Publications by authors named "Michael R Jacobs"

243 Publications

Feasibility of Using Daily Home High-Flow Nasal Therapy in COPD Patients Following a Recent COPD Hospitalization.

Chronic Obstr Pulm Dis 2021 Nov 4. Epub 2021 Nov 4.

Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, United States.

Rationale: High-flow nasal therapy (HFNT) has beneficial effects in patients hospitalized with acute hypoxemic respiratory failure. HFNT has not been extensively studied following hospitalization for an Acute Exacerbation of COPD (AECOPD).

Objective: We explored the feasibility of conducting a multicentered trial to evaluate the use of HFNT to increase the time to next moderate/ severe exacerbation in patients recently hospitalized for a COPD exacerbation. In this pilot study we measured the hours of home daily HFNT use, maximally tolerated flow rates and temperature, and side effects for a period of 90 days.

Methods: Patients were enrolled in a 90-day open-labeled pilot study of HFNT to determine the safety and feasibility of home use for daily outpatient COPD management. Patients ≥ 40 years of age with prior hospitalization within the past 12 weeks for an acute COPD exacerbation were enrolled. COPD as the primary diagnosis in all patients.

Results: Thirty patients presented for HFNT titration. Two dropped out; one after receiving a lung transplant and the other was lost to follow-up. The remaining 28 patients completed 90 days of HFNT. None withdrew from HFNT due to intolerance. Use of HFNT averaged 6.8 (2.1) hours daily.

Conclusions: Daily home HFNT for up to three months is feasible in COPD patients following hospitalization for an acute exacerbation. Improvements observed in disease specific quality of life, respiratory symptoms and 6 MWD suggest the need for a prospective multicenter controlled clinical trial.
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http://dx.doi.org/10.15326/jcopdf.2021.0236DOI Listing
November 2021

: intriguing aerotolerant gut anaerobe with emerging antimicrobial resistance and pathogenic and probiotic roles in human health.

Gut Microbes 2021 Jan-Dec;13(1):1922241

Digestive Diseases Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.

is the type strain for the genus , a group of gram-negative anaerobic bacteria that commonly colonize the gastrointestinal tract of numerous species. First isolated in the 1930s from a clinical specimen as , the strain was re-classified to form the new genus in 2006. Currently, the genus consists of 15 species, 10 of which are listed as 'validly named' (, and ) and 5 'not validly named' (, and ) by the List of Prokaryotic names with Standing in Nomenclature. The genus has been associated with reports of both beneficial and pathogenic effects in human health. Herein, we review the literature on the history, ecology, diseases, antimicrobial resistance, and genetics of this bacterium, illustrating the effects of on human and animal health.
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http://dx.doi.org/10.1080/19490976.2021.1922241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253142PMC
January 2022

A γ-lactam siderophore antibiotic effective against multidrug-resistant Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter spp.

Eur J Med Chem 2021 Aug 8;220:113436. Epub 2021 Apr 8.

Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH, 44106, USA; Department of Biochemistry, Case Western Reserve University, Cleveland, OH, 44106, USA; Department of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA; Geriatric Research, Education and Clinical Center, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH, 44106, USA; Departments of Pharmacology, Molecular Biology & Microbiology, And Proteomics & Bioinformatics, Case Western Reserve University, Cleveland, OH, 44106, USA; CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, OH, 44106, USA. Electronic address:

Serious infections caused by multidrug-resistant (MDR) organisms (Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii) present a critical need for innovative drug development. Herein, we describe the preclinical evaluation of YU253911, 2, a novel γ-lactam siderophore antibiotic with potent antimicrobial activity against MDR Gram-negative pathogens. Penicillin-binding protein (PBP) 3 was shown to be a target of 2 using a binding assay with purified P. aeruginosa PBP3. The specific binding interactions with P. aeruginosa were further characterized with a high-resolution (2.0 Å) X-ray structure of the compound's acylation product in P. aeruginosa PBP3. Compound 2 was shown to have a concentration >1 μg/ml at the 6 h time point when administered intravenously or subcutaneously in mice. Employing a meropenem resistant strain of P. aeruginosa, 2 was shown to have dose-dependent efficacy at 50 and 100 mg/kg q6h dosing in a mouse thigh infection model. Lastly, we showed that a novel γ-lactam and β-lactamase inhibitor (BLI) combination can effectively lower minimum inhibitory concentrations (MICs) against carbapenem resistant Acinetobacter spp. that demonstrated decreased susceptibility to 2 alone.
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http://dx.doi.org/10.1016/j.ejmech.2021.113436DOI Listing
August 2021

Recent advances in rapid antimicrobial susceptibility testing systems.

Expert Rev Mol Diagn 2021 Jun 20;21(6):563-578. Epub 2021 May 20.

Section Head of Microbiology, Robert J. Tomsich Pathology & Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.

Introduction: Until recently antimicrobial susceptibility testing (AST) methods based on the demonstration of phenotypic susceptibility in 16-24 h remained largely unchanged.

Areas Covered: Advances in rapid phenotypic and molecular-based AST systems.

Expert Opinion: AST has changed over the past decade, with many rapid phenotypic and molecular methods developed to demonstrate phenotypic or genotypic resistance, or biochemical markers of resistance such as β-lactamases associated with carbapenem resistance. Most methods still require isolation of bacteria from specimens before both legacy and newer methods can be used. Bacterial identification by MALDI-TOF mass spectroscopy is now widely used and is often key to the interpretation of rapid AST results. Several PCR arrays are available to detect the most frequent pathogens associated with bloodstream infections and their major antimicrobial resistance genes. Many advances in whole-genome sequencing of bacteria and fungi isolated by culture as well as directly from clinical specimens have been made but are not yet widely available. High cost and limited throughput are the major obstacles to uptake of rapid methods, but targeted use, continued development and decreasing costs are expected to result in more extensive use of these increasingly useful methods.
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http://dx.doi.org/10.1080/14737159.2021.1924679DOI Listing
June 2021

Detection of mcr-1 gene in a clinical Escherichia coli strain in North Carolina: first report.

