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Showing 1 - 200 of 406 Journals sorted alphabetically
ACS Symposium Series     Full-text available via subscription   (SJR: 0.189, CiteScore: 0)
Acta Biochimica et Biophysica Sinica     Hybrid Journal   (Followers: 5, SJR: 0.79, CiteScore: 2)
Adaptation     Hybrid Journal   (Followers: 9, SJR: 0.143, CiteScore: 0)
Advances in Nutrition     Hybrid Journal   (Followers: 53, SJR: 2.196, CiteScore: 5)
Aesthetic Surgery J.     Hybrid Journal   (Followers: 6, SJR: 1.434, CiteScore: 1)
Aesthetic Surgery J. Open Forum     Open Access  
African Affairs     Hybrid Journal   (Followers: 66, SJR: 1.869, CiteScore: 2)
Age and Ageing     Hybrid Journal   (Followers: 90, SJR: 1.989, CiteScore: 4)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 19, SJR: 1.376, CiteScore: 3)
American Entomologist     Full-text available via subscription   (Followers: 8)
American Historical Review     Hybrid Journal   (Followers: 169, SJR: 0.467, CiteScore: 1)
American J. of Agricultural Economics     Hybrid Journal   (Followers: 44, SJR: 2.113, CiteScore: 3)
American J. of Clinical Nutrition     Hybrid Journal   (Followers: 177, SJR: 3.438, CiteScore: 6)
American J. of Epidemiology     Hybrid Journal   (Followers: 197, SJR: 2.713, CiteScore: 3)
American J. of Health-System Pharmacy     Full-text available via subscription   (Followers: 52, SJR: 0.595, CiteScore: 1)
American J. of Hypertension     Hybrid Journal   (Followers: 25, SJR: 1.322, CiteScore: 3)
American J. of Jurisprudence     Hybrid Journal   (Followers: 19, SJR: 0.281, CiteScore: 1)
American J. of Legal History     Full-text available via subscription   (Followers: 9, SJR: 0.116, CiteScore: 0)
American Law and Economics Review     Hybrid Journal   (Followers: 27, SJR: 1.053, CiteScore: 1)
American Literary History     Hybrid Journal   (Followers: 16, SJR: 0.391, CiteScore: 0)
Analysis     Hybrid Journal   (Followers: 22, SJR: 1.038, CiteScore: 1)
Animal Frontiers     Hybrid Journal   (Followers: 1)
Annals of Behavioral Medicine     Hybrid Journal   (Followers: 16, SJR: 1.423, CiteScore: 3)
Annals of Botany     Hybrid Journal   (Followers: 38, SJR: 1.721, CiteScore: 4)
Annals of Oncology     Hybrid Journal   (Followers: 56, SJR: 5.599, CiteScore: 9)
Annals of the Entomological Society of America     Full-text available via subscription   (Followers: 10, SJR: 0.722, CiteScore: 1)
Annals of Work Exposures and Health     Hybrid Journal   (Followers: 34, SJR: 0.728, CiteScore: 2)
Antibody Therapeutics     Open Access  
AoB Plants     Open Access   (Followers: 4, SJR: 1.28, CiteScore: 3)
Applied Economic Perspectives and Policy     Hybrid Journal   (Followers: 17, SJR: 0.858, CiteScore: 2)
Applied Linguistics     Hybrid Journal   (Followers: 59, SJR: 2.987, CiteScore: 3)
Applied Mathematics Research eXpress     Hybrid Journal   (Followers: 1, SJR: 1.241, CiteScore: 1)
Arbitration Intl.     Full-text available via subscription   (Followers: 21)
Arbitration Law Reports and Review     Hybrid Journal   (Followers: 14)
Archives of Clinical Neuropsychology     Hybrid Journal   (Followers: 30, SJR: 0.731, CiteScore: 2)
Aristotelian Society Supplementary Volume     Hybrid Journal   (Followers: 3)
Arthropod Management Tests     Hybrid Journal   (Followers: 2)
Astronomy & Geophysics     Hybrid Journal   (Followers: 44, SJR: 0.146, CiteScore: 0)
Behavioral Ecology     Hybrid Journal   (Followers: 52, SJR: 1.871, CiteScore: 3)
Bioinformatics     Hybrid Journal   (Followers: 337, SJR: 6.14, CiteScore: 8)
Biology Methods and Protocols     Hybrid Journal  
Biology of Reproduction     Full-text available via subscription   (Followers: 9, SJR: 1.446, CiteScore: 3)
Biometrika     Hybrid Journal   (Followers: 20, SJR: 3.485, CiteScore: 2)
BioScience     Hybrid Journal   (Followers: 29, SJR: 2.754, CiteScore: 4)
Bioscience Horizons : The National Undergraduate Research J.     Open Access   (Followers: 1, SJR: 0.146, CiteScore: 0)
Biostatistics     Hybrid Journal   (Followers: 17, SJR: 1.553, CiteScore: 2)
BJA : British J. of Anaesthesia     Hybrid Journal   (Followers: 186, SJR: 2.115, CiteScore: 3)
BJA Education     Hybrid Journal   (Followers: 65)
Brain     Hybrid Journal   (Followers: 68, SJR: 5.858, CiteScore: 7)
Briefings in Bioinformatics     Hybrid Journal   (Followers: 50, SJR: 2.505, CiteScore: 5)
Briefings in Functional Genomics     Hybrid Journal   (Followers: 3, SJR: 2.15, CiteScore: 3)
British J. for the Philosophy of Science     Hybrid Journal   (Followers: 36, SJR: 2.161, CiteScore: 2)
British J. of Aesthetics     Hybrid Journal   (Followers: 25, SJR: 0.508, CiteScore: 1)
British J. of Criminology     Hybrid Journal   (Followers: 604, SJR: 1.828, CiteScore: 3)
British J. of Social Work     Hybrid Journal   (Followers: 86, SJR: 1.019, CiteScore: 2)
British Medical Bulletin     Hybrid Journal   (Followers: 6, SJR: 1.355, CiteScore: 3)
British Yearbook of Intl. Law     Hybrid Journal   (Followers: 34)
Bulletin of the London Mathematical Society     Hybrid Journal   (Followers: 4, SJR: 1.376, CiteScore: 1)
Cambridge J. of Economics     Hybrid Journal   (Followers: 70, SJR: 0.764, CiteScore: 2)
Cambridge J. of Regions, Economy and Society     Hybrid Journal   (Followers: 12, SJR: 2.438, CiteScore: 4)
Cambridge Quarterly     Hybrid Journal   (Followers: 10, SJR: 0.104, CiteScore: 0)
Capital Markets Law J.     Hybrid Journal   (Followers: 2, SJR: 0.222, CiteScore: 0)
Carcinogenesis     Hybrid Journal   (Followers: 2, SJR: 2.135, CiteScore: 5)
Cardiovascular Research     Hybrid Journal   (Followers: 14, SJR: 3.002, CiteScore: 5)
Cerebral Cortex     Hybrid Journal   (Followers: 48, SJR: 3.892, CiteScore: 6)
CESifo Economic Studies     Hybrid Journal   (Followers: 22, SJR: 0.483, CiteScore: 1)
Chemical Senses     Hybrid Journal   (Followers: 1, SJR: 1.42, CiteScore: 3)
Children and Schools     Hybrid Journal   (Followers: 6, SJR: 0.246, CiteScore: 0)
Chinese J. of Comparative Law     Hybrid Journal   (Followers: 5, SJR: 0.412, CiteScore: 0)
Chinese J. of Intl. Law     Hybrid Journal   (Followers: 22, SJR: 0.329, CiteScore: 0)
Chinese J. of Intl. Politics     Hybrid Journal   (Followers: 10, SJR: 1.392, CiteScore: 2)
Christian Bioethics: Non-Ecumenical Studies in Medical Morality     Hybrid Journal   (Followers: 10, SJR: 0.183, CiteScore: 0)
Classical Receptions J.     Hybrid Journal   (Followers: 27, SJR: 0.123, CiteScore: 0)
Clean Energy     Open Access   (Followers: 1)
Clinical Infectious Diseases     Hybrid Journal   (Followers: 69, SJR: 5.051, CiteScore: 5)
Communication Theory     Hybrid Journal   (Followers: 24, SJR: 2.424, CiteScore: 3)
Communication, Culture & Critique     Hybrid Journal   (Followers: 27, SJR: 0.222, CiteScore: 1)
Community Development J.     Hybrid Journal   (Followers: 27, SJR: 0.268, CiteScore: 1)
Computer J.     Hybrid Journal   (Followers: 9, SJR: 0.319, CiteScore: 1)
Conservation Physiology     Open Access   (Followers: 3, SJR: 1.818, CiteScore: 3)
Contemporary Women's Writing     Hybrid Journal   (Followers: 9, SJR: 0.121, CiteScore: 0)
Contributions to Political Economy     Hybrid Journal   (Followers: 6, SJR: 0.906, CiteScore: 1)
Critical Values     Full-text available via subscription  
Current Developments in Nutrition     Open Access   (Followers: 2)
Current Legal Problems     Hybrid Journal   (Followers: 29)
Current Zoology     Full-text available via subscription   (Followers: 3, SJR: 1.164, CiteScore: 2)
Database : The J. of Biological Databases and Curation     Open Access   (Followers: 9, SJR: 1.791, CiteScore: 3)
Digital Scholarship in the Humanities     Hybrid Journal   (Followers: 14, SJR: 0.259, CiteScore: 1)
Diplomatic History     Hybrid Journal   (Followers: 21, SJR: 0.45, CiteScore: 1)
DNA Research     Open Access   (Followers: 5, SJR: 2.866, CiteScore: 6)
Dynamics and Statistics of the Climate System     Open Access   (Followers: 4)
Early Music     Hybrid Journal   (Followers: 17, SJR: 0.139, CiteScore: 0)
Econometrics J.     Hybrid Journal   (Followers: 32, SJR: 2.926, CiteScore: 1)
Economic J.     Hybrid Journal   (Followers: 113, SJR: 5.161, CiteScore: 3)
Economic Policy     Hybrid Journal   (Followers: 46, SJR: 3.584, CiteScore: 3)
ELT J.     Hybrid Journal   (Followers: 24, SJR: 0.942, CiteScore: 1)
English Historical Review     Hybrid Journal   (Followers: 56, SJR: 0.612, CiteScore: 1)
English: J. of the English Association     Hybrid Journal   (Followers: 17, SJR: 0.1, CiteScore: 0)
Environmental Entomology     Full-text available via subscription   (Followers: 11, SJR: 0.818, CiteScore: 2)
Environmental Epigenetics     Open Access   (Followers: 2)
Environmental History     Hybrid Journal   (Followers: 26, SJR: 0.408, CiteScore: 1)
EP-Europace     Hybrid Journal   (Followers: 3, SJR: 2.748, CiteScore: 4)
Epidemiologic Reviews     Hybrid Journal   (Followers: 9, SJR: 4.505, CiteScore: 8)
ESHRE Monographs     Hybrid Journal  
Essays in Criticism     Hybrid Journal   (Followers: 19, SJR: 0.113, CiteScore: 0)
European Heart J.     Hybrid Journal   (Followers: 66, SJR: 9.315, CiteScore: 9)
European Heart J. - Cardiovascular Imaging     Hybrid Journal   (Followers: 10, SJR: 3.625, CiteScore: 3)
European Heart J. - Cardiovascular Pharmacotherapy     Full-text available via subscription   (Followers: 2)
European Heart J. - Quality of Care and Clinical Outcomes     Hybrid Journal  
European Heart J. : Case Reports     Open Access  
European Heart J. Supplements     Hybrid Journal   (Followers: 8, SJR: 0.223, CiteScore: 0)
European J. of Cardio-Thoracic Surgery     Hybrid Journal   (Followers: 9, SJR: 1.681, CiteScore: 2)
European J. of Intl. Law     Hybrid Journal   (Followers: 201, SJR: 0.694, CiteScore: 1)
European J. of Orthodontics     Hybrid Journal   (Followers: 5, SJR: 1.279, CiteScore: 2)
European J. of Public Health     Hybrid Journal   (Followers: 20, SJR: 1.36, CiteScore: 2)
European Review of Agricultural Economics     Hybrid Journal   (Followers: 10, SJR: 1.172, CiteScore: 2)
European Review of Economic History     Hybrid Journal   (Followers: 30, SJR: 0.702, CiteScore: 1)
European Sociological Review     Hybrid Journal   (Followers: 43, SJR: 2.728, CiteScore: 3)
Evolution, Medicine, and Public Health     Open Access   (Followers: 12)
Family Practice     Hybrid Journal   (Followers: 16, SJR: 1.018, CiteScore: 2)
Fems Microbiology Ecology     Hybrid Journal   (Followers: 16, SJR: 1.492, CiteScore: 4)
Fems Microbiology Letters     Hybrid Journal   (Followers: 28, SJR: 0.79, CiteScore: 2)
Fems Microbiology Reviews     Hybrid Journal   (Followers: 32, SJR: 7.063, CiteScore: 13)
Fems Yeast Research     Hybrid Journal   (Followers: 13, SJR: 1.308, CiteScore: 3)
Food Quality and Safety     Open Access   (Followers: 1)
Foreign Policy Analysis     Hybrid Journal   (Followers: 24, SJR: 1.425, CiteScore: 1)
Forest Science     Hybrid Journal   (Followers: 8, SJR: 0.89, CiteScore: 2)
