#Colistin heteroresistance and the involvement of the PmrAB regulatory system in #Acinetobacter baumannii (Antimicrob Agents Chemother., abstract)

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

Colistin heteroresistance and the involvement of the PmrAB regulatory system in Acinetobacter baumannii

Yannick Charretier a#, Seydina M. Diene a, Damien Baud a, Sonia Chatellier b, Emmanuelle Santiago-Allexant c, Alex van Belkum d, Ghislaine Guigon c and Jacques Schrenzel a

Author Affiliations: a Genomic Research Laboratory, Service of Infectious Diseases, Geneva University Hospitals, Geneva, Switzerland. b Innovation Unit, bioMérieux SA, La Balme Les Grottes, France. c Innovation Unit, bioMérieux SA, Marcy l’Etoile, France. d Data Analytics Unit, bioMérieux SA, La Balme Les Grottes, France.

 

ABSTRACT

Multidrug-resistant Acinetobacter baumannii infection has recently emerged as a worldwide clinical problem and colistin is increasingly being used for last resort therapy. Despite its favorable bacterial killing, resistance and heteroresistance (HR) to colistin have been described. The purpose of the present study is to investigate the role of the PmrAB regulatory pathway in laboratory-selected mutants representative of global epidemic strains. From three unrelated A. baumanniiclinical strains (Sequence Type 2, 3 and 20), eight colistin resistant mutants were selected. Half of the mutants showed HR to colistin according to the reference method (Population Analysis Profiling), whereas the other half exhibited stable resistance. M12I mutation within pmrA and M308R, S144KLAGS and P170L mutations for pmrB, were associated with HR to colistin while T235I, A226T and P233S mutations within pmrB were associated with stable resistance. The transcripts levels of the pmrCAB operon were upregulated in all the mutants. Compensatory mutations were explored for some mutants. A single mutant (T235I) displayed a compensatory mutation through ISAba1 mobilization within the pmrB gene that was associated with the loss of colistin resistance. The mutant resistance phenotype associated with T235I was partially restored in a trans-complementation assay turning to HR. The level of colistin resistance is correlated with the level of expression of pmrC in the trans-complemented strains. This report shows the role of different mutations in the PmrAB regulatory pathway and warns on the development of colistin HR that could be present but not easily detected through routine testing.

 

FOOTNOTES

#Address correspondence to Yannick Charretier, yannick.charretier@genomic.ch.

Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Colistin; Acinetobacter baumannii.

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Extinction of #Zika virus and #Usutu virus by lethal #mutagenesis reveals different patterns of sensitivity to three mutagenic drugs (Antimicrob Agents Chemother., abstract)

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

Extinction of Zika virus and Usutu virus by lethal mutagenesis reveals different patterns of sensitivity to three mutagenic drugs

Maria Rosaria Bassi a, Raquel Navarro Sempere a, Prashansa Meyn a, Charlotta Polacek b and Armando Arias a#

Author Affiliations: Technical University of Denmark, National Veterinary Instiutute (DTU Vet), Kemitorvet, 2800 Lyngby, Denmark{a}; Statens Serum Institut, Copenhagen, Denmark{b}

 

