Publisher: Oxford University Press   (Total: 411 journals)

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Showing 1 - 200 of 411 Journals sorted alphabetically
ACS Symposium Series     Full-text available via subscription   (Followers: 3, 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: 58, SJR: 2.196, CiteScore: 5)
Aesthetic Surgery J.     Hybrid Journal   (Followers: 7, SJR: 1.434, CiteScore: 1)
Aesthetic Surgery J. Open Forum     Open Access   (Followers: 1)
African Affairs     Hybrid Journal   (Followers: 72, SJR: 1.869, CiteScore: 2)
Age and Ageing     Hybrid Journal   (Followers: 94, SJR: 1.989, CiteScore: 4)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 20, SJR: 1.376, CiteScore: 3)
American Entomologist     Hybrid Journal   (Followers: 8)
American Historical Review     Hybrid Journal   (Followers: 208, SJR: 0.467, CiteScore: 1)
American J. of Agricultural Economics     Hybrid Journal   (Followers: 53, SJR: 2.113, CiteScore: 3)
American J. of Clinical Nutrition     Hybrid Journal   (Followers: 221, SJR: 3.438, CiteScore: 6)
American J. of Epidemiology     Hybrid Journal   (Followers: 220, SJR: 2.713, CiteScore: 3)
American J. of Health-System Pharmacy     Full-text available via subscription   (Followers: 62, SJR: 0.595, CiteScore: 1)
American J. of Hypertension     Hybrid Journal   (Followers: 28, 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: 10, SJR: 0.116, CiteScore: 0)
American Law and Economics Review     Hybrid Journal   (Followers: 29, SJR: 1.053, CiteScore: 1)
American Literary History     Hybrid Journal   (Followers: 18, SJR: 0.391, CiteScore: 0)
Analysis     Hybrid Journal   (Followers: 25, SJR: 1.038, CiteScore: 1)
Animal Frontiers     Hybrid Journal   (Followers: 2)
Annals of Behavioral Medicine     Hybrid Journal   (Followers: 15, SJR: 1.423, CiteScore: 3)
Annals of Botany     Hybrid Journal   (Followers: 38, SJR: 1.721, CiteScore: 4)
Annals of Oncology     Hybrid Journal   (Followers: 61, SJR: 5.599, CiteScore: 9)
Annals of the Entomological Society of America     Full-text available via subscription   (Followers: 11, SJR: 0.722, CiteScore: 1)
Annals of Work Exposures and Health     Hybrid Journal   (Followers: 36, 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: 63, 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: 22)
Arbitration Law Reports and Review     Hybrid Journal   (Followers: 14)
Archives of Clinical Neuropsychology     Hybrid Journal   (Followers: 32, SJR: 0.731, CiteScore: 2)
Aristotelian Society Supplementary Volume     Hybrid Journal   (Followers: 2)
Arthropod Management Tests     Hybrid Journal   (Followers: 2)
Astronomy & Geophysics     Hybrid Journal   (Followers: 47, SJR: 0.146, CiteScore: 0)
Behavioral Ecology     Hybrid Journal   (Followers: 55, SJR: 1.871, CiteScore: 3)
Bioinformatics     Hybrid Journal   (Followers: 386, SJR: 6.14, CiteScore: 8)
Biology Methods and Protocols     Hybrid Journal   (Followers: 1)
Biology of Reproduction     Full-text available via subscription   (Followers: 11, SJR: 1.446, CiteScore: 3)
Biometrika     Hybrid Journal   (Followers: 20, SJR: 3.485, CiteScore: 2)
BioScience     Hybrid Journal   (Followers: 30, SJR: 2.754, CiteScore: 4)
Bioscience Horizons : The National Undergraduate Research J.     Open Access   (Followers: 3, SJR: 0.146, CiteScore: 0)
Biostatistics     Hybrid Journal   (Followers: 18, SJR: 1.553, CiteScore: 2)
BJA : British J. of Anaesthesia     Hybrid Journal   (Followers: 216, SJR: 2.115, CiteScore: 3)
BJA Education     Hybrid Journal   (Followers: 68)
Brain     Hybrid Journal   (Followers: 75, SJR: 5.858, CiteScore: 7)
Briefings in Bioinformatics     Hybrid Journal   (Followers: 53, 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: 40, SJR: 2.161, CiteScore: 2)
British J. of Aesthetics     Hybrid Journal   (Followers: 24, SJR: 0.508, CiteScore: 1)
British J. of Criminology     Hybrid Journal   (Followers: 620, SJR: 1.828, CiteScore: 3)
British J. of Social Work     Hybrid Journal   (Followers: 98, 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: 35)
Bulletin of the London Mathematical Society     Hybrid Journal   (Followers: 3, SJR: 1.376, CiteScore: 1)
Cambridge J. of Economics     Hybrid Journal   (Followers: 73, 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: 15, SJR: 3.002, CiteScore: 5)
Cerebral Cortex     Hybrid Journal   (Followers: 54, SJR: 3.892, CiteScore: 6)
CESifo Economic Studies     Hybrid Journal   (Followers: 25, SJR: 0.483, CiteScore: 1)
Chemical Senses     Hybrid Journal   (Followers: 1, SJR: 1.42, CiteScore: 3)
Children and Schools     Hybrid Journal   (Followers: 8, 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: 24, SJR: 0.329, CiteScore: 0)
Chinese J. of Intl. Politics     Hybrid Journal   (Followers: 11, 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: 29, SJR: 0.123, CiteScore: 0)
Clean Energy     Open Access   (Followers: 3)
Clinical Infectious Diseases     Hybrid Journal   (Followers: 77, SJR: 5.051, CiteScore: 5)
Communication Theory     Hybrid Journal   (Followers: 28, SJR: 2.424, CiteScore: 3)
Communication, Culture & Critique     Hybrid Journal   (Followers: 29, SJR: 0.222, CiteScore: 1)
Community Development J.     Hybrid Journal   (Followers: 28, 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: 11, SJR: 0.121, CiteScore: 0)
Contributions to Political Economy     Hybrid Journal   (Followers: 7, SJR: 0.906, CiteScore: 1)
Critical Values     Full-text available via subscription  
Current Developments in Nutrition     Open Access   (Followers: 5)
Current Legal Problems     Hybrid Journal   (Followers: 29)
Current Zoology     Full-text available via subscription   (Followers: 4, SJR: 1.164, CiteScore: 2)
Database : The J. of Biological Databases and Curation     Open Access   (Followers: 10, SJR: 1.791, CiteScore: 3)
Digital Scholarship in the Humanities     Hybrid Journal   (Followers: 15, SJR: 0.259, CiteScore: 1)
Diplomatic History     Hybrid Journal   (Followers: 24, 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: 34, SJR: 2.926, CiteScore: 1)
Economic J.     Hybrid Journal   (Followers: 123, SJR: 5.161, CiteScore: 3)
Economic Policy     Hybrid Journal   (Followers: 51, SJR: 3.584, CiteScore: 3)
ELT J.     Hybrid Journal   (Followers: 25, SJR: 0.942, CiteScore: 1)
English Historical Review     Hybrid Journal   (Followers: 58, SJR: 0.612, CiteScore: 1)
