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

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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Life in a Droplet: Microbial Ecology in Microscopic Surface Wetness

Frontiers in Microbiology ◽

10.3389/fmicb.2021.655459 ◽

2021 ◽

Vol 12 ◽

Author(s):

Tomer Orevi ◽

Nadav Kashtan

Keyword(s):

Microbial Ecology ◽

Response Competition ◽

Genetic Material ◽

Liquid Films ◽

Bulk Liquid ◽

Specific Level ◽

Surface Wetness ◽

Microbial Life ◽

Antibiotic Response ◽

Microscopic Surface

While many natural and artificial surfaces may appear dry, they are in fact covered by thin liquid films and microdroplets invisible to the naked eye known as microscopic surface wetness (MSW). Central to the formation and the retention of MSW are the deliquescent properties of hygroscopic salts that prevent complete drying of wet surfaces or that drive the absorption of water until dissolution when the relative humidity is above a salt-specific level. As salts are ubiquitous, MSW occurs in many microbial habitats, such as soil, rocks, plant leaf, and root surfaces, the built environment, and human and animal skin. While key properties of MSW, including very high salinity and segregation into droplets, greatly affect microbial life therein, it has been scarcely studied, and systematic studies are only in their beginnings. Based on recent findings, we propose that the harsh micro-environment that MSW imposes, which is very different from bulk liquid, affects key aspects of bacterial ecology including survival traits, antibiotic response, competition, motility, communication, and exchange of genetic material. Further research is required to uncover the fundamental principles that govern microbial life and ecology in MSW. Such research will require multidisciplinary science cutting across biology, physics, and chemistry, while incorporating approaches from microbiology, genomics, microscopy, and computational modeling. The results of such research will be critical to understand microbial ecology in vast terrestrial habitats, affecting global biogeochemical cycles, as well as plant, animal, and human health.

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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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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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Biochemical profile and resistance phenotype of bacteria isolated from the operating site departments of the National Reference University Hospital of N’Djamena

World Journal of Advanced Research and Reviews ◽

10.30574/wjarr.2021.10.1.0189 ◽

2021 ◽

Vol 10 (1) ◽

pp. 381-396

Author(s):

Bessimbaye Nadlaou ◽

Djimadoum Mbanga ◽

Issakou Bakarnga-Via ◽

Claude Oualé ◽

Nicolas Barro ◽

...

Keyword(s):

Average Rate ◽

University Hospital ◽

Beta Lactam ◽

Beta Lactams ◽

Surgical Services ◽

National Reference ◽

Beta Lactam Antibiotics ◽

Medical Microbiology ◽

Normal Period ◽

Staphylococcus Spp

The aim is to assess the level of contamination of wound bacteria in operated patients in the surgical departments of the National Reference University Hospital (CHURN) of N’Djamena. From August 1, 2018 to August 1, 2019, an observational culture study on wound pus was carried out in patients operated on from the surgical services of the N’Djamena CHURN according to standard methods of medical microbiology. Of the 1092 patients operated on, 565 patients were released within a normal period of hospitalization and 527 in contact with the pathogens were maintained. Significant differences were observed between the proportions of positive (86%) and sterile (14%) cultures; female (30.36%) and male (69.63%) operated subjects with probabilities of 0.02 and 0.001 respectively. Escherichia coli were the most common germs (32.7%), followed by Staphylococcus spp (20.9%). The bacteria isolated were resistant to beta-lactam antibiotics at an average rate of 40%, only imipenem, a last-resort antibiotic, was very sensitive (99.5%). In view of these results, we recommend that prescribers avoid prescribing antibiotics without laboratory evidence for fear of losing the beta-lactams permanently.

