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Showing 1 - 200 of 370 Journals sorted alphabetically
Acta Biochimica et Biophysica Sinica     Hybrid Journal   (Followers: 6, SJR: 0.881, h-index: 38)
Adaptation     Hybrid Journal   (Followers: 8, SJR: 0.111, h-index: 4)
Aesthetic Surgery J.     Hybrid Journal   (Followers: 6, SJR: 1.538, h-index: 35)
African Affairs     Hybrid Journal   (Followers: 59, SJR: 1.512, h-index: 46)
Age and Ageing     Hybrid Journal   (Followers: 85, SJR: 1.611, h-index: 107)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 16, SJR: 0.935, h-index: 80)
American Entomologist     Full-text available via subscription   (Followers: 6)
American Historical Review     Hybrid Journal   (Followers: 138, SJR: 0.652, h-index: 43)
American J. of Agricultural Economics     Hybrid Journal   (Followers: 40, SJR: 1.441, h-index: 77)
American J. of Epidemiology     Hybrid Journal   (Followers: 170, SJR: 3.047, h-index: 201)
American J. of Hypertension     Hybrid Journal   (Followers: 23, SJR: 1.397, h-index: 111)
American J. of Jurisprudence     Hybrid Journal   (Followers: 17)
American J. of Legal History     Full-text available via subscription   (Followers: 6, SJR: 0.151, h-index: 7)
American Law and Economics Review     Hybrid Journal   (Followers: 25, SJR: 0.824, h-index: 23)
American Literary History     Hybrid Journal   (Followers: 12, SJR: 0.185, h-index: 22)
Analysis     Hybrid Journal   (Followers: 23)
Annals of Botany     Hybrid Journal   (Followers: 36, SJR: 1.912, h-index: 124)
Annals of Occupational Hygiene     Hybrid Journal   (Followers: 28, SJR: 0.837, h-index: 57)
Annals of Oncology     Hybrid Journal   (Followers: 49, SJR: 4.362, h-index: 173)
Annals of the Entomological Society of America     Full-text available via subscription   (Followers: 8, SJR: 0.642, h-index: 53)
Annals of Work Exposures and Health     Hybrid Journal  
AoB Plants     Open Access   (Followers: 4, SJR: 0.78, h-index: 10)
Applied Economic Perspectives and Policy     Hybrid Journal   (Followers: 19, SJR: 0.884, h-index: 31)
Applied Linguistics     Hybrid Journal   (Followers: 51, SJR: 1.749, h-index: 63)
Applied Mathematics Research eXpress     Hybrid Journal   (Followers: 1, SJR: 0.779, h-index: 11)
Arbitration Intl.     Full-text available via subscription   (Followers: 20)
Arbitration Law Reports and Review     Hybrid Journal   (Followers: 13)
Archives of Clinical Neuropsychology     Hybrid Journal   (Followers: 26, SJR: 0.96, h-index: 71)
Aristotelian Society Supplementary Volume     Hybrid Journal   (Followers: 2, SJR: 0.102, h-index: 20)
Arthropod Management Tests     Hybrid Journal   (Followers: 2)
Astronomy & Geophysics     Hybrid Journal   (Followers: 47, SJR: 0.144, h-index: 15)
Behavioral Ecology     Hybrid Journal   (Followers: 50, SJR: 1.698, h-index: 92)
Bioinformatics     Hybrid Journal   (Followers: 309, SJR: 4.643, h-index: 271)
Biology Methods and Protocols     Hybrid Journal  
Biology of Reproduction     Full-text available via subscription   (Followers: 9, SJR: 1.646, h-index: 149)
Biometrika     Hybrid Journal   (Followers: 19, SJR: 2.801, h-index: 90)
BioScience     Hybrid Journal   (Followers: 30, SJR: 2.374, h-index: 154)
Bioscience Horizons : The National Undergraduate Research J.     Open Access   (Followers: 1, SJR: 0.213, h-index: 9)
Biostatistics     Hybrid Journal   (Followers: 16, SJR: 1.955, h-index: 55)
BJA : British J. of Anaesthesia     Hybrid Journal   (Followers: 149, SJR: 2.314, h-index: 133)
BJA Education     Hybrid Journal   (Followers: 64, SJR: 0.272, h-index: 20)
Brain     Hybrid Journal   (Followers: 61, SJR: 6.097, h-index: 264)
Briefings in Bioinformatics     Hybrid Journal   (Followers: 44, SJR: 4.086, h-index: 73)
Briefings in Functional Genomics     Hybrid Journal   (Followers: 4, SJR: 1.771, h-index: 50)
British J. for the Philosophy of Science     Hybrid Journal   (Followers: 34, SJR: 1.267, h-index: 38)
British J. of Aesthetics     Hybrid Journal   (Followers: 26, SJR: 0.217, h-index: 18)
British J. of Criminology     Hybrid Journal   (Followers: 528, SJR: 1.373, h-index: 62)
British J. of Social Work     Hybrid Journal   (Followers: 83, SJR: 0.771, h-index: 53)
British Medical Bulletin     Hybrid Journal   (Followers: 7, SJR: 1.391, h-index: 84)
British Yearbook of Intl. Law     Hybrid Journal   (Followers: 27)
Bulletin of the London Mathematical Society     Hybrid Journal   (Followers: 3, SJR: 1.474, h-index: 31)
Cambridge J. of Economics     Hybrid Journal   (Followers: 58, SJR: 0.957, h-index: 59)
Cambridge J. of Regions, Economy and Society     Hybrid Journal   (Followers: 11, SJR: 1.067, h-index: 22)
Cambridge Quarterly     Hybrid Journal   (Followers: 11, SJR: 0.1, h-index: 7)
Capital Markets Law J.     Hybrid Journal   (Followers: 1)
Carcinogenesis     Hybrid Journal   (Followers: 2, SJR: 2.439, h-index: 167)
Cardiovascular Research     Hybrid Journal   (Followers: 12, SJR: 2.897, h-index: 175)
Cerebral Cortex     Hybrid Journal   (Followers: 41, SJR: 4.827, h-index: 192)
CESifo Economic Studies     Hybrid Journal   (Followers: 16, SJR: 0.501, h-index: 19)
Chemical Senses     Hybrid Journal   (Followers: 1, SJR: 1.436, h-index: 76)
Children and Schools     Hybrid Journal   (Followers: 6, SJR: 0.211, h-index: 18)
Chinese J. of Comparative Law     Hybrid Journal   (Followers: 3)
Chinese J. of Intl. Law     Hybrid Journal   (Followers: 21, SJR: 0.737, h-index: 11)
Chinese J. of Intl. Politics     Hybrid Journal   (Followers: 9, SJR: 1.238, h-index: 15)
Christian Bioethics: Non-Ecumenical Studies in Medical Morality     Hybrid Journal   (Followers: 11, SJR: 0.191, h-index: 8)
Classical Receptions J.     Hybrid Journal   (Followers: 24, SJR: 0.1, h-index: 3)
Clinical Infectious Diseases     Hybrid Journal   (Followers: 59, SJR: 4.742, h-index: 261)
Clinical Kidney J.     Open Access   (Followers: 4, SJR: 0.338, h-index: 19)
Community Development J.     Hybrid Journal   (Followers: 24, SJR: 0.47, h-index: 28)
Computer J.     Hybrid Journal   (Followers: 7, SJR: 0.371, h-index: 47)
Conservation Physiology     Open Access   (Followers: 2)
Contemporary Women's Writing     Hybrid Journal   (Followers: 11, SJR: 0.111, h-index: 3)
Contributions to Political Economy     Hybrid Journal   (Followers: 5, SJR: 0.313, h-index: 10)
Critical Values     Full-text available via subscription  
Current Legal Problems     Hybrid Journal   (Followers: 26)
Current Zoology     Full-text available via subscription   (SJR: 0.999, h-index: 20)
Database : The J. of Biological Databases and Curation     Open Access   (Followers: 11, SJR: 1.068, h-index: 24)
Digital Scholarship in the Humanities     Hybrid Journal   (Followers: 12)
Diplomatic History     Hybrid Journal   (Followers: 19, SJR: 0.296, h-index: 22)
DNA Research     Open Access   (Followers: 4, SJR: 2.42, h-index: 77)
Dynamics and Statistics of the Climate System     Open Access   (Followers: 3)
Early Music     Hybrid Journal   (Followers: 15, SJR: 0.124, h-index: 11)
Economic Policy     Hybrid Journal   (Followers: 63, SJR: 2.052, h-index: 52)
ELT J.     Hybrid Journal   (Followers: 25, SJR: 1.26, h-index: 23)
English Historical Review     Hybrid Journal   (Followers: 51, SJR: 0.311, h-index: 10)
English: J. of the English Association     Hybrid Journal   (Followers: 13, SJR: 0.144, h-index: 3)
Environmental Entomology     Full-text available via subscription   (Followers: 11, SJR: 0.791, h-index: 66)
Environmental Epigenetics     Open Access   (Followers: 1)
Environmental History     Hybrid Journal   (Followers: 26, SJR: 0.197, h-index: 25)
EP-Europace     Hybrid Journal   (Followers: 2, SJR: 2.201, h-index: 71)
Epidemiologic Reviews     Hybrid Journal   (Followers: 10, SJR: 3.917, h-index: 81)
ESHRE Monographs     Hybrid Journal  
Essays in Criticism     Hybrid Journal   (Followers: 16, SJR: 0.1, h-index: 6)
European Heart J.     Hybrid Journal   (Followers: 49, SJR: 6.997, h-index: 227)
European Heart J. - Cardiovascular Imaging     Hybrid Journal   (Followers: 8, SJR: 2.044, h-index: 58)
European Heart J. - Cardiovascular Pharmacotherapy     Full-text available via subscription   (Followers: 1)
European Heart J. - Quality of Care and Clinical Outcomes     Hybrid Journal  
European Heart J. Supplements     Hybrid Journal   (Followers: 7, SJR: 0.152, h-index: 31)
European J. of Cardio-Thoracic Surgery     Hybrid Journal   (Followers: 8, SJR: 1.568, h-index: 104)
European J. of Intl. Law     Hybrid Journal   (Followers: 159, SJR: 0.722, h-index: 38)
European J. of Orthodontics     Hybrid Journal   (Followers: 4, SJR: 1.09, h-index: 60)
European J. of Public Health     Hybrid Journal   (Followers: 22, SJR: 1.284, h-index: 64)
European Review of Agricultural Economics     Hybrid Journal   (Followers: 11, SJR: 1.549, h-index: 42)
European Review of Economic History     Hybrid Journal   (Followers: 28, SJR: 0.628, h-index: 24)
European Sociological Review     Hybrid Journal   (Followers: 41, SJR: 2.061, h-index: 53)
Evolution, Medicine, and Public Health     Open Access   (Followers: 11)
Family Practice     Hybrid Journal   (Followers: 11, SJR: 1.048, h-index: 77)
Fems Microbiology Ecology     Hybrid Journal   (Followers: 9, SJR: 1.687, h-index: 115)
Fems Microbiology Letters     Hybrid Journal   (Followers: 20, SJR: 1.126, h-index: 118)
Fems Microbiology Reviews     Hybrid Journal   (Followers: 25, SJR: 7.587, h-index: 150)
Fems Yeast Research     Hybrid Journal   (Followers: 13, SJR: 1.213, h-index: 66)
Foreign Policy Analysis     Hybrid Journal   (Followers: 22, SJR: 0.859, h-index: 10)
Forestry: An Intl. J. of Forest Research     Hybrid Journal   (Followers: 16, SJR: 0.903, h-index: 44)
Forum for Modern Language Studies     Hybrid Journal   (Followers: 6, SJR: 0.108, h-index: 6)
