#Vancomycin #resistance #gene cluster, vanC, in the #gut #microbiome of acute #leukemia #patients undergoing intensive #chemotherapy (PLoS One, abstract)

[Source: PLoS One, full page: (LINK). Abstract, edited.]


Vancomycin-resistance gene cluster, vanC, in the gut microbiome of acute leukemia patients undergoing intensive chemotherapy

Armin Rashidi , Zhigang Zhu, Thomas Kaiser, Dawn A. Manias, Shernan G. Holtan, Tauseef Ur Rehman, Daniel J. Weisdorf, Alexander Khoruts, Gary M. Dunny, Christopher Staley

Published: October 10, 2019 / DOI: https://doi.org/10.1371/journal.pone.0223890



Two recent reports suggested that the less common, less virulent enterococcal species, Enterococcus gallinarum and E. casseliflavus, with low-level vancomycin resistance due to chromosomally encoded vanC1 and vanC2/3, may influence host immunity. We reported that peri-transplant gut colonization with E. gallinarum and E. casseliflavus is associated with lower mortality after allogeneic hematopoietic cell transplantation (HCT). Because most acute leukemia patients undergoing HCT have received intensive chemotherapy (usually requiring prolonged hospitalization) for their underlying disease before HCT, we hypothesized that some may have acquired vanC-positive enterococci during chemotherapy. Therefore, we evaluated the presence of the vanC gene cluster using vanC1 and vanC2/3 qPCR in thrice-weekly collected stool samples from 20 acute leukemia patients undergoing intensive chemotherapy. We found that an unexpectedly large proportion of patients have detectable vanC1 and vanC2/3 (15% and 35%, respectively) in at least one stool sample. Comparing qPCR results with 16S rRNA gene sequencing results suggested that E. gallinarum may reach high abundances, potentially persisting into HCT and influencing transplant outcomes.


Citation: Rashidi A, Zhu Z, Kaiser T, Manias DA, Holtan SG, Rehman TU, et al. (2019) Vancomycin-resistance gene cluster, vanC, in the gut microbiome of acute leukemia patients undergoing intensive chemotherapy. PLoS ONE 14(10): e0223890. https://doi.org/10.1371/journal.pone.0223890

Editor: Senthilnathan Palaniyandi, University of Kentucky, UNITED STATES

Received: July 26, 2019; Accepted: October 1, 2019; Published: October 10, 2019

Copyright: © 2019 Rashidi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: Raw sequencing data are deposited under accession number SRP141394 at the NCBI SRA.

Funding: This work was supported by grants from the University of Minnesota (Medical School Innovation award and Foundation grant for new faculty) to AR. In addition, funding from Achieving Cures Together and Hubbard Broadcasting Foundation supported this research. TK received partial support from the Masonic Cancer Center at the University of Minnesota. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Keywords: Antibiotics; Drugs Resistance; Vancomycin; Enterococci; Enterococcus gallinarum; Cancer; Leukemia.



#Plasmid #Dissemination and #Selection of a #MDR #Klebsiella pneumoniae Strain during #Transplant-Associated #Antibiotic #Therapy (mBio, abstract)

[Source: mBio, full page: (LINK). Abstract, edited.]

Plasmid Dissemination and Selection of a Multidrug-Resistant Klebsiella pneumoniae Strain during Transplant-Associated Antibiotic Therapy

Sean Conlan, Anna F. Lau, Clay Deming, Christine D. Spalding, ShihQueen Lee-Lin, Pamela J. Thomas, Morgan Park, John P. Dekker, Karen M. Frank, Tara N. Palmore, Julia A. Segre

Robert A. Bonomo, Editor

DOI: 10.1128/mBio.00652-19



Antibiotics, which are used both to prevent and to treat infections, are a mainstay therapy for lifesaving procedures such as transplantation. For this reason, and many others, increased antibiotic resistance among human-associated pathogens, such as the carbapenem-resistant Enterobacteriaceae species, is of grave concern. In this study, we report on a hematopoietic stem cell transplant recipient in whom cultures detected the emergence of carbapenem resistance and spread across five strains of bacteria that persisted for over a year. Carbapenem resistance in Citrobacter freundii, Enterobacter cloacae, Klebsiella aerogenes, and Klebsiella pneumoniae was linked to a pair of plasmids, each carrying the Klebsiella pneumoniae carbapenemase gene (blaKPC). Surveillance cultures identified a carbapenem-susceptible strain of Citrobacter freundii that may have become resistant through horizontal gene transfer of these plasmids. Selection of a multidrug-resistant Klebsiella pneumoniae strain was also detected following combination antibiotic therapy. Here we report a plasmid carrying the blaKPC gene with broad host range that poses the additional threat of spreading to endogenous members of the human gut microbiome.



Antibiotic-resistant bacteria are a serious threat to medically fragile patient populations. The spread of antibiotic resistance through plasmid-mediated mechanisms is of grave concern as it can lead to the conversion of endogenous patient-associated strains to difficult-to-treat pathogens.