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The Ultra-Broad-Spectrum Beta-lactamase Inhibitor QPX7728 Restores the Potency of Multiple Oral Beta-lactam Antibiotics against Beta-lactamase Producing Strains of Resistant Enterobacterales

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02168-21 ◽

2021 ◽

Author(s):

Olga Lomovskaya ◽

Debora Rubio-Aparicio ◽

Ruslan Tsivkovski ◽

Jeff Loutit ◽

Michael Dudley

Keyword(s):

Broad Spectrum ◽

Resistance Mechanisms ◽

Beta Lactamase ◽

Beta Lactam ◽

Beta Lactams ◽

Intrinsic Resistance ◽

Beta Lactamases ◽

Beta Lactam Antibiotics ◽

The Impact ◽

Lactamase Inhibitor

QPX7728 is a cyclic boronate ultra-broad-spectrum beta-lactamase inhibitor, with potent activity against both serine and metallo beta-lactamases. QPX7728 can be delivered systemically by the IV or oral route of administration. Oral β-lactam antibiotics alone or in combination with QPX7728 were evaluated for 1) sensitivity to hydrolysis by various common beta-lactamases and inhibition of hydrolysis by QPX7728; 2) the impact of non-beta-lactamase-mediated resistance mechanisms on potency of beta-lactams; and 3) in vitro activity against a panel of clinical strains producing diverse beta-lactamases. The carbapenem tebipenem had stability for many serine beta-lactamases from all molecular classes followed by cephalosporin ceftibuten. Addition of QPX7728 to tebipenem, ceftibuten and mecillinam completely reversed beta-lactamase-mediated resistance in cloned beta-lactamases from serine and metallo enzyme classes; the degree of potentiation of other beta-lactams varied according to the beta-lactamase produced. Tebipenem, ceftibuten and cefixime had the lowest MICs against laboratory strains with various combinations of beta-lactamases and the intrinsic drug-resistance mechanisms of porin and efflux mutations. There was a high degree of correlation between potency of various combinations against cloned beta-lactamases and efflux/porin mutants and the activity against clinical isolates, showing the importance of both inhibition of beta-lactamase along with minimal impact of general intrinsic resistance mechanisms affecting the beta-lactam. Tebipenem and ceftibuten appeared to be the best beta-lactam antibiotics when combined with QPX7728 for activity against Enterobacterales that produce serine or metallo beta-lactamases.

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Safety of intravenous push administration of beta-lactams within a healthcare system

American Journal of Health-System Pharmacy ◽

10.1093/ajhp/zxaa044 ◽

2020 ◽

Vol 77 (9) ◽

pp. 701-708 ◽

Cited By ~ 1

Author(s):

Kassandra Marsh ◽

Nabeela Ahmed ◽

Arnold Decano ◽

Yanina Dubrovskaya ◽

Shin-Pung (Polly) Jen ◽

...

Keyword(s):

New York ◽

Small Volume ◽

Beta Lactam ◽

New York University ◽

Beta Lactams ◽

Drug Shortage ◽

Surgical Prophylaxis ◽

Future Studies ◽

Beta Lactam Antibiotics ◽

Critical Patients

Abstract Purpose A critical shortage of small-volume parenteral solutions in late 2017 led hospitals to develop strategies to ensure availability for critical patients, including administration of antibiotics as intravenous push (IVP). Minimal literature has been published to date that assesses the safety of administration of beta-lactams via this route. Therefore, the purpose of this study was to evaluate the safety of IVP administration of select beta-lactam antibiotics. Methods We performed a retrospective review of IVP administrations of aztreonam, ceftriaxone, cefepime, and meropenem at two campuses of the New York University Langone Health system after October 2017. Patients receiving surgical prophylaxis or more than one IVP antibiotic simultaneously were excluded. The primary endpoint was adverse events (ADE) following IVP administration of antibiotics. Results We evaluated 1000 patients who received IVP aztreonam (n = 43), ceftriaxone (n = 544), cefepime (n = 368) or meropenem (n = 45). There were 10 (1%) ADE observed, 5 of which were allergic reactions. Four ADE were neurotoxicity related to IVP cefepime. Based on the Naranjo score, 1 adverse event was “probably” and 3 were “possibly” related to cefepime IVP administration. Lastly, only 1 report of phlebitis was observed with the use of IVP ceftriaxone. Conclusions The use of IVP as an alternative to intravenous piggyback (IVPB) during times of drug shortage for select beta-lactam antibiotics appears to be safe, and ADE are similar to those previously described for IVPB administration. Future studies evaluating clinical outcomes between IVP and IVPB administration may be of benefit.