French History     Hybrid Journal   (Followers: 32, SJR: 0.123, h-index: 10)
French Studies     Hybrid Journal   (Followers: 20, SJR: 0.119, h-index: 7)
French Studies Bulletin     Hybrid Journal   (Followers: 10, SJR: 0.102, h-index: 3)
Gastroenterology Report     Open Access   (Followers: 2)
Genome Biology and Evolution     Open Access   (Followers: 10, SJR: 3.22, h-index: 39)
Geophysical J. Intl.     Hybrid Journal   (Followers: 34, SJR: 1.839, h-index: 119)
German History     Hybrid Journal   (Followers: 25, SJR: 0.437, h-index: 13)
GigaScience     Open Access   (Followers: 3)
Global Summitry     Hybrid Journal  
Glycobiology     Hybrid Journal   (Followers: 14, SJR: 1.692, h-index: 101)
Health and Social Work     Hybrid Journal   (Followers: 49, SJR: 0.505, h-index: 40)
Health Education Research     Hybrid Journal   (Followers: 12, SJR: 0.814, h-index: 80)
Health Policy and Planning     Hybrid Journal   (Followers: 20, SJR: 1.628, h-index: 66)
Health Promotion Intl.     Hybrid Journal   (Followers: 21, SJR: 0.664, h-index: 60)
History Workshop J.     Hybrid Journal   (Followers: 27, SJR: 0.313, h-index: 20)
Holocaust and Genocide Studies     Hybrid Journal   (Followers: 24, SJR: 0.115, h-index: 13)
Human Molecular Genetics     Hybrid Journal   (Followers: 9, SJR: 4.288, h-index: 233)
Human Reproduction     Hybrid Journal   (Followers: 79, SJR: 2.271, h-index: 179)
Human Reproduction Update     Hybrid Journal   (Followers: 17, SJR: 4.678, h-index: 128)
Human Rights Law Review     Hybrid Journal   (Followers: 60, SJR: 0.7, h-index: 21)
ICES J. of Marine Science: J. du Conseil     Hybrid Journal   (Followers: 53, SJR: 1.233, h-index: 88)
ICSID Review     Hybrid Journal   (Followers: 10)
ILAR J.     Hybrid Journal   (Followers: 1, SJR: 1.099, h-index: 51)
IMA J. of Applied Mathematics     Hybrid Journal   (SJR: 0.329, h-index: 26)
IMA J. of Management Mathematics     Hybrid Journal   (Followers: 2, SJR: 0.351, h-index: 20)
IMA J. of Mathematical Control and Information     Hybrid Journal   (Followers: 2, SJR: 0.661, h-index: 28)
IMA J. of Numerical Analysis - advance access     Hybrid Journal   (SJR: 2.032, h-index: 44)
Industrial and Corporate Change     Hybrid Journal   (Followers: 8, SJR: 1.37, h-index: 81)
Industrial Law J.     Hybrid Journal   (Followers: 30, SJR: 0.184, h-index: 15)
Information and Inference     Free  
Integrative and Comparative Biology     Hybrid Journal   (Followers: 8, SJR: 1.911, h-index: 90)
Interacting with Computers     Hybrid Journal   (Followers: 10, SJR: 0.529, h-index: 59)
Interactive CardioVascular and Thoracic Surgery     Hybrid Journal   (Followers: 5, SJR: 0.743, h-index: 35)
Intl. Affairs     Hybrid Journal   (Followers: 52, SJR: 1.264, h-index: 53)
Intl. Data Privacy Law     Hybrid Journal   (Followers: 28)
Intl. Health     Hybrid Journal   (Followers: 5, SJR: 0.835, h-index: 15)
Intl. Immunology     Hybrid Journal   (Followers: 3, SJR: 1.613, h-index: 111)
Intl. J. for Quality in Health Care     Hybrid Journal   (Followers: 33, SJR: 1.593, h-index: 69)
Intl. J. of Constitutional Law     Hybrid Journal   (Followers: 60, SJR: 0.613, h-index: 19)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 147, SJR: 4.381, h-index: 145)
Intl. J. of Law and Information Technology     Hybrid Journal   (Followers: 4, SJR: 0.247, h-index: 8)
Intl. J. of Law, Policy and the Family     Hybrid Journal   (Followers: 29, SJR: 0.307, h-index: 15)
Intl. J. of Lexicography     Hybrid Journal   (Followers: 8, SJR: 0.404, h-index: 18)
Intl. J. of Low-Carbon Technologies     Open Access   (Followers: 1, SJR: 0.457, h-index: 12)
Intl. J. of Neuropsychopharmacology     Open Access   (Followers: 3, SJR: 1.69, h-index: 79)
Intl. J. of Public Opinion Research     Hybrid Journal   (Followers: 9, SJR: 0.906, h-index: 33)
Intl. J. of Refugee Law     Hybrid Journal   (Followers: 33, SJR: 0.231, h-index: 21)
Intl. J. of Transitional Justice     Hybrid Journal   (Followers: 13, SJR: 0.833, h-index: 12)
Intl. Mathematics Research Notices     Hybrid Journal   (Followers: 1, SJR: 2.052, h-index: 42)
Intl. Political Sociology     Hybrid Journal   (Followers: 31, SJR: 1.339, h-index: 19)
Intl. Relations of the Asia-Pacific     Hybrid Journal   (Followers: 18, SJR: 0.539, h-index: 17)
Intl. Studies Perspectives     Hybrid Journal   (Followers: 7, SJR: 0.998, h-index: 28)
Intl. Studies Quarterly     Hybrid Journal   (Followers: 39, SJR: 2.184, h-index: 68)
Intl. Studies Review     Hybrid Journal   (Followers: 18, SJR: 0.783, h-index: 38)
ISLE: Interdisciplinary Studies in Literature and Environment     Hybrid Journal   (Followers: 1, SJR: 0.155, h-index: 4)
ITNOW     Hybrid Journal   (Followers: 2, SJR: 0.102, h-index: 4)
J. of African Economies     Hybrid Journal   (Followers: 15, SJR: 0.647, h-index: 30)
J. of American History     Hybrid Journal   (Followers: 43, SJR: 0.286, h-index: 34)
J. of Analytical Toxicology     Hybrid Journal   (Followers: 13, SJR: 1.038, h-index: 60)
J. of Antimicrobial Chemotherapy     Hybrid Journal   (Followers: 13, SJR: 2.157, h-index: 149)
J. of Antitrust Enforcement     Hybrid Journal   (Followers: 1)
J. of Applied Poultry Research     Hybrid Journal   (Followers: 3, SJR: 0.563, h-index: 43)
J. of Biochemistry     Hybrid Journal   (Followers: 43, SJR: 1.341, h-index: 96)
J. of Chromatographic Science     Hybrid Journal   (Followers: 16, SJR: 0.448, h-index: 42)
J. of Church and State     Hybrid Journal   (Followers: 11, SJR: 0.167, h-index: 11)
J. of Competition Law and Economics     Hybrid Journal   (Followers: 35, SJR: 0.442, h-index: 16)
J. of Complex Networks     Hybrid Journal   (Followers: 1, SJR: 1.165, h-index: 5)
J. of Conflict and Security Law     Hybrid Journal   (Followers: 13, SJR: 0.196, h-index: 15)
J. of Consumer Research     Full-text available via subscription   (Followers: 43, SJR: 4.896, h-index: 121)
J. of Crohn's and Colitis     Hybrid Journal   (Followers: 10, SJR: 1.543, h-index: 37)
J. of Cybersecurity     Hybrid Journal   (Followers: 3)
J. of Deaf Studies and Deaf Education     Hybrid Journal   (Followers: 9, SJR: 0.69, h-index: 36)
J. of Design History     Hybrid Journal   (Followers: 16, SJR: 0.166, h-index: 14)
J. of Economic Entomology     Full-text available via subscription   (Followers: 6, SJR: 0.894, h-index: 76)
J. of Economic Geography     Hybrid Journal   (Followers: 39, SJR: 2.909, h-index: 69)
J. of Environmental Law     Hybrid Journal   (Followers: 23, SJR: 0.457, h-index: 20)
J. of European Competition Law & Practice     Hybrid Journal   (Followers: 19)
J. of Experimental Botany     Hybrid Journal   (Followers: 14, SJR: 2.798, h-index: 163)
J. of Financial Econometrics     Hybrid Journal   (Followers: 23, SJR: 1.314, h-index: 27)
J. of Global Security Studies     Hybrid Journal   (Followers: 3)
J. of Heredity     Hybrid Journal   (Followers: 4, SJR: 1.024, h-index: 76)
J. of Hindu Studies     Hybrid Journal   (Followers: 7, SJR: 0.186, h-index: 3)
J. of Hip Preservation Surgery     Open Access  
J. of Human Rights Practice     Hybrid Journal   (Followers: 20, SJR: 0.399, h-index: 10)
J. of Infectious Diseases     Hybrid Journal   (Followers: 39, SJR: 4, h-index: 209)
J. of Insect Science     Open Access   (Followers: 8, SJR: 0.388, h-index: 31)

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Journal Cover Journal of Antimicrobial Chemotherapy
  [SJR: 2.157]   [H-I: 149]   [13 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0305-7453 - ISSN (Online) 1460-2091
   Published by Oxford University Press Homepage  [370 journals]
  • mcr-1 and mcr-2 variant genes identified in Moraxella species isolated
           from pigs in Great Britain from 2014 to 2015
    • Authors: AbuOun M; Stubberfield EJ, Duggett NA, et al.
      Abstract: AbstractObjectivesTo determine the occurrence of mcr-1 and mcr-2 genes in Gram-negative bacteria isolated from healthy pigs in Great Britain.MethodsGram-negative bacteria (n = 657) isolated from pigs between 2014 and 2015 were examined by WGS.ResultsVariants of mcr-1 and mcr-2 were identified in Moraxella spp. isolated from pooled caecal contents of healthy pigs at slaughter collected from six farms in Great Britain. Other bacteria, including Escherichia coli from the same farms, were not detected harbouring mcr-1 or mcr-2. A Moraxella porci-like isolate, MSG13-C03, harboured MCR-1.10 with 98.7% identity to MCR-1, and a Moraxella pluranimalium-like isolate, MSG47-C17, harboured an MCR-2.2 variant with 87.9% identity to MCR-2, from E. coli; the isolates had colistin MICs of 1–2 mg/L. No intact insertion elements were identified in either MSG13-C03 or MSG47-C17, although MSG13-C03 harboured the conserved nucleotides abutting the ISApl1 composite transposon found in E. coli plasmids and the intervening ∼2.6 kb fragment showed 97% identity. Six Moraxella osloensis isolates were positive for phosphoethanolamine transferase (EptA). They shared 62%–64.5% identity to MCR-1 and MCR-2, with colistin MICs from 2 to 4 mg/L. Phylogenetic analysis indicated that MCR and EptA have evolved from a common ancestor. In addition to mcr, the β-lactamase gene, blaBRO-1, was found in both isolates, whilst the tetracycline resistance gene, tetL, was found in MSG47-C17.ConclusionsOur results add further evidence for the mobilization of the mcr-pap2 unit from Moraxella via composite transposons leading to its global dissemination. The presence of mcr-pap2 from recent Moraxella isolates indicates they may comprise a reservoir for mcr.
      PubDate: 2017-08-11
  • Plazomicin activity against polymyxin-resistant Enterobacteriaceae,
           including MCR-1-producing isolates
    • Authors: Denervaud-Tendon V; Poirel L, Connolly LE, et al.
