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Publisher: Oxford University Press   (Total: 370 journals)

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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: 60, SJR: 1.512, h-index: 46)
Age and Ageing     Hybrid Journal   (Followers: 84, SJR: 1.611, h-index: 107)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 15, SJR: 0.935, h-index: 80)
American Entomologist     Full-text available via subscription   (Followers: 6)
American Historical Review     Hybrid Journal   (Followers: 129, SJR: 0.652, h-index: 43)
American J. of Agricultural Economics     Hybrid Journal   (Followers: 41, SJR: 1.441, h-index: 77)
American J. of Epidemiology     Hybrid Journal   (Followers: 159, 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: 16)
American J. of Legal History     Full-text available via subscription   (Followers: 5, 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: 24)
Annals of Botany     Hybrid Journal   (Followers: 35, SJR: 1.912, h-index: 124)
Annals of Occupational Hygiene     Hybrid Journal   (Followers: 26, SJR: 0.837, h-index: 57)
Annals of Oncology     Hybrid Journal   (Followers: 47, 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: 3, 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: 48, SJR: 1.698, h-index: 92)
Bioinformatics     Hybrid Journal   (Followers: 246, 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: 28, 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: 142, SJR: 2.314, h-index: 133)
BJA Education     Hybrid Journal   (Followers: 66, SJR: 0.272, h-index: 20)
Brain     Hybrid Journal   (Followers: 60, SJR: 6.097, h-index: 264)
Briefings in Bioinformatics     Hybrid Journal   (Followers: 45, 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: 25, SJR: 0.217, h-index: 18)
British J. of Criminology     Hybrid Journal   (Followers: 524, SJR: 1.373, h-index: 62)
British J. of Social Work     Hybrid Journal   (Followers: 82, 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  
Carcinogenesis     Hybrid Journal   (Followers: 2, SJR: 2.439, h-index: 167)
Cardiovascular Research     Hybrid Journal   (Followers: 11, SJR: 2.897, h-index: 175)
Cerebral Cortex     Hybrid Journal   (Followers: 40, 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: 8, 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: 19, SJR: 0.1, h-index: 3)
Clinical Infectious Diseases     Hybrid Journal   (Followers: 58, 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: 6, 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: 18, 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: 14, SJR: 0.124, h-index: 11)
Economic Policy     Hybrid Journal   (Followers: 59, SJR: 2.052, h-index: 52)
ELT J.     Hybrid Journal   (Followers: 25, SJR: 1.26, h-index: 23)
English Historical Review     Hybrid Journal   (Followers: 48, 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: 9, 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: 8, 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: 152, 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: 12, 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: 40, 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: 8, 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: 21, 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: 31, SJR: 0.123, h-index: 10)
French Studies     Hybrid Journal   (Followers: 19, 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: 9, 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: 48, 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: 19, 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: 26, SJR: 0.313, h-index: 20)
Holocaust and Genocide Studies     Hybrid Journal   (Followers: 23, SJR: 0.115, h-index: 13)
Human Molecular Genetics     Hybrid Journal   (Followers: 9, SJR: 4.288, h-index: 233)
Human Reproduction     Hybrid Journal   (Followers: 78, SJR: 2.271, h-index: 179)
Human Reproduction Update     Hybrid Journal   (Followers: 18, SJR: 4.678, h-index: 128)
Human Rights Law Review     Hybrid Journal   (Followers: 59, 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: 9)
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: 29, 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: 51, 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: 32, SJR: 1.593, h-index: 69)
Intl. J. of Constitutional Law     Hybrid Journal   (Followers: 59, SJR: 0.613, h-index: 19)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 134, 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: 32, 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: 17, 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: 38, 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: 40, 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: 12, 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: 34, 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: 12, SJR: 0.196, h-index: 15)
J. of Consumer Research     Full-text available via subscription   (Followers: 41, SJR: 4.896, h-index: 121)
J. of Crohn's and Colitis     Hybrid Journal   (Followers: 9, 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: 15, 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: 18)
J. of Experimental Botany     Hybrid Journal   (Followers: 14, SJR: 2.798, h-index: 163)
J. of Financial Econometrics     Hybrid Journal   (Followers: 21, 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: 40, SJR: 4, h-index: 209)
J. of Insect Science     Open Access   (Followers: 9, SJR: 0.388, h-index: 31)

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Journal Cover Journal of Antimicrobial Chemotherapy
  [SJR: 2.157]   [H-I: 149]   [12 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]
  • Global epidemiology of CTX-M β-lactamases: temporal and geographical
           shifts in genotype
    • Authors: Bevan ER; Jones AM, Hawkey PM.
      Pages: 2145 - 2155
      Abstract: AbstractGlobally, rates of ESBL-producing Enterobacteriaceae are rising. We undertook a literature review, and present the temporal trends in blaCTX-M epidemiology, showing that blaCTX-M-15 and blaCTX-M-14 have displaced other genotypes in many parts of the world. Explanations for these changes can be attributed to: (i) horizontal gene transfer (HGT) of plasmids; (ii) successful Escherichia coli clones; (iii) ESBLs in food animals; (iv) the natural environment; and (v) human migration and access to basic sanitation. We also provide explanations for the changing epidemiology of blaCTX-M-2 and blaCTX-M-27. Modifiable anthropogenic factors, such as poor access to basic sanitary facilities, encourage the spread of blaCTX-M and other antimicrobial resistance (AMR) genes, such as blaNDM, blaKPC and mcr-1. We provide further justification for novel preventative and interventional strategies to reduce transmission of these AMR genes.
      PubDate: 2017-05-25
      DOI: 10.1093/jac/dkx146
      Issue No: Vol. 72, No. 8 (2017)
  • Repurposing of nucleoside- and nucleobase-derivative drugs as antibiotics
           and biofilm inhibitors
    • Authors: Yssel AJ; Vanderleyden JJ, Steenackers HP.
      Pages: 2156 - 2170
      Abstract: AbstractThere is an urgent need for new antibacterial drugs that are robust against the development of resistance. Drug repurposing is a cost-effective strategy to fast-track the drug development process. Here we examine why the nucleoside and nucleobase analogue drugs in particular present an attractive class for repurposing. Some of these drugs have already been evaluated for their potential as antibacterial agents. In addition to inhibiting bacterial growth and survival, some also act synergistically with antibiotics, and as such can enhance the therapeutic spectrum of currently available antibiotics. Furthermore, nucleoside and nucleobase analogue drugs can inhibit bacterial virulence and biofilm formation. Biofilms are known to impart antibiotic tolerance and are associated with chronic infections. Targeting biofilm formation thus renders pathogens more susceptible to antibiotic treatment and host immune defences. Moreover, specific analogues have properties that make them less susceptible to the development of resistance. Thus, nucleoside and nucleobase analogue drugs ought to be considered as new weapons in our fight against pathogenic bacteria.
      PubDate: 2017-05-30
      DOI: 10.1093/jac/dkx151
      Issue No: Vol. 72, No. 8 (2017)
  • HIV-1 strains belonging to large phylogenetic clusters show accelerated
           escape from integrase inhibitors in cell culture compared with viral
           isolates from singleton/small clusters
    • Authors: Brenner BG; Ibanescu R, Oliveira M, et al.
      Pages: 2171 - 2183
      Abstract: AbstractObjectives: Viral phylogenetics revealed two patterns of HIV-1 spread among MSM in Quebec. While most HIV-1 strains (n = 2011) were associated with singleton/small clusters (cluster size 1–4), 30 viral lineages formed large networks (cluster size 20–140), contributing to 42% of diagnoses between 2011 and 2015. Herein, tissue culture selections ascertained if large cluster lineages possessed higher replicative fitness than singleton/small cluster isolates, allowing for viral escape from integrase inhibitors.Methods: Primary HIV-1 isolates from large 20+ cluster (n = 11) or singleton/small cluster (n = 6) networks were passaged in vitro in escalating concentrations of dolutegravir, elvitegravir and lamivudine for 24–36 weeks. Sanger and deep sequencing assessed genotypic changes under selective drug pressure.Results: Large cluster HIV-1 isolates selected for resistance to dolutegravir, elvitegravir and lamivudine faster than HIV-1 strains forming small clusters. With dolutegravir, large cluster HIV-1 variants acquired solitary R263K (n = 7), S153Y (n = 1) or H51Y (n = 1) mutations as the dominant quasi-species within 8–12 weeks as compared with small cluster lineages where R263K (n = 1/6), S153Y (1/6) or WT species (4/6) were observed after 24 weeks. Interestingly, dolutegravir-associated mutations compromised viral replicative fitness, precluding escalations in concentrations beyond 5–10 nM. With elvitegravir, large cluster variants more rapidly acquired first mutations (T66I, A92G, N155H or S147G) by week 8 followed by sequential accumulation of multiple mutations leading to viral escape (>10 μM) by week 24.Conclusions: Further studies are needed to understand virological features of large cluster viruses that may favour their transmissibility, replicative competence and potential to escape selective antiretroviral drug pressure.