J Glob Antimicrob Resist 2021 06 28;25:154-156. Epub 2021 Mar 28.

Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jgar.2021.03.014DOI Listing
June 2021

The Mechanisms of Benefit of High-Flow Nasal Therapy in Stable COPD.

J Clin Med 2020 Nov 26;9(12). Epub 2020 Nov 26.

Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.

High-flow nasal therapy (HFNT) is a unique system that delivers humidified, heated oxygen-enriched air via nasal cannula at high flow rates. It is a promising therapy for chronic obstructive pulmonary disease (COPD) patients. Several studies have examined the physiologic effects of this therapy in the patient population and have revealed that it improves mucociliary clearance, reduces nasopharyngeal dead space, and subsequently increases CO washout. It also improves alveolar recruitment and gas exchange. These mechanisms may explain the promising results observed in recently published studies that examined the role of HFNT in stable COPD patients.
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http://dx.doi.org/10.3390/jcm9123832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760186PMC
November 2020

Co-Morbidity Patterns Identified Using Latent Class Analysis of Medications Predict All-Cause Mortality Independent of Other Known Risk Factors: The COPDGene Study.

Clin Epidemiol 2020 27;12:1171-1181. Epub 2020 Oct 27.

Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Purpose: Medication patterns include all medications in an individual's clinical profile. We aimed to identify chronic co-morbidity treatment patterns through medication use among COPDGene participants and determine whether these patterns were associated with mortality, acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and quality of life.

Materials And Methods: Participants analyzed here completed Phase 1 (P1) and/or Phase 2 (P2) of COPDGene. Latent class analysis (LCA) was used to identify medication patterns and assign individuals into unobserved LCA classes. Mortality, AECOPD, and the St. George's Respiratory Questionnaire (SGRQ) health status were compared in different LCA classes through survival analysis, logistic regression, and Kruskal-Wallis test, respectively.

Results: LCA identified 8 medication patterns from 32 classes of chronic comorbid medications. A total of 8110 out of 10,127 participants with complete covariate information were included. Survival analysis adjusted for covariates showed, compared to a low medication use class, mortality was highest in participants with hypertension+diabetes+statin+antiplatelet medication group. Participants in hypertension+SSRI+statin medication group had the highest odds of AECOPD and the highest SGRQ score at both P1 and P2.

Conclusion: Medication pattern can serve as a good indicator of an individual's comorbidities profile and improves models predicting clinical outcomes.
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http://dx.doi.org/10.2147/CLEP.S279075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602898PMC
October 2020

The Evolving Role of the Clinical Microbiology Laboratory in Identifying Resistance in Gram-Negative Bacteria: An Update.

Infect Dis Clin North Am 2020 12 30;34(4):659-676. Epub 2020 Sep 30.

Department of Pathology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH, USA.

The evolution of resistance to antimicrobial agents in gram-negatives has challenged the role of the clinical microbiology laboratory to implement new methods for their timely detection. Recent development has enabled the use of novel methods for more rapid pathogen identification, antimicrobial susceptibility testing, and detection of resistance markers. Commonly used methods improve the rapidity of resistance detection from both cultured bacteria and specimens. This review focuses on the commercially available systems available together with their technical performance and possible clinical impact.
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http://dx.doi.org/10.1016/j.idc.2020.08.001DOI Listing
December 2020

AbGRI4, a novel antibiotic resistance island in multiply antibiotic-resistant Acinetobacter baumannii clinical isolates.

J Antimicrob Chemother 2020 10;75(10):2760-2768

J. Craig Venter Institute, Rockville, MD, USA.

Objectives: To investigate the genomic context of a novel resistance island (RI) in multiply antibiotic-resistant Acinetobacter baumannii clinical isolates and global isolates.

Methods: Using a combination of long and short reads generated from the Oxford Nanopore and Illumina platforms, contiguous chromosomes and plasmid sequences were determined. BLAST-based analysis was used to identify the RI insertion target.

Results: Genomes of four multiply antibiotic-resistant A. baumannii clinical strains, from a US hospital system, belonging to prevalent MLST ST2 (Pasteur scheme) and ST281 (Oxford scheme) clade F isolates were sequenced to completion. A class 1 integron carrying aadB (tobramycin resistance) and aadA2 (streptomycin/spectinomycin resistance) was identified. The class 1 integron was 6.8 kb, bounded by IS26 at both ends, and embedded in a new target location between an α/β-hydrolase and a reductase. Due to its novel insertion site and unique RI composition, we suggest naming this novel RI AbGRI4. Molecular analysis of global A. baumannii isolates identified multiple AbGRI4 RI variants in non-ST2 clonal lineages, including variations in the resistance gene cassettes, integron backbone and insertion breakpoints at the hydrolase gene.

Conclusions: A novel RI insertion target harbouring a class 1 integron was identified in a subgroup of ST2/ST281 clinical isolates. Variants of the RI suggested evolution and horizontal transfer of the RI across clonal lineages. Long- and short-read hybrid assembly technology completely resolved the genomic context of IS-bounded RIs, which was not possible using short reads alone.
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http://dx.doi.org/10.1093/jac/dkaa266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556812PMC
October 2020

A γ-Lactam Siderophore Antibiotic Effective against Multidrug-Resistant Gram-Negative Bacilli.

J Med Chem 2020 06 2;63(11):5990-6002. Epub 2020 Jun 2.

Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106, United States.