      Abstract: AbstractObjectivesPlazomicin, a novel aminoglycoside with in vitro activity against MDR Gram-negative organisms, is under development to treat patients with serious enterobacterial infections. We evaluated the activity of plazomicin and comparators against colistin-resistant enterobacterial isolates.MethodsSusceptibility to plazomicin and comparators was tested by broth microdilution for a collection of 95 colistin-resistant enterobacterial isolates collected from 29 hospitals in eight countries. Forty-two isolates (Klebsiella pneumoniae and Klebsiella oxytoca) possessed chromosomally encoded resistance mechanisms to colistin, 21 isolates (Escherichia coli and Salmonella enterica) expressed the mcr-1 gene, 8 isolates (Serratia, Proteus, Morganella and Hafnia) were intrinsically resistant to colistin and 24 isolates (K. pneumoniae, E. coli and Enterobacter spp.) had undefined, non-mcr-1 mechanisms. Susceptibility profiles were defined according to CLSI for aminoglycosides and to EUCAST for colistin and tigecycline.ResultsPlazomicin inhibited 89.5% and 93.7% of the colistin-resistant enterobacterial isolates at ≤ 2 and ≤4 mg/L, respectively. MICs of plazomicin were ≤2 mg/L for all of the mcr-1 positive isolates and ≤4 mg/L for all the intrinsic colistin-resistant Enterobacteriaceae. Non-susceptibility to currently marketed aminoglycosides was common: amikacin, 16.8%; gentamicin, 47.4%; and tobramycin, 63.2%. Plazomicin was the most potent aminoglycoside tested with an MIC90 of 4 mg/L, compared with 32, >64 and 64 mg/L for amikacin, gentamicin and tobramycin, respectively.ConclusionsPlazomicin displayed potent activity against colistin-resistant clinical enterobacterial isolates, including those expressing the mcr-1 gene. Plazomicin was more active than other aminoglycosides against this collection of isolates. The further development of plazomicin for the treatment of infections due to MDR Enterobacteriaceae is warranted.
      PubDate: 2017-08-10
  • Dental staining after doxycycline use in children
    • Authors: Pöyhönen H; Nurmi M, Peltola V, et al.
      Abstract: AbstractBackgroundThe use of doxycycline has been avoided before 8 years of age due to known dental staining caused by tetracyclines, although doxycycline differs from classical tetracyclines in many ways. Doxycycline is still an important antimicrobial agent, but its dental safety is not well studied.ObjectivesTo examine the state of permanent teeth after doxycycline exposure in children <8 years of age.MethodsDetails of doxycycline treatment were collected from medical records. After the eruption of permanent teeth the dental status was examined by an experienced paediatric dentist for detection of dental staining and enamel hypoplasia. The resulting dental photographs were evaluated by a second independent experienced paediatric dentist.ResultsThe mean age of 38 study subjects at the time of doxycycline treatment was 4.7 years (range 0.6–7.9 years, SD 2.3). The doxycycline dose was 10 mg/kg/day (varying from 8 to 10 mg/kg/day) for the first 2–3 days and 5 mg/kg/day (varying from 2.5 to 10 mg/kg/day) thereafter. The mean length of the treatment was 12.5 days (SD 6.0) and ranged from 2 to 28 days. Tetracycline-like staining or enamel hypoplasia of developing teeth was detected in none of the subjects.ConclusionsDoxycycline treatment of small children does not seem to induce permanent tooth staining.
      PubDate: 2017-08-07
  • In vitro activity of plazomicin against β-lactamase-producing
           carbapenem-resistant Enterobacteriaceae (CRE)
    • Authors: Zhang Y; Kashikar A, Bush K.
      Abstract: AbstractBackgroundCarbapenem-resistant Enterobacteriaceae (CRE) represent an urgent threat because few drugs are available to treat infections caused by these pathogens. Plazomicin is a novel aminoglycoside that recently completed a Phase 3 clinical trial for treatment of infections caused by CRE.MethodsA set of 110 characterized unique CRE patient isolates from central Indiana healthcare centres was tested by microbroth dilution for susceptibility to plazomicin, and to reference aminoglycosides and carbapenems. WGS was conducted to analyse the isolate with an elevated plazomicin MIC.ResultsThe isolates, 107 of which produced KPC carbapenemases, were 97.3% and 100% non-susceptible to meropenem and imipenem, respectively, with variable rates of non-susceptibility to amikacin (76.4%), gentamicin (18.2%), kanamycin (91.8%) and tobramycin (96.4%). MIC50/MIC90 values for plazomicin were the lowest of all the drugs tested: 0.5/0.5 mg/L for 96 KPC-producing Klebsiella pneumoniae isolates and 0.5/1 mg/L for all 110 carbapenemase-producing isolates. Higher MIC50/MIC90 values were observed for the other antibiotics tested: amikacin (32/32 mg/L), gentamicin (1/16 mg/L), kanamycin (>64/>64 mg/L), tobramycin (32/64 mg/L), imipenem (8/32 mg/L) and meropenem (≥16/≥16 mg/L). Only one isolate, an NDM-1-producing K. pneumoniae strain that carried the armA 16S rRNA methyltransferase gene, was resistant to plazomicin, with an MIC of 256 mg/L; this strain was cross-resistant to all the other antibiotics tested.ConclusionsPlazomicin demonstrated the most potent overall in vitro inhibitory activity of all the aminoglycosides and carbapenems in the study, and has the potential to be an effective agent for the treatment of infections caused by CRE.
      PubDate: 2017-08-01
  • Identification of a novel qnrA allele, qnrA8 , in environmental Shewanella
    • Authors: Melvold JA; Wyrsch ER, McKinnon J, et al.
      Abstract: Sir,
      PubDate: 2017-08-01
  • Screening for synergistic activity of antimicrobial combinations against
           carbapenem-resistant Enterobacteriaceae using inkjet printer-based
    • Authors: Brennan-Krohn T; Truelson KA, Smith KP, et al.
      Abstract: AbstractBackgroundSynergistic combination antimicrobial therapy may provide new options for treatment of MDR infections. However, comprehensive in vitro synergy data are limited and facile methods to perform synergy testing in a clinically actionable time frame are unavailable.ObjectivesTo systematically investigate a broad range of antibiotic combinations for evidence of synergistic activity against a collection of carbapenem-resistant Enterobacteriaceae (CRE) isolates.MethodsWe made use of an automated method for chequerboard array synergy testing based on inkjet printer technology in the HP D300 digital dispenser to test 56 pairwise antimicrobial combinations of meropenem, aztreonam, cefepime, colistin, gentamicin, levofloxacin, chloramphenicol, fosfomycin, trimethoprim/sulfamethoxazole, minocycline and rifampicin, as well as the double carbapenem combination of meropenem and ertapenem.ResultsIn a screening procedure, we tested these combinations against four CRE strains and identified nine antibiotic combinations that showed potential clinically relevant synergy. In confirmatory testing using 10 CRE strains, six combinations demonstrated clinically relevant synergy with both antimicrobials at the minimum fractional inhibitory concentration (FICI-MIN) in the susceptible or intermediate range in at least one trial. These included two novel combinations: minocycline plus colistin and minocycline plus meropenem. In 80% of strains at least one combination demonstrated clinically relevant synergy, but the combinations that demonstrated synergy varied from strain to strain.ConclusionsThis work establishes the foundation for future systematic, broad-range investigations into antibiotic synergy for CRE, emphasizes the need for individualized synergy testing and demonstrates the utility of inkjet printer-based technology for the performance of automated antimicrobial synergy assays.
      PubDate: 2017-07-31
  • Population pharmacokinetics of teicoplanin administered by subcutaneous or
           intravenous route and simulation of optimal loading dose regimen
    • Authors: Cazaubon Y; Venisse N, Mimoz O, et al.
      Abstract: AbstractObjectivesTo investigate the population pharmacokinetics of teicoplanin in patients treated by the subcutaneous (sc) and/or intravenous (iv) route.Patients and methodsNon-linear mixed-effects modelling described teicoplanin concentrations from 98 patients with infection caused by Gram-positive cocci. Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA) of various dosage regimens.ResultsTeicoplanin concentrations were best described by a two-compartment model with clearance predicted by estimated glomerular filtration rate. Estimated absorption rate constant (between-subject variability) was 0.039 h−1 (77%), clearance was 0.305 L/h (28%), central volume was 10.3 L (49%), inter-compartmental clearance was 4.42 L/h (66%) and peripheral volume was 97.4 L (51%). The sc route was associated with lower initial Cmin and AUC (day 3: loading phase) compared with the iv route. This difference appeared to vanish after 14 days, with comparable simulated PTAs based on the Cmin and AUC for all tested dosages (400, 600, 800 and 1000 mg every 12 h). However, a loading dose regimen with five administrations of either 400 or 600 mg was not sufficient to achieve the target Cmin (≥15 mg/L) for both routes. Also, PTAs for higher MIC (≥1.0 mg/L) were poor with all regimens for both routes.ConclusionsThis is the first study examining the pharmacokinetic/pharmacodynamic implications of using the sc route for teicoplanin. Subcutaneous administration is associated with lower Cmin and AUC values after the loading phase compared with iv administration. Therefore, iv administration should be preferred in the first few days of therapy. This study also shows that loading doses of teicoplanin higher than currently recommended should be used to improve PTA.
      PubDate: 2017-07-31
  • Antiretroviral therapy in geriatric HIV patients: the GEPPO cohort study
    • Authors: Nozza S; Malagoli A, Maia L, et al.
      Abstract: J Antimicrob Chemother 2017; 72: 2879–2886
      PubDate: 2017-07-26
  • HIV-1 DNA ultra-deep sequencing analysis at initiation of the dual therapy
           dolutegravir + lamivudine in the maintenance DOLULAM pilot study
    • Authors: Charpentier C; Montes B, Perrier M, et al.
      Abstract: AbstractBackgroundThe DOLULAM study assessed the efficacy of dolutegravir + lamivudine dual therapy to maintain virological suppression in heavily treatment-experienced HIV-1-infected adults. No virological failure occurred during the first year of the dual therapy.ObjectivesA virological substudy was conducted to assess the prevalence of M184I/V mutations at dual therapy initiation using historical DNA/RNA genotypes and baseline DNA genotype obtained by next-generation sequencing (NGS).MethodsHIV-1 RT sequences were obtained from DNA and/or historical RNA using Sanger technology. HIV-1 DNA RT and integrase NGS was performed using Illumina® technology.ResultsAmong the 27 patients enrolled in the DOLULAM study, historical HIV DNA and RNA Sanger sequences were available in 14 and 18 patients, respectively. At the initiation of DOLULAM, DNA NGS genotypes showed that 45% and 21% of the patients harboured minority resistant variants (MRV) in RT and integrase, respectively. Combining all available genotype data, an M184I/V was observed in 17 of 27 (63%) of the patients. Most M184V were detected in historical RNA genotypes (n = 8 of 11), whereas M184I were exclusively detected in DNA genotypes (n = 10, including 7 as MRV). Ten patients displayed defective viral genomes in cellular reservoirs, all including M184I and stop codons. At the time of DOLULAM initiation, M184V was observed in DNA NGS in five patients, including one as MRV.ConclusionsThese first NGS data on HIV DNA at initiation of a switch study showed (i) a high proportion of patients harbouring defective viral genomes, whose mutation M184I is a marker, and (ii) a low number of patients in whom M184V remained as a major viral variant in PBMCs.
      PubDate: 2017-07-26
  • Dolutegravir plus abacavir/lamivudine works in adolescents, but size
    • Authors: Bossacoma Busquets F; Noguera-Julian A, Sanchez E, et al.
      Abstract: Sir,
      PubDate: 2017-07-26
  • soxRS induces colistin hetero-resistance in Enterobacter asburiae and
           Enterobacter cloacae by regulating the acrAB-tolC efflux pump
    • Authors: Telke AA; Olaitan A, Morand S, et al.
