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

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.

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

10.1101/2020.09.19.304873 ◽

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.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01267-20 ◽

2020 ◽

Vol 64 (11) ◽

Cited By ~ 1

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.

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Growing Menace of Antibacterial Resistance in Clinical Isolates ofPseudomonas aeruginosain Nepal: An Insight of Beta-Lactamase Production

BioMed Research International ◽

10.1155/2016/6437208 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Shamshul Ansari ◽

Rabindra Dhital ◽

Sony Shrestha ◽

Sangita Thapa ◽

Ram Puri ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Antibiotic Resistance ◽

Opportunistic Pathogen ◽

Resistance Rate ◽

Diffusion Method ◽

Beta Lactamase ◽

Beta Lactam ◽

Beta Lactam Antibiotics ◽

Microbiological Methods ◽

Immunosuppressed Patients

Introduction. Pseudomonas aeruginosais the most frequently isolated organism as it acts as the opportunistic pathogen and can cause infections in immunosuppressed patients. The production of different types of beta-lactamases renders this organism resistant to many commonly used antimicrobials. Therefore, the aim of this study was to document the antibiotic resistance rate inPseudomonas aeruginosaisolated from different clinical specimens.Methods. Pseudomonas aeruginosarecovered was identified by standard microbiological methods. Antibiotic susceptibility testing was performed by modified Kirby-Bauer disc diffusion method following Clinical and Laboratory Standard Institute (CLSI) guidelines and all the suspected isolates were tested for the production of ESBLs, MBLs, and AmpC.Results.Out of total (178) isolates, 83.1% were recovered from the inpatient department (IPD). Majority of the isolates mediated resistance towards the beta-lactam antibiotics, while nearly half of the isolates were resistant to ciprofloxacin. Most of the aminoglycosides used showed resistance rate up to 75% but amikacin proved to be better option. No resistance to polymyxin was observed. ESBLs, MBLs, and AmpC mediated resistance was seen in 33.1%, 30.9%, and 15.7% isolates, respectively.Conclusions. Antibiotic resistance rate and beta-lactamase mediated resistance were high. Thus, regular surveillance of drug resistance is of utmost importance.

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Inherent protection of bacteria from beta-lactam antibiotics by wet-dry cycles with microscopic surface wetness

10.1101/2020.11.09.373787 ◽

2020 ◽

Author(s):

Yana Beizman-Magen ◽

Maor Grinberg ◽

Tomer Orevi ◽

Nadav Kashtan

Keyword(s):

Model Organism ◽

Liquid Films ◽

Interspecies Interactions ◽

Beta Lactam ◽

Beta Lactams ◽

Surface Wetness ◽

Beta Lactam Antibiotics ◽

Hygroscopic Salts ◽

Antibiotic Response ◽

Microscopic Surface

AbstractA large portion of bacterial life occurs on surfaces that are not constantly saturated with water and experience recurrent wet-dry cycles. While soil, plant leaves and roots, and many indoor surfaces may appear dry when not saturated with water, they are in fact often covered by thin liquid films and microdroplets, invisible to the naked eye, known as microscopic surface wetness (MSW). Such MSW, resulting from the condensation of water vapor to hygroscopic salts, is ubiquitous yet largely underexplored. A wide variety of antibiotics are abundant in environments where MSW occurs, yet little is known about bacterial response to antibiotics in wet-dry cycles and under MSW conditions. Using E. coli as a model organism, we show, through a combination of experiments and computational modeling, that bacteria are considerably more protected from beta-lactams under wet-dry cycles with MSW phases, than they are under constantly wet conditions. This is due to the combined effect of several mechanisms, including tolerance triggered by inherent properties of MSW, i.e., high salt concentrations and slow cell growth, and the deactivation of antibiotics due to physicochemical properties of MSW. Remarkably, we also find evidence for a cross-protection effect, where addition of lethal doses of antibiotic before drying significantly increases cells’ survival under MSW. As wet-dry cycles with MSW and beta-lactams, as well as other antibiotics, are common in vast terrestrial microbial habitats, our findings are expected to have significant implications for how we understand antibiotic response, population dynamics, and interspecies interactions in these globally important microbial ecosystems.