Treatment of multidrug-resistant Gram-negative bacterial pathogens represents a critical clinical need. Here, we report a novel γ-lactam pyrazolidinone that targets penicillin-binding proteins (PBPs) and incorporates a siderophore moiety to facilitate uptake into the periplasm. The MIC values of γ-lactam YU253434, , are reported along with the finding that is resistant to hydrolysis by all four classes of β-lactamases. The druglike characteristics and mouse PK data are described along with the X-ray crystal structure of binding to its target PBP3.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590959PMC
June 2020

Bacterial contamination and septic transfusion reaction rates associated with platelet components before and after introduction of primary culture: experience at a US Academic Medical Center 1991 through 2017.

Transfusion 2020 05 1;60(5):974-985. Epub 2020 May 1.

Department of Pathology and Medicine, University Hospitals Cleveland Medical Center and Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.

Background: The high incidence of septic transfusion reactions (STRs) led to testing being mandated by AABB from 2004. This was implemented by primary culture of single-donor apheresis platelets (APs) from 2004 and prestorage pooled platelets (PSPPs) from 2007.

Study Design/methods: Platelet (PLT) aliquots were cultured at issue and transfusion reactions evaluated at our hospital. Bacterial contamination and STR rates (shown as rates per million transfusions in Results) were evaluated before and after introduction of primary culture by blood centers that used a microbial detection system (BacT/ALERT, bioMerieux) or enhanced bacterial detection system (eBDS, Haemonetics).

Results: A total of 28,457 PLTs were cultured during pre-primary culture periods (44.7% APs; 55.3% at-issue pooled PLTs [AIPPs]) and 97,595 during post-primary culture periods (79.3% APs; 20.7% PSPPs). Forty-three contaminated units were identified in preculture and 34 in postculture periods (rates, 1511 vs. 348; p < 0.0001). Contamination rates of APs were significantly lower than AIPPs in the preculture (393 vs. 2415; p < 0.0001) but not postculture period compared to PSPPs (387 vs. 198; p = 0.9). STR rates (79 vs. 90; p = 0.98) were unchanged with APs but decreased considerably with pooled PLTs (826 vs. 50; p = 0.0006). Contamination (299 vs. 324; p = 0.84) and STR rates (25 vs. 116; p = 0.22) were similar for PLTs tested by BacT/ALERT and eBDS primary culture methods. A change in donor skin preparation method in 2012 was associated with decreased contamination and STR rates.

Conclusion: Primary culture significantly reduced bacterial contamination and STR associated with pooled but not AP PLTs. Measures such as secondary testing near time of use or pathogen reduction are needed to further reduce STRs.
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http://dx.doi.org/10.1111/trf.15780DOI Listing
May 2020

ARGONAUT II Study of the Activity of Plazomicin against Carbapenemase-Producing Klebsiella pneumoniae.

Antimicrob Agents Chemother 2020 04 21;64(5). Epub 2020 Apr 21.

Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA

Plazomicin was tested against 697 recently acquired carbapenem-resistant isolates from the Great Lakes region of the United States. Plazomicin MIC and MIC values were 0.25 and 1 mg/liter, respectively; 680 isolates (97.6%) were susceptible (MICs of ≤2 mg/liter), 9 (1.3%) intermediate (MICs of 4 mg/liter), and 8 (1.1%) resistant (MICs of >32 mg/liter). Resistance was associated with -, -, or -encoded 16S rRNA methyltransferases in all except 1 isolate.
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http://dx.doi.org/10.1128/AAC.00012-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179617PMC
April 2020

Monitoring Ceftazidime-Avibactam and Aztreonam Concentrations in the Treatment of a Bloodstream Infection Caused by a Multidrug-Resistant Enterobacter sp. Carrying Both Klebsiella pneumoniae Carbapenemase-4 and New Delhi Metallo-β-Lactamase-1.

Clin Infect Dis 2020 08;71(4):1095-1098

Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.

In an infection with an Enterobacter sp. isolate producing Klebsiella pneumoniae Carbapenemase-4 and New Delhi Metallo-β-Lactamase-1 in the United States, recognition of the molecular basis of carbapenem resistance allowed for successful treatment by combining ceftazidime-avibactam and aztreonam. Antimicrobial synergy testing and therapeutic drug monitoring assessed treatment adequacy.
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http://dx.doi.org/10.1093/cid/ciz1155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428388PMC
August 2020

Longitudinal Colonization With Streptococcus pneumoniae During the First Year of Life in a Healthy Newborn Cohort.

J Pediatric Infect Dis Soc 2020 Sep;9(4):442-448

Department of Medicine, Case Western Reserve School of Medicine, Cleveland, Ohio, USA.

Background: The objective of this study was to characterize longitudinal colonization with Streptococcus pneumoniae during the first year of life within a community newborn infant cohort, and assess the relationship between antibiotic exposure and colonization with antibiotic-resistant organisms.

Methods: During April 2013-February 2014, 326 infants were enrolled from an urban academic hospital well-baby nursery. At ages 4, 8, and 12 months, we collected antibiotic data, other exposure data, and nasopharyngeal cultures for pneumococcal isolation.

Results: Follow-up visits were completed for 211, 158, and 144 infants at ages 4, 8, and 12 months, respectively. By 12 months, 33% of infants attending the visits had ever been exposed to antibiotics, 67% if exposures to maternal antibiotics at birth are included. Pneumococci were isolated at 38/839 (4.5%) visits from 38 infants, including one 13-valent conjugate vaccine (PCV13) serotype (6A). There were 1 (0.3%), 15 (7%), 7 (4%), and 15 (10%) infants who were colonized at 0-, 4-, 8-, and 12-month visits, respectively. By age 12 months, at least 35 (11%) infants had ever been colonized. Sixteen isolates (42%) exhibited nonsusceptibility to at least 1 antibiotic. Infants with recent antibiotic exposure were not more likely to be colonized or to harbor nonsusceptible organisms.