      Abstract: AbstractBackgroundColistin is the last drug option for the treatment of MDR Gram-negative bacterial infections. Several types of resistance to colistin have been identified, including hetero-resistance, which has been observed in several Gram-negative pathogens. During a routine surveillance project on antimicrobial resistance, we found abnormal colistin-resistant Enterobacter asburiae and Enterobacter cloacae isolates. E. cloacae is an intestinal commensal bacterium and a well-known opportunistic nosocomial pathogen.ObjectivesTo characterize the molecular mechanism of colistin hetero-resistance in Enterobacter spp.MethodsSeveral approaches (WGS, transposome mutagenesis and RT–PCR analysis) were used to discover the molecular mechanism of colistin hetero-resistance.ResultsGenomic analysis of mutant clones generated by transposome mutagenesis suggests that hetero-resistance is linked with overexpression of the acrAB-tolC efflux pump. Transcriptional analysis further found that naturally elevated soxRS triggers the induction of the acrAB-tolC efflux pump proteins followed by the development of colistin hetero-resistance in E. asburiae and E. cloacae. Transcriptional analysis results were further verified as demonstrating the development of hetero-resistance in colistin-susceptible strains by plasmid-based overexpression of soxRS.ConclusionsOur observations highlight the importance of such findings, which previously were only superficially described because of the challenges associated with their detection, in the context of common modes of colistin resistance in Gram-negative bacteria. This study constitutes a unique demonstration of efflux-based high-level colistin hetero-resistance, controlled by a soxRS regulator in Gram-negative bacteria.
      PubDate: 2017-07-25
  • Tenofovir disoproxil fumarate/emtricitabine plus ritonavir-boosted
           lopinavir or cobicistat-boosted elvitegravir as a single-tablet regimen
           for HIV post-exposure prophylaxis
    • Authors: Inciarte AA; Leal LL, González EE, et al.
      Abstract: AbstractObjectivesTo assess HIV-1 post-exposure prophylaxis (PEP) non-completion at day 28, comparing ritonavir-boosted lopinavir versus cobicistat-boosted elvitegravir as a single-tablet regimen (STR), using tenofovir disoproxil fumarate/emtricitabine with both of these therapies.MethodsA prospective, open, randomized clinical trial was performed. Individuals attending the emergency room due to potential sexual exposure to HIV and who met criteria for PEP were randomized 1:3 into two groups receiving either 400/100 mg of lopinavir/ritonavir (n = 38) or 150/150 mg of elvitegravir/cobicistat (n = 119), with both groups also receiving 245/200 mg of tenofovir disoproxil fumarate/emtricitabine. Five follow-up visits were scheduled at days 1, 10, 28, 90 and 180. The primary endpoint was PEP non-completion at day 28. Secondary endpoints were adherence, adverse effects and rate of seroconversions. Clinical number: NCT08431173.ResultsMedian age was 32 years and 95% were males. PEP non-completion at day 28 was 36% (n = 57), with a trend to be higher in the lopinavir/ritonavir arm [lopinavir/ritonavir 47% (n = 18) versus elvitegravir/cobicistat 33% (n = 39), P = 0.10]. We performed a modified ITT analysis including only those patients who attended on day 1. PEP non-completion in this subgroup was higher in the lopinavir/ritonavir arm than in the elvitegravir/cobicistat arm (33% versus 15%, respectively, P = 0.04). Poor adherence was significantly higher in the lopinavir/ritonavir arm versus the elvitegravir/cobicistat arm (47% versus 9%, respectively, P < 0.0001). Adverse events were reported by 73 patients (59%), and were significantly more common in the lopinavir/ritonavir arm (90% versus 49%, P = 0.0001). A seroconversion was observed in the elvitegravir/cobicistat arm in a patient with multiple exposures before and after PEP.ConclusionsA higher PEP non-completion, poor adherence and adverse events were observed in patients allocated to the lopinavir/ritonavir arm, suggesting that STR elvitegravir/cobicistat is a well-tolerated antiretroviral for PEP.
      PubDate: 2017-07-25
  • Resolution of porphyria cutanea tarda in HIV and mixed HCV coinfection
           after direct-acting antiviral (DAA) therapy
    • Authors: Bruzzone BB; Magnani OO, Sticchi LL, et al.
      Abstract: Sir,
      PubDate: 2017-07-25
  • Lord Soulsby of Swaffham Prior, 23 June 1926–8 May 2017
    • Authors: Wise R.
      Abstract: Ernest Jackson Lawson Soulsby, better known as Baron Soulsby of Swaffham Prior, led an extraordinarily varied life. He was brought up on a farm in Westmoreland (which is still farmed by the family) and then trained as a veterinarian at Royal (Dick) Veterinary College, Edinburgh, Scotland. From the beginning his interest focused on parasitology with his first publication appearing in 1954.1 His first research base was Bristol, then Cambridge followed by Pennsylvania, from where he travelled widely earning the irreverent title of ‘the Pan Am Professor of Parasitology’!
      PubDate: 2017-07-24
  • Penetration of linezolid into synovial fluid and muscle tissue after
           elective arthroscopy
    • Authors: Schwameis RR; Syré SS, Sarahrudi KK, et al.
      Abstract: AbstractObjectivesPenetration of antibiotics into synovial fluid is crucial to combat septic arthritis efficiently. Since linezolid may be used for treatment of septic arthritis when methicillin-resistant bacterial strains are suspected, we investigated its target-site concentrations in synovial fluid.Patients and methodsTen patients undergoing elective knee arthroscopy were included in this study. Subjects received a single dose of 600 mg of linezolid intravenously and linezolid concentrations were measured in plasma and by using microdialysis in muscle tissue and synovial fluid. Pharmacokinetic/pharmacodynamic calculations to predict bacterial killing ability were performed using CLSI breakpoints and MIC90 for clinical isolates.ResultsAll 10 subjects tolerated linezolid well. As indicated by AUCtissue/AUCfree plasma ratios of 0.76 ± 0.34 (synovial fluid) and 0.98 ± 0.62 (muscle tissue) linezolid penetrated well into the knee gap and tissue. In synovial fluid AUC0–24/MIC ratios for bacteria with an MIC of 1, 2 and 4 mg/L were 86.8 ± 47.0, 43.4 ± 23.5 and 21.7 ± 11.8, respectively.ConclusionsLinezolid may be used to treat septic arthritis caused by bacterial strains with an MIC ≤1 mg/L. Assuming a pharmacokinetic/pharmacodynamic target of > 50 for AUC0–24/MIC, when treating strains with an MIC >1 mg/L treatment surveillance is warranted. However, pharmacokinetic/pharmacodynamic targets for tissue are poorly understood and clinical data are needed to verify our assumptions.
      PubDate: 2017-07-24
  • Validation of adapted daily dose definitions for hospital antibacterial
           drug use evaluation: a multicentre study
    • Authors: Först G; de With K, Weber N, et al.
      Abstract: AbstractBackgroundThe WHO/ATC (Anatomical Therapeutic Chemical) index DDD (WHO-DDD) is commonly used for drug consumption measurement. Discrepancies between WHO-DDD and actual prescribed daily doses (PDD) in hospitals have prompted alternative dose definitions adapted to doses recommended in hospital practice guidelines [recommended daily doses (RDD)].MethodsIn order to validate RDD we performed modified point prevalence surveys in 24 acute care hospitals and recorded 20620 PDD of antibiotics given to 4226 adult patients on the day of the survey and the 6 preceding days. We calculated RDD and WHO-DDD and compared them with PDD.ResultsThe rate of RDD corresponding to PDD was higher than the corresponding rate for WHO-DDD (pooled data, 55% versus 30%) and the differences were similar across the hospital sample, but varied according to drug/drug class, route of administration, indication and renal function. RDD underestimated actual consumption by 14% overall, while WHO-DDD overestimated total antibacterial consumption by 28% (pooled data; median values RDD −10% versus WHO-DDD +32%). The deviations of estimated from actual drug use volumes were largest for β-lactams (RDD −11% versus WHO-DDD +49%), in particular for penicillins (−11% versus +64%), if WHO-DDD were used.ConclusionsHospital antibiotic consumption surveillance systems using current WHO-DDD should address the uneven discrepancies between actual prescribing and consumption estimates according to drug class that may lead to misclassification in benchmark analyses. We recommend using validated RDD as a supplementary measure to the WHO-DDD for detailed analyses.
      PubDate: 2017-07-24
  • Determination of alternative ceftolozane/tazobactam dosing regimens for
           patients with infections due to Pseudomonas aeruginosa with MIC values
           between 4 and 32 mg/L
    • Authors: Natesan S; Pai MP, Lodise TP.
      Abstract: AbstractBackgroundOptimization of the antibiotics for patients with infections due to MDR Pseudomonas aeruginosa (MDR-PA) often requires consideration of alternate dose and infusion times that can be influenced by renal function.ObjectivesWe sought to identify ceftolozane/tazobactam dosing schemes that optimized the probability of target attainment (PTA) against infections due to MDR-PA with ceftolozane/tazobactam MICs between 4 and 32 mg/L across different categories of renal function.MethodsA prior validated ceftolozane/tazobactam population pharmacokinetic model was used for Monte Carlo simulation of 128 alternate permutations of dose, infusion time and renal function in 5000 cases/permutation. Four ceftolozane/tazobactam doses (250/125 mg to 2/1 g) every 8 h with infusion durations of 1–7 h and as continuous infusions were simulated. The model simulated ceftolozane/tazobactam clearance as a function of creatinine clearance (CLCR) within four categories of estimated renal function: 15–29, 30–50, 51–120 and 121–180 mL/min. The PTA was benchmarked on 40% free ceftolozane/tazobactam concentration time above the MIC.ResultsThe 512 alternate scenarios identified the current ceftolozane/tazobactam dose of 1/0.5 g to be optimal for MICs ≤32 mg/L (CLCR 15–50 mL/min), ≤16 mg/L (CLCR 51–120 mL/min) and ≤8 mg/L (CLCR 121–180 mL/min). Extended infusion of 4–5 h had a higher PTA than shorter and continuous infusions in simulations of augmented renal clearance across infections with MICs of 4–32 mg/L.ConclusionsExtended infusion ceftolozane/tazobactam regimens should be investigated as a potential dosing solution to improve the PTA against infections due to MDR-PA with higher ceftolozane/tazobactam MICs.
      PubDate: 2017-07-21
  • Influence of ABCB11 and HNF4 α genes on daclatasvir plasma concentration:
           preliminary pharmacogenetic data from the Kineti-C study
    • Authors: Cusato J; De Nicolò A, Boglione L, et al.
      Abstract: AbstractBackgroundDaclatasvir is an inhibitor of HCV non-structural 5A protein and is a P-glycoprotein substrate. Pharmacogenetics has had a great impact on previous anti-HCV therapies, particularly considering the association of IL-28B polymorphisms with dual therapy outcome.ObjectivesWe investigated the association between daclatasvir plasma concentrations at 2 weeks and 1 month of therapy and genetic variants (SNPs) in genes encoding transporters and nuclear factors (ABCB1, ABCB11 and HNF4α).Patients and methodsAllelic discrimination was achieved through real-time PCR, whereas plasma concentrations were evaluated through LC–MS/MS.ResultsFifty-two patients were analysed, all enrolled in the Kineti-C study. HNF4α 975 C > G polymorphism was found to be associated with the daclatasvir plasma concentrations at 2 weeks (P = 0.009) and 1 month of therapy (P = 0.006). Linear regression analysis suggested that, at 2 weeks of therapy, age, baseline BMI and haematocrit were significant predictors of daclatasvir concentrations, whereas at 1 month of therapy ABCB111131 CC and HNF4α CG/GG genotypes were significant predictors of daclatasvir concentrations.ConclusionsThese are the first and preliminary results from our clinical study focusing on daclatasvir pharmacogenetics, showing that this approach could have a role in the era of new anti-HCV therapies.