      PubDate: 2017-05-02
      DOI: 10.1093/jac/dkx118
      Issue No: Vol. 72, No. 8 (2017)
  • Emergence of vanA Enterococcus faecium in Denmark, 2005–15
    • Authors: Hammerum AM; Baig S, Kamel Y, et al.
      Pages: 2184 - 2190
      Abstract: AbstractObjectives: To describe the changing epidemiology of vancomycin-resistant Enterococcus faecium and Enterococcus faecalis in clinical samples in Denmark 2005–15 according to species and van type, and, furthermore, to investigate the genetic relatedness of the clinical E. faecium isolates from 2015.Methods: During 2005–14, all clinical VRE isolates were tested for the presence of vanA/B/C genes by PCR. In 2015, all clinical VRE isolates were whole-genome sequenced. From the WGS data, the presence of van genes and MLST STs were extracted in silico. Core-genome MLST (cgMLST) analysis was performed for the vancomycin-resistant E. faecium isolates.Results: During 2005–15, 1043 vanA E. faecium, 25 vanB E. faecium, 4 vanA E. faecalis and 28 vanB E. faecalis were detected. The number of VRE was <50 isolates/year until 2012 to > 200 isolates/year in 2013–15. In 2015, 368 vanA E. faecium and 1 vanB E. faecium were detected along with 1 vanA E. faecalis and 1 vanB E. faecalis. cgMLST subdivided the 368 vanA E. faecium isolates into 33 cluster types (CTs), whereas the vanB E. faecium isolate belonged to a different CT. ST203-CT859 was most prevalent (51%), followed by ST80-CT14 (22%), ST117-CT24 (6%), ST80-CT866 (4%) and ST80-CT860 (2%). Comparison with the database, previous studies and personal communications with neighbouring countries revealed that the novel cluster ST203-CT859 emerged in December 2014 and spread to the south of Sweden and the Faroe Islands during 2015.Conclusions: VRE increased in Denmark during 2005–15 due to the emergence of several vanA E. faecium clones.
      PubDate: 2017-05-25
      DOI: 10.1093/jac/dkx138
      Issue No: Vol. 72, No. 8 (2017)
  • Elucidation of Mycobacterium abscessus aminoglycoside and capreomycin
           resistance by targeted deletion of three putative resistance genes
    • Authors: Rominski A; Selchow P, Becker K, et al.
      Pages: 2191 - 2200
      Abstract: AbstractObjectives:Mycobacterium abscessus is innately resistant to a variety of drugs thereby limiting therapeutic options. Bacterial resistance to aminoglycosides (AGs) is conferred mainly by AG-modifying enzymes, which often have overlapping activities. Several putative AG-modifying enzymes are encoded in the genome of M. abscessus. The aim of this study was to investigate the molecular basis underlying AG resistance in M. abscessus.Methods:M. abscessus deletion mutants deficient in one of three genes potentially involved in AG resistance, aac(2ʹ), eis1 and eis2, were generated by targeted gene inactivation, as were combinatorial double and triple deletion mutants. MICs were determined to study susceptibility to a variety of AG drugs and to capreomycin.Results: Deletion of aac(2ʹ) increased susceptibility of M. abscessus to kanamycin B, tobramycin, dibekacin and gentamicin C. Deletion of eis2 increased susceptibility to capreomycin, hygromycin B, amikacin and kanamycin B. Deletion of eis1 did not affect drug susceptibility. Equally low MICs of apramycin, arbekacin, isepamicin and kanamycin A for WT and mutant strains indicate that these drugs are not inactivated by either AAC(2ʹ) or Eis enzymes.Conclusions:M. abscessus expresses two distinct AG resistance determinants, AAC(2ʹ) and Eis2, which confer clinically relevant drug resistance.
      PubDate: 2017-05-09
      DOI: 10.1093/jac/dkx125
      Issue No: Vol. 72, No. 8 (2017)
  • Acinetobacter baumannii transfers the bla NDM-1 gene via outer membrane
    • Authors: Chatterjee S; Mondal A, Mitra S, et al.
      Pages: 2201 - 2207
      Abstract: AbstractObjectives: To investigate the transmission of the gene encoding New Delhi metallo-β-lactamase-1 (blaNDM-1) through outer membrane vesicles (OMVs) released from an Acinetobacter baumannii strain (A_115).Methods: Isolation and purification of OMVs by density gradient from a carbapenem-resistant clinical strain of A. baumannii harbouring plasmid-mediated blaNDM-1 and aac(6′)-Ib-cr genes was performed. DNA was purified from the OMVs and used for PCR and dot-blot analysis. Vesicles treated with DNase I and proteinase K were used to transform A. baumannii ATCC 19606 and Escherichia coli JM109 strains. MIC values for the transformants were determined, followed by PCR and restriction digestion of plasmids. PFGE was done for A_115 and transformants of ATCC 19606 and JM109.Results: The A. baumannii strain (ST 1462) released vesicles (25–100 nm) during in vitro growth at late log phase. PCR and dot-blot analysis confirmed the presence of blaNDM-1 and aac(6′)-Ib-cr genes in intravesicular DNA. blaNDM-1 and aac(6′)-Ib-cr genes were transferred to both the A. baumannii ATCC 19606 and E. coli JM109 recipient cells. The transformation frequency of the purified OMVs was in the range of 10−5–10−6 and gradually reduced with storage of OMVs. The sizes of the plasmids in the transformants and their restriction digestion patterns were identical to the plasmid in A_115. The transformants showed elevated MIC values of the β-lactam group of antibiotics, which confirmed the presence of a blaNDM-1-harbouring plasmid.Conclusions: This is the first experimental evidence of intra- and inter-species transfer of a plasmid harbouring a blaNDM-1 gene in A. baumannii via OMVs with high transformation frequency.
      PubDate: 2017-05-12
      DOI: 10.1093/jac/dkx131
      Issue No: Vol. 72, No. 8 (2017)
  • Role of DNA gyrase and topoisomerase IV mutations in fluoroquinolone
           resistance of Capnocytophaga spp. clinical isolates and laboratory mutants
    • Authors: Ehrmann E; Jolivet-Gougeon A, Bonnaure-Mallet M, et al.
      Pages: 2208 - 2212
      Abstract: AbstractObjectives:Capnocytophaga spp. are often reported to cause bacteraemia and extra-oral infections and are characterized by their significant contribution to resistance to β-lactam and macrolide–lincosamide–streptogramin antibiotics in the human oral microbiota. The implication of mutations in the quinolone resistance-determining region (QRDR) of DNA gyrase A and B (gyrA and gyrB) and topoisomerase IV (parC and parE) of fluoroquinolone (FQ)-resistant Capnocytophaga spp., hitherto unknown, was explored in this study.Methods: Two reference strains (Capnocytophaga gingivalis ATCC 33624 and Capnocytophaga sputigena ATCC 33612) and four Capnocytophaga spp. isolated from clinical samples were studied. Nine in vitro FQ-resistant mutants, derived from two reference strains and one FQ-susceptible clinical isolate, were selected by successive inoculations onto medium containing levofloxacin. MICs of ofloxacin, norfloxacin, ciprofloxacin, levofloxacin and moxifloxacin were determined. The presumed QRDRs of GyrA, GyrB, ParC and ParE from Capnocytophaga spp. were determined by sequence homology to Bacteroides fragilis and Escherichia coli. PCR primers were designed to amplify the presumed QRDR genetic region of Capnocytophaga spp. and sequence analyses were performed using the BLAST program at the National Center for Biotechnology Information.Results and conclusions:gyrA mutations leading to a substitution from amino acid position 80 to 86 were systematically detected in Capnocytophaga spp. with ciprofloxacin MIC >1 mg/L and considered as the primary target of FQs. No mutational alteration in the QRDR of gyrB was detected. Other mutations in parC and parE led to spontaneous amino acid substitutions of DNA topoisomerase IV subunit B with no alteration in FQ susceptibility.
      PubDate: 2017-04-26
      DOI: 10.1093/jac/dkx119
      Issue No: Vol. 72, No. 8 (2017)
  • Presence of Type I-F CRISPR/Cas systems is associated with antimicrobial
           susceptibility in Escherichia coli
    • Authors: Aydin S; Personne Y, Newire E, et al.