Conclusions: Within a hospital birth cohort followed in the community, pneumococcal colonization and related antibiotic resistance were lower than previously reported, likely associated with PCV13 use. Antibiotic exposure was not associated with subsequent colonization with resistant isolates. The influence of other environmental factors needs further study.
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http://dx.doi.org/10.1093/jpids/piz068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495909PMC
September 2020

A two-part phase 1 study to establish and compare the safety and local tolerability of two nasal formulations of XF-73 for decolonisation of Staphylococcus aureus: A previously investigated 0.5mg/g viscosified gel formulation versus a modified formulation.

J Glob Antimicrob Resist 2020 06 7;21:171-180. Epub 2019 Oct 7.

Department of Medicine and Division of Infectious Diseases and HIV Medicine, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA.

Objectives: Successful decolonisation of nasal Staphylococcus aureus (SA) carriage by mupirocin is limited by increasing drug resistance. This randomised, open-label, phase 1 study compared the safety and local tolerability of two nasal formulations of XF-73, a novel porphyrinic antibacterial with rapid intrinsic activity against SA.

Methods: The study was performed in 60 healthy adults. In Part 1, eight non-SA carriers were randomised to groups of four subjects each and were treated with XF-73 concentrations of 0.5mg/g 2% gel or 2.0mg/g 2% gel. In Part 2, 52 persistent SA carriers were randomised to groups of 13 subjects each and were treated with XF-73 concentrations of 0.5mg/g 2% gel, 2.0mg/g 2% gel, 0.5mg/g 4% gel or 4% viscosified placebo gel. Plasma pharmacokinetic and pharmacodynamic studies were performed. Antistaphylococcal activity was assessed as the presence/absence of SA and by quantification of colonisation using a semiquantitative scale (SA score).

Results: 56 subjects (8/8 from Part 1 and 48/52 from Part 2) completed the study, with 47/60 comprising the pharmacokinetic population and 48/60 the pharmacodynamic population. There was no measurable systemic absorption of XF-73. XF-73 treatment was associated with rapid reduction in SA score in all subjects. The most common treatment-emergent adverse events (TEAEs) were rhinorrhoea and nasal dryness (15.5% each in Parts 1 and 2). TEAEs were mild and resolved spontaneously.

Conclusion: XF-73 was well tolerated with minimal side effects at doses of 0.5mg/g 2% gel and 2.0mg/g 2% gel. These findings support further development of XF-73.
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http://dx.doi.org/10.1016/j.jgar.2019.09.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136135PMC
June 2020

Association of Laboratory Methods, Colonization Density, and Age With Detection of Streptococcus pneumoniae in the Nasopharynx.

Am J Epidemiol 2019 12;188(12):2110-2119

Center for American Indian Health, Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland.

Culture-based methods for detecting Streptococcus pneumoniae in the nasopharynx lack sensitivity. In this study, we aimed to compare the performance of culture and molecular methods in detecting pneumococcus in the nasopharynx of healthy individuals and to evaluate the associations of age and colonization density with detection. Between 2010 and 2012, nasopharyngeal specimens were collected from healthy individuals living on Navajo Nation and White Mountain Apache Tribal lands in the United States. Pneumococci were detected by means of broth-enrichment culture and autolysin-encoding gene (lytA) quantitative polymerase chain reaction (qPCR). Among 982 persons evaluated (median age, 18.7 years; 47% male), 35% were culture-positive and an additional 27% were qPCR-positive. Agreement between culture and qPCR was 70.9% but was higher among children (age <18 years) (75.9%-84.4%) than among adults (age ≥18 years) (61.0%-74.6%). The mean density of colonization was lower for culture-negative samples (3.14 log10 copies/mL) than for culture-positive samples (5.02 log10 copies/mL), overall and for all age groups. The percent culture-positive increased with increasing density, exceeding 80% at densities of ≥10,000 copies/mL. Mean colonization density decreased with age. Use of qPCR improved detection of pneumococcus in the nasopharynx of healthy individuals. This finding was most notable among adults, probably because of improved detection of low-density colonization.
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http://dx.doi.org/10.1093/aje/kwz191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036660PMC
December 2019

Complete Genome Sequence of a Parabacteroides distasonis Strain (CavFT hAR46) Isolated from a Gut Wall-Cavitating Microlesion in a Patient with Severe Crohn's Disease.

Microbiol Resour Announc 2019 Sep 5;8(36). Epub 2019 Sep 5.

Division of Gastroenterology & Liver Disease, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) of the digestive tract in humans. There is evidence that could contribute to IBD. Here, we present the complete genome sequence of a strain designated CavFT-hAR46, which was isolated from a gut intramural cavernous fistulous tract (CavFT) microlesion in a CD patient.
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http://dx.doi.org/10.1128/MRA.00585-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728636PMC
September 2019

Compartmentalization of anti-oxidant and anti-inflammatory gene expression in current and former smokers with COPD.

Respir Res 2019 Aug 20;20(1):190. Epub 2019 Aug 20.

Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St., E7622, Baltimore, MD, 21205, USA.

Background: Patients with chronic obstructive pulmonary disease (COPD) have high oxidative stress associated with the severity of the disease. Nuclear factor erythroid-2 related factor 2 (Nrf2)-directed stress response plays a critical role in the protection of lung cells to oxidative stress by upregulating antioxidant genes in response to tobacco smoke. There is a critical gap in our knowledge about Nrf-2 regulated genes in active smokers and former-smokers with COPD in different cell types from of lungs and surrogate peripheral tissues.

Methods: We compared the expression of Nrf2 and six of its target genes in alveolar macrophages, nasal, and bronchial epithelium and peripheral blood mononuclear cells (PBMCs) in current and former smokers with COPD. We compared cell-type specific of Nrf2 and its target genes as well as markers of oxidative and inflammatory stress.