      PubDate: 2017-07-21
  • Is there any difference in quality of prescribing between antibacterials
           and antifungals' Results from the first global point prevalence study
           (Global PPS) of antimicrobial consumption and resistance from 53 countries
    • Authors: Yusuf E; Versporten A, Goossens H.
      Abstract: AbstractObjectivesTo compare the quality of antibacterial with antifungal prescribing in the world.MethodsData from the global point prevalence study (Global PPS) were used. The Global PPS took place on any one day between February and June 2015 in 335 participating hospitals from 53 countries. It collected demographic data on patients treated with antimicrobials and data on prescription characteristics of the antimicrobials. For the present study, the quality of antibiotic prescription was compared with antifungal prescription using logistic regression analysis. The following indicators were compared: the presence of the reason for prescription and stop/review date in notes, and compliance with a local guideline.ResultsThere were 48565 antimicrobial prescriptions for 34731 patients [median age 63 years (range 0–106); 52.6% male] in the Global PPS. Among these antimicrobials, 43513 (89.6%) were antibacterials and 2062 were antifungals for systematic use, and these data were used in this study. Reasons for prescriptions [77.7% versus 71.8%, OR 1.4 (95% CI 1.2–1.5)] and stop/review dates [38.3% versus 31.9%, OR 1.3 (1.2–1.5)] were found more often in notes for antibacterials than for antifungals. Antibacterials were prescribed less often according to local guidelines than antifungals [57.0% versus 71.0%, OR 0.6 (0.5–0.6)].ConclusionsThere are differences in the quality of antibacterial and antifungal prescribing and we identified opportunities that can be used to improve the quality of antimicrobial prescribing.
      PubDate: 2017-07-21
  • PointFinder: a novel web tool for WGS-based detection of antimicrobial
           resistance associated with chromosomal point mutations in bacterial
    • Authors: Zankari E; Allesøe R, Joensen KG, et al.
      Abstract: AbstractBackgroundAntibiotic resistance is a major health problem, as drugs that were once highly effective no longer cure bacterial infections. WGS has previously been shown to be an alternative method for detecting horizontally acquired antimicrobial resistance genes. However, suitable bioinformatics methods that can provide easily interpretable, accurate and fast results for antimicrobial resistance associated with chromosomal point mutations are still lacking.MethodsPhenotypic antimicrobial susceptibility tests were performed on 150 isolates covering three different bacterial species: Salmonella enterica, Escherichia coli and Campylobacter jejuni. The web-server ResFinder-2.1 was used to identify acquired antimicrobial resistance genes and two methods, the novel PointFinder (using BLAST) and an in-house method (mapping of raw WGS reads), were used to identify chromosomal point mutations. Results were compared with phenotypic antimicrobial susceptibility testing results.ResultsA total of 685 different phenotypic tests associated with chromosomal resistance to quinolones, polymyxin, rifampicin, macrolides and tetracyclines resulted in 98.4% concordance. Eleven cases of disagreement between tested and predicted susceptibility were observed: two C. jejuni isolates with phenotypic fluoroquinolone resistance and two with phenotypic erythromycin resistance and five colistin-susceptible E. coli isolates with a detected pmrB V161G mutation when assembled with Velvet, but not when using SPAdes or when mapping the reads.ConclusionsPointFinder proved, with high concordance between phenotypic and predicted antimicrobial susceptibility, to be a user-friendly web tool for detection of chromosomal point mutations associated with antimicrobial resistance.
      PubDate: 2017-07-19
  • Dynamics and phylogenetic relationships of HIV-1 transmitted drug
           resistance according to subtype in Italy over the years 2000–14
    • Authors: Fabeni LL; Alteri CC, Di Carlo DD, et al.
      Abstract: AbstractBackgroundTransmitted drug-resistance (TDR) remains a critical aspect for the management of HIV-1-infected individuals. Thus, studying the dynamics of TDR is crucial to optimize HIV care.MethodsIn total, 4323 HIV-1 protease/reverse-transcriptase sequences from drug-naive individuals diagnosed in north and central Italy between 2000 and 2014 were analysed. TDR was evaluated over time. Maximum-likelihood and Bayesian phylogenetic trees with bootstrap and Bayesian-probability supports defined transmission clusters.ResultsMost individuals were males (80.2%) and Italian (72.1%), with a median (IQR) age of 37 (30–45) years. MSM accounted for 42.2% of cases, followed by heterosexuals (36.4%). Non-B subtype infections accounted for 30.8% of the overall population and increased over time (<2005–14: 19.5%–38.5%, P < 0.0001), particularly among Italians (<2005–14: 6.5%–28.8%, P < 0.0001). TDR prevalence was 8.8% and increased over time in non-B subtypes (<2005–14: 2%–7.1%, P = 0.018). Overall, 467 transmission clusters (involving 1207 individuals; 27.9%) were identified. The prevalence of individuals grouping in transmission clusters increased over time in both B (<2005–14: 12.9%–33.5%, P = 0.001) and non-B subtypes (<2005–14: 18.4%–41.9%, P = 0.006). TDR transmission clusters were 13.3% within the overall cluster observed and dramatically increased in recent years (<2005–14: 14.3%–35.5%, P = 0.005). This recent increase was mainly due to non-B subtype-infected individuals, who were also more frequently involved in large transmission clusters than those infected with a B subtype [median number of individuals in transmission clusters: 7 (IQR 6–19) versus 4 (3–4), P = 0.047].ConclusionsThe epidemiology of HIV transmission changed greatly over time; the increasing number of transmission clusters (sometimes with drug resistance) shows that detection and proper treatment of the multi-transmitters is a major target for controlling HIV spread.
      PubDate: 2017-07-19
  • CD4 T cell decline following HIV seroconversion in individuals with and
           without CXCR4-tropic virus
    • Authors: Ghosn J; Bayan T, Meixenberger K, et al.
      Abstract: AbstractBackgroundThe natural clinical and immunological courses following HIV seroconversion with CXCR4-tropic or dual-mixed (X4/DM) viruses are controversial. We compared spontaneous immunological outcome in patients harbouring an X4/DM virus at the time of seroconversion with those harbouring a CCR5-tropic (R5) virus.MethodsData were included from patients participating in CASCADE, a large cohort collaboration of HIV seroconverters, with ≥2 years of follow-up since seroconversion. The HIV envelope gene was sequenced from frozen plasma samples collected at enrolment, and HIV tropism was determined using Geno2Pheno (false-positive rate 10%). The spontaneous CD4 T cell evolution was compared by modelling CD4 kinetics using linear mixed-effects models with random intercept and random slope.ResultsA total of 1387 patients were eligible. Median time between seroconversion and enrolment was 1 month (range 0–3). At enrolment, 202 of 1387 (15%) harboured an X4/DM-tropic virus. CD4 decrease slopes were not significantly different according to HIV-1 tropism during the first 30 months after seroconversion. No marked change in these results was found after adjusting for age, year of seroconversion and baseline HIV viral load. Time to antiretroviral treatment initiation was not statistically different between patients harbouring an R5 (20.76 months) and those harbouring an X4/DM-tropic virus (22.86 months, logrank test P = 0.32).Conclusions: In this large cohort collaboration, 15% of the patients harboured an X4/DM virus close to HIV seroconversion. Patients harbouring X4/DM-tropic viruses close to seroconversion did not have an increased risk of disease progression, estimated by the decline in CD4 T cell count or time to combined ART initiation.
      PubDate: 2017-07-19
  • Risk factors for subtherapeutic levels of posaconazole tablet
    • Authors: Tang LA; Marini BL, Benitez L, et al.
      Abstract: AbstractBackgroundPosaconazole is the prophylactic antifungal of choice for patients with haematological malignancies at high risk of invasive fungal infections (IFIs). Studies have demonstrated that subtherapeutic concentrations of posaconazole are associated with breakthrough fungal infections and specific risk factors for subtherapeutic troughs associated with the suspension formulation have been identified. However, these risk factors have not been evaluated in a large patient population with the recently approved tablet formulation.ObjectivesTo determine the risk factors for subtherapeutic posaconazole troughs associated with the tablet formulation in patients receiving posaconazole as IFI prophylaxis.Patients and methodsFrom 1 February 2013 to 31 March 2015 all posaconazole serum trough concentrations were evaluated. A total of 157 patients receiving posaconazole tablet for prophylaxis during induction therapy for haematological malignancies and allogeneic stem cell transplant recipients with graft-versus-host disease were included for analysis.ResultsOverall, 28 patients (18%) had subtherapeutic troughs (<700 ng/mL). Patients were more likely to have subtherapeutic troughs if they had diarrhoea (n = 24; 83%) (P < 0.001), were receiving a proton pump inhibitor (n = 27; 93%) (P = 0.016) and weighed >90 kg (n = 14; 48%) (P = 0.047).ConclusionsWhile the posaconazole tablet has provided more consistent therapeutic concentrations when compared with the suspension there may still be a role for therapeutic drug monitoring (TDM). These results may guide us to a specific population in which TDM is necessary to identify subtherapeutic troughs.
      PubDate: 2017-07-19
  • ESGAP inventory of target indicators assessing antibiotic prescriptions: a
           cross-sectional survey
    • Authors: Howard P; Huttner B, Beovic B, et al.
      Abstract: AbstractBackgroundA variety of indicators is commonly used to monitor antibiotic prescriptions as part of national antimicrobial stewardship (AMS) programmes.ObjectivesTo make an inventory of indicators that assess antibiotic prescriptions and are linked to specific targets and incentives, at a national level.MethodsA cross-sectional survey (three-item questionnaire) was conducted in 2017 among all ESGAP (ESCMID Study Group for Antimicrobial stewardshiP) members, coming from 23 European countries and 16 non-European countries.ResultsAlmost all (20/23, 87%) European countries belonging to the ESGAP network participated, as well as one non-European country. Computerized systems routinely linking antibiotic prescriptions to clinical diagnoses were reported for only two countries (Turkey and Croatia). Only 6/21 (29%) countries had national indicators with both clear targets and incentives (Bulgaria, Croatia, France, the Netherlands, Norway and Portugal). We identified a total of 21 different indicators used in these countries, 16 concerning inpatients (9 quality indicators and 7 quantity metrics) and 8 concerning outpatients (all quantity metrics); some indicators were used in both settings. Three types of incentives were used: financing mechanism, hospitals’ accreditation and public reporting. Some respondents reported that such indicators with both clear targets and incentives were used at a regional level in their country (e.g. Andalusia in Spain and England in the UK).ConclusionsNational indicators, with clear targets and incentives, are not commonly used in Europe and we observed wide variations between countries regarding the selected indicators, the units of measure and the chosen targets.
      PubDate: 2017-07-19
  • Has primary care antimicrobial use really been increasing' Comparison
           of changes in different prescribing measures for a complete geographic
           population 1995–2014
    • Authors: Neilly MJ; Guthrie B, Hernandez Santiago V, et al.