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Correlation of pharmacodynamic parameters of five beta-lactam antibiotics with therapeutic efficacies in an animal model.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.12.2686 ◽

1996 ◽

Vol 40 (12) ◽

pp. 2686-2690 ◽

Cited By ~ 36

Author(s):

F Soriano ◽

P García-Corbeira ◽

C Ponte ◽

R Fernández-Roblas ◽

I Gadea

Keyword(s):

Linear Regression Analysis ◽

Inoculum Size ◽

Beta Lactam ◽

Beta Lactams ◽

Time Curve ◽

Beta Lactam Antibiotics ◽

Concentration Time ◽

Intraperitoneal Infection ◽

Different Doses

The MIC is the main microbiologic parameter used to predict the efficacies of antibiotics. However, it is well known that MICs may vary according to the inoculum size used (inoculum effect), especially with some beta-lactam antibiotics. In order to correlate the pharmacologic and microbiologic properties of some beta-lactams, an experimental model of intraperitoneal infection caused by Escherichia coli in nonneutropenic and neutro-penic mice was developed. The animals were treated with three different doses of either ampicillin, piperacillin, aztreonam, cefazolin, or cefotaxime. The linear regression analysis obtained in our model shows a better correlation between in vitro activity and efficacy when the MICs considered were those obtained with a large inoculum (ca. 1 x 10(8) CFU/ml) instead of the standard inoculum (5 x 10(5) CFU/ml). The correlations for the MICs obtained with the large inoculum were 0.78 for log2 maximum concentration of drug in serum (Cmax)/ MIC, 0.72 the time that the concentrations exceeded the MIC, and 0.79 for log2 area under the serum concentration-time curve (AUC)/MIC at 24 h in nonneutropenic mice. The corresponding values in neutropenic mice, also for the MICs obtained with the large inoculum, were 0.54, 0.68, and 0.64, respectively, at 24 h. A good correlation was also obtained for the same parameters in nonneutropenic mice at 48 h. The values of Cmax, AUC, and the time that the concentrations exceeded the MIC were parallel among the antibiotics studied, and our study confirms that the time that the levels in serum exceed the MIC is a significant parameter determining the efficacies of beta-lactam antibiotics, but the correlation is much better when the MICs obtained with the large inoculum instead of those obtained with the standard (low) inoculum are considered.

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Hematological Effects Associated with Beta-Lactam Use

Drug Intelligence & Clinical Pharmacy ◽

10.1177/106002808602001101 ◽

1986 ◽

Vol 20 (11) ◽

pp. 833-836 ◽

Cited By ~ 4

Author(s):

Lesia M. Babiak ◽

Michael J. Rybak

Keyword(s):

Coagulation Cascade ◽

Close Monitoring ◽

Beta Lactam ◽

Beta Lactams ◽

Drug Induced ◽

Antimicrobial Spectrum ◽

Beta Lactam Antibiotics ◽

Normal Platelet ◽

Hematological Effects ◽

Life Threatening

Beta-lactam antibiotics have continued to be the mainstay of antiinfective treatment. Newer agents, such as the third-generation cephalosporins or ureidopenicillins, have the advantage of a broader antimicrobial spectrum and improved pharmacokinetics. The beta-lactams are often promoted as alternatives to more toxic antibiotic regimens. However, several of the beta-lactams have been shown to produce hematological effects, some of which can be life threatening. The primary hematological effects appear to be inhibition of normal platelet function and the coagulation cascade, which is reflected by changes in bleeding times and increases in prothrombin time and activated partial thromboplastin time, respectively. Although not all patients will develop bleeding problems associated with these agents, close monitoring of patients with risk factors for bleeding and dosage adjustments may help to avert these drug-induced hematological problems.

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