Results: We enrolled 89 patients; expression all Nrf2 target gene measured were significantly higher in the bronchial epithelium from smokers compared to non-smokers. None were elevated in alveolar macrophages and only one was elevated in each of the other compartments.

Conclusion: Bronchial epithelium is the most responsive tissue for transcriptional activation of Nrf2 target genes in active smokers compared to former-smokers with COPD that correlated with oxidative stress and inflammatory markers. There were no consistent trends in gene expression in other cell types tested.

Trial Registration: Clinicaltrials.gov : NCT01335971.
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http://dx.doi.org/10.1186/s12931-019-1164-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700818PMC
August 2019

Review of current transfusion therapy and blood banking practices.

Blood Rev 2019 11 25;38:100593. Epub 2019 Jul 25.

Verax Biomedical Incorporated, USA. Electronic address:

Transfusion Medicine is a dynamically evolving field. Recent high-quality research has reshaped the paradigms guiding blood transfusion. As increasing evidence supports the benefit of limiting transfusion, guidelines have been developed and disseminated into clinical practice governing optimal transfusion of red cells, platelets, plasma and cryoprecipitate. Concepts ranging from transfusion thresholds to prophylactic use to maximal storage time are addressed in guidelines. Patient blood management programs have developed to implement principles of patient safety through limiting transfusion in clinical practice. Data from National Hemovigilance Surveys showing dramatic declines in blood utilization over the past decade demonstrate the practical uptake of current principles guiding patient safety. In parallel with decreasing use of traditional blood products, the development of new technologies for blood transfusion such as freeze drying and cold storage has accelerated. Approaches to policy decision making to augment blood safety have also changed. Drivers of these changes include a deeper understanding of emerging threats and adverse events based on hemovigilance, and an increasing healthcare system expectation to align blood safety decision making with approaches used in other healthcare disciplines.
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http://dx.doi.org/10.1016/j.blre.2019.100593DOI Listing
November 2019

Nacubactam Enhances Meropenem Activity against Carbapenem-Resistant Klebsiella pneumoniae Producing KPC.

Antimicrob Agents Chemother 2019 08 25;63(8). Epub 2019 Jul 25.

Louis Stokes Cleveland VA Medical Center, Research Service, Cleveland, Ohio, USA

Carbapenem-resistant (CRE) are resistant to most antibiotics, making CRE infections extremely difficult to treat with available agents. carbapenemases (KPC-2 and KPC-3) are predominant carbapenemases in CRE in the United States. Nacubactam is a bridged diazabicyclooctane (DBO) β-lactamase inhibitor that inactivates class A and C β-lactamases and exhibits intrinsic antibiotic and β-lactam "enhancer" activity against In this study, we examined a collection of meropenem-resistant isolates carrying or ; meropenem-nacubactam restored susceptibility. Upon testing isogenic strains producing KPC-2 variants with single-residue substitutions at important Ambler class A positions (K73, S130, R164, E166, N170, D179, K234, E276, etc.), the K234R variant increased the meropenem-nacubactam MIC compared to that for the strain producing KPC-2, without increasing the meropenem MIC. Correspondingly, nacubactam inhibited KPC-2 (apparent [ ]31 ± 3 μM) more efficiently than the K234R variant ( 270 ± 27 μM) and displayed a faster acylation rate ( ), which was 5,815 ± 582 M s for KPC-2 versus 247 ± 25 M s for the K234R variant. Unlike avibactam, timed mass spectrometry revealed an intact sulfate on nacubactam and a novel peak (+337 Da) with the K234R variant. Molecular modeling of the K234R variant showed significant catalytic residue (i.e., S70, K73, and S130) rearrangements that likely interfere with nacubactam binding and acylation. Nacubactam's aminoethoxy tail formed unproductive interactions with the K234R variant's active site. Molecular modeling and docking observations were consistent with the results of biochemical analyses. Overall, the meropenem-nacubactam combination is effective against carbapenem-resistant Moreover, our data suggest that β-lactamase inhibition by nacubactam proceeds through an alternative mechanism compared to that for avibactam.
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http://dx.doi.org/10.1128/AAC.00432-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658744PMC
August 2019

Rapid Replacement of Acinetobacter baumannii Strains Accompanied by Changes in Lipooligosaccharide Loci and Resistance Gene Repertoire.

mBio 2019 03 26;10(2). Epub 2019 Mar 26.

Department of Medicine, Case Western Reserve University and CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology, Cleveland, Ohio, USA.

The population structure of health care-associated pathogens reflects patterns of diversification, selection, and dispersal over time. Empirical data detailing the long-term population dynamics of nosocomial pathogens provide information about how pathogens adapt in the face of exposure to diverse antimicrobial agents and other host and environmental pressures and can inform infection control priorities. Extensive sequencing of clinical isolates from one hospital spanning a decade and a second hospital in the Cleveland, OH, metropolitan area over a 3-year time period provided high-resolution genomic analysis of the metapopulation. Genomic analysis demonstrated an almost complete replacement of the predominant strain groups with a new, genetically distinct strain group during the study period. The new group, termed clade F, differs from other global clone 2 (GC2) strains of in several ways, including its antibiotic resistance and lipooligosaccharide biosynthesis genes. Clade F strains are part of a large phylogenetic group with broad geographic representation. Phylogenetic analysis of single-nucleotide variants in core genome regions showed that although the Cleveland strains are phylogenetically distinct from those isolated from other locations, extensive intermixing of strains from the two hospital systems was apparent, suggesting either substantial exchange of strains or a shared, but geographically restricted, external pool from which infectious isolates were drawn. These findings document the rapid evolution of strains in two hospitals, with replacement of the predominant clade by a new clade with altered lipooligosaccharide loci and resistance gene repertoires. Multidrug-resistant (MDR) is a difficult-to-treat health care-associated pathogen. Knowing the resistance genes present in isolates causing infection aids in empirical treatment selection. Furthermore, knowledge of the genetic background can assist in tracking patterns of transmission to limit the spread of infections in hospitals. The appearance of a new genetic background in strains with a different set of resistance genes and cell surface structures suggests that strong selective pressures exist, even in highly MDR pathogens. Because the new strains have levels of antimicrobial resistance similar to those of the strains that were displaced, we hypothesize that other features, including host colonization and infection, may confer additional selective advantages and contribute to their increased prevalence.
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http://dx.doi.org/10.1128/mBio.00356-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437055PMC
March 2019