ABSTRACT

Flaviviruses constitute an increasing source of public health concern with growing numbers of pathogens causing disease, and a geographic spread to temperate climates. Despite a large body of evidence supporting mutagenesis as a conceivable antiviral strategy, there is currently no data on the sensitivity to increased mutagenesis for Zika virus (ZIKV) and Usutu virus (USUV), two emerging flaviviral threats. In this study, we demonstrate that both viruses are sensitive to three ribonucleosides that have shown mutagenic activity against other RNA viruses – favipiravir, ribavirin and 5-fluorouracil – while they remain unaffected by a mutagenic deoxyribonucleoside. Serial cell culture passages of ZIKV in the presence of these compounds resulted in the rapid extinction of infectivity, suggesting elevated sensitivity to mutagenesis. USUV extinction was achieved when a 10-fold dilution was applied between every passage, but not in experiments involving undiluted virus, indicating an overall lower susceptibility than ZIKV. Although both viruses are inhibited by the same three drugs, ZIKV is relatively more susceptive to serial passage in the presence of purine analogues (favipiravir and ribavirin) while USUV replication is suppressed more efficiently by 5-fluorouracil. These differences in sensitivity typically correlate with the increases in the mutation frequencies observed in each nucleoside treatment. These results are relevant to the development of efficient therapies based on lethal mutagenesis, and support the rational selection of different mutagenic nucleosides for each pathogen. We will discuss the implications of these results to the fidelity of flavivirus replication, and the design of antiviral therapies based on lethal mutagenesis.

 

FOOTNOTES

#Address correspondence to Armando Arias, arae@vet.dtu.dk

Copyright © 2018 Bassi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Flavivirus; Antivirals; Zika Virus; Usutu Virus; Ribavirin; Favipiravir; 5-Fluorouracil.

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#Neisseria meningitidis #antimicrobial #resistance in #Italy, 2006-2016 (Antimicrob Agents Chemother., abstract)

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

Neisseria meningitidis antimicrobial resistance in Italy, 2006-2016

Paola Vacca1, Cecilia Fazio1, Arianna Neri1, Luigina Ambrosio1, Annapina Palmieri1 and Paola Stefanelli1#

Author Affiliations: 1 Department Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy

 

ABSTRACT

The aim of the study was to evaluate the antimicrobial susceptibility of 866 Neisseria meningitidis invasive strains during 11-years of surveillance in Italy. Two and six strains were resistant to ciprofloxacin and rifampin, respectively. Forty-five percent were penicillin intermediate (PenI) associated with hypervirulent serogroup C clonal complex 11. All the strains were susceptible to cephalosporins.

 

FOOTNOTES

#Corresponding author: Dr. Paola Stefanelli, Phone: +39 06 49902126, Fax: +39 06 49387112, Email: paola.stefanelli@iss.it

Copyright © 2018 Vacca et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Antibiotics; Drugs Resistance; Neisseria meningitidis; Ciprofloxacin; Rifampin.

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#Safety, pharmacokinetics, and #immunogenicity of a co-formulated cocktail of 3 #human #mAbs targeting #Ebola virus glycoprotein in healthy adults: a randomised, first-in-human phase 1 study (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Safety, pharmacokinetics, and immunogenicity of a co-formulated cocktail of three human monoclonal antibodies targeting Ebola virus glycoprotein in healthy adults: a randomised, first-in-human phase 1 study

Sumathi Sivapalasingam, MD, Mohamed Kamal, PhD, Rabih Slim, PhD, Romana Hosain, MD, Weiping Shao, PhD, Randall Stoltz, MD, Joseph Yen, PhD, Laura G Pologe, PhD, Yuan Cao, PhD, Michael Partridge, PhD, Giane Sumner, PhD, Leah Lipsich, PhD

Published: 18 June 2018 / DOI: https://doi.org/10.1016/S1473-3099(18)30397-9

© 2018 Elsevier Ltd. All rights reserved.

 

Summary

Background

REGN3470-3471-3479 is a co-formulated cocktail of three human monoclonal antibodies targeting three non-overlapping epitopes on Ebola virus. We investigated safety, tolerability, pharmacokinetics, and anti-drug antibodies in healthy adults.