      Pages: 2213 - 2218
      Abstract: AbstractBackground: Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and their associated cas genes are sequence-specific DNA nuclease systems found in bacteria and archaea. CRISPR/Cas systems use RNA transcripts of previously acquired DNA (spacers) to target invading genetic elements with the same sequence, including plasmids. In this research we studied the relationship between CRISPR/Cas systems and multidrug resistance in Escherichia coli.Methods: The presence of Type I-E and Type I-F CRISPR systems was investigated among 82 antimicrobial-susceptible and 96 MDR clinical E. coli isolates by PCR and DNA sequencing. Phylogrouping and MLST were performed to determine relatedness of isolates. RT–PCR was performed to ascertain the expression of associated cas genes.Results: Type I-F CRISPR was associated with the B2 phylogroup and was significantly overrepresented in the susceptible group (22.0%) compared with the MDR group (2.1%). The majority of CRISPR I-F-containing isolates had spacer sequences that matched IncF and IncI plasmids. RT–PCR demonstrated that Type I-F cas genes were expressed and therefore potentially functional.Conclusions: The CRISPR I-F system is more likely to be found in antimicrobial-susceptible E. coli. Given that the Type I-F system is expressed in WT isolates, we suggest that this difference could be due to the CRISPR system potentially interfering with the acquisition of antimicrobial resistance plasmids, maintaining susceptibility in these isolates.
      PubDate: 2017-05-23
      DOI: 10.1093/jac/dkx137
      Issue No: Vol. 72, No. 8 (2017)
  • Evolution and dissemination of the Klebsiella pneumoniae clonal group 258
           throughout Israeli post-acute care hospitals, 2008–13
    • Authors: Adler A; Lifshitz Z, Gordon M, et al.
      Pages: 2219 - 2224
      Abstract: AbstractObjectives: The KPC-producing Klebsiella pneumoniae (KPC-KP) clonal group (CG) 258 has disseminated throughout Israeli post-acute care hospitals (PACHs). The objectives of the study were (i) to describe the evolution and (ii) to understand the dissemination modes of CG 258 in the PACH system in Israel.Methods: KPC-KP surveillance cultures isolates were collected in Israeli PACHs in three national point-prevalence surveys: 2008, 2011 and 2013. CG 258 was identified by pilv-l PCR. WGS was performed for CG 258 isolates from 9 of 14 PACHs and data extracted for core-genome MLST (cgMLST) and for capsule polysaccharide gene cluster analysis.Results: The proportional representation of CG 258 among the KPC-KP isolates increased from 72 of 104 isolates (69.2%) in 2008 to 113 of 133 isolates (85%) in 2011 (P = 0.004 for 2008 versus 2011) and remained high in 2013 [56 of 67 isolates (83.6%)]. All isolates were related to CG 258 clade 2. cgMLST phylogenetic analysis showed relative convergence in the 2008 survey, with increasing diversification in the subsequent surveys. A predominantly institutional dissemination pattern was observed only in centre F from southern Israel. A predominantly regional dissemination pattern was observed in the two PACHs in Jerusalem. The other PACHs were characterized by a combined institutional and generalized pattern, with the majority of isolates clustering within the same PACH and survey.Conclusions: CG 258 clade 2 has retained its predominance despite increased diversification. Although interchanging of CG 258 strains occurred between most PACHs, local spread is the leading cause of its dissemination.
      PubDate: 2017-05-09
      DOI: 10.1093/jac/dkx135
      Issue No: Vol. 72, No. 8 (2017)
  • The complete nucleotide sequence of an IncP-2 megaplasmid unveils a mosaic
           architecture comprising a putative novel bla VIM-2 -harbouring transposon
           in Pseudomonas aeruginosa
    • Authors: Botelho J; Grosso F, Quinteira S, et al.
      Pages: 2225 - 2229
      Abstract: AbstractObjectives: In Pseudomonas aeruginosa, blaVIM-2 has been mostly associated with a chromosomal location and rarely with a plasmid backbone. Until now, only three complete blaVIM-2-carrying plasmid sequences have been described in this species. Here we explore the modular structure of pJB37, the first blaVIM-2-carrying megaplasmid described in P. aeruginosa.Methods: The complete nucleotide sequence of plasmid pJB37 was determined with an Illumina HiSeq, with de novo assembly by SPAdes, annotation by RAST and searching for antimicrobial resistance genes and virulence factors. Conjugation assays were conducted.Results: Megaplasmid pJB37 (464 804 bp long and GC content of 57.2%) comprised: an IncP-2 repA-oriV-parAB region; a conjugative transfer region (traF, traG, virD2 and trbBCDEJLFGI genes); Tn6356, a new putative blaVIM-2-carrying transposon; heavy metal (mercury and tellurite) resistance operons; and an arsenal of virulence genes. Plasmid pJB37 was transferable by conjugation to a spontaneous rifampicin-resistant mutant of P. aeruginosa PAO1. Here, a blaVIM-2-harbouring In58 integron was associated with a new complex transposable structure, herein named Tn6356, suggesting that In58 was most likely acquired by insertion of this element.Conclusions: The mosaic arrangement exhibited by the pJB37 IncP-2 megaplasmid, which highlights the vast assembly potential of distinct genetic elements in a Pseudomonas widespread plasmid platform, gives new insights into bacterial adaptation and evolution.
      PubDate: 2017-05-12
      DOI: 10.1093/jac/dkx143
      Issue No: Vol. 72, No. 8 (2017)
  • Effects of an autoinducer analogue on antibiotic tolerance in Pseudomonas
    • Authors: Amoh T; Murakami K, Kariyama R, et al.
      Pages: 2230 - 2240
      Abstract: AbstractObjectives: Antibiotic tolerance causes chronic, refractory and persistent infections. In order to advance the development of a new type of drug for the treatment of infectious diseases, we herein investigated the effects of a newly synthesized analogue of the Pseudomonas aeruginosa quorum-sensing autoinducer named AIA-1 (autoinducer analogue) on antibiotic tolerance in P. aeruginosa.Methods: A P. aeruginosa luminescent strain derived from PAO1 was injected into neutropenic ICR mice and bioluminescence images were acquired for a period of time after treatments with antibiotics and AIA-1. In vitro susceptibility testing and killing assays for the planktonic and biofilm cells of PAO1 were performed using antibiotics and AIA-1. The expression of quorum-sensing-related genes was examined using real-time PCR.Results:In vivo and in vitro assays showed that AIA-1 alone did not exert any bactericidal effects and also did not affect the MICs of antibiotics. However, the combined use of AIA-1 and antibiotics exerted markedly stronger therapeutic effects against experimental infection than antibiotics alone. The presence of AIA-1 also enhanced the killing effects of antibiotics in planktonic and biofilm cells. Although AIA-1 did not inhibit the expression of lasB and rhlA genes, which are directly regulated by quorum sensing, it clearly suppressed expression of the rpoS gene.Conclusions: The new compound, AIA-1, did not alter the antibiotic susceptibility of P. aeruginosa by itself; however, its addition enhanced the antibacterial activity of antibiotics. AIA-1 did not inhibit quorum sensing, but reduced the antibiotic tolerance of P. aeruginosa by suppressing rpoS gene expression.
      PubDate: 2017-05-16
      DOI: 10.1093/jac/dkx132
      Issue No: Vol. 72, No. 8 (2017)
  • Major role of pKpQIL-like plasmids in the early dissemination of KPC-type
           carbapenemases in the UK
    • Authors: Doumith MM; Findlay JJ, Hirani HH, et al.
      Pages: 2241 - 2248
      Abstract: AbstractObjectives:Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae were first seen in the UK in 2003 and have been increasingly reported since 2010, largely owing to an ongoing outbreak in North-West England. We examined the role of clonal spread and plasmid transmission in their emergence.Methods: Isolates comprised KPC-positive K. pneumoniae (n = 33), Escherichia coli (n = 7) and Enterobacter spp. (n = 4) referred to the national reference laboratory between 2008 and 2010 from 17 UK centres, including three in North-West England. Isolates were typed by MLST. Plasmids were transferred by electroporation and characterized by PCR or sequencing. PCR screening assays were developed to distinguish plasmid pKpQIL variants.Results: The K. pneumoniae isolates included 10 STs, of which three belonged to clonal group (CG) 258. CG258 (n = 19) isolates were detected in 13 centres but accounted for only 7/19 (36.8%) of those from North-West England. Most KPC-producers (37/44, 84.1%), including 16/19 CG258 K. pneumoniae, carried blaKPC on IncFIIK2 plasmids. Sequencing of a subset of these plasmids (n = 11) revealed similarities with published pKpQIL. One variant, pKpQIL-UK [identified in K. pneumoniae CG258 (n = 5) and ST468 (n = 1) isolates from distinct centres] had only a few nucleotide changes from classical pKpQIL, whereas pKpQIL-D1 (n = 1) and pKpQIL-D2 (n = 4), from isolates of various species in the North-West, harboured large variations, reflecting replacement of the partitioning and replication functions and potentially thereby facilitating spread. PCR revealed that 36/37 (97.3%) IncFIIK2-type plasmids in KPC-positive isolates had pKpQIL markers.Conclusions: pKpQIL-like plasmids played a major role in the early dissemination of KPC enzymes in the UK.