Targeting Multidrug-Resistant spp.: Sulbactam and the Diazabicyclooctenone β-Lactamase Inhibitor ETX2514 as a Novel Therapeutic Agent.

mBio 2019 03 12;10(2). Epub 2019 Mar 12.

Louis Stokes Cleveland Veterans Affairs Medical Center Research Service, Cleveland, Ohio, USA

Multidrug-resistant (MDR) spp. poses a significant therapeutic challenge in part due to the presence of chromosomally encoded β-lactamases, including class C -derived cephalosporinases (ADC) and class D oxacillinases (OXA), as well as plasmid-mediated class A β-lactamases. Importantly, OXA-like β-lactamases represent a gap in the spectrum of inhibition by recently approved β-lactamase inhibitors such as avibactam and vaborbactam. ETX2514 is a novel, rationally designed, diazabicyclooctenone inhibitor that effectively targets class A, C, and D β-lactamases. We show that addition of ETX2514 significantly increased the susceptibility of clinical isolates to sulbactam. AdeB and AdeJ were identified to be key efflux constituents for ETX2514 in The combination of sulbactam and ETX2514 was efficacious against carrying , , , and in a neutropenic murine thigh infection model. We also show that, , ETX2514 inhibited ADC-7 ( / 1.0 ± 0.1 × 10 M s) and OXA-58 ( / 2.5 ± 0.3 × 10 M s). Cocrystallization of ETX2514 with OXA-24/40 revealed hydrogen bonding interactions between ETX2514 and residues R261, S219, and S128 of OXA-24/40 in addition to a chloride ion occupied in the active site. Further, the C3 methyl group of ETX2514 shifts the position of M223. In conclusion, the sulbactam-ETX2514 combination possesses a broadened inhibitory range to include class D β-lactamases as well as class A and C β-lactamases and is a promising therapeutic candidate for infections caused by MDR spp. The number and diversity of β-lactamases are steadily increasing. The emergence of β-lactamases that hydrolyze carbapenems poses a significant threat to our antibiotic armamentarium. The explosion of OXA enzymes that are carbapenem hydrolyzers is a major challenge (carbapenem-hydrolyzing class D [CHD]). An urgent need exists to discover β-lactamase inhibitors with class D activity. The sulbactam-ETX2514 combination demonstrates the potential to become a treatment regimen of choice for spp. producing class D β-lactamases.
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http://dx.doi.org/10.1128/mBio.00159-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414696PMC
March 2019

Beyond Piperacillin-Tazobactam: Cefepime and AAI101 as a Potent β-Lactam-β-Lactamase Inhibitor Combination.

Antimicrob Agents Chemother 2019 05 25;63(5). Epub 2019 Apr 25.

EA 3826 (Thérapeutiques Anti-Infectieuses), IRS2 Nantes Biotech, Université de Nantes, France

Impeding, as well as reducing, the burden of antimicrobial resistance in Gram-negative pathogens is an urgent public health endeavor. Our current antibiotic armamentarium is dwindling, while major resistance determinants (e.g., extended-spectrum β-lactamases [ESBLs]) continue to evolve and disseminate around the world. One approach to attack this problem is to develop novel therapies that will protect our current agents. AAI101 is a novel penicillanic acid sulfone β-lactamase inhibitor similar in structure to tazobactam, with one important difference. AAI101 possesses a strategically placed methyl group that gives the inhibitor a net neutral charge, enhancing bacterial cell penetration. AAI101 paired with cefepime, also a zwitterion, is in phase III of clinical development for the treatment of serious Gram-negative infections. Here, AAI101 was found to restore the activity of cefepime against class A ESBLs (e.g., CTX-M-15) and demonstrated increased potency compared to that of piperacillin-tazobactam when tested against an established isogenic panel. The enzymological properties of AAI101 further revealed that AAI101 possessed a unique mechanism of β-lactamase inhibition compared to that of tazobactam. Additionally, upon reaction with AAI101, CTX-M-15 was modified to an inactive state. Notably, the efficacy of cefepime-AAI101 was demonstrated using a mouse septicemia model, indicating the ability of AAI101 to bolster significantly the therapeutic efficacy of cefepime The combination of AAI101 with cefepime represents a potential carbapenem-sparing treatment regimen for infections suspected to be caused by expressing ESBLs.
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http://dx.doi.org/10.1128/AAC.00105-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6496078PMC
May 2019

Symptoms of anxiety and depression and use of anxiolytic-hypnotics and antidepressants in current and former smokers with and without COPD - A cross sectional analysis of the COPDGene cohort.

J Psychosom Res 2019 03 7;118:18-26. Epub 2019 Jan 7.

Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, USA; Iowa Neuroscience Institute, Carver College of Medicine, University of Iowa, Iowa City, IA, USA; Department of Pulmonary, Critical Care, and Sleep Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA. Electronic address:

Objectives: To compare the frequency of anxiety/depressive symptoms and use of anxiolytic-hypnotics/antidepressants in smokers with and without COPD and to identify characteristics associated with having unmedicated symptoms.