Methods

This randomised, double-blind, placebo-controlled, dose-escalation study was done at a phase 1 unit in the USA. Healthy adults, aged 18–60 years, with a body-mass index of 18·0–30·0 kg/m2 were randomly assigned (3:1) to receive a single intravenous dose of REGN3470-3471-3479 or placebo on day 1 (baseline) in one of the four sequential ascending intravenous dose cohorts (3 mg/kg, 15 mg/kg, 60 mg/kg, and 150 mg/kg). Site investigators and participants were masked to the treatment assignment, whereas designated personnel at the site who prepared and generated the study medication were aware of the randomisation treatment assignments. The primary outcome was safety and the secondary outcomes were the pharmacokinetic profiles and immunogenicity. Study assessments were done the day before study drug administration, on the day of drug administration, on day 2 (before discharge), on days 3, 4, 8, 15, 29, 57, 85, 113, and 141, and at the end of study on day 169. The safety analysis included all randomised participants who received study drug. This trial is registered with ClinicalTrials.gov, number NCT002777151.

Findings

Between May 18, 2016, and October 27, 2016, 70 adults were screened and 24 participants were enrolled in the study. 18 participants were assigned to and received REGN3470-3471-3479, and six participants were assigned to and received placebo as a single intravenous infusion. 19 treatment-emergent adverse events occurred in the combined REGN3470-3471-3479 treatment groups, and four treatment-emergent adverse events occurred in combined placebo groups. Adverse events were transient and mild-to-moderate in severity. The most common treatment-emergent adverse event was headache (six [33%] of 18 participants in the combined REGN3470-3471-3479 group vs none of six participants in the placebo group. Headaches were mild-to-moderate in severity, with onset between 2 h and 27 days after start of study drug infusion. There were no deaths, serious adverse events, or adverse events that led to study discontinuation. The pharmacokinetics of each antibody was linear, with mean half-lives of 27·3 days for REGN3471, 21·7 days for REGN3470, and 23·3 days for REGN3479. No participants tested positive for anti-REGN3470, anti-REGN3471, or anti-REGN3479 antibodies.

Interpretation

REGN3470-3471-3479 was well tolerated, displayed linear pharmacokinetics, and did not lead to detectable immunogenicity. These data support further clinical development of REGN3470-3471-3479 as a single-dose therapeutic drug for acute Ebola virus infection.

Funding

The Department of Health and Human Services, the Office of the Assistant Secretary for Preparedness and Response, and the Biomedical Advanced Research and Development Authority.

Keywords: Ebola; Monoclonal Antibodies.

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Current #level and #rate of #warming determine #emissions #budgets under ambitious #mitigation (Nat Geosci., abstract)

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

Current level and rate of warming determine emissions budgets under ambitious mitigation

Nicholas J. Leach, Richard J. Millar, Karsten Haustein, Stuart Jenkins, Euan Graham & Myles R. Allen

Nature Geoscience (2018)
Abstract

Some of the differences between recent estimates of the remaining budget of carbon dioxide (CO2) emissions consistent with limiting warming to 1.5 °C arise from different estimates of the level of warming to date relative to pre-industrial conditions, but not all. Here we show that, for simple geometrical reasons, the combination of both the level and rate of human-induced warming provides a remarkably accurate prediction of remaining emission budgets to peak warming across a broad range of scenarios, if budgets are expressed in terms of CO2-forcing-equivalent emissions. These in turn predict CO2 emissions budgets if (but only if) the fractional contribution of non-CO2 drivers to warming remains approximately unchanged, as it does in some ambitious mitigation scenarios, indicating a best-estimate remaining budget for 1.5 °C of about 22 years’ current emissions from mid-2017, with a ‘likely’ (1 standard error) range of 13–32 years. This provides a simple, transparent and model-independent metric of progress towards an ambitious temperature stabilization goal that could be used to inform the Paris Agreement stocktake process. It is less applicable to less ambitious goals. Alternative definitions of current warming and scenarios for non-CO2 drivers give lower 1.5 °C budgets. Lower budgets based on the MAGICC simple modelling system widely used in integrated assessment studies reflect its relatively high simulated current warming rates.

Keywords: Climate Change; Global Warming; International Cooperation.

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#Human #infection of novel #avian #influenza A(#H7N4) virus (J Infect., abstract)

[Source: Journal of Infection, full page: (LINK). Abstract, edited.]