Forestry: An Intl. J. of Forest Research     Hybrid Journal   (Followers: 16, SJR: 1.133, CiteScore: 3)
Forum for Modern Language Studies     Hybrid Journal   (Followers: 6, SJR: 0.104, CiteScore: 0)
French History     Hybrid Journal   (Followers: 33, SJR: 0.118, CiteScore: 0)
French Studies     Hybrid Journal   (Followers: 21, SJR: 0.148, CiteScore: 0)
French Studies Bulletin     Hybrid Journal   (Followers: 10, SJR: 0.152, CiteScore: 0)
Gastroenterology Report     Open Access   (Followers: 2)
Genome Biology and Evolution     Open Access   (Followers: 16, SJR: 2.578, CiteScore: 4)
Geophysical J. Intl.     Hybrid Journal   (Followers: 39, SJR: 1.506, CiteScore: 3)
German History     Hybrid Journal   (Followers: 23, SJR: 0.161, CiteScore: 0)
GigaScience     Open Access   (Followers: 5, SJR: 5.022, CiteScore: 7)
Global Summitry     Hybrid Journal   (Followers: 1)
Glycobiology     Hybrid Journal   (Followers: 13, SJR: 1.493, CiteScore: 3)
Health and Social Work     Hybrid Journal   (Followers: 57, SJR: 0.388, CiteScore: 1)
Health Education Research     Hybrid Journal   (Followers: 16, SJR: 0.854, CiteScore: 2)
Health Policy and Planning     Hybrid Journal   (Followers: 24, SJR: 1.512, CiteScore: 2)
Health Promotion Intl.     Hybrid Journal   (Followers: 22, SJR: 0.812, CiteScore: 2)
History Workshop J.     Hybrid Journal   (Followers: 33, SJR: 1.278, CiteScore: 1)
Holocaust and Genocide Studies     Hybrid Journal   (Followers: 28, SJR: 0.105, CiteScore: 0)
Human Communication Research     Hybrid Journal   (Followers: 15, SJR: 2.146, CiteScore: 3)
Human Molecular Genetics     Hybrid Journal   (Followers: 9, SJR: 3.555, CiteScore: 5)
Human Reproduction     Hybrid Journal   (Followers: 72, SJR: 2.643, CiteScore: 5)
Human Reproduction Open     Open Access   (Followers: 1)
Human Reproduction Update     Hybrid Journal   (Followers: 20, SJR: 5.317, CiteScore: 10)
Human Rights Law Review     Hybrid Journal   (Followers: 62, SJR: 0.756, CiteScore: 1)
ICES J. of Marine Science: J. du Conseil     Hybrid Journal   (Followers: 58, SJR: 1.591, CiteScore: 3)
ICSID Review : Foreign Investment Law J.     Hybrid Journal   (Followers: 10)
ILAR J.     Hybrid Journal   (Followers: 2, SJR: 1.732, CiteScore: 4)
IMA J. of Applied Mathematics     Hybrid Journal   (SJR: 0.679, CiteScore: 1)
IMA J. of Management Mathematics     Hybrid Journal   (SJR: 0.538, CiteScore: 1)
IMA J. of Mathematical Control and Information     Hybrid Journal   (Followers: 2, SJR: 0.496, CiteScore: 1)
IMA J. of Numerical Analysis - advance access     Hybrid Journal   (SJR: 1.987, CiteScore: 2)
Industrial and Corporate Change     Hybrid Journal   (Followers: 9, SJR: 1.792, CiteScore: 2)
Industrial Law J.     Hybrid Journal   (Followers: 39, SJR: 0.249, CiteScore: 1)
Inflammatory Bowel Diseases     Hybrid Journal   (Followers: 47, SJR: 2.511, CiteScore: 4)
Information and Inference     Free  
Innovation in Aging     Open Access  
Integrative and Comparative Biology     Hybrid Journal   (Followers: 9, SJR: 1.319, CiteScore: 2)
Integrative Biology     Full-text available via subscription   (Followers: 6, SJR: 1.36, CiteScore: 3)
Integrative Organismal Biology     Open Access  
Interacting with Computers     Hybrid Journal   (Followers: 11, SJR: 0.292, CiteScore: 1)
Interactive CardioVascular and Thoracic Surgery     Hybrid Journal   (Followers: 7, SJR: 0.762, CiteScore: 1)
Intl. Affairs     Hybrid Journal   (Followers: 66, SJR: 1.505, CiteScore: 3)
Intl. Data Privacy Law     Hybrid Journal   (Followers: 26)
Intl. Health     Hybrid Journal   (Followers: 6, SJR: 0.851, CiteScore: 2)
Intl. Immunology     Hybrid Journal   (Followers: 3, SJR: 2.167, CiteScore: 4)
Intl. J. for Quality in Health Care     Hybrid Journal   (Followers: 36, SJR: 1.348, CiteScore: 2)
Intl. J. of Constitutional Law     Hybrid Journal   (Followers: 64, SJR: 0.601, CiteScore: 1)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 246, SJR: 3.969, CiteScore: 5)
Intl. J. of Law and Information Technology     Hybrid Journal   (Followers: 5, SJR: 0.202, CiteScore: 1)
Intl. J. of Law, Policy and the Family     Hybrid Journal   (Followers: 28, SJR: 0.223, CiteScore: 1)
Intl. J. of Lexicography     Hybrid Journal   (Followers: 10, SJR: 0.285, CiteScore: 1)
Intl. J. of Low-Carbon Technologies     Open Access   (Followers: 1, SJR: 0.403, CiteScore: 1)
Intl. J. of Neuropsychopharmacology     Open Access   (Followers: 3, SJR: 1.808, CiteScore: 4)
Intl. J. of Public Opinion Research     Hybrid Journal   (Followers: 11, SJR: 1.545, CiteScore: 1)
Intl. J. of Refugee Law     Hybrid Journal   (Followers: 38, SJR: 0.389, CiteScore: 1)
Intl. J. of Transitional Justice     Hybrid Journal   (Followers: 11, SJR: 0.724, CiteScore: 2)
Intl. Mathematics Research Notices     Hybrid Journal   (Followers: 1, SJR: 2.168, CiteScore: 1)
Intl. Political Sociology     Hybrid Journal   (Followers: 40, SJR: 1.465, CiteScore: 3)
Intl. Relations of the Asia-Pacific     Hybrid Journal   (Followers: 23, SJR: 0.401, CiteScore: 1)
Intl. Studies Perspectives     Hybrid Journal   (Followers: 9, SJR: 0.983, CiteScore: 1)
Intl. Studies Quarterly     Hybrid Journal   (Followers: 49, SJR: 2.581, CiteScore: 2)
Intl. Studies Review     Hybrid Journal   (Followers: 25, SJR: 1.201, CiteScore: 1)
ISLE: Interdisciplinary Studies in Literature and Environment     Hybrid Journal   (Followers: 2, SJR: 0.15, CiteScore: 0)
ITNOW     Hybrid Journal   (Followers: 1, SJR: 0.103, CiteScore: 0)
J. of African Economies     Hybrid Journal   (Followers: 17, SJR: 0.533, CiteScore: 1)
J. of American History     Hybrid Journal   (Followers: 46, SJR: 0.297, CiteScore: 1)
J. of Analytical Toxicology     Hybrid Journal   (Followers: 14, SJR: 1.065, CiteScore: 2)
J. of Antimicrobial Chemotherapy     Hybrid Journal   (Followers: 15, SJR: 2.419, CiteScore: 4)
J. of Antitrust Enforcement     Hybrid Journal   (Followers: 1)
J. of Applied Poultry Research     Hybrid Journal   (Followers: 5, SJR: 0.585, CiteScore: 1)
J. of Biochemistry     Hybrid Journal   (Followers: 41, SJR: 1.226, CiteScore: 2)
J. of Breast Imaging     Full-text available via subscription  
J. of Burn Care & Research     Hybrid Journal   (Followers: 10, SJR: 0.768, CiteScore: 2)

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Similar Journals
Journal Cover
Journal of Antimicrobial Chemotherapy
Journal Prestige (SJR): 2.419
Citation Impact (citeScore): 4
Number of Followers: 15  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0305-7453 - ISSN (Online) 1460-2091
Published by Oxford University Press Homepage  [406 journals]
  • Characterization of a new transferable MDR plasmid carrying the pbp5 gene
           from a clade B commensal Enterococcus faecium
    • Authors: Morroni G; Brenciani A, Litta-Mulondo A, et al.
      Pages: 843 - 850
      Abstract: ObjectivesTo evaluate the transferability of antibiotic resistance from an MDR clade B Enterococcus faecium and to characterize the genetic elements involved.MethodsThe erm(B)-positive strain E. faecium 37BA (donor) and strains E. faecium 64/3 and Listeria welshimeri 11857RF (recipients) were used in mating experiments. Donors and transconjugants were characterized using MIC assays, PFGE, Southern blotting and hybridization, quantitative RT–PCR (RT–qPCR), next-generation sequencing and PCR mapping.ResultsOne E. faecium and one L. welshimeri transconjugant were selected for in-depth investigation. Both acquired an ∼40 kb plasmid carrying erm(B). An additional plasmid of ∼200 kb, encoding the full conjugation machinery, was detected in the donor and in the E. faecium transconjugant. Next-generation sequencing revealed a new 40 396 bp plasmid that was designated pEf37BA; it contained 10 antibiotic resistance genes, tet(M), tet(L), erm(B), aadE, sat4, aphA, spw, lsa(E), lnu(B) and pbp5, resulting from the recombination of pM7M2 of E. faecium with an MDR chromosomal region of Erysipelothrix rhusiopathiae. A pbp5-carrying circular form was also detected. The PBP5 amino acid sequence differed from the C46 variant by two mutations (S39T and D644N). Its expression was documented in both transconjugants. pEf37BA persisted in the absence of selective pressure.ConclusionsThe MDR clade B E. faecium plasmid, deriving from the recombination of two different resistance regions, carried a pbp5 element and was transferable to different bacterial species. This finding further documents the dissemination of ampicillin resistance among community-associated E. faecium and the key role of commensal strains in the spread of antibiotic resistance.
      PubDate: Thu, 10 Jan 2019 00:00:00 GMT
      DOI: 10.1093/jac/dky549
      Issue No: Vol. 74, No. 4 (2019)
  • Faecal phageome of healthy individuals: presence of antibiotic resistance
           genes and variations caused by ciprofloxacin treatment
    • Authors: Fernández-Orth D; Miró E, Brown-Jaque M, et al.
      Pages: 854 - 864
      Abstract: ObjectivesAntimicrobial resistance genes (ARGs) can be transferred by means of mobile genetic elements, which play a critical role in the dissemination of resistance in the bacterial community. ARG transmission within mobile genetic elements has been reported in plasmids and transposons but less frequently in bacteriophages. Here, the bacteriophage fraction of seven human faecal samples was purified and deep-sequenced to detect the presence of ARGs in the phage particles.MethodsSeven faecal samples (five from healthy individuals and two from a patient before and after receiving ciprofloxacin treatment) were used to extract phage DNA, which was purified and then sequenced in a MiSeq (Illumina). Generated reads were checked for quality and assembled, and then the generated contigs analysed with Kraken, PHASTER, VirSorter and Prokka. Some genes were also validated by quantitative PCR.ResultsAnalysis of the purified phage DNA by Kraken identified from 4 to 266 viruses in the samples. The viral fraction corresponded mainly to the order Caudovirales, including phages from the Siphoviridae and Myoviridae families. Bacterial genes associated with antimicrobial resistance were detected in the viral DNA, as confirmed by quantitative PCR. Higher densities of ARG-carrying phage particles were observed in the post- versus pre-ciprofloxacin treatment sample.ConclusionsThe finding of ARGs in phage particles supports the description of phages as mobile elements contributing to the dissemination of bacterial antibiotic resistance and suggests ciprofloxacin treatment may play a role in the release of ARG-carrying particles, thereby increasing resistance.
      PubDate: Thu, 10 Jan 2019 00:00:00 GMT
      DOI: 10.1093/jac/dky540
      Issue No: Vol. 74, No. 4 (2019)
  • The antimicrobial resistome in relation to antimicrobial use and
           biosecurity in pig farming, a metagenome-wide association study in nine
           European countries
    • Authors: Van Gompel L; Luiken R, Sarrazin S, et al.