Methods: Cross-sectional analysis of ambulatory, current/former smokers ≥10 pack years enrolled in the COPDGene study. We measured anxiety/depressive symptoms using the Hospital Anxiety and Depression Scale (subscales ≥8), recorded anxiolytic-hypnotic/antidepressant use, and defined unmedicated symptoms as elevated anxiety/depressive symptoms and not on medications. Regression analysis identified characteristics associated with having unmedicated symptoms.

Key Results: Of 5331 current/former smokers (45% with and 55% without COPD), 1332 (25.0%) had anxiety/depressive symptoms. Anxiety symptoms were similar in frequency in smokers with and without COPD (19.7% overall), while depressive symptoms were most frequent in severe-very severe COPD at 20.7% (13.1% overall). In the entire cohort, 1135 (21.2%) were on medications. Anxiolytic-hypnotic use was highest in severe-very severe COPD (range 7.6%-12.0%), while antidepressant use showed no significant variation in smokers with and without COPD (range 14.7%-17.1%). Overall, 881 (66% of those with symptoms) had unmedicated symptoms, which was associated with African American race (adjusted OR 2.95, 95% CI 2.25-3.87), male gender (adjusted OR 1.93, 95% CI 1.57-2.36), no health insurance (adjusted OR 2.38, 95% CI 1.30-4.35), severe-very severe COPD (adjusted OR 1.48, 95% CI 1.04-2.11), and higher respiratory symptoms/exacerbation history (adjusted OR 2.21, 95% CI 1.62-3.02).

Conclusions: Significant unmet mental health care needs exist in current and former smokers with and without COPD. One in five have unmedicated symptoms, identified by key demographic and clinical characteristics.

Primary Funding Source: National Institutes of Health and The COPD Foundation.
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http://dx.doi.org/10.1016/j.jpsychores.2019.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383809PMC
March 2019

Effects of Roflumilast on Rehospitalization and Mortality in Patients.

Chronic Obstr Pulm Dis 2018 Dec 20;6(1):74-85. Epub 2018 Dec 20.

Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania.

Hospitalization for chronic obstructive pulmonary disease (COPD) exacerbation portends the greatest risk of rehospitalization and mortality. Treatments that prevent hospitalizations could significantly lessen COPD morbidity and mortality. We performed a prospective, randomized, double-blind, placebo-controlled study of roflumilast 500 ug daily versus placebo in patients hospitalized for acute COPD exacerbation. Primary outcome was time to all-cause mortality or non-elective rehospitalization at 180 days post-randomization. Secondary outcomes were death or hospitalization from a respiratory cause, quality of life, change in health status, forced expiratory volume in 1 second (FEV) and roflumilast tolerance. A total of 64 patients with moderate to severe COPD (FEV, 37.6 ± 16.4% predicted; 61% female, 61.6 ± 7.9 years old) were assigned to roflumilast or placebo. No deaths occurred in the follow-up period. There was no difference in the time to first readmission between the roflumilast and placebo groups (46.1 days versus 47.3 days respectively, =0.93). There were 29 and 30 readmissions in the roflumilast and placebo groups, respectively (=0.47). The St George's Respiratory Questionnaire (SGRQ) decreased 10.8 points and 7.8 points in the roflumilast and placebo groups, respectively and were not different. EuroQuality of Life Five Dimension scale (EQ5D) scores improved, but not significantly in either group. Weight loss and nausea were more common with roflumilast but not different from placebo. Change in glycosylated hemoglobin percentage (HgbA1C%) was not different between groups. Sub-analysis for the impact of chronic bronchitis did not affect outcomes. In this pilot study conducted in patients hospitalized with an exacerbation of COPD, roflumilast did not affect time to all-cause rehospitalization, quality of life, FEV or any other measured parameter.
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http://dx.doi.org/10.15326/jcopdf.6.1.2018.0139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373589PMC
December 2018

Effect of Lung Volume Reduction Surgery on Respiratory Muscle Strength in Advanced Emphysema.

Chronic Obstr Pulm Dis 2018 Oct 12;6(1):40-50. Epub 2018 Oct 12.

Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania.

Long-term effects of lung volume reduction surgery (LVRS) on respiratory muscle strength and effects of age, sex, and emphysema pattern on these changes are unknown. Therefore, we aimed to determine the long-term effect of LVRS on respiratory muscle strength changes in severe emphysema. The National Emphysema Treatment Trial was a prospective controlled multicentered trial, comparing LVRS to optimal medical treatment on survival and maximal exercise capacity. We examined percentage change in maximum inspiratory pressure (MIP) from baseline to 36 months follow-up to determine impact of LVRS as well as age, sex, emphysema pattern and exercise capacity on changes in MIP compared to medical treatment. LVRS individuals had significantly greater increases in MIP from baseline compared to medical individuals at all follow-ups (LVRS 19.8 ± 42.3%, medical 3.2 ± 29.3%, <0.0001, 12 months). The LVRS group had significant decreases in total lung capacity (TLC), residual volume (RV), functional residual capacity (FRC) and RV/TLC compared to the medical arm at all follow-up periods. Males and individuals 65-70 years of age had significantly greater increases in MIP following LVRS compared to the medical arm at all follow-ups; this same relationship was seen at up to 24 months for low exercise capacity, upper lobe predominant emphysema. LVRS significantly increases inspiratory muscle strength up to 3 years post-operatively, with male sex, age 65-70 years and low exercise capacity, upper lobe predominant emphysema especially associated with increased MIP. Inspiratory muscle strength increases were associated with decreases in non-invasive markers of dynamic hyperinflation, suggesting that LVRS allows inspiratory muscles to return to their optimal length-tension relationship.
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http://dx.doi.org/10.15326/jcopdf.6.1.2018.0188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373585PMC
October 2018

ARGONAUT-I: Activity of Cefiderocol (S-649266), a Siderophore Cephalosporin, against Gram-Negative Bacteria, Including Carbapenem-Resistant Nonfermenters and with Defined Extended-Spectrum β-Lactamases and Carbapenemases.