      Abstract: AbstractObjectivesTo elucidate how population trends in total antimicrobials dispensed in the community translate into individual exposure.MethodsRetrospective, population-based observational study of all antimicrobial prescribing in a Scottish region in financial years 1995, 2000 and 2005–14. Analysis of temporal changes in all antimicrobials and specific antimicrobials measured in: WHO DDD per 1000 population; prescriptions per 1000 population; proportion of population with ≥1 prescription; mean number of prescriptions per person receiving any; mean DDD per prescription.ResultsAntimicrobial DDD increased between 1995 and 2014, from 5651 to 6987 per 1000 population [difference 1336 (95% CI 1309–1363)]. Prescriptions per 1000 fell (from 821 to 667, difference –154, –151 to –157), as did the proportion prescribed any antimicrobial [from 39.3% to 30.8% (–8.5, –8.4 to –8.6)]. Rising mean DDD per prescription, from 6.88 in 1995 to 10.47 in 2014 (3.59, 3.55–3.63), drove rising total DDD. In the under-5s, every measure fell over time (68.2% fall in DDD per 1000; 60.7% fall in prescriptions per 1000). Among 5–64 year olds, prescriptions per 1000 were lowest in 2014 but among older people, despite a reduction since 2010, the 2014 rate was still higher than in 2000. Trends in individual antimicrobials provide some explanation for overall trends.ConclusionsRising antimicrobial volumes up to 2011 were mainly due to rising DDD per prescription. Trends in dispensed drug volumes do not readily translate into information on individual exposure, which is more relevant for adverse consequences including emergence of resistance.
      PubDate: 2017-07-19
  • Molecular mechanisms of clofazimine resistance in Mycobacterium
    • Authors: Yew W; Liang D, Chan DP, et al.
      Abstract: Sir,
      PubDate: 2017-07-19
  • IS 26 -mediated formation of a virulence and resistance plasmid in
           Salmonella Enteritidis
    • Authors: Wong M; Chan E, Chen S.
      Abstract: AbstractObjectivesTo characterize a novel virulence–resistance plasmid pSE380T carried by a Salmonella enterica serotype Enteritidis clinical strain SE380.MethodsThe plasmid pSE380T was conjugated to Escherichia coli strain J53 and sequenced by PacBio RSII, followed by subsequent annotation and genetic analysis.ResultsSequence analysis of this plasmid revealed that the entire Salmonella Enteritidis-specific virulence plasmid, pSEN, had been incorporated into an IncHI2 MDR plasmid, which comprises the cephalosporin and fosfomycin resistance determinants blaCTX-M-14 and fosA3. Based on BLAST analysis and scrutiny of insertion footprints, the insertion event was found to involve a replicative transposition process mediated by IS26, an IS element frequently detected in various resistance plasmids. The resulting pSE380T plasmid also comprises backbone elements of IncHI2 and IncFIA plasmids, producing a rare fusion product that simultaneously encodes functional features of both, i.e. virulence, resistance and high transmissibility.ConclusionsThis is a novel hybrid plasmid mediating MDR and virulence from a clinical Salmonella Enteritidis strain. This plasmid is likely to be transmissible amongst various serotypes of Salmonella and other Enterobacteriaceae species, rendering a wide range of bacterial pathogens resistant to cephalosporins and fosfomycin, and further enhancing their virulence potential. It will be important to monitor the spread and further evolution of this plasmid among the Enterobacteriaceae strains.
      PubDate: 2017-07-18
  • Monitoring microevolution of OXA-48-producing Klebsiella pneumoniae ST147
           in a hospital setting by SMRT sequencing
    • Authors: Zautner AE; Bunk B, Pfeifer Y, et al.
      Abstract: AbstractObjectivesCarbapenemase-producing Klebsiella pneumoniae pose an increasing risk for healthcare facilities worldwide. A continuous monitoring of ST distribution and its association with resistance and virulence genes is required for early detection of successful K. pneumoniae lineages. In this study, we used WGS to characterize MDR blaOXA-48-positive K. pneumoniae isolated from inpatients at the University Medical Center Göttingen, Germany, between March 2013 and August 2014.MethodsClosed genomes for 16 isolates of carbapenemase-producing K. pneumoniae were generated by single molecule real-time technology using the PacBio RSII platform.ResultsEight of the 16 isolates showed identical XbaI macrorestriction patterns and shared the same MLST, ST147. The eight ST147 isolates differed by only 1–25 SNPs of their core genome, indicating a clonal origin. Most of the eight ST147 isolates carried four plasmids with sizes of 246.8, 96.1, 63.6 and 61.0 kb and a novel linear plasmid prophage, named pKO2, of 54.6 kb. The blaOXA-48 gene was located on a 63.6 kb IncL plasmid and is part of composite transposon Tn1999.2. The ST147 isolates expressed the yersinabactin system as a major virulence factor. The comparative whole-genome analysis revealed several rearrangements of mobile genetic elements and losses of chromosomal and plasmidic regions in the ST147 isolates.ConclusionsSingle molecule real-time sequencing allowed monitoring of the genetic and epigenetic microevolution of MDR OXA-48-producing K. pneumoniae and revealed in addition to SNPs, complex rearrangements of genetic elements.
      PubDate: 2017-07-17
  • CD4 cell count response to first-line combination ART in HIV-2+ patients
           compared with HIV-1+ patients: a multinational, multicohort European study
    • Authors: Wittkop L; Arsandaux J, Trevino A, et al.
      Abstract: AbstractBackgroundCD4 cell recovery following first-line combination ART (cART) is poorer in HIV-2+ than in HIV-1+ patients. Only large comparisons may allow adjustments for demographic and pretreatment plasma viral load (pVL).MethodsART-naive HIV+ adults from two European multicohort collaborations, COHERE (HIV-1 alone) and ACHIeV2e (HIV-2 alone), were included, if they started first-line cART (without NNRTIs or fusion inhibitors) between 1997 and 2011. Patients without at least one CD4 cell count before start of cART, without a pretreatment pVL and with missing a priori-defined covariables were excluded. Evolution of CD4 cell count was studied using adjusted linear mixed models.ResultsWe included 185 HIV-2+ and 30321 HIV-1+ patients with median age of 46 years (IQR 36–52) and 37 years (IQR 31–44), respectively. Median observed pretreatment CD4 cell counts/mm3 were 203 (95% CI 100–290) in HIV-2+ patients and 223 (95% CI 100–353) in HIV-1+ patients. Mean observed CD4 cell count changes from start of cART to 12 months were +105 (95% CI 77–134) in HIV-2+ patients and +202 (95% CI 199–205) in HIV-1+ patients, an observed difference of 97 cells/mm3 in 1 year. In adjusted analysis, the mean CD4 cell increase was overall 25 CD4 cells/mm3/year lower (95% CI 5–44; P = 0.0127) in HIV-2+ patients compared with HIV-1+ patients.ConclusionsA poorer CD4 cell increase during first-line cART was observed in HIV-2+ patients, even after adjusting for pretreatment pVL and other potential confounders. Our results underline the need to identify more potent therapeutic regimens or strategies against HIV-2.
      PubDate: 2017-07-17
  • Patterns of dispensed non-medical prescriber prescriptions for antibiotics
           in primary care across England: a retrospective analysis
    • Authors: Courtenay M; Gillespie D, Lim R.
      Abstract: AbstractObjectivesTo describe the patterns of dispensed non-medical prescriber (NMP) prescriptions for antibiotics in primary care across England between 2011 and 2015.MethodsA retrospective analysis of dispensed antibiotic prescriptions, written by NMPs and medical prescribers between 2011 and 2015 in primary care in England, obtained from the National Health Service Business Services Authority.ResultsBetween 2011 and 2015, the number of NMPs (mainly nurses but also pharmacists and small numbers of allied health professionals) in England, who have independent prescribing capability, has risen by over one-third to nearly 30000. Most of these prescribers provide a broad range of services in primary care. The rate of dispensed NMP prescriptions for antibiotics over this period has increased, as has the percentage of all primary care antibiotics dispensed that were prescribed by NMPs, which is currently nearly 8%. The most commonly dispensed NMP antibiotic prescriptions were penicillin, sulphonamides, trimethoprim, macrolides, tetracyclines and nitrofurantoin.ConclusionsIncreasing numbers of NMPs are working in primary care in England and managing infections. Antibiotics prescribed by this group align with surveillance reports of antibiotic use in primary care. With the numbers of NMPs being set to rise further, they form an important group to involve in antimicrobial stewardship efforts.
      PubDate: 2017-07-17
  • RNA and DNA Sanger sequencing versus next-generation sequencing for HIV-1
           drug resistance testing in treatment-naive patients
    • Authors: Alidjinou EK; Deldalle JJ, Hallaert CC, et al.
      Abstract: AbstractBackgroundSanger sequencing of plasma RNA is the standard method for HIV-1 drug resistance testing in treatment-naive patients, but is limited by the non-detection of resistance-associated mutations (RAMs) with prevalence below approximately 20%.ObjectivesWe compared RNA and DNA Sanger sequencing (RSS and DSS) with RNA next-generation sequencing (NGS) for RAM detection in HIV-1 reverse transcriptase (RT), protease (PR) and integrase (IN) genes.MethodsSanger sequencing was performed on RNA and DNA, following the recommendations of the French Agency for AIDS Research (ANRS). NGS was performed on RNA using the HIV-1 Drug Resistance Assay, v. 3.0 (Roche) on the 454 GS Junior sequencer. The IAS-USA list was used to identify RAMs. ANRS, Rega and Stanford algorithms were used for drug resistance interpretation.ResultsThe study included 48 ART-naive patients. The number of patients with at least one major RAM was 3, 3, 4 and 8 when using RSS, DSS, NGS 20% and NGS 5%, respectively. Numerous minor mutations were detected in patients, especially in the protease gene. None of the methods detected any major mutation in the integrase gene. Overall, the mutation detection rate was similar between RSS and DSS, and higher with NGS 20%. Differences in drug resistance interpretation were found between algorithms. No impact of the minority RAMs detected by NGS was found on the short-term treatment outcome.ConclusionsDSS does not clearly improve the detection of RAMs in ART-naive patients, as compared with RSS. NGS allows detection of additional minority RAMs; however, their clinical relevance requires further investigation.
      PubDate: 2017-07-14
  • Antimicrobial susceptibility testing of Arcobacter butzleri : development
           and application of a new protocol for broth microdilution
    • Authors: Riesenberg A; Frömke C, Stingl K, et al.
      Abstract: AbstractObjectivesTo develop a standard reference broth microdilution method for antimicrobial susceptibility testing (AST) of Arcobacter butzleri. The protocol was subsequently applied to a collection of A. butzleri isolates from different sources.MethodsBroth microdilution susceptibility testing was performed on eight A. butzleri isolates in three media: non-supplemented CAMHB, CAMHB + 2% FBS and CAMHB + 5% FBS. The MIC values were read after 24 and 48 h of incubation at 35 ± 2 °C in ambient air. A logistic regression model was used to determine the combination of medium and incubation time yielding the most homogeneous results. Subsequently, the protocol was applied to 65 A. butzleri isolates to determine their MICs of 31 antimicrobial agents.ResultsThe statistical analysis revealed that the most homogeneous MIC values were obtained with CAMHB + 5% FBS and reading of MIC values after 24 h of incubation. The standardized method was successful for AST of all 65 A. butzleri isolates. MIC values were distributed unimodally for most antimicrobial agents. However, one field isolate showed elevated MIC values of gentamicin, streptomycin, tetracycline and trimethoprim/sulfamethoxazole.ConclusionsThis study presents a new protocol for AST of A. butzleri by broth microdilution and shows the distribution of MIC values of 31 antimicrobial agents for a collection of A. butzleri isolates from different origins.
      PubDate: 2017-07-13
  • Ceftaroline efficacy against high-MIC clinical Staphylococcus aureus
           isolates in an in vitro hollow-fibre infection model
    • Authors: Singh R; Almutairi M, Alm RA, et al.
