#Oseltamivir #resistance in #severe #influenza A #H1N1pdm09 #pneumonia and #ARDS: a #French multicenter observational cohort study (Clin Infect Dis., abstract)

[Source: Clinical Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Clin Infect Dis. 2019 Sep 20. pii: ciz904. doi: 10.1093/cid/ciz904. [Epub ahead of print]

Oseltamivir resistance in severe influenza A(H1N1)pdm09 pneumonia and acute respiratory distress syndrome: a French multicenter observational cohort study.

Behillil S1, May F2,3, Fourati S4, Luyt CE5, Chicheportiche T5, Sonneville R6, Tandjaoui-Lambiotte Y7, Roux D8, Guérin L9, Mayaux J10, Maury E11, Ferré A12, Georger JF13, Voiriot G14, Enouf V1, van der Werf S1, Dessap AM2,3, de Prost N2,3.

Author information: 1 Unité de Génétique Moléculaire des Virus à ARN et Centre National de Référence des Virus des Infections Respiratoires (dont la grippe), Institut Pasteur, Université Paris Diderot, Sorbonne Paris Cité, Paris, France. 2 Service de Réanimation Médicale, Hôpitaux Universitaires Henri Mondor-Albert Chenevier, Assistance Publique-Hôpitaux de Paris, Créteil, France. 3 Groupe de Recherche Clinique CARMAS, Université Paris-Est Créteil, IMRB, Créteil,  France. 4 Département de Microbiologie, Hôpitaux Universitaires Henri Mondor-Albert Chenevier, Assistance Publique-Hôpitaux de Paris, Créteil, France. 5 Service de Médecine Intensive Réanimation, Hôpital de La Pitié Salpétrière, Assistance Publique-Hôpitaux de Paris, Paris, France. 6 Service de Médecine Intensive Réanimation, Hôpital Bichat Claude Bernard, Assistance Publique-Hôpitaux de Paris, Paris, France. 7 Service de Réanimation médico-chirurgicale, Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, Bobigny, France. 8 Service de réanimation médico-chirurgicale, Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, Colombes,  France; IAME, Université Paris Diderot, Paris, France. 9 Service de réanimation médicale, Hôpital Bicètre, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicètre, France. 10 Service de Réanimation Médicale et Pneumologie, Hôpital de La Pitié Salpétrière, Assistance Publique-Hôpitaux de Paris, Paris, France. 11 Service de Réanimation Médicale, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris, Paris, France. 12 Service de Réanimation, Centre hospitalier de Versailles, Le Chesnay, France. 13 Service de Réanimation, Centre hospitalier Intercommunal de Villeneuve Saint-Georges, Villeneuve Saint-Georges, France. 14 Service de Réanimation Médicale, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France.



In a multicenter cohort study including 22 oseltamivir-treated patients with influenza A(H1N1)pdm09 acute respiratory distress syndrome, prevalence of the H275Y substitution in the neuraminidase, responsible for highly reduced sensitivity to oseltamivir, was 23%. Patients infected with the H275Y mutant virus had higher day-28 mortality than others (80% vs 12%; p=0.011).

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

KEYWORDS: Influenza A Virus, H1N1 Subtype; Oseltamivir; Pneumonia, Viral; Respiratory Distress Syndrome, Adult

PMID: 31538643 DOI: 10.1093/cid/ciz904

Keywords: Seasonal Influenza; H1N1pdm09; Antivirals; Drugs Resistance; Oseltamivir; Pneumonia; ARDS; France.



Replicative #fitness of seasonal #influenza A viruses with decreased susceptibility to #baloxavir (J Infect Dis., abstract)

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

Replicative fitness of seasonal influenza A viruses with decreased susceptibility to baloxavir

Anton Chesnokov, Mira C Patel, Vasiliy P Mishin, Juan A De La Cruz, Lori Lollis, Ha T Nguyen, Vivien Dugan, David E Wentworth, Larisa V Gubareva

The Journal of Infectious Diseases, jiz472, https://doi.org/10.1093/infdis/jiz472

Published: 21 September 2019



Susceptibility of influenza A viruses to baloxavir can be affected by changes at amino acid residue 38 in polymerase acidic (PA) protein. Information on replicative fitness of PA-I38-substituted viruses remains sparse. We demonstrated that substitutions I38L/M/S/T not only had a differential effect on baloxavir susceptibility (9- to 116-fold), but also on in vitro replicative fitness. While I38L conferred undiminished growth, other substitutions led to mild attenuation. In a ferret model, control viruses outcompeted those carrying I38M or I38T substitutions, although their advantage was limited. These findings offer insights into the attributes of baloxavir resistant viruses needed for informed risk assessment.