English: J. of the English Association     Hybrid Journal   (Followers: 21, SJR: 0.1, CiteScore: 0)
Environmental Entomology     Full-text available via subscription   (Followers: 12, 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: 22, SJR: 0.113, CiteScore: 0)
European Heart J.     Hybrid Journal   (Followers: 67, 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   (Followers: 1)
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: 235, 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: 22, SJR: 1.36, CiteScore: 2)
European Review of Agricultural Economics     Hybrid Journal   (Followers: 12, 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: 45, 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: 18, SJR: 1.492, CiteScore: 4)
Fems Microbiology Letters     Hybrid Journal   (Followers: 28, SJR: 0.79, CiteScore: 2)
Fems Microbiology Reviews     Hybrid Journal   (Followers: 37, SJR: 7.063, CiteScore: 13)
Fems Yeast Research     Hybrid Journal   (Followers: 14, SJR: 1.308, CiteScore: 3)
Food Quality and Safety     Open Access   (Followers: 1)
Foreign Policy Analysis     Hybrid Journal   (Followers: 25, 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: 36, 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: 3)
Genome Biology and Evolution     Open Access   (Followers: 17, SJR: 2.578, CiteScore: 4)
Geophysical J. Intl.     Hybrid Journal   (Followers: 38, SJR: 1.506, CiteScore: 3)
German History     Hybrid Journal   (Followers: 26, SJR: 0.161, CiteScore: 0)
GigaScience     Open Access   (Followers: 6, SJR: 5.022, CiteScore: 7)
Global Summitry     Hybrid Journal   (Followers: 1)
Glycobiology     Hybrid Journal   (Followers: 11, SJR: 1.493, CiteScore: 3)
Health and Social Work     Hybrid Journal   (Followers: 69, SJR: 0.388, CiteScore: 1)
Health Education Research     Hybrid Journal   (Followers: 19, SJR: 0.854, CiteScore: 2)
Health Policy and Planning     Hybrid Journal   (Followers: 26, SJR: 1.512, CiteScore: 2)
Health Promotion Intl.     Hybrid Journal   (Followers: 27, SJR: 0.812, CiteScore: 2)
History Workshop J.     Hybrid Journal   (Followers: 33, SJR: 1.278, CiteScore: 1)
Holocaust and Genocide Studies     Hybrid Journal   (Followers: 30, SJR: 0.105, CiteScore: 0)
Human Communication Research     Hybrid Journal   (Followers: 15, SJR: 2.146, CiteScore: 3)
Human Molecular Genetics     Hybrid Journal   (Followers: 11, SJR: 3.555, CiteScore: 5)
Human Reproduction     Hybrid Journal   (Followers: 77, SJR: 2.643, CiteScore: 5)
Human Reproduction Open     Open Access   (Followers: 1)
Human Reproduction Update     Hybrid Journal   (Followers: 19, SJR: 5.317, CiteScore: 10)
Human Rights Law Review     Hybrid Journal   (Followers: 66, 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: 12)
ILAR J.     Hybrid Journal   (Followers: 3, 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: 11, SJR: 1.792, CiteScore: 2)
Industrial Law J.     Hybrid Journal   (Followers: 44, SJR: 0.249, CiteScore: 1)
Inflammatory Bowel Diseases     Hybrid Journal   (Followers: 45, SJR: 2.511, CiteScore: 4)
Information and Inference     Free  
Innovation in Aging     Open Access   (Followers: 1)
Insect Systematics and Diversity     Hybrid Journal  
Integrative and Comparative Biology     Hybrid Journal   (Followers: 10, SJR: 1.319, CiteScore: 2)
Integrative Biology     Full-text available via subscription   (Followers: 5, SJR: 1.36, CiteScore: 3)
Integrative Organismal Biology     Open Access  
Interacting with Computers     Hybrid Journal   (Followers: 10, SJR: 0.292, CiteScore: 1)
Interactive CardioVascular and Thoracic Surgery     Hybrid Journal   (Followers: 7, SJR: 0.762, CiteScore: 1)
Intl. Affairs     Hybrid Journal   (Followers: 70, SJR: 1.505, CiteScore: 3)
Intl. Data Privacy Law     Hybrid Journal   (Followers: 22)
Intl. Health     Hybrid Journal   (Followers: 7, 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: 39, SJR: 1.348, CiteScore: 2)
Intl. J. of Constitutional Law     Hybrid Journal   (Followers: 56, SJR: 0.601, CiteScore: 1)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 286, 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: 20, SJR: 0.223, CiteScore: 1)
Intl. J. of Lexicography     Hybrid Journal   (Followers: 9, 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: 39, SJR: 0.389, CiteScore: 1)
Intl. J. of Transitional Justice     Hybrid Journal   (Followers: 14, SJR: 0.724, CiteScore: 2)
Intl. Mathematics Research Notices     Hybrid Journal   (Followers: 1, SJR: 2.168, CiteScore: 1)
Intl. Political Sociology     Hybrid Journal   (Followers: 41, SJR: 1.465, CiteScore: 3)
Intl. Relations of the Asia-Pacific     Hybrid Journal   (Followers: 25, SJR: 0.401, CiteScore: 1)
Intl. Studies Perspectives     Hybrid Journal   (Followers: 9, SJR: 0.983, CiteScore: 1)
Intl. Studies Quarterly     Hybrid Journal   (Followers: 55, SJR: 2.581, CiteScore: 2)
Intl. Studies Review     Hybrid Journal   (Followers: 24, 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: 18, SJR: 0.533, CiteScore: 1)
J. of American History     Hybrid Journal   (Followers: 52, 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: 16, 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: 43, SJR: 1.226, CiteScore: 2)
J. of Breast Imaging     Full-text available via subscription   (Followers: 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: 16  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0305-7453 - ISSN (Online) 1460-2091
Published by Oxford University Press Homepage  [411 journals]
  • Antibiotics targeting bacterial ribosomal subunit biogenesis
    • Authors: Champney W.
      Pages: 787 - 806
      Abstract: This article describes 20 years of research that investigated a second novel target for ribosomal antibiotics, the biogenesis of the two subunits. Over that period, we have examined the effect of 52 different antibiotics on ribosomal subunit formation in six different microorganisms. Most of the antimicrobials we have studied are specific, preventing the formation of only the subunit to which they bind. A few interesting exceptions have also been observed. Forty-one research publications and a book chapter have resulted from this investigation. This review will describe the methodology we used and the fit of our results to a hypothetical model. The model predicts that inhibition of subunit assembly and translation are equivalent targets for most of the antibiotics we have investigated.