      PubDate: 2017-05-11
      DOI: 10.1093/jac/dkx141
      Issue No: Vol. 72, No. 8 (2017)
  • Genomic epidemiology of global VIM-producing Enterobacteriaceae
    • Authors: Matsumura Y; Peirano G, Devinney R, et al.
      Pages: 2249 - 2258
      Abstract: AbstractBackground: International data on the molecular epidemiology of Enterobacteriaceae with VIM carbapenemases are limited.Methods: We performed short read (Illumina) WGS on a global collection of 89 VIM-producing clinical Enterobacteriaceae (2008–14).Results: VIM-producing (11 varieties within 21 different integrons) isolates were mostly obtained from Europe. Certain integrons with blaVIM were specific to a country in different species and clonal complexes (CCs) (In87, In624, In916 and In1323), while others had spread globally among various Enterobacteriaceae species (In110 and In1209). Klebsiella pneumoniae was the most common species (n = 45); CC147 from Greece was the most prevalent clone and contained In590-like integrons with four different blaVIMs. Enterobacter cloacae complex was the second most common species and mainly consisted of Enterobacter hormaechei (Enterobacter xiangfangensis, subsp. steigerwaltii and Hoffmann cluster III). CC200 (from Croatia and Turkey), CC114 (Croatia, Greece, Italy and the USA) and CC78 (from Greece, Italy and Spain) containing blaVIM-1 were the most common clones among the E. cloacae complex.Conclusions: This study highlights the importance of surveillance programmes using the latest molecular techniques in providing insight into the characteristics and global distribution of Enterobacteriaceae with blaVIMs.
      PubDate: 2017-05-16
      DOI: 10.1093/jac/dkx148
      Issue No: Vol. 72, No. 8 (2017)
  • Towards the early detection of β-lactamase-producing Enterobacteriaceae
           by MALDI-TOF MS analysis
    • Authors: Oviaño M; Gómara M, Barba M, et al.
      Pages: 2259 - 2262
      Abstract: AbstractObjectives: Development of a novel MALDI-TOF MS-based method for the rapid detection of ESBL-producing Enterobacteriaceae.Methods: The method was evaluated in terms of sensitivity, specificity and turnaround time regarding the antibiotic used (cefotaxime, ceftazidime, ceftriaxone, cefpodoxime or cefepime) and the performance of the automated MBT STAR-BL software (Bruker Daltonik GmbH, Germany) relative to qualitative interpretation of spectra for detecting β-lactamase resistance by MALDI-TOF MS (Bruker Daltonik) in a collection of 11 isogenic Escherichia coli control strains expressing different β-lactamases. Finally, for clinical validation, β-lactamase activity was determined under previously evaluated conditions in 100 clinical isolates previously characterized by PCR and sequencing.Results: Clinical validation of the assay showed 100% sensitivity and specificity for detecting β-lactam resistance in 30 min by measuring hydrolysis of ceftriaxone (0.50 mg/mL) with the automated MBT STAR-BL software. Regarding the antibiotics evaluated, ceftriaxone yielded 70% more positive results than cefotaxime, 80% more than ceftazidime and 20% more than cefpodoxime, with 100% specificity. Cefepime revealed 100% sensitivity, but only 27% specificity. For the same incubation time, the automated software yielded on average 41% more positive results in relation to detecting resistance than qualitative interpretation of spectra.Conclusions: Our clinical validation of the method proved it to be highly reliable, simple to perform and time saving, transforming β-lactam resistance detection by MALDI-TOF MS into a ready-to-use technique in clinical laboratories.
      PubDate: 2017-04-24
      DOI: 10.1093/jac/dkx127
      Issue No: Vol. 72, No. 8 (2017)
  • The quinoline bromoquinol exhibits broad-spectrum antifungal activity and
           induces oxidative stress and apoptosis in Aspergillus fumigatus
    • Authors: Ben Yaakov D; Shadkchan Y, Albert N, et al.
      Pages: 2263 - 2272
      Abstract: AbstractObjectives: Over the last 30 years, the number of invasive fungal infections among immunosuppressed patients has increased significantly, while the number of effective systemic antifungal drugs remains low. The aim of this study was to identify and characterize antifungal compounds that inhibit fungus-specific metabolic pathways not conserved in humans.Methods: We screened a diverse compound library for antifungal activity in the pathogenic mould Aspergillus fumigatus. We determined the in vitro activity of bromoquinol by MIC determination against a panel of fungi, bacteria and cell lines. The mode of action of bromoquinol was determined by screening an Aspergillus nidulans overexpression genomic library for resistance-conferring genes and by RNAseq analysis in A. fumigatus. In vivo efficacy was tested in Galleria mellonella and murine models of A. fumigatus infection.Results: Screening of a diverse chemical library identified three compounds interfering with fungal iron utilization. The most potent, bromoquinol, shows potent wide-spectrum antifungal activity that was blocked in the presence of exogenous iron. Mode-of-action analysis revealed that overexpression of the dba secondary metabolite cluster gene dbaD, encoding a metabolite transporter, confers bromoquinol resistance in A. nidulans, possibly by efflux. RNAseq analysis and subsequent experimental validation revealed that bromoquinol induces oxidative stress and apoptosis in A. fumigatus. Bromoquinol significantly reduced mortality rates of G. mellonella infected with A. fumigatus, but was ineffective in a murine model of infection.Conclusions: Bromoquinol is a promising antifungal candidate with a unique mode of action. Its activity is potentiated by iron starvation, as occurs during in vivo growth.
      PubDate: 2017-05-05
      DOI: 10.1093/jac/dkx117
      Issue No: Vol. 72, No. 8 (2017)
  • Antimicrobial susceptibility of clinical isolates of Neisseria gonorrhoeae
           to alternative antimicrobials with therapeutic potential
    • Authors: Lagacé-Wiens PS; Adam HJ, Laing NM, et al.
      Pages: 2273 - 2277
      Abstract: AbstractBackground: The prevalence of MDR Neisseria gonorrhoeae is increasing globally and represents a public health emergency. Development and approval of new anti-gonococcal agents may take years. As a concurrent approach to developing new antimicrobials, the laboratory and clinical evaluation of currently licensed antimicrobials not widely used for the treatment of gonorrhoea may provide new options for the treatment of gonococcal infections.Objectives: To determine the in vitro activity of nine alternative, currently licensed and late-development antimicrobials with the potential to treat gonococcal infections against 112 clinical isolates of N. gonorrhoeae resistant to one or multiple antimicrobials.Methods: The MICs of conventional anti-gonococcal antimicrobials (penicillin, ceftriaxone, cefixime, azithromycin, ciprofloxacin, tetracycline and spectinomycin) and alternative antimicrobials (ertapenem, gentamicin, netilmicin, tigecycline, eravacycline, fosfomycin, linezolid, ceftazidime/avibactam and ceftaroline) were determined by agar dilution.Results: Ertapenem and the novel cephalosporins demonstrated similar MIC values to the third-generation cephalosporins, but increased MICs were observed for isolates with increased cefixime and ceftriaxone MICs. Tigecycline and eravacycline had MIC values below expected serum concentrations for all isolates tested. The aminoglycosides gentamicin and netilmicin were generally more potent than spectinomycin, with netilmicin demonstrating the greatest potency. Fosfomycin MICs were elevated compared with other agents, but remained within the MIC range for susceptible organisms, while linezolid MICs were generally higher than those for organisms considered resistant.Conclusions: Among potentially therapeutically useful alternative agents, the aminoglycosides, eravacycline, tigecycline and fosfomycin had good in vitro activity. The novel cephalosporins and ertapenem had comparable activity to cefixime and ceftriaxone.