Cap-dependent endonuclease inhibitor, replicative fitness, polymerase acidic protein, influenza, drug resistance, ferret, baloxavir acid, antiviral

Issue Section: Brief Report

This content is only available as a PDF.

Author notes

These authors contributed equally to this article and share first authorship

Published by Oxford University Press for the Infectious Diseases Society of America 2019. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Keywords: Influenza A; Antivirals; Drugs Resistance; Baloxavir.


Characterization of #cefotaxime #resistant #urinary #Escherichia coli from primary care in South-West #England 2017–18 (J Antimicrob Chemother., abstract)

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

Characterization of cefotaxime-resistant urinary Escherichia coli from primary care in South-West England 2017–18

Jacqueline Findlay, Virginia C Gould, Paul North, Karen E Bowker, Martin O Williams, Alasdair P MacGowan, Matthew B Avison

Journal of Antimicrobial Chemotherapy, dkz397, https://doi.org/10.1093/jac/dkz397

Published: 20 September 2019




Third-generation cephalosporin-resistant Escherichia coli from community-acquired urinary tract infections are increasingly reported worldwide. We sought to determine and characterize the mechanisms of cefotaxime resistance employed by urinary E. coli obtained from primary care, over 12 months, in Bristol and surrounding counties in South-West England.


Cefalexin-resistant E. coli isolates were identified from GP-referred urine samples using disc susceptibility testing. Cefotaxime resistance was determined by subsequent plating onto MIC breakpoint plates. β-Lactamase genes were detected by PCR. WGS was performed on 225 isolates and analyses were performed using the Center for Genomic Epidemiology platform. Patient information provided by the referring general practices was reviewed.


Cefalexin-resistant E. coli (n = 900) isolates were obtained from urines from 146 general practices. Following deduplication by patient approximately 69% (576/836) of isolates were cefotaxime resistant. WGS of 225 isolates identified that the most common cefotaxime-resistance mechanism was blaCTX-M carriage (185/225), followed by plasmid-mediated AmpCs (pAmpCs) (17/225), AmpC hyperproduction (13/225), ESBL blaSHV variants (6/225) or a combination of both blaCTX-M and pAmpC (4/225). Forty-four STs were identified, with ST131 representing 101/225 isolates, within which clade C2 was dominant (54/101). Ciprofloxacin resistance was observed in 128/225 (56.9%) of sequenced isolates, predominantly associated with fluoroquinolone-resistant clones ST131 and ST1193.


Most cefalexin-resistant E. coli isolates were cefotaxime resistant, predominantly caused by blaCTX-M carriage. The correlation between cefotaxime resistance and ciprofloxacin resistance was largely attributable to the high-risk pandemic clones ST131 and ST1193. Localized epidemiological data provide greater resolution than regional data and can be valuable for informing treatment choices in the primary care setting.


© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Antibiotics; Drugs Resistance; Cephalosporins; Fluoroquinolones; E. Coli; UTI; Cefalexin; Cefotaxime; UK; England.


#Global #trends in #antimicrobial #resistance in #animals in low- and middle-income countries (Science, abstract)

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

Global trends in antimicrobial resistance in animals in low- and middle-income countries

Thomas P. Van Boeckel1,2,6,*,†,  João Pires1,6,†, Reshma Silvester2, Cheng Zhao1, Julia Song3,4, Nicola G. Criscuolo1, Marius Gilbert5, Sebastian Bonhoeffer6,‡, Ramanan Laxminarayan1,2,4,‡

1 Institute for Environmental Decisions, ETH Zurich, Zurich, Switzerland. 2 Center for  Disease Dynamics, Economics and Policy, New Delhi, India. 3 Department of Ecology and Evolutionary Biology, Princeton University, Princeton, NJ, USA. 4 Princeton Environmental Institute, Princeton University, Princeton, NJ, USA. 5 Université Libre de Bruxelles (ULB), Brussels, Belgium. 6 Institute for Integrative Biology, ETH Zurich, Zurich, Switzerland.

*Corresponding author. Email: thomas.vanboeckel@env.ethz.ch

† These authors contributed equally to this work.

‡ These authors contributed equally to this work.

Science  20 Sep 2019: Vol. 365, Issue 6459, eaaw1944 / DOI: 10.1126/science.aaw1944


Livestock antibiotic resistance

Most antibiotic use is for livestock, and it is growing with the increase in global demand for meat. It is unclear what the increase in demand for antibiotics means for the occurrence of drug resistance in animals and risk to humans. Van Boeckel et al. describe the global burden of antimicrobial resistance in animals on the basis of systematic reviews over the past 20 years (see the Perspective by Moore). There is a clear increase in the number of resistant bacterial strains occurring in chickens and pigs. The current study provides a much-needed baseline model for low- and middle-income countries and provides a “one health” perspective to which future data can be added.