      PubDate: Mon, 13 Jan 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkz544
      Issue No: Vol. 75, No. 4 (2020)
  • Antimicrobial activity of honey in periodontal disease: a systematic
    • Authors: Hbibi A; Sikkou K, Khedid K, et al.
      Pages: 807 - 826
      Abstract: BackgroundHoney has shown positive antimicrobial and anti-inflammatory actions in several dermatological studies; however, it is unclear if it could be effective in the treatment of periodontal disease.ObjectivesTo answer the question: Does honey have antimicrobial activity against periodontopathogens'MethodsSix electronic databases were screened from initiation to 31 January 2019 for randomized clinical trials (RCTs) and controlled in vitro studies exploring the antimicrobial effect of honey against periodontopathogens. Honey’s botanical origin, periopathogens that showed microbial susceptibility to honey, MICs, microbial growth conditions, control product and clinical follow-up were the main investigated outcomes. The risk of bias (RoB) of included RCTs was assessed using the Cochrane Collaboration RoB tool. The RoB of in vitro studies was evaluated based on the Sarkis-Onofre judgement model adapted to the context of honey.ResultsA total of 1448 publications were found as search results in the screened databases. Sixteen eligible papers were included based on predetermined inclusion criteria. Retained studies included 5 RCTs and 11 in vitro controlled trials. Manuka and multifloral honeys were the most studied varieties. The tested honeys showed a significant antimicrobial action, with different MICs, against eight periopathogens. Four of the five RCTs showed a high RoB, while 4 of the 11 retained in vitro studies showed a medium RoB.ConclusionsHoney showed a significant antimicrobial activity against all targeted periopathogens. Additional experiments are required to explore the entire antimicrobial spectrum of honey towards all pathogens involved in periodontal disease.
      PubDate: Thu, 16 Jan 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkz527
      Issue No: Vol. 75, No. 4 (2020)
  • Safety of high-dose ivermectin: a systematic review and meta-analysis
    • Authors: Navarro M; Camprubí D, Requena-Méndez A, et al.
      Pages: 827 - 834
      Abstract: BackgroundIvermectin is a key anthelmintic for the control of neglected tropical diseases. The main indications for population-level control with ivermectin through mass drug administration are onchocerciasis and lymphatic filariasis; however, there is interest in using higher, fixed-dose regimens for the control of scabies, soil-transmitted helminths and malaria. Safety data for these higher-dose regimens are needed.MethodsA systematic literature review and meta-analysis on the safety and doses of ivermectin was conducted. Eligible studies reported patient-level data and, for the meta-analysis, clinical trials reporting data on doses ≥200 and ≥400 μg/kg were included. Incidence ratios were used to compare adverse events by severity and organ system affected.ResultsThe systematic search identified six studies for inclusion, revealing no differences in the number of individuals experiencing adverse events. A descriptive analysis of these clinical trials for a variety of indications showed no difference in the severity of the adverse events between standard (up to 400 μg/kg) and higher doses of ivermectin. Organ system involvement only showed an increase in ocular events in the higher-dose group in one trial for the treatment of onchocerciasis, all of them transient and mild to moderate in intensity.ConclusionsAlthough within this review the safety of high-dose ivermectin appears to be comparable to standard doses, there are not enough data to support a recommendation for its use in higher-than-approved doses. Ocular adverse events, despite being transient, are of concern in onchocerciasis patients. These data can inform programme managers and guide operational research activities as new approaches for the use of ivermectin are evaluated.
      PubDate: Mon, 20 Jan 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkz524
      Issue No: Vol. 75, No. 4 (2020)
  • Large-scale genome mining allows identification of neutral polymorphisms
           and novel resistance mutations in genes involved in Candida albicans
           resistance to azoles and echinocandins
    • Authors: Sitterlé E; Coste A, Obadia T, et al.
      Pages: 835 - 848
      Abstract: BackgroundThe genome of Candida albicans displays significant polymorphism. Point mutations in genes involved in resistance to antifungals may either confer phenotypic resistance or be devoid of phenotypic consequences.ObjectivesTo catalogue polymorphisms in azole and echinocandin resistance genes occurring in susceptible strains in order to rapidly pinpoint relevant mutations in resistant strains.MethodsGenome sequences from 151 unrelated C. albicans strains susceptible to fluconazole and caspofungin were used to create a catalogue of non-synonymous polymorphisms in genes involved in resistance to azoles (ERG11, TAC1, MRR1 and UPC2) or echinocandins (FKS1). The potential of this catalogue to reveal putative resistance mutations was tested in 10 azole-resistant isolates, including 1 intermediate to caspofungin. Selected mutations were analysed by mutagenesis experiments or mutational prediction effect.ResultsIn the susceptible strains, we identified 126 amino acid substitutions constituting the catalogue of phenotypically neutral polymorphisms. By excluding these neutral substitutions, we identified 22 additional substitutions in the 10 resistant strains. Among these substitutions, 10 had already been associated with resistance. The remaining 12 were in Tac1p (n = 6), Upc2p (n = 2) and Erg11p (n = 4). Four out of the six homozygous substitutions in Tac1p (H263Y, A790V, H839Y and P971S) conferred increases in azole MICs, while no effects were observed for those in Upc2p. Additionally, two homozygous substitutions (Y64H and P236S) had a predicted conformation effect on Erg11p.ConclusionsBy establishing a catalogue of neutral polymorphisms occurring in genes involved in resistance to antifungal drugs, we provide a useful resource for rapid identification of mutations possibly responsible for phenotypic resistance in C. albicans.
      PubDate: Fri, 10 Jan 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkz537
      Issue No: Vol. 75, No. 4 (2020)
  • A novel multiresistance gene cluster located on a plasmid-borne transposon
           in Listeria monocytogenes
    • Authors: Yan H; Yu R, Li D, et al.
      Pages: 868 - 872
      Abstract: ObjectivesTo identify the genetic context and the transferability of the multiresistance gene lsa(E) in Listeria monocytogenes.MethodsMICs were determined by broth microdilution. Transferability of lsa(E) was investigated by conjugation, electrotransformation and natural transformation. The lsa(E)-carrying plasmid was sequenced using the Illumina MiSeq and PacBio RSII platforms. The presence of translocatable units (TUs) was examined by PCR.ResultsThe 85 555 bp non-conjugative multiresistance plasmid pNH1 from L. monocytogenes harboured nine antimicrobial resistance genes including a multiresistance gene cluster, consisting of the genes aphA3, erm(B), aadE, spw, lsa(E) and lnu(B), and in addition the genes dfrG, tet(S) and catA8 were also located on plasmid pNH1 The multiresistance gene cluster, and each of the genes tet(S), catA8 and cadA were flanked by IS1216 elements. PCR identified four types of TUs, consisting of either the multiresistance gene cluster and one copy of IS1216, the catA8 gene and one copy of IS1216, or both, but also the tet(S) gene and one copy of IS1216, respectively. Natural transformation into Streptococcus mutans UA159 yielded transformants that harboured a novel 13 208 bp transposon, designated Tn6659. This transposon consisted of the multiresistance gene cluster bounded by IS1216 copies. All transformants displayed elevated MICs of the respective antimicrobial agents. At the integration site in the transformants, 8 bp direct target duplications (5′-ATTCAAAC-3′) were found immediately up- and downstream of Tn6659.ConclusionsTo the best of our knowledge, this is the first report of this novel multiresistance gene cluster and the gene catA8, flanked by IS1216 elements located on a plasmid of L. monocytogenes. Moreover, a novel functionally active multiresistance transposon was identified.