      PubDate: 2017-05-12
      DOI: 10.1093/jac/dkx147
      Issue No: Vol. 72, No. 8 (2017)
  • Activity of ceftolozane/tazobactam against surveillance and ‘problem’
           Enterobacteriaceae, Pseudomonas aeruginosa and non-fermenters from the
           British Isles
    • Authors: Livermore DM; Mushtaq S, Meunier D, et al.
      Pages: 2278 - 2289
      Abstract: AbstractBackground: We assessed the activity of ceftolozane/tazobactam against consecutive isolates collected in the BSAC Bacteraemia Surveillance from 2011 to 2015 and against ‘problem’ isolates sent to the UK national reference laboratory from July 2015, when routine testing began.Methods: Susceptibility testing was by BSAC agar dilution with resistance mechanisms identified by PCR and interpretive reading.Results: Data were reviewed for 6080 BSAC surveillance isolates and 5473 referred organisms. Ceftolozane/tazobactam had good activity against unselected ESBL producers in the BSAC series, but activity was reduced against ertapenem-resistant ESBL producers, which were numerous among reference submissions. AmpC-derepressed Enterobacter spp. were widely resistant, but Escherichia coli with raised chromosomal AmpC frequently remained susceptible, as did Klebsiella pneumoniae with acquired DHA-1-type AmpC. Carbapenemase-producing Enterobacteriaceae were mostly resistant, except for ceftazidime-susceptible isolates with OXA-48-like enzymes. Ceftolozane/tazobactam was active against 99.8% of the BSAC Pseudomonas aeruginosa isolates; against referred P. aeruginosa it was active against 99.7% with moderately raised efflux, 94.7% with strongly raised efflux and 96.6% with derepressed AmpC. Resistance in P. aeruginosa was largely confined to isolates with metallo-β-lactamases (MBLs) or ESBLs. MICs for referred Burkholderia spp. and Stenotrophomonas maltophilia were 2–4-fold lower than those of ceftazidime.Conclusions: Ceftolozane/tazobactam is active against ESBL-producing Enterobacteriaceae; gains against other problem Enterobacteriaceae groups were limited. Against P. aeruginosa it overcame the two most prevalent mechanisms (up-regulated efflux and derepressed AmpC) and was active against 51.9% of isolates non-susceptible to all other β-lactams, rising to 80.9% if ESBL and MBL producers were excluded.
      PubDate: 2017-05-16
      DOI: 10.1093/jac/dkx136
      Issue No: Vol. 72, No. 8 (2017)
  • Evaluation of daptomycin combinations with cephalosporins or gentamicin
           against Streptococcus mitis group strains in an in vitro model of
           simulated endocardial vegetations (SEVs)
    • Authors: Yim J; Smith JR, Singh NB, et al.
      Pages: 2290 - 2296
      Abstract: AbstractObjectives: Among viridans group streptococcal infective endocarditis (IE), the Streptococcus mitis group is the most common aetiological organism. Treatment of IE caused by the S. mitis group is challenging due to the high frequency of β-lactam resistance, drug allergy and intolerability of mainstay antimicrobial agents such as vancomycin or gentamicin. Daptomycin has been suggested as an alternative therapeutic option in these scenarios based on its excellent susceptibility profile against S. mitis group strains. However, the propensity of many S. mitis group strains to rapidly evolve stable, high-level daptomycin resistance potentially limits this approach.Methods: We evaluated the activity of 6 mg/kg/day daptomycin alone or in combination with gentamicin, ceftriaxone or ceftaroline against two daptomycin-susceptible S. mitis group strains over 96 h in a pharmacokinetic/pharmacodynamic model of simulated endocardial vegetations.Results: Daptomycin alone was not bactericidal and high-level daptomycin resistance evolved at 96 h in both organisms. Combinations of daptomycin + ceftriaxone and daptomycin + ceftaroline demonstrated enhanced killing activity compared with each antibiotic alone and prevented emergence of daptomycin resistance at 96 h. Use of gentamicin as an adjunctive agent neither improved the efficacy of daptomycin nor prevented the development of daptomycin resistance.Conclusions: Addition of ceftriaxone or ceftaroline to daptomycin improves the bactericidal activity against S. mitis group strains and prevents daptomycin resistance emergence. Further investigation with combinations of daptomycin and β-lactams in a large number of strains is warranted to fully elucidate the clinical implications of such combinations for treatment of S. mitis group IE.
      PubDate: 2017-05-05
      DOI: 10.1093/jac/dkx130
      Issue No: Vol. 72, No. 8 (2017)
  • Pharmacodynamics of dose-escalated ‘front-loading’ polymyxin B
           regimens against polymyxin-resistant mcr-1 -harbouring Escherichia coli
    • Authors: Smith NM; Bulman ZP, Sieron AO, et al.
      Pages: 2297 - 2303
      Abstract: AbstractObjectives: Gram-negative bacteria harbouring the mcr-1 plasmid are resistant to the ‘last-line’ polymyxins and have been reported worldwide. Our objective was to define the impact of increasing the initial polymyxin B dose intensity against an mcr-1-harbouring strain to delineate the impact of plasmid-mediated polymyxin resistance on the dynamics of bacterial killing and resistance.Methods: A hollow fibre infection model (HFIM) was used to simulate polymyxin B regimens against an mcr-1-harbouring Escherichia coli (MIC 8 mg/L) over 10 days. Four escalating polymyxin B ‘front-loading’ regimens (3.33, 6.66, 13.3 or 26.6 mg/kg for one dose followed by 1.43 mg/kg every 12 h starting 12 h later) simulating human pharmacokinetics were utilized in the HFIM. A mechanism-based, mathematical model was developed using S-ADAPT to characterize bacterial killing.Results: The 3.33 mg/kg ‘front-loading’ regimen resulted in regrowth mirroring the growth control. The 6.66, 13.3 and 26.6 mg/kg ‘front-loading’ regimens resulted in maximal bacterial reductions of 1.91, 3.79 and 6.14 log10 cfu/mL, respectively. Irrespective of the early polymyxin B exposure (24 h AUC), population analysis profiles showed similar growth of polymyxin B-resistant subpopulations. The HFIM data were well described by the mechanism-based model integrating three subpopulations (susceptible, intermediate and resistant). Compared with the susceptible subpopulation of mcr-1-harbouring E. coli, the resistant subpopulation had an approximately 10-fold lower rate of killing due to polymyxin B treatment.Conclusions: Manipulating initial dose intensity of polymyxin B was not able to overcome plasmid-mediated resistance due to mcr-1 in E. coli. This reinforces the need to develop new combinatorial strategies to combat these highly resistant Gram-negative bacteria.
      PubDate: 2017-05-15
      DOI: 10.1093/jac/dkx121
      Issue No: Vol. 72, No. 8 (2017)
  • Optimization of linezolid therapy in the critically ill: the effect of
           adjusted infusion regimens
    • Authors: Taubert M; Zander J, Frechen S, et al.
      Pages: 2304 - 2310
      Abstract: AbstractObjectives: Insufficient linezolid levels, which are associated with a poorer outcome, are often observed in ICU patients who receive standard dosing. Although strategies to overcome these insufficient levels have been discussed, appropriate alternative dosing regimens remain to be identified.Methods: Various infusion regimens (1200–3600 mg/day; q6h, q8h, q12h and continuous) were simulated in 67 000 ICU patients. The probability of attaining pharmacodynamic targets (T>MIC ≥85%, AUC/MIC ≥100, cumulative fraction of response for Staphylococcus aureus and Enterococcus spp., PTA for an MIC of 0.5–4 mg/L) as well as the avoidance of toxic concentrations and concentrations constantly below the MIC (lack of antibiotic effect) or inside a mutant selection window (resistance development) were evaluated.Results: Best target attainment according to T>MIC was observed for continuous infusions, followed by q6h, q8h and q12h. A substantially reduced target attainment was observed in patients with acute respiratory distress syndrome (ARDS). In patients without ARDS, 1200 mg/day was insufficient irrespective of the regimen, while a dose of 1400 mg/day administered q6h or by continuous infusions provided an acceptable target attainment (e.g. cumulative fraction of response with regards to T>MIC ≥93%). Higher rates of potentially toxic trough concentrations (28% versus 12%) and concentrations constantly inside the mutant selection window (15% versus <0.1%) were observed with continuous infusions compared with q6h infusions (1400 mg/day, patients without ARDS).Conclusions: Irrespective of the regimen, 1200 mg/day linezolid might be insufficient for the treatment of ICU patients. Patients without ARDS might particularly benefit from q6h infusions with increased daily doses (e.g. 1400 mg/day).
