scholarly journals Analysis of beta-lactam heteroresistance in CRE suggests a stage in the spectrum of antibiotic resistance

2020 ◽  
Author(s):  
Victor I. Band ◽  
David S. Weiss
Keyword(s):  
Antibiotic Resistance ◽  
Resistance Gene ◽  
Bacterial Population ◽  
Antibiotic Usage ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Carbapenem Resistant ◽  
Major Shift ◽  
Resistant Cells

AbstractAntibiotic resistance is a growing crisis that threatens many aspects of modern healthcare. Dogma is that resistance often develops due to acquisition of a resistance gene or mutation, and that when this occurs, all the cells in the bacterial population are phenotypically resistant which we term “homogenous resistance”. In contrast, heteroresistance (HR) is a form of antibiotic resistance where only a subset of cells within a bacterial population are resistant to a given drug. These resistant cells can rapidly replicate in the presence of the antibiotic and cause treatment failures. If and how HR and homogenous resistance are related is unclear. Using carbapenem-resistant Enterobacterales (CRE), we show that HR to beta-lactams develops over years of antibiotic usage and that it is gradually supplanted by homogenous resistance. This suggests the possibility that HR may often develop before homogenous resistance and frequently be a stage in its progression, representing a major shift in our understanding of the evolution of antibiotic resistance.

scholarly journals Heteroresistance to beta-lactam antibiotics may often be a stage in the progression to antibiotic resistance

PLoS Biology ◽  
2021 ◽  
Vol 19 (7) ◽  
pp. e3001346
Author(s):  
Victor I. Band ◽  
David S. Weiss
Keyword(s):  
Antibiotic Resistance ◽  
Resistance Gene ◽  
Bacterial Population ◽  
Antibiotic Usage ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Beta Lactam Antibiotics ◽  
Carbapenem Resistant ◽  
Major Shift ◽  
Resistant Cells

Antibiotic resistance is a growing crisis that threatens many aspects of modern healthcare. Dogma is that resistance often develops due to acquisition of a resistance gene or mutation and that when this occurs, all the cells in the bacterial population are phenotypically resistant. In contrast, heteroresistance (HR) is a form of antibiotic resistance where only a subset of cells within a bacterial population are resistant to a given drug. These resistant cells can rapidly replicate in the presence of the antibiotic and cause treatment failures. If and how HR and resistance are related is unclear. Using carbapenem-resistant Enterobacterales (CRE), we provide evidence that HR to beta-lactams develops over years of antibiotic usage and that it is gradually supplanted by resistance. This suggests the possibility that HR may often develop before resistance and frequently be a stage in its progression, potentially representing a major shift in our understanding of the evolution of antibiotic resistance.

scholarly journals In Vivo Activity of QPX7728, an Ultrabroad-Spectrum Beta-Lactamase Inhibitor, in Combination with Beta-Lactams against Carbapenem-Resistant Klebsiella pneumoniae

2020 ◽  
Vol 64 (11) ◽  
Author(s):  
Mojgan Sabet ◽  
Ziad Tarazi ◽  
David C. Griffith
Keyword(s):  
Klebsiella Pneumoniae ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Bacterial Killing ◽  
Clinical Issue ◽  
Content Type ◽  
Beta Lactam Antibiotics ◽  
Carbapenem Resistant ◽  
Lactamase Inhibitor

ABSTRACT Resistance to beta-lactams has created a major clinical issue. QPX7728 is a novel ultrabroad-spectrum cyclic boronic acid beta-lactamase inhibitor with activity against both serine and metallo-beta-lactamases developed to address this resistance for use in combination with beta-lactam antibiotics. The objective of these studies was to evaluate the activity of QPX7728 in combination with multiple beta-lactams against carbapenem-resistant Klebsiella pneumoniae isolates in a neutropenic mouse thigh infection model. Neutropenic mice were infected with strains with potentiated beta-lactam MICs of ≤2 mg/liter in the presence of 8 mg/liter QPX7728. Two strains of carbapenem-resistant K. pneumoniae were tested with aztreonam, biapenem, cefepime, ceftazidime, ceftolozane, and meropenem alone or in combination with 12.5, 25, or 50 mg/kg of body weight of QPX7728 every 2 hours for 24 hours. Treatment with all beta-lactams alone either was bacteriostatic or allowed for bacterial growth. The combination of QPX7728 plus each of these beta-lactams produced bacterial killing at all QPX7728 doses tested. Overall, these data suggest that QPX7728 administered in combination with different partner beta-lactam antibiotics may have utility in the treatment of bacterial infections due to carbapenem-resistant K. pneumoniae.