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Molecular Detection of Carbapenem Resistant Gram Negative Bacterial Isolates from Dogs

Indian Journal of Animal Research ◽

10.18805/ijar.b-4297 ◽

2021 ◽

Author(s):

Surya Sankar ◽

Thresia . ◽

Anu Bosewell ◽

M. Mini

Keyword(s):

Companion Animals ◽

Multidrug Resistant ◽

Beta Lactam ◽

Gram Negative ◽

Extended Spectrum Beta Lactamase ◽

Beta Lactam Antibiotics ◽

Carbapenem Resistant ◽

Carbapenemase Gene ◽

Line Of Therapy ◽

Encoding Genes

Background: Carbapenems are beta-lactam antibiotics that are considered as the last line of therapy against multidrug resistant extended spectrum beta-lactamase. The resistance to carbapenems predominantly through carbapenemase is one of the most important emerging health problems worldwide in the therapy of clinical infections. The objective of the present study is to determine the presence of carbapenemase encoding genes among Gram- negative bacterial spp. associated with clinical infections in dogs. Methods: 30 Escherichia coli, 11 Klebsiella pneumoniae and three Pseudomonas aeruginosa isolated from urine, swabs from lesional skin and anterior vagina of dogs presented with different clinical ailments formed the samples for the study. Polymerase chain reaction was carried out to detect the presence of carbapenemase encoding genes viz., KPC, NDM, OXA, VIM and IMP among the isolates.Result: Out of the 44 Gram- negative isolates tested, 28 (76.3%) were positive for at least one tested carbapenemase gene. The highest frequency of carbapenemase recorded was for NDM followed by OXA-181, KPC, OXA-48 and VIM. Our study identified a high prevalence of carbapenemases among companion animals like dogs which could act as potential source of transmission of these resistance bacteria or their genomes to humans.

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Full-Genome Sequencing Identifies in the Genetic Background Several Determinants That Modulate the Resistance Phenotype in Methicillin-Resistant Staphylococcus aureus Strains Carrying the Novel mecC Gene

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02500-16 ◽

2017 ◽

Vol 61 (3) ◽

Cited By ~ 9

Author(s):

Catarina Milheiriço ◽

Hermínia de Lencastre ◽

Alexander Tomasz

Keyword(s):

Staphylococcus Aureus ◽

Antibiotic Resistance ◽

Genetic Background ◽

Beta Lactam ◽

Methicillin Resistant ◽

Content Type ◽

Resistance Phenotype ◽

Beta Lactam Antibiotics ◽

Oxacillin Resistance ◽

Mrsa Strains

ABSTRACT Most methicillin-resistant Staphylococcus aureus (MRSA) strains are resistant to beta-lactam antibiotics due to the presence of the mecA gene, encoding an extra penicillin-binding protein (PBP2A) that has low affinity for virtually all beta-lactam antibiotics. Recently, a new resistance determinant—the mecC gene—was identified in S. aureus isolates recovered from humans and dairy cattle. Although having typically low MICs to beta-lactam antibiotics, MRSA strains with the mecC determinant are also capable of expressing high levels of oxacillin resistance when in an optimal genetic background. In order to test the impact of extensive beta-lactam selection on the emergence of mecC-carrying strains with high levels of antibiotic resistance, we exposed the prototype mecC-carrying MRSA strain, LGA251, to increasing concentrations of oxacillin. LGA251 was able to rapidly adapt to high concentrations of oxacillin in growth medium. In such laboratory mutants with increased levels of oxacillin resistance, we identified mutations in genes with no relationship to the mecC regulatory system, indicating that the genetic background plays an important role in the establishment of the levels of oxacillin resistance. Our data also indicate that the stringent stress response plays a critical role in the beta-lactam antibiotic resistance phenotype of MRSA strains carrying the mecC determinant.

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Studies on monocyclic .BETA.-lactam antibiotics. Part I. Synthesis of 4-substituted monocyclic .BETA.-lactams by a lewis acid-mediated reaction.