      Pages: 865 - 876
      Abstract: ObjectivesPrevious studies in food-producing animals have shown associations between antimicrobial use (AMU) and resistance (AMR) in specifically isolated bacterial species. Multi-country data are scarce and only describe between-country differences. Here we investigate associations between the pig faecal mobile resistome and characteristics at the farm-level across Europe.MethodsA cross-sectional study was conducted among 176 conventional pig farms from nine European countries. Twenty-five faecal samples from fattening pigs were pooled per farm and acquired resistomes were determined using shotgun metagenomics and the Resfinder reference database, i.e. the full collection of horizontally acquired AMR genes (ARGs). Normalized fragments resistance genes per kilobase reference per million bacterial fragments (FPKM) were calculated. Specific farm-level data (AMU, biosecurity) were collected. Random-effects meta-analyses were performed by country, relating farm-level data to relative ARG abundances (FPKM).ResultsTotal AMU during fattening was positively associated with total ARG (total FPKM). Positive associations were particularly observed between widely used macrolides and tetracyclines, and ARGs corresponding to the respective antimicrobial classes. Significant AMU-ARG associations were not found for β-lactams and only few colistin ARGs were found, despite high use of these antimicrobial classes in younger pigs. Increased internal biosecurity was directly related to higher abundances of ARGs mainly encoding macrolide resistance. These effects of biosecurity were independent of AMU in mutually adjusted models.ConclusionsUsing resistome data in association studies is unprecedented and adds accuracy and new insights to previously observed AMU-AMR associations. Major components of the pig resistome are positively and independently associated with on-farm AMU and biosecurity conditions.
      PubDate: Mon, 14 Jan 2019 00:00:00 GMT
      DOI: 10.1093/jac/dky518
      Issue No: Vol. 74, No. 4 (2019)
  • The ionophore oxyclozanide enhances tobramycin killing of Pseudomonas
           aeruginosa biofilms by permeabilizing cells and depolarizing the membrane
    • Authors: Maiden M; Zachos M, Waters C.
      Pages: 894 - 906
      Abstract: ObjectivesTo assess the ability of oxyclozanide to enhance tobramycin killing of Pseudomonas aeruginosa biofilms and elucidate its mechanism of action.MethodsTwenty-four hour biofilms formed by the P. aeruginosa strain PAO1 and cystic fibrosis (CF) isolates were tested for susceptibility to oxyclozanide and tobramycin killing using BacTiter-Glo™ and cfu. Biofilm dispersal was measured using crystal violet staining. Membrane potential and permeabilization were quantified using DiOC2(3) and TO-PRO-3, respectively. ResultsHere we show that the ionophore anthelmintic oxyclozanide, combined with tobramycin, significantly increased killing of P. aeruginosa biofilms over each treatment alone. This combination also significantly accelerated the killing of cells within biofilms and stationary phase cultures and it was effective against 4/6 CF clinical isolates tested, including a tobramycin-resistant strain. Oxyclozanide enhanced the ability of additional aminoglycosides and tetracycline to kill P. aeruginosa biofilms. Finally, oxyclozanide permeabilized cells within the biofilm, reduced the membrane potential and increased tobramycin accumulation within cells of mature P. aeruginosa biofilms.ConclusionsOxyclozanide enhances aminoglycoside and tetracycline activity against P. aeruginosa biofilms by reducing membrane potential, permeabilizing cells and enhancing tobramycin accumulation within biofilms. We propose that oxyclozanide counteracts the adaptive resistance response of P. aeruginosa to aminoglycosides, increasing both their maximum activity and rate of killing. As oxyclozanide is widely used in veterinary medicine for the treatment of parasitic worm infections, this combination could offer a new approach for the treatment of biofilm-based P. aeruginosa infections, repurposing oxyclozanide as an anti-biofilm agent.
      PubDate: Tue, 08 Jan 2019 00:00:00 GMT
      DOI: 10.1093/jac/dky545
      Issue No: Vol. 74, No. 4 (2019)
  • Repurposing ethyl bromopyruvate as a broad-spectrum antibacterial
    • Authors: Kumar A; Boradia V, Thakare R, et al.
      Pages: 912 - 920
      Abstract: BackgroundThe emergence of drug-resistant bacteria is a major hurdle for effective treatment of infections caused by Mycobacterium tuberculosis and ESKAPE pathogens. In comparison with conventional drug discovery, drug repurposing offers an effective yet rapid approach to identifying novel antibiotics.MethodsEthyl bromopyruvate was evaluated for its ability to inhibit M. tuberculosis and ESKAPE pathogens using growth inhibition assays. The selectivity index of ethyl bromopyruvate was determined, followed by time–kill kinetics against M. tuberculosis and Staphylococcus aureus. We first tested its ability to synergize with approved drugs and then tested its ability to decimate bacterial biofilm. Intracellular killing of M. tuberculosis was determined and in vivo potential was determined in a neutropenic murine model of S. aureus infection.ResultsWe identified ethyl bromopyruvate as an equipotent broad-spectrum antibacterial agent targeting drug-susceptible and -resistant M. tuberculosis and ESKAPE pathogens. Ethyl bromopyruvate exhibited concentration-dependent bactericidal activity. In M. tuberculosis, ethyl bromopyruvate inhibited GAPDH with a concomitant reduction in ATP levels and transferrin-mediated iron uptake. Apart from GAPDH, this compound inhibited pyruvate kinase, isocitrate lyase and malate synthase to varying extents. Ethyl bromopyruvate did not negatively interact with any drug and significantly reduced biofilm at a 64-fold lower concentration than vancomycin. When tested in an S. aureus neutropenic thigh infection model, ethyl bromopyruvate exhibited efficacy equal to that of vancomycin in reducing bacterial counts in thigh, and at 1/25th of the dosage.ConclusionsEthyl bromopyruvate exhibits all the characteristics required to be positioned as a potential broad-spectrum antibacterial agent.
      PubDate: Fri, 25 Jan 2019 00:00:00 GMT
      DOI: 10.1093/jac/dky555
      Issue No: Vol. 74, No. 4 (2019)
  • Antimicrobial resistance monitoring in commensal enterococci from healthy
           cattle, pigs and chickens across Europe during 2004–14 (EASSA Study)
    • Authors: de Jong A; Simjee S, Rose M, et al.
      Pages: 921 - 930
      Abstract: ObjectivesThe European Antimicrobial Susceptibility Surveillance in Animals (EASSA) programme collects zoonotic and commensal bacteria from healthy food-producing animals at slaughter and tracks their susceptibility to medically important antibiotics. Results for enterococci, collected over three time periods, are presented.MethodsIntestinal contents from cattle, pigs and chickens were randomly sampled (five or six countries/host; at least four abattoirs/country; one sample/animal/farm) for isolation of enterococci; antimicrobial susceptibilities were centrally assessed by CLSI agar dilution. Clinical breakpoints (CLSI) and epidemiological cut-off values (EUCAST) were applied for data interpretation.ResultsIn total, 2435 Enterococcus faecium and 1389 Enterococcus faecalis strains were recovered. Seven E. faecium/faecalis strains were linezolid resistant. One E. faecium strain was non-WT (NWT), with a daptomycin MIC of 8 mg/L. Clinical vancomycin resistance was very low or absent; eight strains had decreased susceptibility (MICs of 8 mg/L). Two strains were clinically resistant to tigecycline. Little resistance to ampicillin or gentamicin was observed. Clinical resistance of E. faecium to quinupristin/dalfopristin was slightly higher (2.2%–33.6%) and 38.5%–83.2% of the strains were classified NWT. Very high resistance to tetracycline (67.4%–79.1%) and erythromycin (27.1%–57.0%) was noted for E. faecium and E. faecalis in pigs and chickens. For both of these compounds, similar NWT results were observed for Enterococcus hirae (n = 935), Enterococcus durans (n = 286) and Enterococcus casseliflavus (n = 154) whereas the percentage of NWT for linezolid, tigecycline and vancomycin was generally zero or low.ConclusionsIn this pan-EU survey of commensal enterococci, antibiotic susceptibility varied widely between antibiotics, animal species, countries and enterococcal species. Clinical resistance to antibiotics that are critically important for human medicine was absent or low, except for erythromycin.
      PubDate: Tue, 08 Jan 2019 00:00:00 GMT
      DOI: 10.1093/jac/dky537
      Issue No: Vol. 74, No. 4 (2019)
  • Relatively high rates of cefotaxime- and ceftriaxone-non-susceptible
           isolates among group B streptococci with reduced penicillin susceptibility
           (PRGBS) in Japan
    • Authors: Kitamura M; Kimura K, Ido A, et al.
      Pages: 931 - 934
      Abstract: ObjectivesWe have previously identified group B Streptococcus (GBS) clinical isolates with reduced penicillin susceptibility (PRGBS) that were non-susceptible to cefotaxime; however, the rates of cefotaxime and ceftriaxone non-susceptibility among PRGBS isolates have never been reported. Therefore, we first determined the MICs of 22 antibacterial drugs/compounds for 74 PRGBS isolates and then determined the rates of cefotaxime and ceftriaxone non-susceptibility among these isolates.MethodsWe used 74 clinical PRGBS isolates, previously collected in Japan and confirmed to harbour relevant amino acid substitutions in PBP2X. We also used 80 penicillin-susceptible GBS (PSGBS) clinical isolates as controls. The MICs of 22 antibacterial drugs/compounds for all 154 GBS isolates were determined via microdilution and/or agar dilution methods, as recommended by the CLSI.ResultsThe rates of non-susceptibility/resistance to ampicillin, cefotaxime, ceftriaxone and levofloxacin for the 80 PSGBS isolates were 0%, 0%, 0% and 30%, respectively, but were 15% (P = 0.0003), 28% (P < 0.0001), 36% (P < 0.0001) and 93% (P < 0.0001) for the 74 PRGBS isolates, respectively. No PRGBS isolates were identified to be non-susceptible to meropenem, doripenem, vancomycin, quinupristin/dalfopristin, daptomycin or linezolid.ConclusionsWe found that cefotaxime- and ceftriaxone-non-susceptible PRGBS isolates occur at relatively high rates in Japan. Importantly, this finding suggests that the range of drugs likely to be effective in treating PRGBS infections may be limited compared with those available for PSGBS infections; therefore, clinicians should exercise care when considering drug choice and efficacy for PRGBS infections.
      PubDate: Fri, 11 Jan 2019 00:00:00 GMT
      DOI: 10.1093/jac/dky542
      Issue No: Vol. 74, No. 4 (2019)
  • A bedaquiline/clofazimine combination regimen might add activity to the
           treatment of clinically relevant non-tuberculous mycobacteria
    • Authors: Ruth M; Sangen J, Remmers K, et al.
      Pages: 935 - 943
      Abstract: BackgroundNon-tuberculous mycobacteria (NTM) infections are hard to treat. New antimicrobial drugs and smarter combination regimens are needed.ObjectivesOur aim was to determine the in vitro activity of bedaquiline against NTM and assess its synergy with established antimycobacterials.MethodsWe determined MICs of bedaquiline for clinically relevant NTM species and Mycobacterium tuberculosis by broth microdilution for 30 isolates. Synergy testing was performed using the chequerboard method for 22 reference strains and clinical isolates of Mycobacterium abscessus (MAB) and Mycobacterium avium complex (MAC). Time–kill kinetics (TK) assays with resistance monitoring of bedaquiline alone and combined with clofazimine were performed for MAB CIP 104536 and M. avium ATCC 700898; bedaquiline/clarithromycin combinations were evaluated against M. avium ATCC 700898. Interactions were assessed for TK experiments based on Bliss independence.ResultsBedaquiline had modest activity against tested NTM, with MICs between <0.007 and 1 mg/L. Bedaquiline showed no interaction with tested drugs against MAB or MAC. Lowest mean fractional inhibitory concentration index (FICI) values were 0.79 with clofazimine for MAB and 0.97 with clofazimine and 0.82 with clarithromycin for MAC. In TK assays, bedaquiline showed a bacteriostatic effect. Clofazimine extended the bacteriostatic activity of bedaquiline against MAB and yielded a slight bactericidal effect against M. avium. The bedaquiline/clofazimine combination slowed emergence of bedaquiline resistance for M. avium but promoted it for MAB. Relative to Bliss independence, bedaquiline/clofazimine showed synergistic interaction over time for MAB and no interaction for M. avium and bedaquiline/clarithromycin showed antagonistic interaction for M. avium.ConclusionsFollowing these in vitro data, a bedaquiline/clofazimine combination might add activity to MAB and MAC treatment. The bedaquiline/clarithromycin combination might have lower activity compared with bedaquiline alone for MAC treatment.
      PubDate: Thu, 10 Jan 2019 00:00:00 GMT
      DOI: 10.1093/jac/dky526
      Issue No: Vol. 74, No. 4 (2019)
  • In vitro activity of apramycin against multidrug-, carbapenem- and
           aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii
    • Authors: Juhas M; Widlake E, Teo J, et al.
