical devices, which may reflect nosocomial transmission. These data suggest several areas where hospitals can intervene to prevent colonization among hospitalized patients, both through robust infection prevention and control practices and antibiotic stewardship programs.
Topics: Humans; Cephalosporins; Carbapenems; Ceftriaxone; Kenya; Cross-Sectional Studies; Anti-Bacterial Agents; Hospitals; Monobactams; Drug Resistance, Microbial; Risk Factors
PubMed: 37406042
DOI: 10.1093/cid/ciad258 -
Antimicrobial Agents and Chemotherapy Jan 2024Cefiderocol is a siderophore cephalosporin designed to target multi-drug-resistant Gram-negative bacteria. Previously, the emergence of cefiderocol non-susceptibility...
Cefiderocol is a siderophore cephalosporin designed to target multi-drug-resistant Gram-negative bacteria. Previously, the emergence of cefiderocol non-susceptibility has been associated with mutations in the chromosomal cephalosporinase (PDC) along with mutations in the PirA and PiuA/D TonB-dependent receptor pathways. Here, we report a clinical case of cefiderocol-resistant that emerged in a patient during treatment. This resistance was associated with mutations not previously reported, suggesting potential novel pathways to cefiderocol resistance.
Topics: Humans; Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Microbial Sensitivity Tests; Monobactams; Pseudomonas aeruginosa; Pseudomonas Infections
PubMed: 38063509
DOI: 10.1128/aac.01009-23 -
Antimicrobial Agents and Chemotherapy May 2024harboring Verona Integron-encoded metallo-β-lactamase enzymes (VIM-CRPA) have been associated with infection outbreaks in several parts of the world. In the US,...
harboring Verona Integron-encoded metallo-β-lactamase enzymes (VIM-CRPA) have been associated with infection outbreaks in several parts of the world. In the US, however, VIM-CRPA remain rare. Starting in December 2018, we identified a cluster of cases in our institution. Herein, we present our epidemiological investigation and strategies to control/manage these challenging infections. This study was conducted in a large academic healthcare system in Miami, FL, between December 2018 and January 2022. Patients were prospectively identified via rapid molecular diagnostics when cultures revealed carbapenem-resistant . Alerts were received in real time by the antimicrobial stewardship program and infection prevention teams. Upon alert recognition, a series of interventions were performed as a coordinated effort. A retrospective chart review was conducted to collect patient demographics, antimicrobial therapy, and clinical outcomes. Thirty-nine VIM-CRPA isolates led to infection in 21 patients. The majority were male (76.2%); the median age was 52 years. The majority were mechanically ventilated ( = 15/21; 71.4%); 47.6% ( = 10/21) received renal replacement therapy at the time of index culture. Respiratory ( = 20/39; 51.3%) or bloodstream ( = 13/39; 33.3%) were the most common sources. Most infections ( = 23/37; 62.2%) were treated with an aztreonam-avibactam regimen. Six patients (28.6%) expired within 30 days of index VIM-CRPA infection. Fourteen isolates were selected for whole genome sequencing. Most of them belonged to ST111 (12/14), and they all carried bla chromosomally. This report describes the clinical experience treating serious VIM-CRPA infections with either aztreonam-ceftazidime/avibactam or cefiderocol in combination with other agents. The importance of implementing infection prevention strategies to curb VIM-CRPA outbreaks is also demonstrated.
Topics: Adult; Female; Humans; Male; Middle Aged; Anti-Bacterial Agents; Antimicrobial Stewardship; Azabicyclo Compounds; Aztreonam; beta-Lactamases; Carbapenems; Ceftazidime; Drug Combinations; Drug Resistance, Multiple, Bacterial; Integrons; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies
PubMed: 38602418
DOI: 10.1128/aac.01474-23