      PubDate: Thu, 23 Jan 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkz545
      Issue No: Vol. 75, No. 4 (2020)
  • Genomic dynamics of species and mobile genetic elements in a prolonged
           blaIMP-4-associated carbapenemase outbreak in an Australian hospital
    • Authors: Kizny Gordon A; Phan H, Lipworth S, et al.
      Pages: 873 - 882
      Abstract: BackgroundHospital outbreaks of carbapenemase-producing organisms, such as blaIMP-4-containing organisms, are an increasing threat to patient safety.ObjectivesTo investigate the genomic dynamics of a 10 year (2006–15) outbreak of blaIMP-4-containing organisms in a burns unit in a hospital in Sydney, Australia.MethodsAll carbapenem-non-susceptible or MDR clinical isolates (2006–15) and a random selection of equivalent or ESBL-producing environmental isolates (2012–15) were sequenced [short-read (Illumina), long-read (Oxford Nanopore Technology)]. Sequence data were used to assess genetic relatedness of isolates (Mash; mapping and recombination-adjusted phylogenies), perform in silico typing (MLST, resistance genes and plasmid replicons) and reconstruct a subset of blaIMP plasmids for comparative plasmid genomics.ResultsA total of 46/58 clinical and 67/96 environmental isolates contained blaIMP-4. All blaIMP-4-positive organisms contained five or more other resistance genes. Enterobacter cloacae was the predominant organism, with 12 other species mainly found in either the environment or patients, some persisting despite several cleaning methods. On phylogenetic analysis there were three genetic clusters of E. cloacae containing both clinical and environmental isolates, and an additional four clusters restricted to either reservoir. blaIMP-4 was mostly found as part of a cassette array (blaIMP-4-qacG2-aacA4-catB3) in a class 1 integron within a previously described IncM2 plasmid (pEl1573), with almost complete conservation of this cassette across the species over the 10 years. Several other plasmids were also implicated, including an IncF plasmid backbone not previously widely described in association with blaIMP-4.ConclusionsGenetic backgrounds disseminating blaIMP-4 can persist, diversify and evolve amongst both human and environmental reservoirs during a prolonged outbreak despite intensive prevention efforts.
      PubDate: Mon, 20 Jan 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkz526
      Issue No: Vol. 75, No. 4 (2020)
  • Comparison of phenotypic and WGS-derived antimicrobial resistance profiles
           of Campylobacter jejuni and Campylobacter coli isolated from cases of
           diarrhoeal disease in England and Wales, 2015–16
    • Authors: Painset A; Day M, Doumith M, et al.
      Pages: 883 - 889
      Abstract: ObjectivesTo compare and evaluate phenotypic and genotypic methods for the detection of antimicrobial resistance (AMR) in Campylobacter jejuni and Campylobacter coli in England and Wales.MethodsWGS data from 528 isolates of Campylobacter spp. (452 C. jejuni and 76 C. coli) from human (494), food (21) and environmental (2) sources, collected between January 2015 and December 2016, and from the PHE culture collection (11) were mapped to genes known to be associated with phenotypic resistance to antimicrobials in the genus. Phenotypic antibiotic susceptibility (erythromycin, ciprofloxacin, tetracycline, gentamicin and streptomycin) testing using an in-agar dilution method was performed on all isolates.ResultsConcordance between phenotypic resistance and the presence of corresponding AMR determinants was 97.5% (515/528 isolates). Only 13 out of 528 isolates (10 C. jejuni and 3 C. coli) had discordant interpretations for at least one of the five antibiotics tested, equating to a total of 15 (0.6%) discrepancies out of 2640 isolate/antimicrobial combinations. Seven discrepant results were genotypically resistant but phenotypically susceptible (major errors) and eight discrepant results were genotypically susceptible but phenotypically resistant (very major errors).ConclusionsThe use of this bioinformatics approach for predicting AMR from WGS data for routine public health surveillance is a reliable method for real-time monitoring of changing AMR patterns in isolates of C. jejuni and C. coli.
      PubDate: Thu, 16 Jan 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkz539
      Issue No: Vol. 75, No. 4 (2020)
  • Absence of the type I-E CRISPR-Cas system in Klebsiella pneumoniae clonal
           complex 258 is associated with dissemination of IncF epidemic resistance
           plasmids in this clonal complex
    • Authors: Tang Y; Fu P, Zhou Y, et al.
      Pages: 890 - 895
      Abstract: BackgroundThe pandemics caused by MDR Klebsiella pneumoniae are mostly due to the global dissemination of high-risk clonal complex 258 (CC258) and related IncF epidemic plasmids. However, the factors leading to the epidemiological advantages of CC258–IncF linkage remain obscure. The Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) and CRISPR-associated protein (CRISPR-Cas) systems, providing adaptive immunity against invading DNA, play an important role in the interactions between plasmids and hosts.ObjectivesTo investigate the relationship between CRISPR-Cas systems and the high-risk linkage CC258–IncF.MethodsCRISPR-Cas loci were detected among 381 collected K. pneumoniae clinical isolates and 207 K. pneumoniae complete genomes available in GenBank. MLST was used to determine the genetic relatedness of these isolates. Nucleotide BLAST was used to search for protospacers on K. pneumoniae plasmids.ResultsWe observed an epidemic correlation between CRISPR-Cas loci, CC258 and IncF plasmids. Interestingly, most type I-E CRISPR-Cas systems identified carried spacers matching the backbone regions of IncF plasmids.ConclusionsOur results suggest that the absence of type I-E CRISPR-Cas systems in K. pneumoniae CC258 is strongly associated with the dissemination of IncF epidemic plasmids, contributing to the global success of the international high-risk linkage CC258–IncF. Our findings provide new information regarding the dissemination and evolution of the high-risk linkage of K. pneumoniae CC258–IncF and pave the way for new strategies to address the problem of antibiotic resistance.
      PubDate: Fri, 31 Jan 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkz538
      Issue No: Vol. 75, No. 4 (2020)
  • Klebsiella pneumoniae ST307 with OXA-181: threat of a high-risk clone and
           promiscuous plasmid in a resource-constrained healthcare setting
    • Authors: Strydom K; Chen L, Kock M, et al.