Keywords: Antibiotics; Drugs Resistance; Klebsiella pneumoniae; Plasmids.


#Neuraminidase #inhibitors susceptibility profiles of highly pathogenic #influenza A (#H5N1) viruses isolated from #avian species in #India (2006-2015) (Antiviral Res., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Antiviral Res. 2018 Oct;158:143-146. doi: 10.1016/j.antiviral.2018.08.007. Epub 2018 Aug 17.

Neuraminidase inhibitors susceptibility profiles of highly pathogenic influenza A (H5N1) viruses isolated from avian species in India (2006-2015).

Sood R1, Kumar N2, Bhatia S2, Chanu KV2, Gupta CL3, Pateriya AK2, Mishra A2, Khandia R2, Mawale N2, Singh VP2.

Author information: 1 ICAR- National Institute of High Security Animal Diseases, Anand Nagar, Bhopal 462022, Madhya Pradesh, India. Electronic address: richa.sood@icar.gov.in. 2 ICAR- National Institute of High Security Animal Diseases, Anand Nagar, Bhopal 462022, Madhya Pradesh, India. 3 Department of Computer Science, University College London, Gower Street, WC1E 6BT, London, UK.



We tested 65 highly pathogenic avian influenza (HPAI) A(H5N1) viruses, isolated from avian species in India between 2006 and 2015, for susceptibility to the FDA approved neuraminidase (NA) inhibitors (NAIs), oseltamivir and zanamivir using a phenotypic fluorescence-based assay. The overall incidence of resistant variants among HPAI A(H5N1) viruses was 7.69% (5/65). The NA inhibition assay identified 3 viruses resistant to oseltamivir (N294S substitution, N2 numbering) and 2 cross-resistant to oseltamivir and zanamivir (E119A or I117V+E119A substitutions), all of which belonged to hemagglutinin (HA) clade 2.2 (5/17) and predominantly circulated in Indian poultry during 2006-2010. In comparison to E119A substitution alone, viruses with I117V+E119A double substitutions showed greater reduction in susceptibility to both oseltamivir and zanamivir. The NAI resistance-associated NA markers, identified in this study, were as a result of naturally occurring mutations. Of note, 48 viruses of HA clade that circulated in Indian poultry during 2011-2015 were susceptible to both oseltamivir and zanamivir. It is essential to monitor NAI susceptibility among human and avian HPAI A(H5N1) viruses that would provide baseline data to develop strategies for pandemic preparedness and therapeutic interventions.

Copyright © 2018 Elsevier B.V. All rights reserved.

KEYWORDS: HPAI A(H5N1) viruses; India; Neuraminidase inhibitors; Oseltamivir; Zanamivir

PMID: 30125616 DOI: 10.1016/j.antiviral.2018.08.007 [Indexed for MEDLINE]

Keywords: Avian Influenza; H5N1; Antivirals; Drugs Resistance; Oseltamivir; Zanamivir; India.


#Detection of #Candida auris #antifungal drug #resistance markers directly from #clinical skin #swabs (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Detection of Candida auris antifungal drug resistance markers directly from clinical skin swabs

Milena Kordalewska, Annie Lee, Yanan Zhao, David S. Perlin

DOI: 10.1128/AAC.01754-19



Accurate and rapid assessment of Candida auris antifungal drug resistance is crucial for effective infection prevention and control actions, and patient management. Here, performance of a molecular diagnostic platform, enabling rapid identification of FKS1 and ERG11 mutations conferring echinocandin and azole resistance, respectively, was evaluated on a panel of clinical skin swabs. Gene sequencing and antifungal susceptibility testing were used as “gold standard”. All swabs were correctly categorized as harboring wild-type or mutant C. auris.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Candida auris; Drugs resistance; Diagnostic tests; Echinocandins.


WCK 5222 (#Cefepime / #Zidebactam) Pharmacodynamic Target Analysis against Metallo-β-lactamase producing #Enterobacteriaceae in the #Neutropenic Mouse #Pneumonia Model (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

WCK 5222 (Cefepime/Zidebactam) Pharmacodynamic Target Analysis against Metallo-β-lactamase producing Enterobacteriaceae in the Neutropenic Mouse Pneumonia Model