      Pages: 944 - 952
      Abstract: ObjectivesWidespread antimicrobial resistance often limits the availability of therapeutic options to only a few last-resort drugs that are themselves challenged by emerging resistance and adverse side effects. Apramycin, an aminoglycoside antibiotic, has a unique chemical structure that evades almost all resistance mechanisms including the RNA methyltransferases frequently encountered in carbapenemase-producing clinical isolates. This study evaluates the in vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii, and provides a rationale for its superior antibacterial activity in the presence of aminoglycoside resistance determinants.MethodsA thorough antibacterial assessment of apramycin with 1232 clinical isolates from Europe, Asia, Africa and South America was performed by standard CLSI broth microdilution testing. WGS and susceptibility testing with an engineered panel of aminoglycoside resistance-conferring determinants were used to provide a mechanistic rationale for the breadth of apramycin activity.ResultsMIC distributions and MIC90 values demonstrated broad antibacterial activity of apramycin against Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., Morganella morganii, Citrobacter freundii, Providencia spp., Proteus mirabilis, Serratia marcescens and A. baumannii. Genotypic analysis revealed the variety of aminoglycoside-modifying enzymes and rRNA methyltransferases that rendered a remarkable proportion of clinical isolates resistant to standard-of-care aminoglycosides, but not to apramycin. Screening a panel of engineered strains each with a single well-defined resistance mechanism further demonstrated a lack of cross-resistance to gentamicin, amikacin, tobramycin and plazomicin.ConclusionsIts superior breadth of activity renders apramycin a promising drug candidate for the treatment of systemic Gram-negative infections that are resistant to treatment with other aminoglycoside antibiotics.
      PubDate: Wed, 09 Jan 2019 00:00:00 GMT
      DOI: 10.1093/jac/dky546
      Issue No: Vol. 74, No. 4 (2019)
  • Pharmacokinetic-pharmacodynamic modelling to investigate in vitro synergy
           between colistin and fusidic acid against MDR Acinetobacter baumannii
    • Authors: Phee L; Kloprogge F, Morris R, et al.
      Pages: 961 - 969
      Abstract: ObjectivesThe potential for synergy between colistin and fusidic acid in the treatment of MDR Acinetobacter baumannii has recently been shown. The aim of this study was to perform an extensive in vitro characterization of this effect using pharmacokinetic-pharmacodynamic modelling (PKPD) of time–kill experiments in order to estimate clinical efficacy.MethodsFor six clinical strains, 312 individual time–kill experiments were performed including 113 unique pathogen–antimicrobial combinations. A wide range of concentrations (0.25–8192 mg/L for colistin and 1–8192 mg/L for fusidic acid) were explored, alone and in combination. PKPD modelling sought to quantify synergistic effects.ResultsA PKPD model confirmed synergy in that colistin EC50 was found to decrease by 83% in the presence of fusidic acid, and fusidic acid maximum increase in killing rate (Emax) also increased 58% in the presence of colistin. Simulations indicated, however, that at clinically achievable free concentrations, the combination may be bacteriostatic in colistin-susceptible strains, but growth inhibition probability was <20% in a colistin-resistant strain. ConclusionsFusidic acid may be a useful agent to add to colistin in a multidrug combination for MDR Acinetobacter baumannii.
      PubDate: Tue, 08 Jan 2019 00:00:00 GMT
      DOI: 10.1093/jac/dky524
      Issue No: Vol. 74, No. 4 (2019)
  • Pharmacokinetics and probability of target attainment for micafungin in
           normal-weight and morbidly obese adults
    • Authors: Wasmann R; Smit C, ter Heine R, et al.
      Pages: 978 - 985
      Abstract: ObjectivesThe rising pandemic of obesity means an increasing number of obese patients who require antimicrobial therapy for serious infections. Micafungin is an echinocandin drug frequently used as therapy or prophylaxis for fungal infections, predominantly with Candida species. In order to maximize the efficacy of micafungin in obese patients, the dose that corresponds to optimal exposure for each obese individual needs to be identified.MethodsWe performed a prospective study in 16 obese and 8 normal-weight healthy subjects with a weight ranging from 61.5–184 kg ( Identifier: NCT03102658). A population pharmacokinetic model was developed and used to simulate several dosing regimens to evaluate the PTA for relevant MICs to define the optimal dose using the pharmacokinetic/pharmacodynamic target of an AUC/MIC ratio above 5000.ResultsTotal body weight was found to be most predictive for CL and V. Simulations showed that a 100 mg dose results in a PTA of >90% in patients weighing ≤125 kg infected with a Candida species having an MIC of 0.016 mg/L. The maintenance dose should be increased to 200 mg in patients >125 kg infected with a Candida species with an MIC of 0.016 mg/L. For an MIC of 0.032 mg/L, a 300 mg maintenance dose is recommended above 125 kg weight. Furthermore, we demonstrate that patients can benefit from a loading dose (i.e. twice the maintenance dose).ConclusionsWe present easy-to-use dose recommendations for obese patients, based on both weight and target MIC, that result in adequate exposure in patients with body weight up to 190 kg.
      PubDate: Tue, 15 Jan 2019 00:00:00 GMT
      DOI: 10.1093/jac/dky554
      Issue No: Vol. 74, No. 4 (2019)
  • CSF penetration of vancomycin in critical care patients with proven or
           suspected ventriculitis: a prospective observational study
    • Authors: Blassmann U; Hope W, Roehr A, et al.
      Pages: 991 - 996
      Abstract: BackgroundVancomycin is recommended for ventriculitis. However, penetration into the CNS is relatively poor.ObjectivesTo investigate the population pharmacokinetics of vancomycin in serum and CSF in critical care patients with proven or suspected CNS infections from neurosurgical procedures.Patients and methodsThis was an observational pharmacokinetic study in critical care patients with proven or suspected CNS infections receiving intravenous vancomycin. Multiple blood and intraventricular CSF samples were collected. Population pharmacokinetic analysis and simulation were undertaken with ADAPT5 and Pmetrics.ResultsA total of 187 blood and CSF samples were collected from 21 patients. The median (range) Cmax and Cmin concentrations in serum were 25.67 (10.60–50.78) and 9.60 (4.46–23.56) mg/L, respectively, with a median daily dose of 2500 (500–4000) mg. The corresponding median concentrations in CSF were 0.65 (<0.24–3.83) mg/L and 0.58 (<0.24–3.95) mg/L, respectively. The median AUC0–24 in serum and CSF was 455.09 and 14.10 mg·h/L, respectively. A three-compartment linear population pharmacokinetic model best fitted the observed data. Vancomycin demonstrated poor penetration into CSF, with a median CSF/serum ratio of 3% and high intersubject pharmacokinetic variability of its penetration.ConclusionsTherapeutic drug monitoring in both serum and CSF and higher daily doses may be an option to ensure adequate trough levels and to optimize patient therapy. Novel dosing strategies designed to reduce renal toxicity, such as administration by continuous infusion, should be investigated in further clinical studies to avoid antibiotic underexposure in CSF.
      PubDate: Sun, 27 Jan 2019 00:00:00 GMT
      DOI: 10.1093/jac/dky543
      Issue No: Vol. 74, No. 4 (2019)
  • Single- and multiple-dose pharmacokinetics and total removal of colistin
           in critically ill patients with acute kidney injury undergoing prolonged
           intermittent renal replacement therapy
    • Authors: Schmidt J; Strunk A, David S, et al.
      Pages: 997 - 1002
      Abstract: BackgroundOwing to the emerging problem of MDR bacteria, interest in ‘old’ antibiotics such as colistin has re-emerged. However, research on the dosing of colistin in patients undergoing renal replacement therapy (RRT), such as prolonged intermittent renal replacement therapy (PIRRT), is scarce.ObjectivesThe aim of this study was to evaluate single- and multiple-dose pharmacokinetics of colistin and its prodrug colistin methanesulfonate in ICU patients with acute kidney injury (AKI) undergoing PIRRT.MethodsWe performed a prospective clinical pharmacokinetic single- and multiple-dose study. Eight ICU patients with AKI undergoing treatment with PIRRT and receiving intravenous colistin were studied on day 1 and days 5–9 of treatment, depending on the timing of dialysis. Six million IU (MIU) of colistin methanesulfonate was administered 8 h prior to the PIRRT session followed by 3 MIU every 8 h. The study was registered under (NCT02556190).ResultsPIRRT removed a considerable amount of colistin and colistin methanesulfonate with a median dialyser plasma CL of 70.1 mL/min (IQR 36.6–96.2) for colistin and 69.3 mL/min (IQR 56.3–318.7) for colistin methanesulfonate. The median amount of colistin in the total collected dialysate was 154 mg (IQR 105–175), corresponding to about 50% of the daily dose. Median colistin peak concentrations accumulated from 5.79 mg/L (IQR 4.14–8.79) on day 1 to 9.49 mg/L (IQR 8.39–10.41) on days 5–9. Cmax was significantly and inversely correlated with body weight.ConclusionsPIRRT eliminates about half of the daily administered colistin dose. Even a 6 MIU loading dose of colistin methanesulfonate may not ensure immediate sufficient colistin plasma levels in all critically ill patients. However, we measured significant colistin accumulation, suggesting that the dose of colistin methanesulfonate should be adjusted according to body weight and RRT intensity.
      PubDate: Tue, 08 Jan 2019 00:00:00 GMT
      DOI: 10.1093/jac/dky511
      Issue No: Vol. 74, No. 4 (2019)
  • Development and external evaluation of a population pharmacokinetic model
           for continuous and intermittent administration of vancomycin in neonates
           and infants using prospectively collected data
    • Authors: Germovsek E; Osborne L, Gunaratnam F, et al.
      Pages: 1003 - 1011
      Abstract: BackgroundVancomycin is commonly used for nosocomial bacterial pathogens causing late-onset septicaemia in preterm infants. We prospectively collected pharmacokinetic data aiming to describe pharmacokinetics and determine covariates contributing to the variability in neonatal vancomycin pharmacokinetics. Further, we aimed to use the model to compare the ratio of AUC24 at steady-state to the MIC (AUC24,ss/MIC) of several intermittent and continuous dosing regimens.MethodsNewborns receiving vancomycin for suspected or confirmed late-onset sepsis were included. Peak and trough concentrations for intermittent vancomycin dosing and steady-state concentrations for continuous vancomycin dosing were measured. NONMEM 7.3 was used for population pharmacokinetic analysis. Monte Carlo simulations were performed to compare dosing schemes.ResultsData from 54 infants were used for model development and from 34 infants for the model evaluation {corrected gestational age [median (range)] = 29 (23.7–41.9) weeks and 28 (23.4–41.7) weeks, respectively}. The final model was a one-compartment model. Weight and postmenstrual age were included a priori, and then no additional covariate significantly improved the model fit. Final model parameter estimates [mean (SEM)]: CL = 5.7 (0.3) L/h/70 kg and V = 39.3 (3.7) L/70 kg. Visual predictive check of the evaluation dataset confirmed the model can predict external data. Simulations using MIC of 1 mg/L showed that for neonates with gestational age ≤25 weeks and postnatal age ≤2 weeks AUC24,ss/MIC was lower with the intermittent regimen (median 482 versus 663).ConclusionsA population pharmacokinetic model for continuous and intermittent vancomycin administration in infants was developed. Continuous administration might be favourable for treating infections caused by resistant microorganisms in very young and immature infants.
      PubDate: Mon, 21 Jan 2019 00:00:00 GMT
      DOI: 10.1093/jac/dky525
      Issue No: Vol. 74, No. 4 (2019)
  • Genetic polymorphisms of ABCB1 (P-glycoprotein) as a covariate influencing
           daptomycin pharmacokinetics: a population analysis in patients with bone
           and joint infection
    • Authors: Bricca R; Goutelle S, Roux S, et al.
      Pages: 1012 - 1020
      Abstract: BackgroundDaptomycin has been recognized as a therapeutic option for the treatment of bone and joint infection (BJI). Gene polymorphism of ABCB1, the gene encoding P-glycoprotein (P-gp), may influence daptomycin pharmacokinetics (PK).ObjectivesWe aimed to examine population PK of daptomycin and its determinants, including genetic factors, in patients with BJI.Patients and methodsWe analysed data from patients who received daptomycin for BJI between 2012 and 2016 in our regional reference centre and who had measured daptomycin concentrations and P-gp genotyping. A population approach was used to analyse PK data. In covariate analysis, we examined the influence of three single nucleotide variations (SNVs) of ABCB1 (3435C > T, 2677G > T/A and 1236C > T) and that of the corresponding haplotype on daptomycin PK parameters. Simulations performed with the final model examined the influence of covariates on the probability to achieve pharmacodynamic (PD) targets.ResultsData from 81 patients were analysed. Daptomycin body CL (CLDAP) correlated with CLCR and was 23% greater in males than in females. Daptomycin central V (V1) was allometrically scaled to body weight and was 25% lower in patients with homozygous CGC ABCB1 haplotype than in patients with any other genotype. Simulations performed with the model showed that sex and P-gp haplotype may influence the PTA for high MIC values and that a dosage of 10 mg/kg/24 h would optimize efficacy.ConclusionsDaptomycin dosages higher than currently recommended should be evaluated in patients with BJI. Gender and P-gp gene polymorphism should be further examined as determinants of dosage requirements.