Science, this issue p. eaaw1944; see also p. 1251


Structured Abstract


The global scale-up in demand for animal protein is the most notable dietary trend of our time. Since 2000, meat production has plateaued in high-income countries but has grown by 68%, 64%, and 40% in Asia, Africa, and South America, respectively. The transition to high-protein diets in low- and middle-income countries (LMICs) has been facilitated by the global expansion of intensive animal production systems in which antimicrobials are used routinely to maintain health and productivity. Globally, 73% of all antimicrobials sold on Earth are used in animals raised for food. A growing body of evidence has linked this practice with the rise of antimicrobial-resistant infections, not just in animals but also in humans. Beyond potentially serious consequences for public health, the reliance on antimicrobials to meet demand for animal protein is a likely threat to the sustainability of the livestock industry, and thus to the livelihood of farmers around the world.


In LMICs, trends in antimicrobial resistance (AMR) in animals are poorly documented. In the absence of systematic surveillance systems, point prevalence surveys represent a largely untapped source of information to map trends in AMR in animals. We use geospatial models to produce global maps of AMR in LMICs and give policy-makers—or a future international panel—a baseline for monitoring AMR levels in animals and target interventions in the regions most affected by the rise of resistance.


We identified 901 point prevalence surveys from LMICs reporting AMR rates in animals for common indicator pathogens: Escherichia coli, Campylobacter spp., nontyphoidal Salmonella spp., and Staphylococcus aureus. From 2000 to 2018, the proportion of antimicrobial compounds with resistance higher than 50% (P50) increased from 0.15 to 0.41 in chickens and from 0.13 to 0.34 in pigs and plateaued between 0.12 and 0.23 in cattle. Global maps of AMR (available at resistancebank.org) show hotspots of resistance in northeastern India, northeastern China, northern Pakistan, Iran, eastern Turkey, the south coast of Brazil, Egypt, the Red River delta in Vietnam, and the areas surrounding Mexico City and Johannesburg. Areas where resistance is just starting to emerge are Kenya, Morocco, Uruguay, southern Brazil, central India, and southern China. Uncertainty in our predictions was greatest in the Andes, the Amazon region, West and Central Africa, the Tibetan plateau, Myanmar, and Indonesia. Dense geographical coverage of point prevalence surveys did not systematically correlate with the presence of hotspots of AMR, such as in Ethiopia, Thailand, Chhattisgarh (India), and Rio Grande do Sul (Brazil). The highest resistance rates were observed with the most commonly used classes of antimicrobials in animal production: tetracyclines, sulfonamides, and penicillins.


The portfolio of antimicrobials used to raise animals for food is rapidly getting depleted, with important consequences for animal health, farmers’ livelihoods, and potentially for human health. Regions affected by the highest levels of AMR should take immediate actions to preserve the efficacy of antimicrobials that are essential in human medicine by restricting their use in animal production. In some middle-income countries, particularly in South America, surveillance must be scaled up to match that of low-income African countries that are currently outperforming them despite more limited resources. Policy-makers coordinating the international response to AMR may consider sparing African countries from the most aggressive measures to restrict access to veterinary drugs, which may undermine livestock-based economic development and rightfully be perceived as unfair. However, in regions where resistance is starting to emerge, there is a window of opportunity to limit the rise of resistance by encouraging a transition to sustainable animal farming practices. High-income countries, where antimicrobials have been used on farms since the 1950s, should support this transition—for example, through a global fund to subsidize improvement in farm-level biosafety and biosecurity.



The global scale-up in demand for animal protein is the most notable dietary trend of our time. Antimicrobial consumption in animals is threefold that of humans and has enabled large-scale animal protein production. The consequences for the development of antimicrobial resistance in animals have received comparatively less attention than in humans. We analyzed 901 point prevalence surveys of pathogens in developing countries to map resistance in animals. China and India represented the largest hotspots of resistance, with new hotspots emerging in Brazil and Kenya. From 2000 to 2018, the proportion of antimicrobials showing resistance above 50% increased from 0.15 to 0.41 in chickens and from 0.13 to 0.34 in pigs. Escalating resistance in animals is anticipated to have important consequences for animal health and, eventually, for human health.

Keywords: Antibiotics; Drugs Resistance; Worldwide; Cattle; Poultry; Pigs.