      Pages: 896 - 902
      Abstract: IntroductionKlebsiella pneumoniae with OXA-48-like enzymes were introduced into Tshwane Tertiary Hospital (TTH) (Pretoria, South Africa) during September 2015, causing nosocomial outbreaks.MethodsPCR methodologies and WGS were used to characterize K. pneumoniae with carbapenemases (n = 124) from TTH (July 2015–December 2016).ResultsPCR was used to track K. pneumoniae ST307 with OXA-181 among 60% of carbapenemase-positive isolates in different wards/units over time and showed the transmission of IncX3 plasmids to other K. pneumoniae clones. WGS identified different ST307 clades: 307_OXA181 (consisting of two lineages, A and B) with OXA-181 on IncX3 plasmids (named p72_X3_OXA181) and clade 307_VIM with VIM-1 on IncFII plasmids. Clade 307_OXA181 lineage B was responsible for the rapid increase and transmission of OXA-181 K. pneumoniae in various wards/units throughout TTH, while the numbers of clade 307_OXA181 lineage A and clade 307_VIM remained low. Separate outbreaks were due to K. pneumoniae ST17 and ST29 with p72_X3_OXA181 plasmids.ConclusionsThe high-risk clone K. pneumoniae ST307 with OXA-181 rapidly spread to different wards/units despite infection and prevention measures. ST307 clades and lineages seemingly acted differently in outbreak situations. This study also highlighted the threat of promiscuous plasmids such as p72_X3_OXA181.
      PubDate: Sat, 18 Jan 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkz550
      Issue No: Vol. 75, No. 4 (2020)
  • Occurrence of NDM-1-producing Morganella morganii and Proteus mirabilis in
           a single patient in Portugal: probable in vivo transfer by conjugation
    • Authors: Aires-de-Sousa M; Ortiz de la Rosa J, Goncalves M, et al.
      Pages: 903 - 906
      Abstract: ObjectivesTo decipher the genetics of acquisition of carbapenemase-encoding genes identified in two carbapenem-resistant Enterobacteriaceae recovered from a single patient in Portugal.MethodsCarbapenemase genes were searched by PCR assays and mating-out assays were performed to further characterize the plasmid support of the carbapenemase genes. Genetic characterization of the plasmid supports was performed by whole-plasmid sequencing using the Illumina technology.ResultsWe identified here two NDM-1-producing isolates, namely a Morganella morganii and a Proteus mirabilis, sharing the same blaNDM-1-positive plasmid. This 154 kb plasmid belonged to the IncA/C2 type, recently renamed IncC, and co-harboured two AmpC β-lactamase genes, namely blaCMY-4 and blaDHA-1, in addition to the 16S rRNA methylase gene armA encoding high-level resistance to aminoglycosides. In addition, the M. morganii isolate produced the CTX-M-33 extended-spectrum β-lactamase possessing weak carbapenemase activity, encoded by another plasmid.ConclusionsWe showed here that, in addition to KPC-type and OXA-181 carbapenemases, which have been identified as widespread in this country, another concern is the emergence of NDM-1-producing enterobacterial isolates in Portugal. We demonstrated here the in vivo plasmid transfer of a blaNDM-1-positive plasmid leading to dissemination of this carbapenemase gene within different enterobacterial species in a single patient.
      PubDate: Thu, 23 Jan 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkz542
      Issue No: Vol. 75, No. 4 (2020)
  • Emergence of ceftriaxone-resistant Neisseria gonorrhoeae strains
           harbouring a novel mosaic penA gene in China
    • Authors: Xiu L; Yuan Q, Li Y, et al.
      Pages: 907 - 910
      Abstract: ObjectivesThe continuous emergence of ceftriaxone-resistant Neisseria gonorrhoeae strains threatens the effectiveness of current treatment regimens for gonorrhoea. The objective of the present study was to characterize three ceftriaxone-resistant N. gonorrhoeae strains with a novel mosaic penA allele isolated in China.MethodsThree ceftriaxone-resistant Neisseria gonorrhoeae strains (GC150, GC161 and GC208) isolated in 2017 were characterized by N. gonorrhoeae multiantigen sequence typing (NG-MAST), MLST and N. gonorrhoeae sequence typing for antimicrobial resistance (NG-STAR). Recombination analyses were performed using the SimPlot software.ResultsThree strains had the same antibiotic resistance profiles, with resistance to ceftriaxone (MIC 0.5 mg/L), ciprofloxacin (MIC 8.0 mg/L), penicillin (MIC 2.0 mg/L) and tetracycline (MIC 2.0–8.0 mg/L). STs were assigned as MLST7360, NG-MAST14292 and NG-STAR1611/NG-STAR1612. The penA gene of these three strains differed from previous ceftriaxone-resistant gonococcal strains and harboured a novel mosaic allele (penA-121.001). Like N. gonorrhoeae FC428, a widely disseminated ceftriaxone-resistant strain that was initially described in Japan in 2015, all strains also possessed substitutions A311V and T483S in PBP2, which are associated with resistance to ceftriaxone. Potential recombination events were detected in penA between N. gonorrhoeae strain FC428 and commensal Neisseria species. Our results provide further evidence that the commensal Neisseria species (Neisseria cinerea and Neisseria perflava) can serve as a reservoir of ceftriaxone resistance-mediating penA sequences in clinical gonococcal strains.ConclusionsThe emergence of such strains may be the result of the interspecies recombination of penA genes between N. gonorrhoeae strain FC428 and commensal Neisseria species.
      PubDate: Fri, 03 Jan 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkz530
      Issue No: Vol. 75, No. 4 (2020)
  • GPC-1, a novel class A carbapenemase detected in a clinical Pseudomonas
           aeruginosa isolate
    • Authors: Schauer J; Gatermann S, Hoffmann D, et al.
      Pages: 911 - 916
      Abstract: ObjectivesTo investigate the carbapenem resistance mechanism of a carbapenem-resistant clinical Pseudomonas aeruginosa isolate.MethodsA carbapenem-resistant P. aeruginosa isolate was recovered from a tracheal swab from a patient of a general ward in central Germany. Various phenotypic tests confirmed production of a carbapenemase that could not be identified further by PCR. A novel bla gene was identified by WGS and its carbapenemase activity was verified by heterologous expression in an Escherichia coli cloning strain. Kinetic parameters of the novel β-lactamase were determined by spectrophotometric measurements using purified enzyme.ResultsWGS confirmed the presence of a novel class A carbapenemase. The novel bla gene was named GPC-1 (GPC standing for German Pseudomonas Carbapenemase) and exhibited 77% amino acid identity to BKC-1. WGS also showed that blaGPC-1 was located on the chromosome surrounded by multiple ISs as part of a 26 kb genetic island. Heterologous expression of GPC-1 in E. coli TOP10 led to increased MICs of penicillins, oxyimino-cephalosporins, aztreonam and imipenem, but not of meropenem or ertapenem. Spectrophotometric measurements supported the MIC studies, but detected a slight hydrolysis of ertapenem and meropenem when using high concentrations of purified enzyme.ConclusionsThe biochemical characterization of GPC-1 emphasizes the ongoing emergence of novel carbapenemases. Strains expressing a weak carbapenemase like GPC-1 might go unrecognized by routine diagnostics due to low MICs for the bacterial strains producing such enzymes.