      PubDate: Wed, 09 Jan 2019 00:00:00 GMT
      DOI: 10.1093/jac/dky541
      Issue No: Vol. 74, No. 4 (2019)
  • Tenofovir DF/emtricitabine/rilpivirine as HIV post-exposure prophylaxis:
           results from a multicentre prospective study
    • Authors: Chauveau M; Billaud E, Bonnet B, et al.
      Pages: 1021 - 1027
      Abstract: ObjectivesSince 2016, French guidelines have recommended the single-tablet regimen of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)/rilpivirine (RPV) as HIV post-exposure prophylaxis (PEP), but few data support this usage. We evaluated the tolerability, treatment completion and occurrence of HIV seroconversion associated with this combination in occupational and non-occupational PEP.Patients and methodsWe conducted an observational, prospective, multicentre, open-label, non-randomized study in five French HIV centres. Adults requiring PEP according to national French guidelines were prescribed TDF/FTC/RPV one pill once a day for 28 days. Clinical and biological tolerability was assessed at week 4; occurrence of HIV seroconversion was evaluated after week 16.ResultsFrom March 2016 to March 2017, 163 courses of PEP were prescribed for 150 sexual exposures (44% heterosexual and 56% MSM) and 13 non-sexual exposures. Five participants stopped PEP after a few days because the source person was HIV uninfected. Of the remaining 158 individuals, 15 (9.5%) were lost to follow-up at week 4, 7 (4.4%) prematurely discontinued PEP [patient’s decision/non-adherence (n = 3) or adverse events (gastrointestinal intolerance n = 3, fatigue n = 1)] and 136 (86.1%) completed the 28 day treatment. Overall, 69.6% of participants declared at least one adverse event, mostly of mild to moderate intensity and no serious adverse events or hepatic or renal toxicity occurred. No HIV seroconversion occurred at week 16.ConclusionsThe low rate of premature treatment interruption, the good tolerability and the absence of documented HIV seroconversion support the current French guidelines of a 28 day course of TDF/FTC/RPV for sexual and non-sexual PEP.
      PubDate: Fri, 25 Jan 2019 00:00:00 GMT
      DOI: 10.1093/jac/dky547
      Issue No: Vol. 74, No. 4 (2019)
  • Progressive increases in fat mass occur in adults living with HIV on
           antiretroviral therapy, but patterns differ by sex and anatomic depot
    • Authors: Debroy P; Sim M, Erlandson K, et al.
      Pages: 1028 - 1034
      Abstract: ObjectivesAlthough weight gain on ART is common, the long-term trajectory of and factors affecting increases in fat mass in people living with HIV are not well described.MethodsMen and women living with HIV in the Modena HIV Metabolic Clinic underwent DXA scans every 6–12 months for up to 10 years (median 4.6 years). Regression modelling in both combined and sex-stratified models determined changes in and clinical factors significantly associated with trunk and leg fat mass over the study period.ResultsA total of 839 women and 1759 men contributed two or more DXA scans. The baseline median age was 44 years and BMI 22.9 kg/m2; 76% were virologically suppressed on ART at baseline. For both sexes, trunk and leg fat consistently increased over the study period, with mean yearly trunk and leg fat gain of 3.6% and 7.5% in women and 6.3% and 10.8% in men, respectively. In multivariate analysis, factors associated with greater fat mass included female sex, per-year ART use (specifically tenofovir disoproxil fumarate and integrase strand transfer inhibitor therapy), per-unit BMI increase, no self-reported physical activity and CD4 nadir <200 cells/mm3.ConclusionsAmong people living with HIV on ART, trunk and leg fat mass increased steadily over a median of 4.6 years of follow up, particularly among women. After controlling for traditional risk factors, HIV- and ART-specific risk factors emerged.
      PubDate: Fri, 18 Jan 2019 00:00:00 GMT
      DOI: 10.1093/jac/dky551
      Issue No: Vol. 74, No. 4 (2019)
  • ‘Real-life’ analysis of the role of antifungal prophylaxis in
           preventing invasive aspergillosis in AML patients undergoing consolidation
           therapy: Sorveglianza Epidemiologica Infezioni nelle Emopatie (SEIFEM)
           2016 study
    • Authors: Del Principe M; Dragonetti G, Verga L, et al.
      Pages: 1062 - 1068
      Abstract: BackgroundWe evaluated the incidence of proven/probable invasive aspergillosis (IA) and the role of antifungal prophylaxis (AP) in a ‘real-life’ setting of patients with AML receiving intensive consolidation therapy.MethodsCases of IA, observed during consolidation in adult/paediatric patients with AML between 2011 and 2015, were retrospectively collected in a multicentre Italian study.ResultsOf 2588 patients, 56 (2.2%) developed IA [43 probable (1.7%) and 13 proven (0.5%)]. IA was diagnosed in 34 of 1137 (2.9%) patients receiving no AP and in 22 of 1451 (1.5%) who were given AP (P = 0.01). Number-needed-to-treat calculation indicates that, on average, 71 patients should have received AP (instead of no AP) for one additional patient to not have IA. Initial antifungal therapy was ‘pre-emptive’ in 36 (64%) patients and ‘targeted’ in 20 (36%) patients. A good response to first-line therapy was observed in 26 (46%) patients, mainly those who received AP [16 of 22 (73%) versus 10 of 34 (29%); P = 0.001]. The overall mortality rate and the mortality rate attributable to IA by day 120 were 16% and 9%, respectively. In multivariate analysis, age ≥60 years (OR = 12.46, 95% CI = 1.13–136.73; P = 0.03) and high-dose cytarabine treatment (OR = 10.56, 95% CI = 1.95–116.74; P = 0.04) independently affected outcome.ConclusionsIn our experience, AP appears to prevent IA from occurring during consolidation. However, although the incidence of IA was low, mortality was not negligible among older patients. Further prospective studies should be carried out particularly in elderly patients treated with high-dose cytarabine to confirm our data and to identify subsets of individuals who may require AP.
      PubDate: Mon, 14 Jan 2019 00:00:00 GMT
      DOI: 10.1093/jac/dky550
      Issue No: Vol. 74, No. 4 (2019)
  • Bovine lactoferrin enhances the efficacy of levofloxacin-based triple
           therapy as first-line treatment of Helicobacter pylori infection: an in
           vitro and in vivo study
    • Authors: Ciccaglione A; Di Giulio M, Di Lodovico S, et al.
      Pages: 1069 - 1077
      Abstract: ObjectivesTo evaluate the in vitro antimicrobial/antivirulence action of bovine lactoferrin and its ability to synergize with levofloxacin against resistant Helicobacter pylori strains and to analyse the effect of levofloxacin, amoxicillin and esomeprazole with and without bovine lactoferrin as the first-line treatment for H. pylori infection.MethodsThe bovine lactoferrin antimicrobial/antivirulence effect was analysed in vitro by MIC/MBC determination and twitching motility against six clinical H. pylori strains and a reference strain. The synergism was evaluated using the chequerboard assay. The prospective therapeutic trial was carried out on two separate patient groups, one treated with esomeprazole/amoxicillin/levofloxacin and the other with esomeprazole/amoxicillin/levofloxacin/bovine lactoferrin. Treatment outcome was determined with the [13C]urea breath test.ResultsIn vitro, bovine lactoferrin inhibited the growth of 50% of strains at 10 mg/mL and expressed 50% bactericidal effect at 40 mg/mL. The combination of levofloxacin and bovine lactoferrin displayed a synergistic effect for all strains, with the best MIC reduction of 16- and 32-fold for levofloxacin and bovine lactoferrin, respectively. Bovine lactoferrin at one-fourth MIC reduced microbial motility significantly for all strains studied. In the in vivo study, 6 of 24 patients recruited had treatment failure recorded with esomeprazole/amoxicillin/levofloxacin (75% success, 95% CI 57.68%–92.32%), and in the group with esomeprazole/amoxicillin/levofloxacin/bovine lactoferrin, 2 out of 53 patients recruited had failure recorded (96.07% success, 95% CI 90.62%–101.38%).ConclusionsBovine lactoferrin can be considered a novel potentiator for restoring susceptibility in resistant H. pylori strains. Bovine lactoferrin added to a triple therapy in first-line treatment potentiates the therapeutic effect.
      PubDate: Mon, 21 Jan 2019 00:00:00 GMT
      DOI: 10.1093/jac/dky510
      Issue No: Vol. 74, No. 4 (2019)
  • Tolerability of high-dose ceftriaxone in CNS infections: a prospective
           multicentre cohort study
    • Authors: Le Turnier P; Navas D, Garot D, et al.
      Pages: 1078 - 1085
      Abstract: BackgroundCeftriaxone is widely used to treat community-acquired CNS bacterial infections. French guidelines for meningitis in adults promote 75–100 mg/kg/day ceftriaxone without an upper limit for dosage, yet little is known about the pharmacology and tolerability of such regimens.Patients and methodsA multicentre prospective cohort study was conducted in adult patients to assess the adverse drug reactions (ADRs) of high-dose ceftriaxone (i.e. daily dosage ≥4 g or ≥75 mg/kg) in CNS infections and to analyse their related factors. Drug causality was systematically assessed by an expert committee who reviewed the medical charts of all included patients.ResultsA total of 196 patients were enrolled over a 31 month period. Median dosage and duration of ceftriaxone were 96.4 mg/kg/day (7 g/day) and 8 days, respectively. Nineteen ceftriaxone-related ADRs (mainly neurological) occurred in 17 patients (8.7%), with only one case of treatment discontinuation (biliary pseudolithiasis). In univariate analysis, older age, male gender, renal impairment and high trough ceftriaxone plasma concentration were associated with ceftriaxone-related ADRs.ConclusionsHigh-dose ceftriaxone for CNS infection administered as recommended by French guidelines in adults was well tolerated overall, suggesting these recommendations could be applied and generalized. In patients with advanced age or renal insufficiency, prescription should be done with caution and therapeutic drug monitoring could be useful.
      PubDate: Tue, 29 Jan 2019 00:00:00 GMT
      DOI: 10.1093/jac/dky553
      Issue No: Vol. 74, No. 4 (2019)
  • Moving beyond unsolicited consultation: additional impact of a structured
           intervention on mortality in Staphylococcus aureus bacteraemia
    • Authors: Pérez-Rodríguez M; Sousa A, López-Cortés L, et al.
      Pages: 1101 - 1107
      Abstract: BackgroundSome evidence-based bundles have tried to standardize the management of Staphylococcus aureus bacteraemia (SAB) to improve the outcome. The aim of our study was to analyse the additional impact on mortality of a structured intervention in patients with SAB.MethodsCompliance with the bundle was evaluated in an ambispective cohort of patients with SAB, which included a retrospective cohort [including patients treated before and after the implementation of a bacteraemia programme (no-BP and BP, respectively)] and a prospective cohort (i-BP), in which an additional specific intervention for bundle application was implemented. Multivariate logistic regression was used to measure the influence of the independent variables including compliance with the bundle on 14 and 30 day crude mortality.ResultsA total of 271 adult patients with SAB were included. Mortality was significantly different among the three groups (no-BP, BP and i-BP): mortality at 14 days was 18% versus 7% versus 2%, respectively, P = 0.002; and mortality at 30 days was 20% versus 12% versus 5%, respectively, P = 0.011. The factors associated with 14 and 30 day mortality in multivariable analysis were heart failure (OR = 7.63 and OR = 2.27, respectively), MRSA infection (OR = 4.02 and OR = 4.37, respectively) and persistent bacteraemia (OR = 11.01 and OR = 7.83, respectively); protective factors were catheter-related bacteraemia (OR = 0.16 and OR = 0.19, respectively) and >75% bundle compliance (OR = 0.15 and OR = 0.199, respectively). Time required to perform the intervention and the follow-up was 50 min (IQR 40–55 min) per patient.ConclusionsHigh-level compliance with a standardized bundle of intervention for management of SAB that requires little time was associated with lower mortality at 14 and 30 days.
      PubDate: Sun, 27 Jan 2019 00:00:00 GMT
      DOI: 10.1093/jac/dky556
      Issue No: Vol. 74, No. 4 (2019)
  • Antibiotic prescribing for respiratory tract complaints in Malta: a
           1 year repeated cross-sectional surveillance study
    • Authors: Saliba-Gustafsson E; Dunberger Hampton A, Zarb P, et al.