scholarly journals Longitudinal assessment of antibiotic resistance gene profiles from the infant gut microbiome

2019 ◽  
Author(s):  
Evelyn Loo ◽  
Amanda Zain ◽  
Gaik Chin Yap ◽  
Rikky W Purbojati ◽  
Daniela I Drautz-Moses ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Cohort Study ◽  
Resistance Gene ◽  
Resistance Genes ◽  
Antibiotic Resistance Gene ◽  
Antibiotic Resistance Genes ◽  
Longitudinal Cohort Study ◽  
First Year ◽  
Beta Lactam ◽  
First Year Of Life

Abstract Background: The rapid spread of multidrug- resistant pathogenic bacteria is a worldwide public health concern. Given the high carriage rate of extended spectrum beta-lactamase (ESBL)- producing Enterobacteriaceae in Asia, we aimed to evaluate community prevalence and dynamics by studying the longitudinal changes in antibiotic resistance gene (ARG) profiles and prevalence of ESBL-producing E coli and K. pneumoniae in the intestinal microbiome of infants participating in the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) study, a longitudinal cohort study of pregnant women and their infants. Methods: We analysed the antibiotic resistance genes profile in the first year of life among 75 infants who had stool samples collected at multiple timepoints using metagenomics. Results: The mean number of ARGs per infant increased with age. The most common ARGs identified confer resistance to aminoglycoside, beta-lactam, macrolide and tetracycline antibiotics; all infants harboured these antibiotic resistance genes at some point in the first year of life. Few ARGs persisted throughout the first year of life. Beta-lactam resistant Escherichia coli and Klebsiella pneumoniae were detected in 4 (5.3%) and 32 (42.7%) of subjects respectively. Conclusion: In this longitudinal cohort study of healthy infants living in a region with high endemic antibacterial resistance, we demonstrate that majority of the infants harboured a number of antibiotic resistance genes in their gut and showed that the infant gut resistome is diverse and dynamic over the first year of life.

scholarly journals Prevalence of Antibiotic Resistance Genes in Air-Conditioning Systems in Hospitals, Farms, and Residences

2019 ◽  
Vol 16 (5) ◽  
pp. 683 ◽  
Author(s):  
Yaying Li ◽  
Hongkai Liao ◽  
Huaiying Yao
Keyword(s):  
Antibiotic Resistance ◽  
Network Analysis ◽  
16S Rrna ◽  
Resistance Gene ◽  
Resistance Genes ◽  
Air Conditioning ◽  
Antibiotic Resistance Gene ◽  
Indoor Environments ◽  
Beta Lactam ◽  
Significant Difference

High-throughput quantitative PCR combined with Illumina sequencing and network analysis were used to characterize the antibiotic resistance gene (ARG) profiles in air-conditioning filters from different environments. In total, 177 ARGs comprising 10 ARG types were determined. The detectable numbers and the relative abundance of ARGs in hospitals and farms were significantly higher than those in city and village residences. Compared to hospitals, farms had a higher level of tetracycline, multidrug, integrase, and macrolide–lincosamide–streptogramin (MLS) B resistance genes but a lower level of beta-lactam resistance genes. The bl3_cpha gene was the most abundant resistance gene subtype in hospital samples with an abundance of 2.01 × 10−4 copies/16S rRNA, while a level of only 5.08 × 10−12 copies/16S rRNA was observed in farm samples. There was no significant difference in bacterial diversity among the hospitals, farms, and residences, and Proteobacteria was the most abundant phylum. Network analysis revealed that Proteobacteria and Actinobacteria were possible hosts of the beta-lactam, MLSB, aminoglycoside, multidrug, sulfonamide, and tetracycline resistance genes. The results demonstrate that ARGs exist in indoor environments and that farms and hospitals are important sources. This study provides a useful reference for understanding the distribution patterns and risk management of ARGs in indoor environments.