      PubDate: Mon, 20 Jan 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkz536
      Issue No: Vol. 75, No. 4 (2020)
  • Effect of colistin-based antibiotic combinations on the eradication of
           persister cells in Pseudomonas aeruginosa
    • Authors: Baek M; Chung E, Jung D, et al.
      Pages: 917 - 924
      Abstract: ObjectivesPersister cells are responsible for antibiotic treatment failure and the emergence of antibiotic resistance. The synergistic lethal effects of antibiotic combinations on persister cells were investigated using Pseudomonas aeruginosa isolates.MethodsPersister assays were performed on P. aeruginosa clinical isolates using colistin, amikacin, ciprofloxacin and cefepime, individually and in combination. ATP concentrations were measured and morphological changes in persister cells were observed using transmission electron microscopy (TEM). The expression of relA, spoT and obg genes was evaluated and persister-cell formation was investigated in a relA and spoT double mutant (ΔrelAΔspoT).ResultsThe P. aeruginosa persister cells were eradicated upon exposure to the colistin-based antibiotic combination colistin + ciprofloxacin. Simultaneous treatment with both antibiotics, rather than sequential treatment, caused more effective eradication. The intracellular ATP concentration was most reduced in colistin persisters. While the spoT gene was only overexpressed in colistin-persister cells, the relA gene was overexpressed in all persister cells compared with untreated parent cells. TEM analysis suggested the possibility that persister cells might be formed by different mechanisms depending on the antibiotic. Cell elongation and cell wall or membrane damage in colistin persisters, DNA condensation in amikacin persisters and outer membrane vesicles in ciprofloxacin persisters were identified.ConclusionsIn P. aeruginosa, the colistin-based antibiotic combination (colistin + ciprofloxacin) was effective for the eradication of persister cells, probably due to the different persister cell-formation mechanisms between the two antibiotics. Simultaneous, rather than sequential, treatment with two antibiotics could be more effective for eradicating persister P. aeruginosa cells.
      PubDate: Thu, 16 Jan 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkz552
      Issue No: Vol. 75, No. 4 (2020)
  • Madurella mycetomatis, the main causative agent of eumycetoma, is highly
           susceptible to olorofim
    • Authors: Lim W; Eadie K, Konings M, et al.
      Pages: 936 - 941
      Abstract: ObjectivesEumycetoma is currently treated with a combination of itraconazole therapy and surgery, with limited success. Recently, olorofim, the lead candidate of the orotomides, a novel class of antifungal agents, entered a Phase II trial for the treatment of invasive fungal infections. Here we determined the activity of olorofim against Madurella mycetomatis, the main causative agent of eumycetoma.MethodsActivity of olorofim against M. mycetomatis was determined by in silico comparison of the target gene, dihydroorotate dehydrogenase (DHODH), and in vitro susceptibility testing. We also investigated the in vitro interaction between olorofim and itraconazole against M. mycetomatis.ResultsM. mycetomatis and Aspergillus fumigatus share six out of seven predicted binding residues in their DHODH DNA sequence, predicting susceptibility to olorofim. Olorofim demonstrated excellent potency against M. mycetomatis in vivo with MICs ranging from 0.004 to 0.125 mg/L and an MIC90 of 0.063 mg/L. Olorofim MICs were mostly one dilution step lower than the itraconazole MICs. In vitro interaction studies demonstrated that olorofim and itraconazole work indifferently when combined.ConclusionsWe demonstrated olorofim has potent in vitro activity against M. mycetomatis and should be further evaluated in vivo as a treatment option for this disease.
      PubDate: Mon, 06 Jan 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkz529
      Issue No: Vol. 75, No. 4 (2020)
  • The EUCAST rapid disc diffusion method for antimicrobial susceptibility
           testing directly from positive blood culture bottles
    • Authors: Jonasson E; Matuschek E, Kahlmeter G.
      Pages: 968 - 978
      Abstract: ObjectivesWith increasing antimicrobial resistance, rapid antimicrobial susceptibility testing (RAST) becomes important, especially in patients with bloodstream infections. EUCAST decided to develop a standardized rapid method, based on EUCAST disc diffusion, to offer susceptibility reports within 4–8 h of a positive blood culture (BC).MethodsBC bottles were spiked with clinical isolates (n = 332) of the seven most relevant sepsis pathogens with a variety of resistance mechanisms. RAST was performed directly from the bottle and zones read after 4, 6 and 8 h. Several variables were investigated, including the effect of using different BC bottles and of a 0–18 h delay between a positive signal and the performance of RAST.ResultsFor five species, most inhibition zones could be read after 4 h. The proportion of results that could be interpreted increased from 75% at 4 h to 84% after 8 h. Categorical agreement against the reference method was good, with error rates of false susceptibility of 0.2%, 0.2% and 0.2% at 4, 6 and 8 h and false resistance of 1.2%, 0.2% and 0.1% at 4, 6 and 8 h, respectively.ConclusionsWith the EUCAST RAST method, reliable AST results can be delivered within 4–8 h of positivity of BC bottles for seven important bloodstream infection pathogens. To reduce the occurrence of errors and to absorb the variability caused by using a non-standardized inoculum, material from different manufacturers and workflow-related delays, we have introduced an area in which interpretation is not permitted, the Area of Technical Uncertainty.
      PubDate: Tue, 04 Feb 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkz548
      Issue No: Vol. 75, No. 4 (2020)
  • Results of the Italian infection-Carbapenem Resistance Evaluation
           Surveillance Trial (iCREST-IT): activity of ceftazidime/avibactam against
           Enterobacterales isolated from urine
    • Authors: Giani T; Antonelli A, Sennati S, et al.