Antimicrob Agents Chemother 2019 01 21;63(1). Epub 2018 Dec 21.

Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA

The activity of the siderophore cephalosporin cefiderocol is targeted against carbapenem-resistant Gram-negative bacteria. In this study, the activity of cefiderocol against characterized carbapenem-resistant complex, , , and strains was determined by microdilution in iron-depleted Mueller-Hinton broth. The MICs against , , and were 1, 0.25, and 0.5 mg/liter, respectively. Against , the MIC was 1 mg/liter for the group harboring OXA-48-like, 2 mg/liter for the group harboring KPC-3, and 8 mg/liter for the group harboring TEM/SHV ESBL, NDM, and KPC-2.
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http://dx.doi.org/10.1128/AAC.01801-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325197PMC
January 2019

Rapid Molecular Diagnostics to Inform Empiric Use of Ceftazidime/Avibactam and Ceftolozane/Tazobactam Against Pseudomonas aeruginosa: PRIMERS IV.

Clin Infect Dis 2019 05;68(11):1823-1830

Department of Medicine, Case Western Reserve University School of Medicine.

Background: Overcoming β-lactam resistance in pathogens such as Pseudomonas aeruginosa is a major clinical challenge. Rapid molecular diagnostics (RMDs) have the potential to inform selection of empiric therapy in patients infected by P. aeruginosa.

Methods: In this study, we used a heterogeneous collection of 197 P. aeruginosa that included multidrug-resistant isolates to determine whether 2 representative RMDs (Acuitas Resistome test and VERIGENE gram-negative blood culture test) could identify susceptibility to 2 newer β-lactam/β-lactamase inhibitor (BL-BLI) combinations, ceftazidime/avibactam (CZA) and ceftolozane/tazobactam (TOL/TAZO).

Results: We found that the studied RMD platforms were able to correctly identify BL-BLI susceptibility (susceptibility sensitivity, 100%; 95% confidence interval [CI], 97%, 100%) for both BLs-BLIs. However, their ability to detect resistance to these BLs-BLIs was lower (resistance sensitivity, 66%; 95% CI, 52%, 78% for TOL/TAZO and 33%; 95% CI, 20%, 49% for CZA).

Conclusions: The diagnostic platforms studied showed the most potential in scenarios where a resistance gene was detected or in scenarios where a resistance gene was not detected and the prevalence of resistance to TOL/TAZO or CZA is known to be low. Clinicians need to be mindful of the benefits and risks that result from empiric treatment decisions that are based on resistance gene detection in P. aeruginosa, acknowledging that such decisions are impacted by the prevalence of resistance, which varies temporally and geographically.
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http://dx.doi.org/10.1093/cid/ciy801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938201PMC
May 2019

Emergence of Resistance to Colistin During the Treatment of Bloodstream Infection Caused by Carbapenemase-Producing .

Open Forum Infect Dis 2018 Apr 23;5(4):ofy054. Epub 2018 Apr 23.

Division of Infectious Diseases and HIV Medicine, Department of Medicine, University Hospitals Cleveland Medical Center, Cleveland, Ohio.

We report the emergence of colistin resistance in carbapenemase (KPC)-producing after 8 days of colistin-based therapy, resulting in relapse of bloodstream infection and death. Disruption of the gene by insertion of a mobile genetic element was found to be the mechanism, which was replicated in vitro after exposure to subinhibitory concentrations of colistin and meropenem.
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http://dx.doi.org/10.1093/ofid/ofy054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913667PMC
April 2018

Mycobactericidal activity of bedaquiline plus rifabutin or rifampin in ex vivo whole blood cultures of healthy volunteers: A randomized controlled trial.

PLoS One 2018 2;13(5):e0196756. Epub 2018 May 2.

School of Medicine, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, Ohio, United States of America.

Background: Bedaquiline, an antimycobacterial agent approved for drug-resistant tuberculosis, is metabolized by CYP3A4, an hepatic enzyme strongly induced by rifampin, an essential part of drug-sensitive tuberculosis treatment. We examined the pharmacokinetic interactions of bedaquiline plus either rifampin or rifabutin in 33 healthy volunteers. This sub-study of that trial examined the mycobactericidal activity of these drugs against intracellular Mycobacterium tuberculosis using ex vivo whole blood culture.

Methods: Subjects were randomly assigned to receive two single 400 mg doses of bedaquiline, alone, and, after a 4 week washout period, in combination with steady-state daily dosing of either rifabutin 300 mg or rifampin 600 mg. Blood samples were collected prior to dosing and at multiple time points subsequently, to measure plasma drug concentrations and bactericidal activity in ex vivo M tuberculosis-infected whole blood cultures (WBA).

Results: Single oral doses of bedaquiline produced readily detectable WBA ex vivo, reaching a maximal effect of -0.28 log/day, with negative values indicating bacterial killing. Plasma concentrations of 355 ng/ml were sufficient for intracellular mycobacteriostasis. Combined dosing with rifampin or rifabutin produced maximal effects of -0.91 and -0.79 log/d, respectively. However, the activity of the rifabutin combination was sustained throughout the dosing interval, thereby producing a greater cumulative or total effect. At low drug concentrations, rifabutin plus bedaquiline yielded greater mycobactericidal activity than the sum of their separate effects. Neither drug metabolites nor cellular drug accumulation could account for this observation.

Conclusions: The combination of rifabutin plus bedaquiline produces sustained intracellular mycobactericidal activity that is greater than the sum of their individual effects. Further studies of the treatment-shortening potential of this combination are warranted.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0196756PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931679PMC
July 2018
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