scholarly journals Antimicrobial susceptibility of isolates of Salmonella enterica subsp. Enterica isolated in Ukraine during the period of 2014–2017

2020 ◽  
Vol 22 (97) ◽  
pp. 58-68
Author(s):  
N. M. Rublenko ◽  
A. M. Holovko
Keyword(s):  
Antibiotic Resistance ◽  
Side Effects ◽  
Nalidixic Acid ◽  
Antimicrobial Susceptibility ◽  
Salmonella Enterica ◽  
Disc Diffusion ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Upward Trend ◽  
Significant Percentage

The results of the study of sensitivity to antibacterial drugs in isolates of Salmonella enterica isolated from poultry are shown in the article. Antibacterial sensitivity was determined by disc diffusion to such drugs: ampicillin, cefoperazone, ceftriaxone, ceftazidime, tetracycline, doxycycline, streptomycin, gentamicin, nalidixic acid, chloramphenicol, ciprofloxacin, trimethoprim. Growth retardation zones were interpreted according to the CLSI standard. Among the isolates tested, a significant percentage of isolates resistant to nalidixic acid and ciprofloxacin were found – (19 (63.3 %) and – 21 (70 %), respectively. A significant number of isolates were also resistant to beta-lactams. In particular, 37 isolates (64.9 %) were resistant to ceftazidime, and 36 (63.1 %) to ceftriaxone. However, ceftriaxone resistance was dominant among S. typhimurium isolates, whereas in Enteritidis this indicator was significantly lower. However, the highest resistance of the studied isolates were shown to the beta-lactam class – cefoperazone (70.17 %). Only 6 isolates (20 %) were sensitive to nalidixic acid but did not detect any isolates sensitive to ciprofloxacin. This is a significant problem because quinolones are used to treat invasive salmonellosis. In this study, 12 (40 %) isolates were sensitive to ampicillin, 9 (30 %) to cefoperazone, 10 (33.3 %) to ceftriaxone and 9 (30 %) to ceftazidime. The lowest number of strains was resistant to trimethoprim – 9 (30 %) and chloramphenicol – 8 (26.6 %). Unfortunately, the use of the latter is limited due to the possibility of serious side effects. Overall, the group of poultry isolates tested reflects a general upward trend in antibiotic resistance. The findings present new data on resistance and provide prospects for further studies on this aspect of salmonellosis.

scholarly journals Stochastic bacterial population dynamics prevent the emergence of antibiotic resistance from single cells

2018 ◽  
Author(s):  
Helen K. Alexander ◽  
R. Craig MacLean
Keyword(s):  
Antibiotic Resistance ◽  
Single Cell ◽  
Bacterial Population ◽  
De Novo ◽  
Single Cells ◽  
Mutant Selection ◽  
Selection Window ◽  
Low Probability ◽  
Emergence Of Resistance ◽  
Resistant Cells

AbstractA better understanding of how antibiotic exposure impacts the evolution of resistance is crucial for designing more sustainable treatment strategies. The conventional approach to relating antibiotic dose to resistance evolution within a bacterial population is to measure the range of concentrations over which resistant strain(s) are selectively favoured over a sensitive strain – the “mutant selection window”. Here, we instead investigate how antibiotic concentration impacts the initial establishment of resistance from single cells, mimicking the clonal expansion of a resistant lineage following mutation or horizontal gene transfer. Using two Pseudomonas aeruginosa strains carrying distinct resistance plasmids, we show that single resistant cells have <5% probability of outgrowth at antibiotic concentrations as low as 1/8th of the resistant strain’s minimum inhibitory concentration. This low probability of establishment is due to detrimental effects of antibiotics on resistant cells, coupled with the inherently stochastic nature of cell division and death on the single-cell level, which leads to loss of many nascent resistant lineages. Our findings suggest that moderate doses of antibiotics, within the traditional mutant selection window, may be more effective at preventing de novo emergence of resistance than predicted by deterministic approaches.Significance statementThe emergence of antibiotic resistance poses a critical threat to the efficacy of antibiotic treatments. A resistant bacterial population must originally arise from a single cell that mutates or acquires a resistance gene. This single cell may, by chance, fail to successfully reproduce before it dies, leading to loss of the nascent resistant lineage. Here we show that antibiotic concentrations that selectively favour resistance are nonetheless sufficient to reduce the chance of outgrowth from a single cell to a very low probability. Our findings suggest that lower antibiotic concentrations than previously thought may be sufficient to prevent, with high probability, emergence of resistance from single cells.