      Pages: 979 - 983
      Abstract: ObjectivesTo assess the in vitro antibacterial activity of ceftazidime/avibactam against a recent Italian collection of carbapenem-resistant Enterobacterales (CRE) isolated from urine specimens.MethodsConsecutive Gram-negative isolates from urine specimens, collected from inpatients in five Italian hospitals during the period October 2016 to February 2017, were screened for CRE phenotype using chromogenic selective medium and identified using MALDI-TOF MS. Antimicrobial susceptibility testing was performed by reference broth microdilution (BMD) and, for ceftazidime/avibactam, also by Etest® CZA. Results were interpreted according to the EUCAST breakpoints. All confirmed CRE were subjected to real-time PCR targeting blaKPC-type, blaVIM-type, blaNDM-type and blaOXA-48-type carbapenemase genes. Non-MBL-producing isolates resistant to ceftazidime/avibactam were subjected to WGS and their resistome and clonality were analysed.ResultsOverall, 318 non-replicate presumptive CRE were collected following screening of 9405 isolates of Enterobacterales (3.4%) on chromogenic selective medium. Molecular analysis revealed that 216 isolates were positive for a carbapenemase gene (of which 92.1%, 2.8%, 1.4% and 1.4% were positive for blaKPC-type, blaOXA-48-type, blaNDM-type and blaVIM-type, respectively). Against the confirmed carbapenemase-producing Enterobacterales (CPE), ceftazidime/avibactam was the most active compound, followed by colistin (susceptibility rates 91.6% and 69.4%, respectively). Compared with BMD, Etest® for ceftazidime/avibactam yielded consistent results (100% category agreement). All class B β-lactamase producers were resistant to ceftazidime/avibactam, while OXA-48 and KPC producers were susceptible, with the exception of seven KPC-producing isolates (4.2%). The latter exhibited an MIC of 16 to >32 mg/L, belonged to ST512, produced KPC-3 and showed alterations in the OmpK35 and Ompk36 porins.ConclusionsCeftazidime/avibactam showed potent in vitro activity against a recent Italian collection of CPE from urine.
      PubDate: Mon, 20 Jan 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkz547
      Issue No: Vol. 75, No. 4 (2020)
  • Susceptibility of invasive Neisseria meningitidis strains isolated in
           Germany to azithromycin, an alternative agent for post-exposure
    • Authors: Krone M; Lâm T, Vogel U, et al.
      Pages: 984 - 987
      Abstract: BackgroundPost-exposure prophylaxis (PEP) for close contacts of invasive meningococcal disease (IMD) cases is recommended in most countries to avoid secondary cases by eradicating supposed meningococcal colonization. Currently, rifampicin, ciprofloxacin and ceftriaxone are recommended in many countries including Germany. Azithromycin has been shown to eradicate meningococcal colonization.ObjectivesTo assess the azithromycin susceptibility of invasive Neisseria meningitidis isolates.MethodsA subset of German invasive meningococcal isolates from 2006–18 was selected for this study. Azithromycin MIC was determined using broth microdilution and agar gradient diffusion.ResultsAzithromycin MICs as determined by broth microdilution ranged from <0.003 to 2 mg/L (median 0.50 mg/L, Q75 1 mg/L). All isolates were susceptible to azithromycin according to the CLSI breakpoint (95% CI 0.0%–1.5%). There was no significant correlation between MICs determined by broth microdilution and agar gradient diffusion. Nevertheless, the two methods were consistent regarding the categorization of all isolates as susceptible.ConclusionsAzithromycin is an eligible antibiotic for PEP of IMD close contacts. It is approved for adults as well as children and may even be used in pregnancy. Because of easier application and lower toxicity, it might be an alternative to rifampicin and ciprofloxacin, as we found no resistant isolates. Since a gonococcal gene associated with elevated azithromycin MICs has been reported in N. meningitidis, careful monitoring of the emergence of resistant strains is nevertheless necessary for meningococci. Lack of concordance of MICs between broth microdilution and agar gradient diffusion needs to be considered.
      PubDate: Thu, 23 Jan 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkz535
      Issue No: Vol. 75, No. 4 (2020)
  • Metallo-β-lactamase resistance in Enterobacteriaceae is an artefact of
           currently utilized antimicrobial susceptibility testing methods
    • Authors: Asempa T; Abdelraouf K, Nicolau D.
      Pages: 997 - 1005
      Abstract: BackgroundMBLs are a major contributor to β-lactam resistance when tested using CAMHB. Despite in vitro resistance, positive outcomes have been reported in MBL-infected patients following carbapenem treatment. The impact of physiological zinc concentrations on this in vitro–in vivo MBL discordance warrants investigation.ObjectivesTo evaluate meropenem in vitro activity against MBL-producing Enterobacteriaceae in zinc-depleted broth (Chelex-CAMHB, EDTA-CAMHB) and assess meropenem efficacy in murine infection models.MethodsNeutropenic mice received a meropenem human-simulated regimen of 2 g q8h or levofloxacin 750 mg q24h (for model validation). Zinc concentrations were determined in conventional CAMHB, zinc-depleted CAMHB and epithelial lining fluid (ELF) of lung-infected mice.ResultsAll MBL-producing isolates (NDM, n = 25; VIM, n = 3; IMP, n = 2) examined were meropenem resistant in CAMHB and susceptible in zinc-depleted CAMHB (5- to 11-fold reduction), with zinc depletion having no impact on levofloxacin MICs. Zinc concentrations (mean ± SD) in CAMHB were 0.959 ± 0.038 mg/L and in both zinc-depleted CAMHB and ELF were <0.002 mg/L. In vivo, levofloxacin displayed predictable efficacy consistent with its phenotypic profile, while meropenem produced >1 log unit bacterial killing despite in vitro resistance in conventional CAMHB.ConclusionsResults indicate that meropenem in vivo efficacy is best represented by the pharmacodynamic profile generated using MICs determined in zinc-depleted media for MBL-producing Enterobacteriaceae. These translational data suggest that the use of conventional CAMHB for MBL susceptibility testing is inappropriate in distinguishing meaningful in vivo resistance given that zinc concentrations are supraphysiological in conventional CAMHB and negligible at infection sites.
      PubDate: Mon, 13 Jan 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkz532
      Issue No: Vol. 75, No. 4 (2020)
  • Implications for IV posaconazole dosing in the era of obesity
    • Authors: Wasmann R; Smit C, van Donselaar M, et al.
      Pages: 1006 - 1013
      Abstract: BackgroundThe prevalence of obesity has shown a dramatic increase over recent decades. Obesity is associated with underdosing of antimicrobial drugs for prophylaxis and treatment. Posaconazole is a broad-spectrum triazole antifungal drug licensed for prophylaxis and treatment of invasive fungal infections. It is unclear how posaconazole should be dosed in obese patients.MethodsWe performed a prospective study investigating the pharmacokinetics of posaconazole in morbidly obese (n = 16) and normal-weight (n = 8) subjects, with a weight ranging between 61.4 and 190 kg, after a 300 or 400 mg IV dose. Population pharmacokinetic modelling was used to assess the effect of body size on posaconazole pharmacokinetics. Identifier: NCT03246386.ResultsTotal body weight best predicted changes in CL and V. Model-based simulations demonstrated that, for treatment of fungal infections, a daily IV dose of 300 mg will result in a PTA of ≥90% in individuals up to 140 kg, after which both twice daily loading and the daily maintenance dose should be increased to 400 mg. For prophylaxis, a 300 mg IV dose is adequate in patients up to 190 kg.ConclusionsBody size has a significant impact on posaconazole CL and V, resulting in a lower exposure in obese subjects compared with normal-weight subjects. For therapeutic use of posaconazole, a dose increase is required in patients above 140 kg. For prophylaxis, a 300 mg IV dose is adequate. For oral treatment, these recommendations can act as a starting point followed by therapeutic drug monitoring.