Human infection of novel avian influenza A(H7N4) virus

Xue-Cheng Tong, Shan-Shan Weng, Feng Xue, Xing Wu, Tian-Min Xu, Wen-Hong Zhang

DOI: https://doi.org/10.1016/j.jinf.2018.06.002

Publication History

Published online: June 10, 2018 – Accepted: June 4, 2018 – Received in revised form: June 2, 2018 – Received:May 20, 2018

 

Highlights

  • We report the first case of avian influenza A(H7N4) infection in human beings.
  • The report suggests that the virus can be transmitted from poultry to humans.
  • The patient infected with the novel avian influenza A(H7N4) was cured.
  • Uninfected close contacts indicate little evidence of human-to-human transmission.

 

Abstract

Multiple reassortant strains of novel, highly pathogenic avian influenza A have recently emerged and spread over the world. Here we report on a 68-year-old woman in Jiangsu, China, with influenza A(H7N4) infection and associated illness, which strongly demonstrating the ability of the virus to spread from animals to humans and thus emphasizing the importance of continuous surveillance of the emerging viruses.

Keywords: Avian influenza A, H7N4, Pneumonia

Abbrevation: AIV, avian influenza virus, CT, computed tomography, CDC, Center for Disease Control and Prevention, PCR, polymerase chain reaction

Xue-Cheng Tong, Shan-Shan Weng contributed equally to this article.

© 2018 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Keywords: Avian Influenza; H7N4; Reassortant Strain; Human; China; Jiangsu.

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#Prevalence of asymptomatic #Zika virus infection: a systematic review (Bull World Health Organ., abstract)

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

Bull World Health Organ. 2018 Jun 1;96(6):402-413D. doi: 10.2471/BLT.17.201541. Epub 2018 Apr 27.

Prevalence of asymptomatic Zika virus infection: a systematic review.

Haby MM1, Pinart M2, Elias V3, Reveiz L3.

Author information: 1 Department of Chemical and Biological Sciences, Universidad de Sonora, Blvd Encinas y Rosales S/N, Colonia Centro, C.P. 83000, Hermosillo, Sonora, Mexico. 2 Cochrane Skin Group, The University of Nottingham, Nottingham, England. 3 Pan American Health Organization, Washington, United States of America.

 

Abstract in English, Arabic, Chinese, French, Russian, Spanish

OBJECTIVE:

To conduct a systematic review to estimate the prevalence of asymptomatic Zika virus infection in the general population and in specific population groups.

METHODS:

We searched PubMed®, Embase® and LILACS online databases from inception to 26 January 2018. We included observational epidemiological studies where laboratory testing was used to confirm positive exposure of participants to Zika virus and in which Zika virus symptom status was also recorded. We excluded studies in which having symptoms of Zika virus was a criterion for inclusion. The main outcome assessed was percentage of all Zika virus-positive participants who were asymptomatic. We used a quality-effects approach and the double arcsine transformation for the meta-analysis.

FINDINGS:

We assessed 753 studies for inclusion, of which 23 were included in the meta-analysis, totalling 11 305 Zika virus-positive participants. The high degree of heterogeneity in the studies (I2  = 99%) suggests that the pooled prevalence of asymptomatic Zika virus-positive participants was probably not a robust estimate. Analysis based on subgroups of the population (general population, returned travellers, blood donors, adults with Guillain-Barré syndrome, pregnant women and babies with microcephaly) was not able to explain the heterogeneity. Funnel and Doi plots showed major asymmetry, suggesting selection bias or true heterogeneity.

CONCLUSION:

Better-quality research is needed, using standardized methods, to determine the true prevalence of asymptomatic Zika virus and whether it varies between populations or over time.

PMID: 29904223 PMCID: PMC5996208 DOI: 10.2471/BLT.17.201541

Keywords: Zika Virus.

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