      PubDate: 2017-05-24
      DOI: 10.1093/jac/dkx149
      Issue No: Vol. 72, No. 8 (2017)
  • Improved power for TB Phase IIa trials using a model-based
           pharmacokinetic–pharmacodynamic approach compared with commonly used
           analysis methods
    • Authors: Svensson RJ; Gillespie SH, Simonsson UH.
      Pages: 2311 - 2319
      Abstract: AbstractBackground: The demand for new anti-TB drugs is high, but development programmes are long and costly. Consequently there is a need for new strategies capable of accelerating this process.Objectives: To explore the power to find statistically significant drug effects using a model-based pharmacokinetic–pharmacodynamic approach in comparison with the methods commonly used for analysing TB Phase IIa trials.Methods: Phase IIa studies of four hypothetical anti-TB drugs (labelled A, B, C and D), each with a different mechanism of action, were simulated using the multistate TB pharmacometric (MTP) model. cfu data were simulated over 14 days for patients taking once-daily monotherapy at four different doses per drug and a reference (10 mg/kg rifampicin). The simulated data were analysed using t-test, ANOVA, mono- and bi-exponential models and a pharmacokinetic–pharmacodynamic model approach (MTP model) to establish their respective power to find a drug effect at the 5% significance level.Results: For the pharmacokinetic–pharmacodynamic model approach, t-test, ANOVA, mono-exponential model and bi-exponential model, the sample sizes needed to achieve 90% power were: 10, 30, 75, 20 and 30 (drug A); 30, 75, 245, 75 and 105 (drug B); 70, >1250, 315, >1250 and >1250 (drug C); and 30, 110, 710, 170 and 185 (drug D), respectively.Conclusions: A model-based design and analysis using a pharmacokinetic–pharmacodynamic approach can reduce the number of patients required to determine a drug effect at least 2-fold compared with current methodologies. This could significantly accelerate early-phase TB drug development.
      PubDate: 2017-05-16
      DOI: 10.1093/jac/dkx129
      Issue No: Vol. 72, No. 8 (2017)
  • In vitro and in vivo activity of biapenem against drug-susceptible and
           rifampicin-resistant Mycobacterium tuberculosis
    • Authors: Kaushik A; Ammerman NC, Tasneen R, et al.
      Pages: 2320 - 2325
      Abstract: AbstractBackground: Biapenem, a carbapenem antibiotic, has been shown to have synergistic bactericidal anti-TB activity when combined with rifampicin both in vitro and in the mouse model of TB chemotherapy. We hypothesized that this synergy would result in biapenem/rifampicin activity against rifampicin-resistant Mycobacterium tuberculosis.Objectives: Our objective was to evaluate the synergy of biapenem/rifampicin against both low- and high-level rifampicin-resistant strains of M. tuberculosis, in vitro and in the mouse model.Methods: Biapenem/rifampicin activity was evaluated using three strains of M. tuberculosis: strain 115R (low-level rifampicin resistance); strain 124R (high-level rifampicin resistance); and the drug-susceptible H37Rv parent strain. Biapenem/rifampicin synergy was evaluated in vitro by chequerboard titration. In vivo, we first conducted a dose-ranging experiment with biapenem against H37Rv in the mouse model. We then evaluated biapenem/rifampicin activity in mice infected with each M. tuberculosis strain.Results:In vitro, synergy was observed between biapenem and rifampicin against H37Rv and strain 115R. In vivo, biapenem exhibited clear dose-dependent activity against H37Rv, with all biapenem doses as active or more active than rifampicin alone. Biapenem and rifampicin had synergistic bactericidal activity against H37Rv in the mouse model; no synergy was observed in mice infected with either of the rifampicin-resistant strains. Biapenem alone was active against all three strains.Conclusions: Our preclinical experiments indicate that biapenem has potential for use as an anti-TB drug, including for use against rifampicin-resistant TB. Thus, biapenem has promise for repurposing as a ‘new’ – and desperately needed – drug for the treatment of drug-resistant TB.
      PubDate: 2017-06-01
      DOI: 10.1093/jac/dkx152
      Issue No: Vol. 72, No. 8 (2017)
  • Are moxifloxacin and levofloxacin equally effective to treat XDR
    • Authors: Maitre T; Petitjean G, Chauffour A, et al.
      Pages: 2326 - 2333
      Abstract: AbstractBackground: Moxifloxacin retains partial activity against some fluoroquinolone-resistant mutants of Mycobacterium tuberculosis. Levofloxacin is presumed to be as active as moxifloxacin against drug-susceptible tuberculosis and to have a better safety profile.Objectives: To compare the in vivo activity of levofloxacin and moxifloxacin against M. tuberculosis strains with various levels of fluoroquinolone resistance.Methods: BALB/c mice were intravenously infected with 106M. tuberculosis H37Rv and three isogenic mutants: GyrA A90V, GyrB E540A and GyrB A543V. Treatment with 50 or 100 mg/kg levofloxacin and 60 or 66 mg/kg moxifloxacin was given orally every 6 h, for 4 weeks.Results: Levofloxacin 50 and 100 mg/kg q6h and moxifloxacin 60 and 66 mg/kg q6h generated AUCs in mice equivalent to those of levofloxacin 750 and 1000 mg/day and moxifloxacin 400 and 800 mg/day, respectively, in humans. Moxifloxacin 60 and 66 mg/kg q6h had bactericidal activity against strain H37Rv (MIC ≤ 0.25 mg/L) and mutants GyrB E540A and GyrB A543V (MIC = 0.5 mg/L). Against mutant GyrA A90V (MIC = 2 mg/L), moxifloxacin 60 mg/kg q6h did not prevent bacillary growth, whereas 66 mg/kg q6h had bacteriostatic activity. Levofloxacin 50 mg/kg q6h had bactericidal activity against H37Rv (MIC ≤ 0.25 mg/L) but not against the mutant strains. Levofloxacin 100 mg/kg q6h had bactericidal activity against H37Rv and mutants GyrB E540A (MIC = 0.5 mg/L) and GyrB A543V (MIC= 1 mg/L) but not against mutant GyrA A90V (MIC = 4 mg/L).Conclusions: All mutations reduced fluoroquinolone activity, even those classified as susceptible according to phenotypic tests. High-dose levofloxacin is less effective than high-dose moxifloxacin against both fluoroquinolone-resistant and -susceptible M. tuberculosis strains in mice.
      PubDate: 2017-05-23
      DOI: 10.1093/jac/dkx150
      Issue No: Vol. 72, No. 8 (2017)
  • Development of a murine vertical transmission model for Toxoplasma gondii
           oocyst infection and studies on the efficacy of bumped kinase inhibitor
           (BKI)-1294 and the naphthoquinone buparvaquone against congenital
    • Authors: Müller J; Aguado-Martínez A, Ortega-Mora L, et al.
      Pages: 2334 - 2341
      Abstract: AbstractObjectives: Establishment of a mouse model for congenital toxoplasmosis based on oral infection with oocysts from Toxoplasma gondii ME49 and its application for investigating chemotherapeutic options against congenital toxoplasmosis.Methods: CD1 mice were mated, orally infected with 5, 25, 100, 500 or 2000 oocysts and monitored for clinical signs and survival of dams and pups until 4 weeks post partum. The parasite burden in infected mice was quantified by real-time PCR in lungs, brains and, in the case of surviving pups, also in eyes. Seroconversion was assessed by ELISA. T. gondii cysts in brain were identified by immunofluorescence. In a second experiment, pregnant CD1 mice challenged with 20 oocysts/mouse were treated with buparvaquone or the calcium-dependent protein kinase 1 inhibitor bumped kinase inhibitor (BKI)-1294 and the outcome of infection was analysed.Results:T. gondii DNA was detected in the brain of all infected animals, irrespective of the infection dose. Seroconversion occurred at 3 weeks post-infection. Most pups born to infected dams died within 1 week post partum, but a small fraction survived until the end of the experiment. T. gondii DNA was detected in the brain of all survivors and half of them exhibited ocular infection. Chemotherapy with both compounds led to dramatically increased numbers of surviving pups and reduced cerebral infection. Most efficient were treatments with BKI-1294, with 100% survivors and only 7% brain-positive pups.Conclusions: BKI-1294 and buparvaquone exert excellent activities against transplacental transmission in pregnant mice.
      PubDate: 2017-05-09
      DOI: 10.1093/jac/dkx134
      Issue No: Vol. 72, No. 8 (2017)
  • Population pharmacokinetics and dosing considerations for the use of
           daptomycin in adult patients with haematological malignancies
    • Authors: Cojutti P; Candoni A, Ramos-Martin V, et al.