      Pages: 1116 - 1124
      Abstract: ObjectivesTo determine the 1 year antibiotic prescribing patterns by GPs for acute respiratory tract complaints (aRTCs) in Malta.MethodsIn this repeated cross-sectional surveillance study, GPs collected data for patients seen for aRTCs during a designated 1 week period each month, between May 2015 and April 2016. GPs received three text reminders during surveillance weeks and were contacted by phone at most four times during the year. GPs also received 3 monthly individual- and aggregate-level feedback reports on their antibiotic prescribing patterns. Descriptive statistics were used to examine patient, consultation and clinical characteristics, and to describe GPs’ prescribing patterns.ResultsParticipating GPs (n = 33) registered 4641 patients with an aRTC, of whom 2122 (45.7%) received an antibiotic prescription. The majority (99.6%) of antibiotics prescribed were broad-spectrum and the most commonly prescribed antibiotics were macrolides (35.5%), followed by penicillins with a β-lactamase inhibitor (33.2%) and second-generation cephalosporins (14.2%). Specifically, co-amoxiclav (33.2%), clarithromycin (19.6%), azithromycin (15.1%) and cefuroxime axetil (10.9%) represented 78.8% of all antibiotics prescribed. Patients with tonsillar exudate (99.1%), purulent sputum (84%), otorrhoea (78%), tender cervical nodes (74.4%) and fever (73.1%) received most antibiotics. The diagnoses that received the highest proportion of antibiotic treatment were tonsillitis (96.3%), otitis media (92.5%) and bronchitis (87.5%). Wide variation in the choice of antibiotic class by diagnosis was observed.ConclusionsGP antibiotic prescribing in Malta is high. The abundant use of broad-spectrum antibiotics, particularly macrolides, is of particular concern and indicates that antibiotics are being used inappropriately. Efforts must be made to improve GP awareness of appropriate antibiotic prescribing.
      PubDate: Tue, 08 Jan 2019 00:00:00 GMT
      DOI: 10.1093/jac/dky544
      Issue No: Vol. 74, No. 4 (2019)
  • Impact of Chief Medical Officer activity on prescribing of antibiotics in
           England: an interrupted time series analysis
    • Authors: Walker A; Curtis H, Goldacre B.
      Pages: 1133 - 1136
      Abstract: BackgroundAntimicrobial resistance is a growing problem, with the need for ‘strong action’ highlighted by the Chief Medical Officer for England in 2013, along with a 5 year antimicrobial resistance strategy.ObjectivesFive years on, we set out to determine if there was a measurable impact from the 5 year antimicrobial resistance strategy on overall antibiotic prescribing in NHS primary care in England.MethodsWe calculated the volume of antibiotic prescription items using annual prescription cost analysis data from 1998 to 2017 and monthly prescribing data from October 2010 to June 2018. Antibiotic prescribing rate was calculated using an age- and sex-adjusted denominator (Specific Therapeutic group Age-sex Related Prescribing Units, STAR-PU). We conducted interrupted time series analysis to measure any change in prescribing rate after the intervention.ResultsAfter several years with a stable rate of antibiotic prescribing, there was a downward change in gradient after 2013: −46.4 items per 1000 STAR-PU per year (95% CI = −61.4 to −31.3). The prescribing rate dropped from 1378 per 1000 STAR-PU per year in 2013 to 1184 in 2017, representing a 14.1% reduction. The reduction is similar for monthly data (16.4%). Assuming causality, when compared with predicted prescribing if the rate of prescribing had continued at the pre-2013 trend, we estimate that 9.7 million antibiotic prescriptions were prevented over the past year by the 5 year antimicrobial resistance strategy. ConclusionsThough we cannot firmly attribute causality for the reduction in prescribing to the 5 year antimicrobial resistance strategy, the magnitude and timing of the change are noteworthy; the substantial change followed a long period of relatively static antibiotic prescribing.
      PubDate: Wed, 23 Jan 2019 00:00:00 GMT
      DOI: 10.1093/jac/dky528
      Issue No: Vol. 74, No. 4 (2019)
  • Cost-effectiveness analysis of a GP- and parent-directed intervention to
           reduce antibiotic prescribing for children with respiratory tract
           infections in primary care
    • Authors: Dekker A; van der Velden A, Luijken J, et al.
      Pages: 1137 - 1142
      Abstract: ObjectivesWe evaluated costs and effects of the RAAK (RAtional Antibiotic use Kids) intervention (GP online training and information booklets for parents), aiming to reduce antibiotic prescribing for children with respiratory tract infection (RTI).MethodsWe conducted a trial-based cost-effectiveness analysis from a societal perspective. We included children consulting the GP with RTI for whom parents kept a 2 week (cost) diary. The antibiotic prescribing rate was the percentage of children receiving an antibiotic prescription at the index consultation and during the 2 weeks of follow-up. The cost difference between the intervention and usual care groups per percentage decrease in antibiotic prescribing was calculated. Bootstrapping was used to assess uncertainty surrounding the outcomes.ResultsCosts and effects of 153 children in the intervention group and 107 children in the usual care group were available for analysis. Antibiotic prescribing was 12% lower in the intervention group and costs were €10.27 higher in the intervention group compared with the usual care group. This resulted in an incremental cost-effectiveness ratio of €0.85 per percentage decrease in antibiotic prescribing. The probability that the intervention was more effective, but more expensive, was 53%, whereas the probability that the intervention was more effective and less expensive compared with usual care was 41%.ConclusionsThe online training for GPs and the information booklet for parents resulted in a decrease in antibiotic prescribing in children with RTI, at very low cost, and should therefore be considered for implementation in primary care.
      PubDate: Fri, 04 Jan 2019 00:00:00 GMT
      DOI: 10.1093/jac/dky552
      Issue No: Vol. 74, No. 4 (2019)
  • Antimicrobial stewardship: an evaluation of structure and process and
           their association with antimicrobial prescribing in NHS hospitals in
    • Authors: Scobie A; Budd E, Harris R, et al.
      Pages: 1143 - 1152
      Abstract: BackgroundRigorous antimicrobial stewardship programmes (ASPs) are an essential strategy against antimicrobial resistance.ObjectivesTo evaluate and score ASPs in acute English NHS hospitals and determine association of ASP scores with antimicrobial prescribing.MethodsASP structure and process were evaluated through an online survey in 148/152 acute hospitals in 2017. Scores were assigned to quality indicators based on resource- and labour-intensiveness, and their association with total and modified WHO-categorized ‘Access’, ‘Watch’ and ‘Reserve’ (AwaRe) prescribing was analysed.ResultsThe survey response rate was 97% with 78% of trusts submitting antimicrobial prescribing data. Over 80% of ASPs contained stewardship teams, policies and access to outpatient parenteral antimicrobial therapy, whilst less than 50% scored well for leadership or funding. High process performance was observed for antimicrobial pre-authorization, prescribing review and feedback, restricted susceptibility reporting, antimicrobial consumption monitoring, adherence to guidelines and junior doctor training. Low process attainment included education of senior prescribers and lack of resistance surveillance data distribution. Between 2016 and 2017, there was no difference in total trust prescribing (P = 0.117) although carbapenem prescribing fell (incidence rate ratio = 0.93, 95% CI 0.88–0.98) in non-teaching hospitals; ‘Watch’ prescribing also increased for specialist hospitals (OR = 1.10, 95% CI 1.01–1.20), as did ‘Reserve’ category prescribing in teaching (OR = 1.58, 95% CI 1.23–3.02) and specialist hospitals (OR = 3.09, 95% CI 2.02–4.74). A high process score was associated with lower ‘Reserve’ prescribing (OR = 0.82, 95% CI 0.67–1.01).ConclusionsAll responding trusts had established ASPs. The association of a scoring system with total and ‘AWaRe’ prescribing to assess effectiveness of ASPs merits further study.
      PubDate: Fri, 11 Jan 2019 00:00:00 GMT
      DOI: 10.1093/jac/dky538
      Issue No: Vol. 74, No. 4 (2019)
  • Emerging threat of triazole-resistant Aspergillus fumigatus
    • Authors: Rybak J; Fortwendel J, Rogers P.
      Pages: 835 - 842
      Abstract: Invasive aspergillosis is a leading cause of morbidity and mortality among immunocompromised populations and is predicted to cause more than 200 000 life-threatening infections each year. Aspergillus fumigatus is the most prevalent pathogen isolated from patients with invasive aspergillosis, accounting for more than 60% of all cases. Currently, the only antifungal agents available with consistent activity against A. fumigatus are the mould-active triazoles and amphotericin B, of which the triazoles commonly represent both front-line and salvage therapeutic options. Unfortunately, the treatment of infections caused by A. fumigatus has recently been further complicated by the global emergence of triazole resistance among both clinical and environmental isolates. Mutations in the A. fumigatus sterol-demethylase gene cyp51A, overexpression of cyp51A and overexpression of efflux pump genes are all known to contribute to resistance, yet much of the triazole resistance among A. fumigatus still remains unexplained. Also lacking is clinical experience with therapeutic options for the treatment of triazole-resistant A. fumigatus infections and mortality associated with these infections remains unacceptably high. Thus, further research is greatly needed to both better understand the emerging threat of triazole-resistant A. fumigatus and to develop novel therapeutic strategies to combat these resistant infections.
      PubDate: Mon, 17 Dec 2018 00:00:00 GMT
      DOI: 10.1093/jac/dky517
      Issue No: Vol. 74, No. 4 (2018)
  • Plasmid-located extended-spectrum β-lactamase gene blaROB-2 in
           Mannheimia haemolytica
    • Authors: Kadlec K; Watts J, Schwarz S, et al.
      Pages: 851 - 853
      Abstract: ObjectivesTo identify and analyse the first ESBL gene from Mannheimia haemolytica.MethodsSusceptibility testing was performed according to CLSI. Plasmids were extracted via alkaline lysis and transferred by electrotransformation. The sequence was determined by WGS and confirmed by Sanger sequencing.ResultsThe M. haemolytica strain 48 showed high cephalosporin MICs. A single plasmid, designated pKKM48, with a size of 4323 bp, was isolated. Plasmid pKKM48 harboured a novel blaROB gene, tentatively designated blaROB-2, and was transferred to Pasteurella multocida B130 and to Escherichia coli JM107. PCR assays and susceptibility testing confirmed the presence and activity of the blaROB-2 gene in the P. multocida and in the E. coli recipient carrying plasmid pKKM48. The transformants had high MICs of all β-lactam antibiotics. An ESBL phenotype was seen in the E. coli transformant when applying the CLSI double-disc confirmatory test for E. coli. The blaROB-2 gene from plasmid pKKM48 differed in three positions from blaROB-1, resulting in two amino acid exchanges and one additional amino acid in the deduced β-lactamase protein. In addition to blaROB-2, pKKM48 harboured mob genes and showed high similarity to other plasmids from Pasteurellaceae.ConclusionsThis study described the first ESBL gene in Pasteurellaceae, which may limit the therapeutic options for veterinarians. The transferability to Enterobacteriaceae with the functional activity of the gene in the new host underlines the possibility of the spread of this gene across species or genus boundaries.
      PubDate: Fri, 14 Dec 2018 00:00:00 GMT
      DOI: 10.1093/jac/dky515
      Issue No: Vol. 74, No. 4 (2018)
  • Effect of fluoroquinolone resistance mutation Thr-82→Ile on
           Clostridioides difficile fitness
    • Authors: Vernon J; Wilcox M, Freeman J.
      Pages: 877 - 884
      Abstract: ObjectivesFluoroquinolone resistance is common among epidemic Clostridioides difficile PCR ribotype (RT) 027 and may have contributed to outbreaks of C. difficile infection (CDI). We investigated the impact of fluoroquinolone mutations on the bacterial fitness (BF) of C. difficile RT027 isolates.MethodsThe BF of seven RT027 mutants with reduced susceptibility to moxifloxacin (moxifloxacin MIC 4–32 mg/L) was compared with their susceptible (moxifloxacin MIC 1–2 mg/L) progenitor strains in competitive batch culture (CBC), cell cytotoxicity and maximal growth rate assays. Comparative fitness dynamics of one gyrA Thr-82→Ile-harbouring isolate (CD3079M) versus the parent strain (CD3079) were also investigated in a continuous co-culture (CC) chemostat model. Mutant and parent strain populations were assessed every 24 h over 8 days using selective and non-selective agars. Sequencing was performed using NEBNext® Ultra™ chemistry and Illumina® HiSeq 3000 technologies.ResultsBF was significantly increased in all Thr-82→Ile isolates (w = 1.08–1.22) in CBC assays (P = 0.002). Gly-429→Val and Gln-434→Lys (gyrB) also showed no burden to fitness (w = 1.24 and 1.18, respectively), but Asp-71→Tyr conferred reduced fitness (w = 0.80). CC results for strains CD3079 and CD3079M (Thr-82→Ile) supported CBC findings; mutant-to-parent ratios differed significantly by 96 h (x¯=1.80, P = 0.025).ConclusionsThe absence of a fitness cost associated with the most prevalent fluoroquinolone resistance mutations may have contributed to the success of RT027. Furthermore, a demonstrable in vitro advantage over fluoroquinolone-susceptible parent strains in CC may contribute to the maintenance of RT027, even in the absence of fluoroquinolone selection pressure.