Agricultural and Biological Chemistry ◽

10.1271/bbb1961.50.839 ◽

1986 ◽

Vol 50 (4) ◽

pp. 839-846

Author(s):

Chosaku YOSHIDA ◽

Takako HORI ◽

Kaishu MOMONOI ◽

Kiyoshi TANAKA ◽

Sumiko KISHIMOTO ◽

...

Keyword(s):

Lewis Acid ◽

Beta Lactam ◽

Beta Lactams ◽

Beta Lactam Antibiotics

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Beta-Lactam Hypersensitivity and Cross-Reactivity

Journal of Pharmacy Practice ◽

10.1177/0897190014546109 ◽

2014 ◽

Vol 27 (6) ◽

pp. 530-544 ◽

Cited By ~ 27

Author(s):

Adrienne T. Terico ◽

Jason C. Gallagher

Keyword(s):

Retrospective Studies ◽

Immunoglobulin E ◽

Cross Reactivity ◽

Side Chains ◽

Beta Lactam ◽

Beta Lactams ◽

Medline Search ◽

Beta Lactam Antibiotics ◽

Drug Classes

Penicillin is the most frequently reported cause of drug allergy, and cross-reactivity of penicillins with other beta-lactam antibiotics is an area of debate. This review evaluates the available data on immunoglobulin E-mediated penicillin hypersensitivity and cross-reactivity with cephalosporin, carbapenem, and monobactam antibiotics. A MEDLINE search was conducted from 1950 to October 2013, and selected references from review articles were also evaluated. There is a wide variety in reported incidences of cross-reactivity between penicillins and cephalosporins or carbapenems, with early retrospective studies suggesting up to 41.7% and 47.4% cross-reactivity, respectively. Conversely, the use of monobactam antibiotics is frequently employed in the case of a penicillin allergy, as prescribers believe that there is no cross-reactivity between the 2 drug classes. More recent prospective studies suggest that the rates of cross-reactivity with cephalosporins and carbapenems are <5% and <1%, respectively. Similarities in penicillin and cephalosporin side chains may play a role in cross-reactivity between these classes. Cross-reactivity with monobactams is essentially negligible; however, there are some clinical data to support an interaction between ceftazidime and aztreonam, due to the similarity of their side chains. The data reviewed suggest that avoidance of other beta-lactams in patients with type 1 hypersensitivity to penicillins should be reconsidered.

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Morphological deconvolution of beta-lactam polyspecificity inE. coli

10.1101/545335 ◽

2019 ◽

Author(s):

William J. Godinez ◽

Helen Chan ◽

Imtiaz Hossain ◽

Cindy Li ◽

Srijan Ranjitkar ◽

...

Keyword(s):

Ex Situ ◽

Exact Nature ◽

Enzyme Specificity ◽

Beta Lactam ◽

Beta Lactams ◽

Penicillin Binding Proteins ◽

E Coli ◽

Beta Lactam Antibiotics ◽

Cell Extracts ◽

The Family

AbstractBeta-lactam antibiotics comprise one of the earliest known classes of antibiotic therapies. These molsecules covalently inhibit enzymes from the family of penicillin-binding proteins, which are essential to the construction of the bacterial cell wall. As a result, beta-lactams have long been known to cause striking changes to cellular morphology. The exact nature of the changes tend to vary by the precise PBPs engaged in the cell since beta-lactams exhibit a range of PBP enzyme specificity. The traditional method for exploring beta-lactam polyspecificity is a gel-based binding assay which is low-throughput and typically runex situin cell extracts. Here, we describe a medium-throughput, image-based assay combined with machine learning methods to automatically profile the activity of beta-lactams inE. colicells. By testing for morphological change across a panel of strains with perturbations to individual PBP enzymes, our approach automatically and quantifiably relates different beta-lactam antibiotics according to their preferences for individual PBPs in cells. We show the potential of our approach for guiding the design of novel inhibitors towards different PBP-binding profiles by recapitulating the activity of two recently-reported PBP inhibitors.

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

10.21203/rs.2.18486/v1 ◽

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.

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