      Pages: 2342 - 2350
      Abstract: AbstractObjectives: To assess the population pharmacokinetics (popPK) of daptomycin at the conventional dose of 6 mg/kg/day in a cohort of oncohaematological patients.Methods: Patients underwent serial blood sampling on day 3 of therapy (before dosing and at 0, 0.5, 1, 2, 3, 5, 7, 9 and 12 h after dosing) to assess the pharmacokinetic profile of daptomycin. PopPK and Monte Carlo simulation were performed to define the probability of target attainment (PTA) with 6, 8, 10 and 12 mg/kg/day of the pharmacokinetic/pharmacodynamic target of AUC24/MIC >1081.Results: Thirty patients were recruited. A two-compartment open model with first-order intravenous input and first-order elimination was developed. Estimated creatinine clearance (CLCR), serum albumin concentration (Alb) and presence of AML were covariates included in the final model. Monte Carlo simulation showed that the conventional 6 mg/kg/day dose resulted in optimal PTAs (≥80%) in the presence of pathogens with an MIC up to 0.5 mg/L only in patients with CLCR 50–100 mL/min/1.73 m2, Alb 26–45 g/L and a haematological diagnosis other than AML. Conversely, higher dosages, up to 12 mg/kg/day, were needed to achieve this goal in the presence of pathogens with an MIC of 0.25–0.5 mg/L in all of the other tested scenarios. In patients with CLCR 101–150 mL/min/1.73 m2 and Alb 15–25 g/L, suboptimal PTAs (<60%) were predicted even with 12 mg/kg/day dosing .Conclusions: Our study provides a strong rationale for considering daptomycin dosages of ≥ 8 mg/kg/day in several clinical scenarios for oncohaematological patients. In some of these scenarios therapeutic drug monitoring could be a useful adjunct for optimized care.
      PubDate: 2017-06-01
      DOI: 10.1093/jac/dkx140
      Issue No: Vol. 72, No. 8 (2017)
  • Antiretroviral-treated HIV-1 patients can harbour resistant viruses in CSF
           despite an undetectable viral load in plasma
    • Authors: Soulie C; Grudé M, Descamps D, et al.
      Pages: 2351 - 2354
      Abstract: AbstractBackground: HIV therapy reduces the CSF HIV RNA viral load (VL) and prevents disorders related to HIV encephalitis. However, these brain disorders may persist in some cases. A large population of antiretroviral-treated patients who had a VL > 1.7 log10 copies/mL in CSF with detectable or undetectable VL in plasma associated with cognitive impairment was studied, in order to characterize discriminatory factors of these two patient populations.Methods: Blood and CSF samples were collected at the time of neurological disorders for 227 patients in 22 centres in France and 1 centre in Switzerland. Genotypic HIV resistance tests were performed on CSF. The genotypic susceptibility score was calculated according to the last Agence Nationale de Recherche sur le Sida et les hépatites virales Action Coordonnée 11 (ANRS AC11) genotype interpretation algorithm.Results: Among the 227 studied patients with VL > 1.7 log10 copies/mL in CSF, 195 had VL detectable in plasma [median (IQR) HIV RNA was 3.7 (2.7–4.7) log10 copies/mL] and 32 had discordant VL in plasma (VL < 1.7 log10 copies/mL). The CSF VL was lower (median 2.8 versus 4.0 log10 copies/mL; P < 0.001) and the CD4 cell count was higher (median 476 versus 214 cells/mm3; P < 0.001) in the group of patients with VL < 1.7 log10 copies/mL in plasma compared with patients with plasma VL > 1.7 log10 copies/mL. Resistance to antiretrovirals was observed in CSF for the two groups of patients.Conclusions: Fourteen percent of this population of patients with cognitive impairment and detectable VL in CSF had well controlled VL in plasma. Thus, it is important to explore CSF HIV (VL and genotype) even if the HIV VL is controlled in plasma because HIV resistance may be observed.
      PubDate: 2017-05-02
      DOI: 10.1093/jac/dkx128
      Issue No: Vol. 72, No. 8 (2017)
  • Multicentre study of posaconazole delayed-release tablet serum level and
           association with hepatotoxicity and QTc prolongation
    • Authors: Pettit NN; Miceli MH, Rivera CG, et al.
      Pages: 2355 - 2358
      Abstract: AbstractObjectives: The association of posaconazole serum concentrations and toxicity is unclear. An assessment of whether levels obtained with the delayed-release tablet (DRT) formulation are correlated with abnormal liver function test (LFT) results and/or QTc prolongation was undertaken.Methods: This was a multicentre, retrospective, observational study of adult patients with cancer between 26 November 2013 and 14 November 2014. Patients were included if they received posaconazole DRT with a posaconazole level obtained between days 5 and 14. Clinical data, including demographics, hepatotoxic medications, posaconazole levels, LFTs and QTc intervals, were obtained. Association of factors with changes in LFTs and QTc prolongation was assessed using linear and logistic regression.Results: One hundred and sixty-six study patients were included. The median posaconazole level was 1250 (range 110–4220) ng/mL and the median time until level was 6 (range 5–14) days. There was a statistically significant increase in AST (P < 0.001), ALT (P < 0.001), alkaline phosphatase (ALK) (P < 0.001), total bilirubin (TBILI) (P < 0.001) and QTc (P = 0.05) from baseline. Posaconazole levels were not associated with increases in AST [β (SE) = −0.33 (2.2), P = 0.88], log ALT [β (SE) = −0.02 (0.03), P = 0.63], ALK [β (SE) = 2.2 (2.9), P = 0.46] and TBILI [β (SE) = −0.01 (0.04), P = 0.88]. For each additional hepatotoxic medication, there was a mean change in TBILI of 0.13 mg/dL (P = 0.02) and ALK of 7.1 U/L (P = 0.09). No statistically significant association between posaconazole level and QTc interval prolongation was found.Conclusions: We did not identify an association between posaconazole serum concentrations and LFT elevations or QTc prolongation. However, some LFTs were found to increase with more hepatotoxic medications administered.
      PubDate: 2017-05-05
      DOI: 10.1093/jac/dkx122
      Issue No: Vol. 72, No. 8 (2017)
  • Randomized comparison of liposomal amphotericin B versus placebo to
           prevent invasive mycoses in acute lymphoblastic leukaemia
    • Authors: Cornely OA; Leguay T, Maertens J, et al.
      Pages: 2359 - 2367
      Abstract: AbstractObjectives: To prevent invasive fungal disease (IFD) in adult patients undergoing remission-induction chemotherapy for newly diagnosed acute lymphoblastic leukaemia (ALL).Patients and methods: In a double-blind multicentre Phase 3 study, patients received prophylactic liposomal amphotericin B (L-AMB) at 5 mg/kg intravenously or placebo twice weekly in a 2:1 random allocation during remission-induction treatment. The primary endpoint was the development of proven or probable IFD. Secondary endpoints included those focused on the safety and tolerability of prophylactic L-AMB.Results: Three hundred and fifty-five patients from 86 centres in Europe and South America received at least one dose of L-AMB (n = 237) or placebo (n = 118). Rates of proven and probable IFD assessed independently were 7.9% (18/228) in the L-AMB group and 11.7% (13/111) in the placebo group (P = 0.24). Rates of possible IFD were 4.8% (11/228) in the L-AMB and 5.4% (6/111) in the placebo group (P = 0.82). The remission-induction phase was a median of 22 days for both groups. Overall mortality was similar between the groups: 7.2% (17/237) for L-AMB and 6.8% (8/118) for placebo (P = 1.00). Hypokalaemia and creatinine increase were significantly more frequent with L-AMB.Conclusions: The IFD rate among adult patients undergoing remission-induction chemotherapy for newly diagnosed ALL was 11.7% in the placebo group, and was not significantly different in patients receiving L-AMB, suggesting that the L-AMB regimen studied is not effective as prophylaxis against IFD. The IFD rate appears higher than previously reported, warranting further investigation. Tolerability of L-AMB was what might be expected. Further studies are needed to determine the optimal antifungal strategy during remission-induction chemotherapy of ALL.
      PubDate: 2017-05-30
      DOI: 10.1093/jac/dkx133
      Issue No: Vol. 72, No. 8 (2017)
  • Efficacy of anidulafungin in 539 patients with invasive candidiasis: a
           patient-level pooled analysis of six clinical trials
    • Authors: Kullberg B; Vasquez J, Mootsikapun P, et al.