scholarly journals 1451. Genetic Analysis of Antibiotic Resistance Profiles of Acinetobacter baumannii Using Whole Genome Sequencing

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S728-S728
Author(s):  
Matthew Brigmon ◽  
Chetan Jinadatha ◽  
Hosoon Choi ◽  
Keith S Kaye ◽  
Yonhui Allton ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Resistance Gene ◽  
Resistance Genes ◽  
Antibiotic Resistance Gene ◽  
Whole Genome ◽  
Department Of Veterans Affairs ◽  
Beta Lactams ◽  
Antibiotic Resistant ◽  
Gene Profiles ◽  
Research Grant

Abstract Background Acinetobacter is known to quickly develop resistance to commonly used antibiotics. Previously we performed whole genome sequencing (WGS) and whole genome multilocus sequence typing (wgMLST) analysis in clinical Acinetobacter isolates to determine sequence types (ST) of these isolates and mapped their distribution. In this study, we sought to characterize the genetic antibiotic resistance patterns in these isolates. Methods Sixty-two clinical Acinetobacter isolates collected in two distinct large tertiary care hospitals in Detroit were analyzed. The samples were subjected to WGS using the NextSeq instrument (Illumina). The contigs were de novo assembled using SPAdes (v3.7.1) and wgMLST analysis was performed using BioNumerics software v7.6. The genomic sequence for each isolate was uploaded in ResFinder 3.2 and known antibiotic resistance genes were analyzed. Results The most common resistance gene found is blaADC-25 conferring resistance to beta-lactams across all STs. Sulfonamide (sul1) and macrolide resistance (mphE/msrE) among STs were also common. ST2 (52%) was predominant for both hospitals (H1 and H2). ST2 in H2 exhibited the presence of the maximum number of resistance genes including resistance to aminoglycosides, macrolides (2), tetracyclines (tetB), beta-lactams, fluoroquinolones (aac(6’)-Ib-cr), sulphonamides (sul1, sul2). ST2 had a slightly different resistance profile of beta-lactams in H1 when compared to H2. ST406 and ST15 exhibited similar antibiotic profiles in both hospitals and a single isolate of ST20 from H2 is highly antibiotic resistant. Table 1. Antimicrobial Drug Resistance Profiles of all Acinetobacter Sequence Types (STs) in H1 and H2. Table 2. Antibiotic Resistance Gene Profiles of Sequence Type 2 (ST2) isolates in H1 and H2. Conclusion This study provides us with a snapshot of antibiotic resistant genes among circulating Acinetobacter isolates prevalent in an area. All hospital isolates demonstrated resistance to beta-lactams. Multidrug resistant ST2 isolates from both hospitals demonstrate similar antibiotic resistance gene profiles suggesting a common circulating strain in the area. No colistin resistance genes were detected in any isolates. Because Acinetobacter infections are predominantly hospital acquired, it is important to continually monitor resistance profiles to determine the trends that may better serve both the patients and infection control practices. Disclosures Chetan Jinadatha, MD, MPH, AHRQ (Research Grant or Support)Department of Veterans Affairs (Other Financial or Material Support, Owner: Department of Veterans Affairs. Licensed to: Xenex Disinfection System, San Antonio, TX)Inventor (Other Financial or Material Support, Methods for organizing the disinfection of one or more items contaminated with biological agents)NiH/NINR (Research Grant or Support)NSF (Research Grant or Support)Xenex Healthcare Services (Research Grant or Support)

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