      Abstract: AbstractObjectivesThe current CLSI and EUCAST clinical susceptible breakpoint for 600 mg q12h dosing of ceftaroline (active metabolite of ceftaroline fosamil) for Staphylococcus aureus is ≤1 mg/L. Efficacy data for S. aureus infections with ceftaroline MIC ≥2 mg/L are limited. This study was designed to generate in-depth pharmacokinetic/pharmacodynamics (PK/PD) understanding of S. aureus isolates inhibited by ≥ 2 mg/L ceftaroline using an in vitro hollow-fibre infection model (HFIM).MethodsThe PK/PD target of ceftaroline was investigated against 12 diverse characterized clinical MRSA isolates with ceftaroline MICs of 2 or 4 mg/L using q8h dosing for 24 h. These isolates carried substitutions in the penicillin-binding domain (PBD) and/or the non-PBD. Additionally, PD responses of mutants with ceftaroline MICs ranging from 2 to 32 mg/L were evaluated against the mean 600 mg q8h human-simulated dose over 72 h.ResultsThe mean stasis, 1 log10-kill and 2 log10-kill PK/PD targets were 29%, 32% and 35% f T>MIC, respectively. In addition, these data suggest that the PK/PD target for MRSA is not impacted by the presence of substitutions in the non-PBD commonly found in isolates with ceftaroline MIC values of ≤ 2 mg/L. HFIM studies with 600 mg q8h dosing demonstrated a sustained long-term bacterial suppression for isolates with ceftaroline MICs of 2 and 4 mg/L.ConclusionsOverall, efficacy was demonstrated against a diverse collection of clinical isolates using HFIM indicating the utility of 600 mg ceftaroline fosamil for S. aureus isolates with MIC ≤4 mg/L using q8h dosing.
      PubDate: 2017-07-13
  • Efficacy and safety of direct antiviral agents in a cohort of cirrhotic
           HCV/HIV-coinfected patients
    • Authors: Navarro J; Laguno M, Vilchez H, et al.
      Abstract: AbstractBackgroundNew direct-acting antiviral agents (DAAs) have shown great efficacy and tolerability in clinical trials and real-life cohorts. However, data are scarce regarding efficacy and safety in cirrhotic HCV/HIV-coinfected patients.MethodsA multicentre prospective analysis was performed in 13 Spanish hospitals, including all cirrhotic HCV/HIV-coinfected patients starting DAA combinations from January to December 2015. Sustained virological response 12 weeks after treatment (SVR12) was analysed. Withdrawal due to toxicity and/or hepatic decompensation and change in liver stiffness measurement (LSM) after HCV treatment were evaluated.ResultsPatients (n = 170) were mostly male (n = 125; 74.3%) with the following HCV genotype (Gt) distribution: Gt-1a, 68 (40%); Gt-1b, 21 (12.4%); Gt-4, 47 (27.6%); and Gt-3, 26 (15.3%). Baseline median LSM was 20.6 kPa (IQR 16.1–33.7) and log10 HCV-RNA 6.1 IU/mL (IQR 5.7–6.5). Most patients had a Child–Pugh class A score (n = 127; 74.7%) and 28 (16.5%) had prior hepatic decompensation. There were 89 (52.4%) pretreated patients with 40.4% (n = 36) of null responders. Preferred regimens were as follows: sofosbuvir/ledipasvir + ribavirin, 43 (25.3%) patients; sofosbuvir + simeprevir + ribavirin, 34 (20%); sofosbuvir/ledipasvir, 26 (15.3%) and sofosbuvir + daclatasvir + ribavirin, 25 (14.7%). Overall SVR12 was 92.9% (158/170), without differences between genotypes. Pretreated patients had lower SVR12 rates compared with naive (88.8% versus 97.5%; P = 0.026). Treatment failures were as follows: 7 (4.1%) relapses; 2 (1.2%) lost to follow-up; 1 (0.6%) toxicity-related discontinuation; 1 (0.6%) hepatic decompensation; and 1 (0.6%) viral breakthrough. On-treatment hepatic decompensation was recorded in four (2.4%) patients (encephalopathy and ascites, two each). Paired LSM in 33 patients showed a decrease of 5.6 kPa (95% CI 1.8–9.2; P = 0.004).ConclusionsIn our cohort of cirrhotic HCV/HIV-coinfected patients, DAAs were highly safe and efficacious. Viral eradication was associated with a significant decrease in liver stiffness.
      PubDate: 2017-07-13
  • Modifications in the pmrB gene are the primary mechanism for the
           development of chromosomally encoded resistance to polymyxins in
           uropathogenic Escherichia coli
    • Authors: Phan M; Nhu N, Achard MS, et al.
      Abstract: AbstractObjectivesPolymyxins remain one of the last-resort drugs to treat infections caused by MDR Gram-negative pathogens. Here, we determined the mechanisms by which chromosomally encoded resistance to colistin and polymyxin B can arise in the MDR uropathogenic Escherichia coli ST131 reference strain EC958.MethodsTwo complementary approaches, saturated transposon mutagenesis and spontaneous mutation induction with high concentrations of colistin and polymyxin B, were employed to select for mutations associated with resistance to polymyxins. Mutants were identified using transposon-directed insertion-site sequencing or Illumina WGS. A resistance phenotype was confirmed by MIC and further investigated using RT–PCR. Competitive growth assays were used to measure fitness cost.ResultsA transposon insertion at nucleotide 41 of the pmrB gene (EC958pmrB41-Tn5) enhanced its transcript level, resulting in a 64- and 32-fold increased MIC of colistin and polymyxin B, respectively. Three spontaneous mutations, also located within the pmrB gene, conferred resistance to both colistin and polymyxin B with a corresponding increase in transcription of the pmrCAB genes. All three mutations incurred a fitness cost in the absence of colistin and polymyxin B.ConclusionsThis study identified the pmrB gene as the main chromosomal target for induction of colistin and polymyxin B resistance in E. coli.
      PubDate: 2017-07-11
  • MCR-2-mediated plasmid-borne polymyxin resistance most likely originates
           from Moraxella pluranimalium
    • Authors: Poirel L; Kieffer N, Fernandez-Garayzabal JF, et al.
      Abstract: Sir,
      PubDate: 2017-07-11
  • Inducibility of Tn 916 conjugative transfer in Enterococcus faecalis by
           subinhibitory concentrations of ribosome-targeting antibiotics
    • Authors: Scornec H; Bellanger X, Guilloteau H, et al.
      Abstract: AbstractBackgroundSome antibiotics induce the dissemination of their own resistance genes by interfering with the regulation of specific mobile genetic elements. In Tn916, subinhibitory concentrations of tetracycline activate the transfer of the element through an anti-attenuation mechanism that relies on the Tet(M) resistance protein, itself encoded by the element.ObjectivesThis work explores the effects of a broad range of antibiotics on the transfer of Tn916 and for which the element does not provide any selective advantage.MethodsA sensitive promoter–reporter fusion approach was developed to test the effects of full antibiotic concentration gradients on gene promoter expression. Sixty molecules, covering most classes of antibiotics, were screened for their ability to modulate the activity of promoter Porf12 controlling the transfer of Tn916. Induction of Tn916 transfer was further demonstrated in mating assays with Enterococcus faecalis donors pre-exposed to subinhibitory concentrations of modulating antibiotics.ResultsSeveral antibiotics, other than tetracyclines, were identified as interfering with Tn916 regulation. Macrolides, lincosamides and streptogramins appeared to activate the transfer of Tn916 at unprecedented levels, in a Tet(M)-independent way that implies a yet undescribed regulatory mechanism for controlling the mobility of the element.ConclusionsThese results demonstrate that some ribosome-targeting antibiotics can induce the transfer of a given mobile genetic element, here Tn916, although it does not provide any resistance determinant for most of the triggering drugs. This implies that specific antibiotic therapies can have dramatic impacts on the dissemination of unexpected and unlinked resistance genes, with the clear risk of reducing our therapeutic potential for later treatments.
      PubDate: 2017-07-10
  • Too much of a good thing: a retrospective study of β-lactam
           concentration–toxicity relationships
    • Authors: Imani S; Buscher H, Marriott D, et al.
      Abstract: AbstractObjectivesTo determine the existence of concentration–toxicity relationships for common β-lactam antibiotic adverse effects and define thresholds above which toxicity is more likely.Patients and methodsRetrospective review of consecutive patients treated with piperacillin, meropenem or flucloxacillin who underwent therapeutic drug monitoring (TDM) at St Vincent’s Hospital (Sydney, Australia) between January 2013 and December 2015. Adverse events investigated included neurotoxicity, nephrotoxicity, hepatotoxicity and opportunistic Clostridium difficile infection. Toxicity was measured using observational grading criteria, clinical assessment and relevant serum biomarkers. These findings were correlated with trough TDM measurements at the time of toxicity presentation.ResultsTDM results from 378 patients (piperacillin = 223, meropenem = 94 and flucloxacillin = 61) were investigated. There was no difference in baseline patient characteristics across antibiotic groups. A statistically significant elevation in mean serum trough concentrations (Cmin) was found in patients diagnosed with neurotoxicity (piperacillin, P < 0.01; meropenem, P = 0.04; flucloxacillin, P = 0.01) and those who developed nephrotoxicity whilst being treated with piperacillin (P < 0.01) or meropenem (P < 0.01). Incidence of hepatotoxicity and C. difficile was not related to Cmin. Threshold concentrations for which there is 50% risk of developing a neurotoxicity event (piperacillin, Cmin >361.4 mg/L; meropenem, Cmin >64.2 mg/L; flucloxacillin, Cmin >125.1 mg/L) or nephrotoxicity (piperacillin, Cmin >452.65 mg/L; meropenem, Cmin >44.45 mg/L) varied across antibiotics.ConclusionsOur data reveal an association between toxic concentrations for a number of β-lactam agents and neurotoxic/nephrotoxic effects. We have defined threshold concentrations above which these toxicities become more likely. Clinicians should balance concerns for therapeutic efficacy with potential toxicity when considering aggressive therapy.
      PubDate: 2017-07-10
  • Successful outpatient parenteral antibiotic therapy delivery via
    • Authors: Tan SJ; Ingram PR, Rothnie AJ, et al.
      Abstract: AbstractObjectivesMost outpatient parenteral antimicrobial therapy (OPAT) services use a hospital-based model of care in which patients remain in proximity to large hospitals facilitating clinical review. We aimed to evaluate clinical outcomes and complication rates for patients living in geographically isolated locations managed by telemedicine-supported OPAT.Methods: This was a retrospective cohort study.ResultsBetween 2011 and 2015, we delivered 88 episodes of care involving 83 adult patients resulting in 2261 days of OPAT. The median age was 56 years, 8 of 83 (10%) were indigenous Australian and the median Charlson comorbidity index score was 2 (IQR 1–4). The median distance of patients’ residence from our hospital was 288 km (IQR 201–715) and the median duration on the programme was 26 days (IQR 14–34). Bone and joint infections accounted for 75% of infections treated. Favourable clinical outcomes (improvement or cure) were achieved in 87% of patients and the unplanned, OPAT-related readmission rate was 8%. Nineteen percent and 10% of patients had drug-related and line-related adverse effects, respectively.ConclusionsDespite a complex case mix, our adverse event and readmission rates are similar to the published literature describing a non-telemedicine model to deliver OPAT. High rates of favourable clinical outcomes and likely cost benefits suggest that telemedicine-supported OPAT is an efficacious and safe substitute for inpatient care in our setting.
      PubDate: 2017-07-10
  • Building a national Infection Intelligence Platform to improve
           antimicrobial stewardship and drive better patient outcomes: the Scottish
    • Authors: Bennie M; Malcolm W, Marwick CA, et al.