      PubDate: Mon, 24 Dec 2018 00:00:00 GMT
      DOI: 10.1093/jac/dky535
      Issue No: Vol. 74, No. 4 (2018)
  • Amino acid changes at the VIM-48 C-terminus result in increased carbapenem
           resistance, enzyme activity and protein stability
    • Authors: Liu Z; Zhang R, Li W, et al.
      Pages: 885 - 893
      Abstract: ObjectivesSince the identification of VIM-1, point substitutions resulting in variants with differing hydrolytic activities have occurred, driving the evolution of the VIM enzymes. We previously detected a novel variant, VIM-48, containing 11 successive amino acid (aa) alterations in the C-terminal region compared with VIM-2. Single aa substitutions significantly change enzyme properties, but the effects of successive aa alterations have not previously been studied. Herein, we aimed to investigate the sequence and biochemical characteristics of VIM-48, including the role of the 11 successive aa substitutions.MethodsVIM-48, VIM-2 and a truncated VIM-D(Δ) mutant missing 11 aa at the C-terminus relative to VIM-48 were characterized by antimicrobial susceptibility testing, protein expression and purification, determination of kinetic parameters, and homology modelling. Protein secondary structure and thermal stability measurements were also performed using circular dichroism spectral analysis.ResultsCompared with blaVIM-2, blaVIM-48 conferred higher resistance to carbapenems. VIM expression in Pseudomonas putida resulted in higher MICs than in E. coli. VIM-48 demonstrated increased hydrolytic activity against carbapenems relative to VIM-2, while VIM-D(Δ) had significantly decreased catalytic efficiency compared with VIM-2 and VIM-48 as a result of aa deletion. In addition, secondary structure analysis revealed that VIM-48 had the greatest proportion of α-helices among the tested enzymes, corresponding to increased thermostability, while VIM-D(Δ) had the lowest proportion of α-helices and decreased thermostability.ConclusionsVIM-48 has increased enzymatic activity and thermostability and increases host β-lactam resistance. Observed changes in the secondary structure of VIM-48 resulted from successive aa alterations. Therefore, VIM evolution likely occurs via both single and successive aa substitutions.
      PubDate: Sat, 22 Dec 2018 00:00:00 GMT
      DOI: 10.1093/jac/dky536
      Issue No: Vol. 74, No. 4 (2018)
  • Potential for repurposing the personal care product preservatives bronopol
    • Authors: Lee V; O’Neill A.
      Pages: 907 - 911
      Abstract: ObjectivesBacterial biofilms represent a major impediment to healing in chronic wounds and are largely refractory to the antibacterial agents currently used in wound management. From a repurposing screen of compounds considered safe for topical application in humans, we report the identification of the personal care product preservatives bronopol and bronidox as broad-spectrum antibiofilm agents and potential candidates for reducing biofilm burden in chronic wounds.MethodsAntibiofilm activity was assessed by viable counting against single-species biofilms of Staphylococcus aureus and Pseudomonas aeruginosa in the Calgary Biofilm Device, and against mixed-species biofilms of the two organisms growing on nitrocellulose discs.ResultsBronopol and bronidox exhibited broad-spectrum antibiofilm activity that encompassed the two major wound pathogens, S. aureus and P. aeruginosa. When impregnated into gauze dressings at their existing maximum authorized concentrations for safe use and placed onto an established mixed-species biofilm, bronopol and bronidox completely eradicated P. aeruginosa and achieved an ∼5 log10 reduction in the S. aureus population. The antibiofilm action of bronopol and bronidox was attributed to their ability to kill slow- or non-growing bacteria found in biofilms, and both compounds exhibited synergistic antibiofilm effects in combination with established wound-treatment agents.ConclusionsBronopol and bronidox kill bacteria regardless of growth state, a property that endows them with broad-spectrum antibiofilm activity. As this effect is observed at concentrations authorized for use on human skin, these compounds represent promising candidates for the treatment of chronic wounds.
      PubDate: Sat, 22 Dec 2018 00:00:00 GMT
      DOI: 10.1093/jac/dky520
      Issue No: Vol. 74, No. 4 (2018)
  • Activity of nacubactam (RG6080/OP0595) combinations against MBL-producing
    • Authors: Mushtaq S; Vickers A, Woodford N, et al.
      Pages: 953 - 960
      Abstract: BackgroundDiazabicyclooctanes (DBOs) are promising β-lactamase inhibitors. Some, including nacubactam (OP0595/RG6080), also bind PBP2 and have an enhancer effect, allowing activity against Enterobacteriaceae with MBLs, which DBOs do not inhibit. We tested the activity of nacubactam/β-lactam combinations against MBL-producing Enterobacteriaceae.MethodsTest panels comprised (i) 210 consecutive Enterobacteriaceae with NDM or VIM MBLs, as referred by UK diagnostic laboratories, and (ii) 99 supplementary MBL-producing Enterobacteriaceae, representing less prevalent phenotypes, species and enzymes. MICs were determined by CLSI agar dilution.ResultsMICs of nacubactam alone were bimodal, clustering at 1–8 mg/L or >32 mg/L; >85% of values for Escherichia coli and Enterobacter spp. fell into the low MIC cluster, whereas Proteeae were universally resistant and the Klebsiella spp. were divided between the two groups. Depending on the prospective breakpoint (4 + 4 or 8 + 4 mg/L), and on whether all isolates were considered or solely the Consecutive Collection, meropenem/nacubactam and cefepime/nacubactam inhibited 80.3%–93.3% of MBL producers, with substantial gains over nacubactam alone. Against the most resistant isolates (comprising 57 organisms with MICs of nacubactam >32 mg/L, cefepime ≥128 mg/L and meropenem ≥128 mg/L), cefepime/nacubactam at 8 + 4 mg/L inhibited 63.2% and meropenem/nacubactam at 8 + 4 mg/L inhibited 43.9%. Aztreonam/nacubactam, incorporating an MBL-stable β-lactam partner, was almost universally active against the MBL producers and, unlike aztreonam/avibactam, had an enhancer effect.ConclusionsNacubactam combinations, including those using MBL-labile β-lactams, e.g. meropenem and cefepime, can overcome most MBL-mediated resistance. This behaviour reflects nacubactam’s direct antibacterial and enhancer activity.
      PubDate: Mon, 24 Dec 2018 00:00:00 GMT
      DOI: 10.1093/jac/dky522
      Issue No: Vol. 74, No. 4 (2018)
  • Comparative efficacy of human-simulated epithelial lining fluid exposures
           of tedizolid, linezolid and vancomycin in neutropenic and immunocompetent
           murine models of staphylococcal pneumonia
    • Authors: Kidd J; Abdelraouf K, Nicolau D.
      Pages: 970 - 977
      Abstract: ObjectivesFew antibiotics are approved to treat Staphylococcus aureus pneumonia. Tedizolid is an oxazolidinone with potent in vitro activity against S. aureus and is currently under investigation for hospital-acquired and ventilator-associated bacterial pneumonia. Limited data exist on the comparative efficacy of tedizolid versus current first-line treatments vancomycin and linezolid in the compromised host. Our objective was to compare the efficacy of human-simulated epithelial lining fluid (ELF) exposures of tedizolid, linezolid and vancomycin against S. aureus in neutropenic and immunocompetent murine pneumonia models.MethodsEight S. aureus isolates (four MRSA and four MSSA) were studied. Neutropenic and immunocompetent mice were inoculated intranasally with bacterial suspensions of 107 and 109 cfu/mL, respectively, then treated for up to 72 h with model-specific regimens of tedizolid, linezolid and vancomycin simulating human ELF exposures after clinical doses. Mice were sacrificed at 24, 48 or 72 h and changes in log10 cfu/lungs were compared with 0 h controls.ResultsMean bacterial burdens at 0 h were 5.81 and 8.17 log10 cfu/lungs for neutropenic and immunocompetent mice, respectively, and increased at 24 h in the absence of antibiotic treatment to 7.97 and 9.00 log10 cfu/lungs, respectively. In neutropenic and immunocompetent mice, tedizolid was associated with bacterial density changes of −2.69 ± 0.62 and −3.57 ± 0.88 log10 cfu/lungs at 72 h, respectively. In both models, tedizolid treatment produced greater bacterial reductions than vancomycin and was not statistically significantly different from linezolid.ConclusionsHuman-simulated ELF exposures of tedizolid demonstrated sustained efficacy in compromised and competent models of pneumonia. Validation of these findings in patients is warranted.
      PubDate: Fri, 14 Dec 2018 00:00:00 GMT
      DOI: 10.1093/jac/dky513
      Issue No: Vol. 74, No. 4 (2018)
  • Protein binding of rifampicin is not saturated when using high-dose
    • Authors: Litjens C; Aarnoutse R, van Ewijk-Beneken Kolmer E, et al.
      Pages: 986 - 990
      Abstract: BackgroundHigher doses of rifampicin are being investigated as a means to optimize response to this pivotal TB drug. It is unknown whether high-dose rifampicin results in saturation of plasma protein binding and a relative increase in protein-unbound (active) drug concentrations.ObjectivesTo assess the free fraction of rifampicin based on an in vitro experiment and data from a clinical trial on high-dose rifampicin.MethodsProtein-unbound rifampicin concentrations were measured in human serum spiked with increasing total concentrations (up to 64 mg/L) of rifampicin and in samples obtained by intensive pharmacokinetic sampling of patients who used standard (10 mg/kg daily) or high-dose (35 mg/kg) rifampicin up to steady-state. The performance of total AUC0–24 to predict unbound AUC0–24 was evaluated.ResultsThe in vitro free fraction of rifampicin remained unaltered (∼9%) up to 21 mg/L and increased up to 13% at 41 mg/L and 17% at 64 mg/L rifampicin. The highest (peak) concentration in vivo was 39.1 mg/L (high-dose group). The arithmetic mean percentage unbound to total AUC0–24in vivo was 13.3% (range = 8.1%–24.9%) and 11.1% (range = 8.6%–13.6%) for the standard group and the high-dose group, respectively (P = 0.214). Prediction of unbound AUC0–24 based on total AUC0–24 resulted in a bias of −0.05% and an imprecision of 13.2%.ConclusionsPlasma protein binding of rifampicin can become saturated, but exposures after high-dose rifampicin are not high enough to increase the free fraction in TB patients with normal albumin values. Unbound rifampicin exposures can be predicted from total exposures, even in the higher dose range.
      PubDate: Fri, 28 Dec 2018 00:00:00 GMT
      DOI: 10.1093/jac/dky527
      Issue No: Vol. 74, No. 4 (2018)
  • SLC22A2 variants and dolutegravir levels correlate with psychiatric
           symptoms in persons with HIV
    • Authors: Borghetti A; Calcagno A, Lombardi F, et al.
      Pages: 1035 - 1043
      Abstract: BackgroundNeuropsychiatric symptoms (NPs) have been reported with dolutegravir use. We hypothesized that increasing dolutegravir trough concentrations (Ctrough) and/or polymorphism in the SLC22A2 gene, encoding the organic cation transporter-2 (OCT2), which is involved in monoamine clearance in the CNS and is inhibited by dolutegravir, might be associated with NPs.MethodsA cross-sectional cohort of HIV-positive patients treated with a dolutegravir-containing regimen underwent determination of allelic discrimination for SLC22A2 808 C → A polymorphism and dolutegravir Ctrough. The Symptom Checklist-90-R [investigating 10 psychiatric dimensions and reporting a general severity index (GSI)], a self-reported questionnaire and the Mini-International Neuropsychiatric Interview were offered to investigate current NPs. The effects of dolutegravir Ctrough and the SLC22A2 gene variant on NPs were explored by multivariable logistic regression.ResultsA cohort of 203 patients was analysed: 71.4% were male, with median age 51 years and 11 years of ART exposure. Median time on dolutegravir was 18 months. Dolutegravir was associated with different antiretroviral combinations (mainly lamivudine, 38.9%, and abacavir/lamivudine, 35.5%). SLC22A2 CA genotype was independently associated with an abnormal GSI [adjusted OR (aOR) 2.43; P = 0.072], anxiety (aOR 2.61; P = 0.044), hostility (aOR 3.76; P = 0.012) and with moderate to severe headache (aOR 5.55; P = 0.037), and dolutegravir Ctrough was associated with hostility (fourth versus first quartile aOR 6.70; P = 0.007) and psychoticism (fourth versus first quartile aOR 19.01; P = 0.008). Other NPs were not associated with SLC22A2 polymorphism or dolutegravir Ctrough.ConclusionsA variant of the OCT2-encoding gene, in addition to or in synergy with higher dolutegravir Ctrough, is associated with a set of NPs observed during dolutegravir therapy.
      PubDate: Fri, 14 Dec 2018 00:00:00 GMT
      DOI: 10.1093/jac/dky508
      Issue No: Vol. 74, No. 4 (2018)
  • HIV-1 drug resistance before initiation or re-initiation of first-line ART
           in eight regions of Mexico: a sub-nationally representative survey
    • Authors: Ávila-Ríos S; García-Morales C, Valenzuela-Lara M, et al.