Conjugative #delivery of #CRISPR-Cas9 for the selective #depletion of #antibiotic-resistant #enterococci (Antimicrob Agents Chemother., abstract)

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

Conjugative delivery of CRISPR-Cas9 for the selective depletion of antibiotic-resistant enterococci

Marinelle Rodrigues, Sara W. McBride, Karthik Hullahalli, Kelli L. Palmer, Breck A. Duerkop

DOI: 10.1128/AAC.01454-19



The innovation of new therapies to combat multidrug-resistant (MDR) bacteria is being outpaced by the continued rise of MDR bacterial infections. Of particular concern are hospital-acquired infections (HAIs) recalcitrant to antibiotic therapies. The Gram-positive intestinal pathobiont Enterococcus faecalis is associated with HAIs and some strains are MDR. Therefore, novel strategies to control E. faecalis populations are needed. We previously characterized an E. faecalis Type II CRISPR-Cas system and demonstrated its utility in the sequence-specific removal of antibiotic resistance determinants. Here we present work describing the adaption of this CRISPR-Cas system into a constitutively expressed module encoded on a pheromone-responsive conjugative plasmid that efficiently transfers to E. faecalis for the selective removal of antibiotic resistance genes. Using in vitro competition assays, we show that these CRISPR-Cas-encoding delivery plasmids, or CRISPR-Cas antimicrobials, can reduce the occurrence of antibiotic resistance in enterococcal populations in a sequence-specific manner. Furthermore, we demonstrate that deployment of CRISPR-Cas antimicrobials in the murine intestine reduces the occurrence of antibiotic-resistant E. faecalis by several orders of magnitude. Finally, we show that E. faecalis donor strains harboring CRISPR-Cas antimicrobials are immune to uptake of antibiotic resistance determinants in vivo. Our results demonstrate that conjugative delivery of CRISPR-Cas antimicrobials may be adaptable for future deployment from probiotic bacteria for exact targeting of defined MDR bacteria or for precision engineering of polymicrobial communities in the mammalian intestine.

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

Keywords: Antibiotics; Drugs Resistance; Enterococcus faecalis; CRISPR; Animal models.


#Antimicrobial #resistance in #MRSA to newer antimicrobial agents (Antimicrob Agents Chemother., abstract)

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

Antimicrobial resistance in methicillin-resistant Staphylococcus aureus to newer antimicrobial agents

Richard R. Watkins, Marisa Holubar, Michael Z. David

DOI: 10.1128/AAC.01216-19



Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) result in significant morbidity and mortality for patients in both community and health care settings. This is primarily due to the difficulty in treating MRSA, which is often resistant to multiple classes of antibiotics. Understanding the mechanisms of antimicrobial resistance (AMR) in MRSA provides insight into the optimal use of antimicrobial agents in clinical practice and also underpins critical aspects of antimicrobial stewardship programs. In this review we delineate the mechanisms, prevalence, and clinical importance of resistance to antibiotics licensed in the past 20 years that target MRSA, as well as new drugs in the pipeline which are likely to be licensed soon. Current gaps in scientific knowledge about MRSA resistance mechanisms are discussed, and topics in the epidemiology of AMR in S. aureus that require further investigation are highlighted.

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

Keywords: Antibiotics; Drugs Resistance; Staphylococcus aureus; MRSA.


#Phenotypic, biochemical and #genetic analysis of #KPC-41, a KPC-3 variant conferring #resistance to #ceftazidime-avibactam and exhibiting reduced #carbapenemase activity (Antimicrob Agents Chemother., abstract)

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

Phenotypic, biochemical and genetic analysis of KPC-41, a KPC-3 variant conferring resistance to ceftazidime-avibactam and exhibiting reduced carbapenemase activity

Linda Mueller, Amandine Masseron, Guy Prod’Hom, Tatiana Galperine, Gilbert Greub, Laurent Poirel, Patrice Nordmann

DOI: 10.1128/AAC.01111-19



A novel KPC variant, KPC-41, was identified in a Klebsiella pneumoniae clinical isolate from Switzerland. This ß-lactamase possessed a three amino-acid insertion (Pro-Asn-Lys) located between amino acids 269 and 270 compared to the KPC-3 amino acid sequence. Cloning and expression of the blaKPC-41 gene in Escherichia coli, followed by determination of MIC values and kinetic parameters, showed that KPC-41, compared to KPC-3, has an increased affinity to ceftazidime and a decreased sensitivity to avibactam, leading to resistance to ceftazidime-avibactam once produced in K. pneumoniae. Furthermore, KPC-41 exhibited a drastic decrease of its carbapenemase activity. This report highlights that a diversity of KPC variants conferring resistance to ceftazidime-avibactam already circulate in Europe.

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

Keywords: Antibiotics; Drugs Resistance; Klebsiella pneumoniae; Ceftazidime; Avibactam.