      Pages: 2368 - 2377
      Abstract: AbstractObjectives: To evaluate the efficacy of anidulafungin for the treatment of candidaemia and invasive candidiasis in a large dataset, including patients with deep-seated tissue candidiasis, neutropenia and infection due to non-albicans Candida species.Methods: Data were pooled from six prospective, multicentre, multinational studies: four open-label, non-comparative studies of anidulafungin and two double-blind, double-dummy, randomized studies of anidulafungin versus caspofungin (clinical trial registrations: NCT00496197, NCT00548262, NCT00537329, NCT00689338, NCT00806351 and NCT00805740; In all studies, patients with culture-confirmed invasive candidiasis received a single intravenous (iv) loading dose of anidulafungin 200 mg on day 1, followed by 100 mg once-daily. Switch to oral fluconazole or voriconazole was permitted after 5–10 days of iv treatment in all studies except one. Antifungal treatment (iv plus oral therapy if applicable) was maintained for ≥14 days after the last positive Candida culture. The primary endpoint was successful global response at end of iv therapy (EOivT) in the modified ITT (mITT) population.Results: In total, 539 patients were included (mITT population). The most common baseline Candida species were Candida albicans (47.9%), Candida glabrata (21.0%), Candida tropicalis (13.7%), Candida parapsilosis (13.2%) and Candida krusei (3.5%). Median duration of anidulafungin iv treatment was 10.0 days. The global response success rate at EOivT was 76.4% (95% CI 72.9%–80.0%). All-cause mortality was 13.0% on day 14 and 19.1% on day 28. Adverse events (AEs) were consistent with the known AE profile for anidulafungin.Conclusions: These data demonstrate that anidulafungin is effective for treatment of candidaemia and invasive candidiasis in a broad patient population.
      PubDate: 2017-04-28
      DOI: 10.1093/jac/dkx116
      Issue No: Vol. 72, No. 8 (2017)
  • Evolution of acute infection with atypical bacteria in a prospective
           cohort of children with community-acquired pneumonia receiving amoxicillin
    • Authors: Nascimento-Carvalho CM; Xavier-Souza G, Vilas-Boas A, et al.
      Pages: 2378 - 2384
      Abstract: AbstractBackground: Atypical bacteria are treatable causative agents of community-acquired pneumonia (CAP). However, there is no conclusive evidence that a child with CAP should receive empirical treatment against such agents.Objectives: We assessed the possibility of association between clinical failure and acute infection by these bacteria among children with CAP treated with amoxicillin.Patients and methods: Patients aged 2–59 months with non-severe CAP received amoxicillin during prospective follow-up. Acute and convalescent blood samples were collected. Probable acute infection by Mycoplasma pneumoniae (specific IgM antibodies), by Chlamydia pneumoniae or Chlamydia trachomatis (specific IgM antibodies and/or IgG/IgA titre change) was investigated. Outcomes were assessed during follow-up at 2, 5 and 14–28 days. Treatment failure included development of danger signs, persistent fever, tachypnoea or death. NCT01200706.Results: Of 787 children, 86 (10.9%; 95% CI = 8.9%–13.3%) had acute M. pneumoniae infection. C. pneumoniae acute infection was found in 79 of 733 (10.8%; 95% CI = 8.7%–13.2%) and C. trachomatis was found in 3 of 28 (10.7%; 95% CI = 2.8%–26.5%) <6 months old. Among patients with or without treatment failure at 2 days, acute M. pneumoniae infection (11.7% versus 10.7%; P = 0.7), acute C. pneumoniae infection (8.5% versus 11.3%; P = 0.3) and acute C. trachomatis infection (16.7% versus 9.1%; P = 0.5) were found. No significant differences were found with regard to treatment failure at the 5 day evaluation. Overall, amoxicillin was substituted in 3.5% versus 2.7% among patients with or without acute infection by one of these bacteria (P = 0.6).Conclusions: The overall substitution rate of amoxicillin was very low. It is not necessary to give an empirical non-β-lactam antibiotic as a first-line option to treat every child between 2 and 59 months old with non-severe CAP.
      PubDate: 2017-05-05
      DOI: 10.1093/jac/dkx126
      Issue No: Vol. 72, No. 8 (2017)
  • Identifying practice-related factors for high-volume prescribers of
           antibiotics in Danish general practice
    • Authors: Aabenhus R; Siersma V, Sandholdt H, et al.
      Pages: 2385 - 2391
      Abstract: AbstractObjectives: In Denmark, general practice is responsible for 75% of antibiotic prescribing in the primary care sector. We aimed to identify practice-related factors associated with high prescribers, including prescribers of critically important antibiotics as defined by WHO, after accounting for case mix by practice.Methods: We performed a nationwide register-based survey of antibiotic prescribing in Danish general practice from 2012 to 2013. The unit of analysis was the individual practice. We used multivariable regression analyses and an assessment of relative importance to identify practice-related factors driving high antibiotic prescribing rates.Results: We included 98% of general practices in Denmark (n = 1962) and identified a 10% group of high prescribers who accounted for 15% of total antibiotic prescriptions and 18% of critically important antibiotic prescriptions. Once case mix had been accounted for, the following practice-related factors were associated with being a high prescriber: lack of access to diagnostic tests in practice (C-reactive protein and urine culture); high use of diagnostic tests (urine culture and strep A throat test); a low percentage of antibiotic prescriptions issued over the phone compared with all antibiotic prescriptions; and a high number of consultations per 1000 patients. We also found that a low number of consultations per 1000 patients was associated with a reduced likelihood of being a high prescriber of antibiotics.Conclusions: An apparent underuse or overuse of diagnostic tests in general practice as well as organizational factors were associated with high-prescribing practices. Furthermore, the choice of antibiotic type seemed less rational among high prescribers.
      PubDate: 2017-04-19
      DOI: 10.1093/jac/dkx115
      Issue No: Vol. 72, No. 8 (2017)
  • Cost-effectiveness of outpatient parenteral antibiotic therapy: a
           simulation modelling approach
    • Authors: Vargas-Palacios AA; Meads DM, Twiddy MM, et al.
      Pages: 2392 - 2400
      Abstract: AbstractObjectives: In the UK, patients who require intravenous antimicrobial (IVA) treatment may receive this in the community through outpatient parenteral antimicrobial therapy (OPAT) services. Services include: IVA administration at a hospital outpatient clinic (HO); IVA administration at home by a general nurse (GN) or a specialist nurse (SN); or patient self-administered (SA) IVA administration following training. There is uncertainty regarding which OPAT services represent value for money; this study aimed to estimate their cost-effectiveness.Methods: A cost-effectiveness decision-analytic model was developed using a simulation technique utilizing data from hospital records and a systematic review of the literature. The model estimates cost per QALY gained from the National Health Service (NHS) perspective for short- and long-term treatment of infections and service combinations across these.Results: In short-term treatments, HO was estimated as the most effective (0.7239 QALYs), but at the highest cost (£973). SN was the least costly (£710), producing 0.7228 QALYs. The combination between SN and HO was estimated to produce 0.7235 QALYs at a cost of £841. For long-term treatments, SN was the most effective (0.677 QALYs), costing £2379, while SA was the least costly at £1883, producing 0.666 QALYs. A combination of SA and SN was estimated to produce 0.672 QALYs at a cost of £2128.Conclusions: SN and SA are cost-effective for short- and long-term treatment of infections, while combining services may represent the second-best alternative for OPAT in the UK.
      PubDate: 2017-05-15
      DOI: 10.1093/jac/dkx123
      Issue No: Vol. 72, No. 8 (2017)
  • ST3268: a geographically widespread primate MRSA clone
    • Authors: Hsu L; Holden MG, Koh T, et al.
      Pages: 2401 - 2403
      Abstract: Sir,
      PubDate: 2017-04-21
      DOI: 10.1093/jac/dkx120
      Issue No: Vol. 72, No. 8 (2017)
  • KPC-3-producing ST167 Escherichia coli from mussels bought at a retail
           market in Tunisia
    • Authors: Mani Y; Mansour W, Mammeri H, et al.
      Pages: 2403 - 2404
      Abstract: Sir,
      PubDate: 2017-05-02
      DOI: 10.1093/jac/dkx124
      Issue No: Vol. 72, No. 8 (2017)
  • Co-occurrence of mcr-1 and bla KPC-2 in a clinical isolate of Escherichia
           coli in Brazil
    • Authors: Dalmolin T; Castro L, Mayer FQ, et al.
      Pages: 2404 - 2406
      Abstract: Sir,
      PubDate: 2017-05-15
      DOI: 10.1093/jac/dkx142
      Issue No: Vol. 72, No. 8 (2017)
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