      Abstract: AbstractBackgroundThe better use of new and emerging data streams to understand the epidemiology of infectious disease and to inform and evaluate antimicrobial stewardship improvement programmes is paramount in the global fight against antimicrobial resistance.ObjectivesTo create a national informatics platform that synergizes the wealth of disjointed, infection-related health data, building an intelligence capability that allows rapid enquiry, generation of new knowledge and feedback to clinicians and policy makers.MethodsA multi-stakeholder community, led by the Scottish Antimicrobial Prescribing Group, secured government funding to deliver a national programme of work centred on three key aspects: (i) technical platform development with record linkage capability across multiple datasets; (ii) a proportionate governance approach to enhance responsiveness; and (iii) generation of new evidence to guide clinical practice.ResultsThe National Health Service Scotland Infection Intelligence Platform (IIP) is now hosted within the national health data repository to assure resilience and sustainability. New technical solutions include simplified ‘data views’ of complex, linked datasets and embedded statistical programs to enhance capability. These developments have enabled responsiveness, flexibility and robustness in conducting population-based studies including a focus on intended and unintended effects of antimicrobial stewardship interventions and quantification of infection risk factors and clinical outcomes.ConclusionsWe have completed the build and test phase of IIP, overcoming the technical and governance challenges, and produced new capability in infection informatics, generating new evidence for improved clinical practice. This provides a foundation for expansion and opportunity for global collaborations.
      PubDate: 2017-07-10
  • Genomic sequences of Streptococcus agalactiae with high-level gentamicin
           resistance, collected in the BSAC bacteraemia surveillance
    • Authors: Doumith M; Mushtaq S, Martin V, et al.
      Abstract: AbstractBackgroundLike other streptococci, Streptococcus agalactiae typically has intrinsic low-level aminoglycoside resistance. High-level gentamicin resistance was seen in 2 of 1125 isolates collected in the BSAC Bacteraemia Surveillance Programme between 2001 and 2014. These organisms, both isolated in 2014, were characterized.MethodsIdentifications were by latex agglutination, MICs by BSAC agar dilution and sequencing by Illumina methodology.ResultsGentamicin MICs were >1024 mg/L versus a species mode of 8 mg/L; both isolates also were unusually ciprofloxacin resistant with MICs of 64 mg/L versus a species mode of 1 mg/L. They were distinct by sequence, but both belonged to the ST19 clone, which occurs globally. Both had aac(6′)-aph(2″), carried by different transposons, explaining their gentamicin resistance, and had gyrA[81:S-L];parC[79:S-Y], accounting for ciprofloxacin resistance.ConclusionsThese are the first multiresistant S. agalactiae with the bifunctional AAC(6′)-APH(2″) enzyme to be reported in the UK for >10 years. Despite belonging to the same clonal complex, the two isolates and their resistance transposons were distinct. Both retained full susceptibility to penicillin, but any penicillin/gentamicin synergy is likely to be lost.
      PubDate: 2017-07-06
  • Antimicrobial resistance in Mycobacterium abscessus complex isolated from
           patients with skin and soft tissue infections at a tertiary teaching
           hospital in Taiwan
    • Authors: Lee M; Sun P, Wu T, et al.
      Abstract: AbstractBackgroundMycobacterium abscessus complex (MABC) is the most common non-tuberculous mycobacterium that causes complicated skin and soft tissue infections (cSSTIs). The selection of antimycobacterial agents for successful treatment of such infections is a critical issue.ObjectivesTo investigate the antimicrobial susceptibility patterns of MABC isolates from skin and soft tissue to a variety of antimycobacterial agents.MethodsSixty-seven MABC isolates were collected and partial gene sequencing of secA1, rpoB and hsp65 was used to classify them into three subspecies: M. abscessus subsp. abscessus (MAB), M. abscessus subsp. massiliense (MMA) and M. abscessus subsp. bolletii (MBO). The MICs of 11 antimycobacterial agents for these 67 isolates were determined using a broth microdilution method and commercial Sensititre RAPMYCOI MIC plates, as recommended by CLSI.ResultsIn total, 28 MAB, 38 MMA and 1 MBO were isolated from patients with cSSTIs at our hospital. Most MABC strains were resistant to ciprofloxacin, doxycycline, imipenem, linezolid, minocycline, moxifloxacin and trimethoprim/sulfamethoxazole. In addition, most MABC strains were intermediately susceptible or resistant to cefoxitin. Eighteen of the 28 MABs and 1 MBO isolate harboured the T28 polymorphism in the erm(41) gene. Two of the 38 MMA isolates had an rrl A2059G point mutation. Most of the MABC strains were susceptible to amikacin and tigecycline.ConclusionsIn Taiwan, amikacin, clarithromycin and tigecycline have good activity against MMA and MAB erm(41) C28 sequevar isolates, whereas amikacin and tigecycline, rather than clarithromycin, have good activity against both MBO and MAB erm(41) T28 sequevar isolates. Clinical trials are warranted to correlate these data with clinical outcomes.
      PubDate: 2017-07-06
  • Quantitative and automated MALDI-TOF MS-based detection of the
           plasmid-mediated quinolone resistance determinant AAC(6′)-Ib-cr in
    • Authors: Oviaño M; Gómara M, Barba M, et al.
      Abstract: Sir,
      PubDate: 2017-07-06
  • Prevalence of gag mutations associated with in vitro resistance to capsid
           inhibitor GS-CA1 in HIV-1 antiretroviral-naive patients
    • Authors: Perrier M; Bertine M, Le Hingrat Q, et al.
      Abstract: Sir,
      PubDate: 2017-07-04
  • The bla OXA-23 -associated transposons in the genome of Acinetobacter spp.
           represent an epidemiological situation of the species encountering
    • Authors: Yoon E; Kim J, Yang J, et al.
      Abstract: AbstractObjectivesHigh rates of carbapenem resistance in the human pathogen Acinetobacter baumannii threaten public health and need to be scrutinized.MethodsA total of 356 A. baumannii and 50 non-baumannii Acinetobacter spp. (NBA) strains collected in 2013 throughout South Korea were studied. The type of blaOXA-23 transposon was determined by PCR mapping and molecular epidemiology was assessed by MLST. Twelve representative strains and two comparative A. baumannii were entirely sequenced by single-molecule real-time sequencing.ResultsThe carbapenem resistance rate was 88% in A. baumannii, mainly due to blaOXA-23, with five exceptional cases associated with ISAba1-blaOXA-51-like. The blaOXA-23 gene in A. baumannii was carried either by Tn2006 (44%) or Tn2009 (54%), with a few exceptions carried by Tn2008 (1.6%). Of the NBA strains, 14% were resistant to carbapenems, two with blaOXA-58 and five with blaOXA-23 associated with Tn2006. The Tn2006-possessing strains belonged to various STs, whereas Tn2008- and Tn2009-possessing strains were limited to ST208 and ST191, respectively. The three transposons were often multiplied in the chromosome, and the gene copy number and the carbapenem MICs presented linear relationships either very strongly for Tn2008 or moderately for Tn2006 and Tn2009.ConclusionsThe dissemination of Tn2006 was facilitated by its capability for intercellular transfer and that of Tn2009 was attributable to successful dissemination of the ST191 bacterial host carrying the transposon. Tn2008 was infrequent because of its insufficient ability to undergo intercellular transfer and the scarce bacterial host A. baumannii ST208. Gene amplification is an adaptive mechanism for bacteria that encounter antimicrobial drugs.
      PubDate: 2017-07-03
  • Quinolone-resistant gyrase mutants demonstrate decreased susceptibility to
    • Authors: Webber MA; Buckner MC, Redgrave LS, et al.
      Abstract: AbstractObjectivesCross-resistance between antibiotics and biocides is a potentially important driver of MDR. A relationship between susceptibility of Salmonella to quinolones and triclosan has been observed. This study aimed to: (i) investigate the mechanism underpinning this; (ii) determine whether the phenotype is conserved in Escherichia coli; and (iii) evaluate the potential for triclosan to select for quinolone resistance.MethodsWT E. coli, Salmonella enterica serovar Typhimurium and gyrA mutants were used. These were characterized by determining antimicrobial susceptibility, DNA gyrase activity and sensitivity to inhibition. Expression of stress response pathways (SOS, RpoS, RpoN and RpoH) was measured, as was the fitness of mutants. The potential for triclosan to select for quinolone resistance was determined.ResultsAll gyrase mutants showed increased triclosan MICs and altered supercoiling activity. There was no evidence for direct interaction between triclosan and gyrase. Identical substitutions in GyrA had different impacts on supercoiling in the two species. For both, there was a correlation between altered supercoiling and expression of stress responses. This was more marked in E. coli, where an Asp87Gly GyrA mutant demonstrated greatly increased fitness in the presence of triclosan. Exposure of parental strains to low concentrations of triclosan did not select for quinolone resistance.ConclusionsOur data suggest gyrA mutants are less susceptible to triclosan due to up-regulation of stress responses. The impact of gyrA mutation differs between E. coli and Salmonella. The impacts of gyrA mutation beyond quinolone resistance have implications for the fitness and selection of gyrA mutants in the presence of non-quinolone antimicrobials.
      PubDate: 2017-07-03
  • Using metagenomics to investigate human and environmental resistomes
    • Authors: Bengtsson-Palme J; Larsson D, Kristiansson E.
      Abstract: AbstractAntibiotic resistance is a global health concern declared by the WHO as one of the largest threats to modern healthcare. In recent years, metagenomic DNA sequencing has started to be applied as a tool to study antibiotic resistance in different environments, including the human microbiota. However, a multitude of methods exist for metagenomic data analysis, and not all methods are suitable for the investigation of resistance genes, particularly if the desired outcome is an assessment of risks to human health. In this review, we outline the current state of methods for sequence handling, mapping to databases of resistance genes, statistical analysis and metagenomic assembly. In addition, we provide an overview of important considerations related to the analysis of resistance genes, and recommend some of the currently used tools and methods that are best equipped to inform research and clinical practice related to antibiotic resistance.
      PubDate: 2017-06-30
  • Origin of the AbGRI1 antibiotic resistance island found in the comM gene
           of Acinetobacter baumannii GC2 isolates
    • Authors: Hamidian M; Hall RM.
      Abstract: Sir,
      PubDate: 2017-06-28
  • Antiretroviral therapy in geriatric HIV patients: the GEPPO cohort study
    • Authors: Nozza S; Malagoli A, Maia L, et al.
      Abstract: AbstractBackgroundGEPPO is a prospective observational multi-centric cohort including HIV-infected geriatric patients. We hypothesized that the GEPPO cohort may help characterize antiretroviral (ARV) prescribing criteria used in real life by Italian infectious disease (ID) physicians.MethodsThis was a cross-sectional study describing the current ARV regimen in a geriatric HIV population (≥65 years). Antiretroviral strategies were categorized as follows: (i) multidrug regimens (MDRs), which comprised triple or mega ART combinations; (ii) less drug regimens (LDRs), which comprised fewer than three ART compounds. Multi-morbidity (MM) was defined as the presence of three or more non-communicable diseases, and polypharmacy (PP) as the use of five or more medications in chronic use. Four alternative combinations (MM+PP+, MM+PP−, MM−PP+, MM−PP−) were used in logistic regression analyses.ResultsA total of 1222 HIV-positive patients were included (median age 70 years). Females composed 16% of the cohort. Median duration of HIV infection was 17 years; 335 population members had been infected for >20 years. MM was present in 64% and PP in 37% of the patients. Treatment consisted of triple therapy in 66.4%, dual therapy in 25.3%, monotherapy in 6.5% and ‘mega-ART’ with more than three drugs in 1.64% of the patients. In multivariate logistic regression MM and PP were predictive for mono-dual, NRTI-sparing and tenofovir disoproxil fumarate (TDF)-sparing combinations. Female gender and age were predictors of unboosted ARV regimens.ConclusionsHigh prevalence of non-conventional ARV regimens in elderly HIV patients suggests that clinicians try to tailor ARV regimens according to age, HIV duration, MM and PP.
      PubDate: 2017-06-10
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