      Pages: 1044 - 1055
      Abstract: BackgroundHIV pretreatment drug resistance (PDR) to NNRTIs in persons initiating ART is increasing in Mexico.ObjectivesTo compare HIV PDR in eight sub-regions of Mexico.Patients and methodsA large PDR survey was implemented in Mexico (September 2017–March 2018) across eight sub-regions. All larger clinics (which provide ART to 90% of all initiators) were included, allocating sample size using the probability-proportional-to-size method. Both antiretroviral-naive and prior antiretroviral-exposed persons were included. HIV PDR levels were estimated from pol Sanger sequences obtained at a WHO-designated laboratory.ResultsA total of 2006 participants were enrolled from 74 clinics. PDR to NNRTIs was higher than to other drug classes (P < 0.0001), crossing the 10% threshold in the North-East, East, South-West and South-East. NNRTI PDR was higher in the South-West (P = 0.02), coinciding with the highest proportion of restarters in this sub-region (14%). We observed higher PDR prevalence to any drug in women compared with men (16.5% versus 12.2%, P = 0.04). After multivariable adjustment, higher NNRTI PDR remained significantly associated with previous antiretroviral exposure in the Centre-North, North-West, South-West and South-East [adjusted OR (aOR): 21, 5, 8 and 25, respectively; P < 0.05]. Genetic network analyses showed high assortativity by sub-region (P < 0.0001), with evidence of drug resistance mutation transmission within local clusters.ConclusionsDiversification of the public health response to HIV drug resistance based on sub-regional characteristics could be considered in Mexico. Higher NNRTI PDR levels were associated with poorer regions, suggesting opportunities to strengthen local HIV programmes. Price and licensing negotiations of drug regimens containing integrase inhibitors are warranted.
      PubDate: Fri, 28 Dec 2018 00:00:00 GMT
      DOI: 10.1093/jac/dky512
      Issue No: Vol. 74, No. 4 (2018)
  • Therapeutic drug monitoring and adverse events of delayed-release
           posaconazole tablets in patients with chronic pulmonary aspergillosis
    • Authors: Kosmidis C; Rodriguez-Goncer I, Rautemaa-Richardson R, et al.
      Pages: 1056 - 1061
      Abstract: BackgroundPosaconazole delayed-release tablets offer better bioavailability than the liquid suspension, but no post-marketing data are available in immunocompetent hosts such as those with chronic pulmonary aspergillosis (CPA).ObjectivesTo explore the pharmacokinetics and adverse event (AE) profile of posaconazole tablets in patients with CPA.MethodsPatients started on posaconazole tablets at the National Aspergillosis Centre (NAC), Manchester, UK between February 2014 and October 2015 were identified from the NAC database and analysed retrospectively. The medical records were reviewed for factors that could affect posaconazole serum levels and the development of AEs.ResultsSeventy-two patients were included; 50 (69%) were male and the mean age was 48.5 ± 12 years. Therapeutic levels (≥1 mg/L) were achieved in 90% of cases on 200 mg versus 90% of cases on 300 mg daily (P = not significant). Based on multivariate analysis, female sex (P = 0.041), a 100 mg daily dose (P < 0.001), asthma (P = 0.01) and bronchiectasis (P = 0.001) were associated with subtherapeutic levels. Forty-nine (68%) patients developed AEs, mainly fatigue (37%), dyspnoea (18%) and nausea (12%). AEs were present on 115/196 (59%) occasions on 300 mg/day and on 45/115 (39%) occasions on 200 mg/day (P < 0.01). The mean level was 1.81 ± 0.96 mg/L for patients reporting no AEs and 1.90 ± 1.11 mg/L for those reporting AEs (P = not significant). Factors associated with AEs of grade ≥2 were a daily dose of 300 versus 200 mg (P = 0.001) and asthma (P = 0.008).ConclusionsA lower-than-recommended posaconazole tablet dose achieved therapeutic levels in most patients and was better tolerated. Males were more likely to achieve a therapeutic level. Underlying conditions affected the degree and frequency of AEs.
      PubDate: Wed, 26 Dec 2018 00:00:00 GMT
      DOI: 10.1093/jac/dky539
      Issue No: Vol. 74, No. 4 (2018)
  • Summary of the safety and tolerability of two treatment regimens of
           ceftaroline fosamil: 600 mg every 8 h versus 600 mg every 12 h
    • Authors: Cheng K; Pypstra R, Yan J, et al.
      Pages: 1086 - 1091
      Abstract: BackgroundThe recommended adult dose of ceftaroline fosamil is 600 mg q12h by 1 h intravenous (iv) infusion for 5–14 days in complicated skin and soft tissue infection (cSSTI) and 5–7 days in community-acquired pneumonia (CAP). A dosage of 600 mg q8h by 2 h iv infusion is approved in some regions for cSSTI patients with Staphylococcus aureus infection where the ceftaroline MIC is 2 or 4 mg/L. This analysis compares the safety profiles of the q8h and q12h regimens.MethodsSafety data from six Phase III, randomized, double-blind clinical trials were collated into the q8h cSSTI pool (ceftaroline fosamil n = 506; NCT01499277) and the q12h pool {ceftaroline fosamil n = 1686; comprising five studies [two cSSTI (NCT00424190 and NCT00423657) and three CAP (NCT01371838, NCT00621504 and NCT00509106)]}.ResultsThe pattern and incidence of adverse events were similar between the q8h and q12h ceftaroline fosamil pools. Most were gastrointestinal and of mild or moderate intensity. Overall, rash intensity was similar between the q8h pool and the q12h pool. For the q8h regimen, there was a higher frequency of rash in some Asian study sites, associated with longer duration of therapy (≥7 days); most cases were mild and resolved following treatment discontinuation. No dose-related vital sign or ECG abnormalities were detected with either regimen.ConclusionsThe q8h regimen in cSSTI was generally well tolerated; the observed safety profile was consistent with the known safety profile of ceftaroline fosamil, reflective of the cephalosporin class and qualitatively consistent with the q12h regimen.
      PubDate: Fri, 28 Dec 2018 00:00:00 GMT
      DOI: 10.1093/jac/dky519
      Issue No: Vol. 74, No. 4 (2018)
  • WGS to determine the extent of Clostridioides difficile transmission in a
           high incidence setting in North Wales in 2015
    • Authors: Eyre D; Shaw R, Adams H, et al.
      Pages: 1092 - 1100
      Abstract: ObjectivesRates of Clostridioides (Clostridium) difficile infection (CDI) are higher in North Wales than elsewhere in the UK. We used WGS to investigate if this is due to increased healthcare-associated transmission from other cases.MethodsHealthcare and community C. difficile isolates from patients across North Wales (February–July 2015) from glutamate dehydrogenase (GDH)-positive faecal samples underwent WGS. Data from patient records, hospital management systems and national antimicrobial use surveillance were used.ResultsOf the 499 GDH-positive samples, 338 (68%) were sequenced and 299 distinct infections/colonizations were identified, 229/299 (77%) with toxin genes. Only 39/229 (17%) toxigenic isolates were related within ≤2 SNPs to ≥1 infections/colonizations from a previously sampled patient, i.e. demonstrated evidence of possible transmission. Independent predictors of possible transmission included healthcare exposure in the last 12 weeks (P = 0.002, with rates varying by hospital), infection with MLST types ST-1 (ribotype 027) and ST-11 (predominantly ribotype 078) compared with all other toxigenic STs (P < 0.001), and cephalosporin exposure in the potential transmission recipient (P = 0.02). Adjusting for all these factors, there was no additional effect of ward workload (P = 0.54) or failure to meet cleaning targets (P = 0.25). Use of antimicrobials is higher in North Wales compared with England and the rest of Wales.ConclusionsLevels of transmission detected by WGS were comparable to previously described rates in endemic settings; other explanations, such as variations in antimicrobial use, are required to explain the high levels of CDI. Cephalosporins are a risk factor for infection with C. difficile from another infected or colonized case.
      PubDate: Sat, 15 Dec 2018 00:00:00 GMT
      DOI: 10.1093/jac/dky523
      Issue No: Vol. 74, No. 4 (2018)
  • Supervised machine learning for the prediction of infection on admission
           to hospital: a prospective observational cohort study
    • Authors: Rawson T; Hernandez B, Moore L, et al.
      Pages: 1108 - 1115
      Abstract: BackgroundInfection diagnosis can be challenging, relying on clinical judgement and non-specific markers of infection. We evaluated a supervised machine learning (SML) algorithm for diagnosing bacterial infection using routinely available blood parameters on presentation to hospital.MethodsAn SML algorithm was developed to classify cases into infection versus no infection using microbiology records and six available blood parameters (C-reactive protein, white cell count, bilirubin, creatinine, ALT and alkaline phosphatase) from 160203 individuals. A cohort of patients admitted to hospital over a 6 month period had their admission blood parameters prospectively inputted into the SML algorithm. They were prospectively followed up from admission to classify those who fulfilled clinical case criteria for a community-acquired bacterial infection within 72 h of admission using a pre-determined definition. Predictive ability was assessed using receiver operating characteristics (ROC) with cut-off values for optimal sensitivity and specificity explored.ResultsOne hundred and four individuals were included prospectively. The median (range) cohort age was 65 (21–98)  years. The majority were female (56/104; 54%). Thirty-six (35%) were diagnosed with infection in the first 72 h of admission. Overall, 44/104 (42%) individuals had microbiological investigations performed. Treatment was prescribed for 33/36 (92%) of infected individuals and 4/68 (6%) of those with no identifiable bacterial infection. Mean (SD) likelihood estimates for those with and without infection were significantly different. The infection group had a likelihood of 0.80 (0.09) and the non-infection group 0.50 (0.29) (P < 0.01; 95% CI: 0.20–0.40). ROC AUC was 0.84 (95% CI: 0.76–0.91).ConclusionsAn SML algorithm was able to diagnose infection in individuals presenting to hospital using routinely available blood parameters.
      PubDate: Sat, 22 Dec 2018 00:00:00 GMT
      DOI: 10.1093/jac/dky514
      Issue No: Vol. 74, No. 4 (2018)
  • Why did some practices not implement new antibiotic prescribing guidelines
           on urinary tract infection' A cohort study and survey in NHS England
           primary care
    • Authors: Croker R; Walker A, Goldacre B.
      Pages: 1125 - 1132
      Abstract: ObjectivesTo describe trends and geographical variation in prescribing of trimethoprim and nitrofurantoin to treat urinary tract infections, to describe variation in implementing guideline change and to compare actions taken to reduce trimethoprim use in high- and low-using Clinical Commissioning Groups (CCGs).MethodsA retrospective cohort study and interrupted time series analysis of English NHS primary care prescribing data, complemented by information obtained through Freedom of Information Act requests to CCGs. The main outcome measures were variation in practice and CCG prescribing ratios geographically and over time, including an interrupted time series, and responses to Freedom of Information requests.ResultsThe amount of trimethoprim prescribed, as a proportion of nitrofurantoin and trimethoprim combined, remained stable and high until 2014, then fell gradually to <50% in 2017; this reduction was more rapid following the introduction of the ‘Quality Premium’. There was substantial variation in the speed of change between CCGs. As of April 2017, for the 10 CCGs with the lowest trimethoprim ratios, 9 had reported at least one of: formulary change, work plan or incentive scheme to change prescribing behaviour. None of the 10 highest-ratio CCGs did so.ConclusionsMany CCGs failed to implement an important change in antibiotic prescribing guidance, and there is strong evidence suggesting that CCGs with minimal prescribing change did little to implement the new guidance. We recommend: (i) a national programme of training and accreditation for medicines optimization pharmacists; and (ii) remedial action for CCGs that fail to implement guidance—with all materials and data shared publicly for both such activities.
      PubDate: Sat, 22 Dec 2018 00:00:00 GMT
      DOI: 10.1093/jac/dky509
      Issue No: Vol. 74, No. 4 (2018)
  • Relocation of Tn2009 and characterization of an ABGRI3-2 from re-sequenced
           genome sequence of Acinetobacter baumannii MDR-ZJ06
    • Authors: Hua X; Xu Q, Zhou Z, et al.
      Pages: 1153 - 1155
      Abstract: Sir,
      PubDate: Mon, 17 Dec 2018 00:00:00 GMT
      DOI: 10.1093/jac/dky521
      Issue No: Vol. 74, No. 4 (2018)
  • Co-occurrence of qnrE1 and blaCTX-M-8 in IncM1 transferable plasmids
           contributing to MDR in different Salmonella serotypes
    • Authors: Soares F; Camargo C, Cunha M, et al.
      Pages: 1155 - 1156
      Abstract: Sir,
      PubDate: Wed, 12 Dec 2018 00:00:00 GMT
      DOI: 10.1093/jac/dky516
      Issue No: Vol. 74, No. 4 (2018)
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