Alexander J. Lepak, Miao Zhao, David R. Andes

DOI: 10.1128/AAC.01648-19



WCK 5222 is a combination of cefepime and the novel β-lactam enhancer (BLE) zidebactam. Zidebactam has a dual mechanism of action involving high-affinity penicillin binding protein (PBP) 2 binding as well as inhibition of Ambler class A, and C, enzymes. In the current study, we evaluated the effect of zidebactam on the cefepime pharmacodynamic target time above MIC (T>MIC) exposure required for efficacy against a diverse group of carbapenem-resistant Enterobacteriaceae (CRE) secondary to MBL-production. Plasma and ELF pharmacokinetic (PK) studies were performed for both cefepime (6.25, 25, and 100 mg/kg) and zidebactam (3.125, 12.5, and 50 mg/kg) after subcutaneous administration to mice. Only total drug was considered as protein binding is <10%. Both drugs exhibited similar PK exposures including terminal elimination half-life (cefepime ∼0.4 h, zidebactam 0.3-0.5 h). The penetration into ELF was concentration dependent for both drugs, reaching 50% and 70% for cefepime and zidebactam, respectively. Dose ranging studies were performed in lung-infected mice with one of eight MBL-producing clinical strains. WCK 5222 was administered in Q4- and Q8-hourly regimens to vary exposures from 0-100% T>MIC. The results were modelled to evaluate the relationship between cefepime T>MIC, when zidebactam was co-administered, and therapeutic effect. The results revealed a strong association between T>MIC and effect (R2 0.82). Net stasis in organism burden occurred at cefepime T>MIC exposures of only 18%. A 1-log kill endpoint was demonstrated for the group of organisms at approximately 31% T>MIC. These target exposures for stasis and 1-log kill are much lower than previously observed cephalosporin monotherapy PK/PD targets.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Enterobacteriaceae; Cefepine; Zidebactam.


#Sequence-based #epidemiology of an #OXA-48 #plasmid during a #hospital #outbreak (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Sequence-based epidemiology of an OXA-48 plasmid during a hospital outbreak

Laura Hidalgo, Mark de Been, Malbert R.C. Rogers, Anita C. Schürch, Jelle Scharringa, Anneke van der Zee, Marc J.M. Bonten, Ad C. Fluit

DOI: 10.1128/AAC.01204-19




A large OXA-48 outbreak in the Netherlands involved the spread of OXA-48producing Enterobacteriaceae among at least 118 patients, suggesting horizontal transfer of this resistance gene through one or more plasmids. Elucidating transmission dynamics of resistance plasmids is hampered by the low resolution of classic typing methods. This study aimed to investigate the molecular epidemiology of plasmids carrying OXA-48 carbapenemase using a next-generation sequencing approach.


A total of 68 OXA-48-producing Enterobacteriaceae isolated from the hospital outbreak, as well as 22 non-outbreak related OXA-48-producing Enterobacteriaceae from the Netherlands, Libya and Turkey were selected. Plasmids were sequenced using the Illumina Miseq platform, and read sets were assembled and analysed.


In all plasmids blaOXA-48 was embedded in transposon Tn1999.2 and located on a ca. 62 kb IncL/M conjugative plasmid in 14 different species. There were a maximum of 2 SNPs (single nucleotide polymorphisms) between the core sequence alignment of all plasmids. Closely related sequence variants of this plasmid were detected in non-outbreak isolates from the Netherlands and other countries. Thirty-one of 89 OXA-48-producing isolates also harboured blaCTX-M-15, which was not located on the blaOXA-48-carrying plasmid. Sequencing of four plasmids harbouring blaCTX-M15 revealed extensive plasmid heterogeneity.


A ca. 62 kb plasmid was responsible for the OXA-48 outbreak in a Dutch hospital. Our findings provide strong evidence for both within-host inter-species and between host dissemination of plasmid-based OXA-48 during a nosocomial outbreak. These findings exemplify the complex epidemiology of carbapenemase producing Enterobacteriaceae (CPE).

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Enterobacteriaceae; Nosocomial Outbreaks; Netherlands.


#Difficult-to-Treat #Antibiotic-Resistant #GramNegative #Pathogens in the #ICU: #Epidemiology, #Outcomes, and #Treatment (Semin Respir Crit Care Med., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Semin Respir Crit Care Med. 2019 Aug;40(4):419-434. doi: 10.1055/s-0039-1696662. Epub 2019 Oct 4.

Difficult-to-Treat Antibiotic-Resistant Gram-Negative Pathogens in the Intensive Care Unit: Epidemiology, Outcomes, and Treatment.

Strich JR1,2, Kadri SS1.

Author information: 1 Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, Maryland. 2 United States Public Health Service, Commissioned Corps, Rockville, Maryland.



Antibiotic resistance among gram-negative pathogens is a world-wide problem that poses a constant threat to patients in the intensive care unit and a therapeutic challenge for the intensivist. Furthermore, the substantial economic burden and increased mortality associated with infections due to highly resistant gram-negative pathogens exacerbate these challenges. Understanding the mechanisms, epidemiology, and risk factors for these infections is paramount to the successful control of outbreaks and for guiding therapy which often entails use of antibiotics with suboptimal efficacy and/or toxicity profiles. In this review we will discuss the global epidemiology, burden, risk factors, and treatment of highly resistant gram-negative infections as they apply to the intensive care population.

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

PMID: 31585469 DOI: 10.1055/s-0039-1696662

Keywords: Antibiotics; Drugs Resistance; Intensive Care; Gram Negative Bacteria.