      PubDate: Thu, 23 Jan 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkz546
      Issue No: Vol. 75, No. 4 (2020)
  • Pharmacokinetic analysis of an extended-pulsed fidaxomicin regimen for the
           treatment of Clostridioides (Clostridium) difficile infection in patients
           aged 60 years and older in the EXTEND randomized controlled trial
    • Authors: Guery B; , Georgopali A, et al.
      Pages: 1014 - 1018
      Abstract: BackgroundFidaxomicin is a recommended treatment for Clostridioides difficile infection (CDI) and reduces CDI recurrence incidence versus vancomycin. An extended-pulsed fidaxomicin (EPFX) regimen further reduces recurrence frequency. However, the pharmacokinetic profile of fidaxomicin in an EPFX regimen is unknown.ObjectivesTo evaluate plasma and stool concentrations of fidaxomicin and its metabolite, OP-1118, after EPFX administration for CDI.MethodsIn the Phase 3b/4 EXTEND trial, patients aged ≥60 years with toxin-confirmed CDI were randomized to receive EPFX (oral fidaxomicin twice daily, Days 1–5; once daily on alternate days, Days 7–25). Fidaxomicin and OP-1118 concentrations were determined using post-dose plasma samples obtained on Days 5 ± 1, 12 ± 1 and 25/26, and post-dose stool samples obtained on Days 5 ± 1, 12 ± 1 and 26 ± 1.ResultsPlasma samples from 14 patients were included in the pharmacokinetic analysis; 12 of these patients provided stool samples. Median (range) plasma concentrations of fidaxomicin on Day 5 ± 1 and Day 25/26 were 0.0252 (0.0038–0.1220) mg/L and 0.0069 (0–0.0887) mg/L, respectively, and those of OP-1118 were 0.0648 (0.0142–0.3250) mg/L and 0.0206 (0–0.3720) mg/L, respectively. Median (range) stool concentrations of fidaxomicin and OP-1118 on Day 26 ± 1 were 272.5 (0–524) mg/kg and 280.5 (0–1120) mg/kg, respectively.ConclusionsEPFX treatment maintained fidaxomicin stool concentrations above the C. difficile MIC90 until Day 26 ± 1. Systemic exposure to fidaxomicin and OP-1118 was low throughout and there was no evidence of accumulation in plasma or stool during treatment.
      PubDate: Mon, 20 Jan 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkz549
      Issue No: Vol. 75, No. 4 (2020)
  • Pharmacokinetic profile and safety of adjusted doses of
           darunavir/ritonavir with rifampicin in people living with HIV
    • Authors: Ebrahim I; Maartens G, Wiesner L, et al.
      Pages: 1019 - 1025
      Abstract: BackgroundDarunavir/ritonavir is better tolerated than lopinavir/ritonavir and has a higher genetic barrier to resistance. Co-administration with rifampicin has been contraindicated as a significant reduction in darunavir exposure is expected. This is a barrier to darunavir/ritonavir use where TB is endemic.ObjectivesTo evaluate the safety and pharmacokinetic profile of adjusted doses of darunavir/ritonavir with rifampicin.MethodsVirally suppressed participants on second-line lopinavir/ritonavir-based ART were switched to darunavir/ritonavir 800/100 mg q24h. In sequence: rifampicin was added; the dose of ritonavir was escalated; and darunavir was increased (darunavir/ritonavir 1600/200 mg q24h and 800/100 mg q12h were given in randomized sequence with rifampicin). Darunavir plasma concentrations were measured on the seventh/last day of each treatment period. To prevent viral rebound, dolutegravir (50 mg q12h) was added during rifampicin administration and for 1 week thereafter. Clinical events, ALT and bilirubin were monitored every 2–3 days during rifampicin administration.ResultsA total of 17/28 participants started study treatment. Six (35.3%) were withdrawn for symptomatic hepatitis with severe ALT elevations, developing after 9–11 days of rifampicin and 2–4 days of ritonavir 200 mg. The study was stopped prematurely due to this high rate of hepatotoxicity. Only four participants completed the study. All hepatotoxicity resolved on withdrawal of study treatment. All participants were successfully re-established on their lopinavir/ritonavir-based regimen. After doubling the darunavir/ritonavir doses on rifampicin, darunavir pre-dose concentrations approached those on standard doses without rifampicin for q12h doses, but not for q24h doses.ConclusionsAdjusted doses of darunavir/ritonavir with rifampicin had unacceptable risk of hepatotoxicity. Darunavir trough concentrations were markedly reduced with the daily adjusted dose.
      PubDate: Mon, 13 Jan 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkz522
      Issue No: Vol. 75, No. 4 (2020)
  • Prevalence of doravirine-associated resistance mutations in HIV-1-infected
           antiretroviral-experienced patients from two large databases in France and
    • Authors: Soulie C; Santoro M, Storto A, et al.
      Pages: 1026 - 1030
      Abstract: ObjectivesDoravirine, a novel NNRTI, selects for specific mutations in vitro, including mutations at reverse transcriptase (RT) positions 106, 108, 188, 227, 230 and 234. The aim of this study was to examine the prevalence of doravirine-associated resistance mutations in HIV-1-infected antiretroviral-experienced patients.MethodsDoravirine-associated resistance mutations identified in vitro or in vivo were studied in a set of 9199 HIV-1 RT sequences from HIV-1 antiretroviral-experienced patients, including 381 NNRTI-failing patients in France and Italy between 2012 and 2017. The following mutations were considered as resistance mutations: V106A/M, V108I, Y188L, G190S, F227C/L/V, M230I/L, L234I, P236L, K103N + Y181C, K103N + P225H and K103N + L100I.ResultsThe frequencies of doravirine-associated resistance mutations (total dataset versus NNRTI-failing patients) were: V106A/M, 0.8% versus 2.6%; V108I, 3.3% versus 9.2%; Y188L, 1.2% versus 2.6%; G190S, 0.3% versus 2.1%; F227C/L/V, 0.5% versus 1.8%; M230I/L, 2.8% versus 0%; L234I, 0.1% versus 0.5%; K103N + Y181C, 3.9% versus 3.9%; K103N + P225H, 2.9% versus 4.7%; and K103N + L100I, 1.7% versus 3.9%, with a significantly higher proportion of these mutations in the NNRTI-failing group (P < 0.05), except for M230I/L and K103N + Y181C. The overall prevalence of sequences with at least one doravirine-associated resistance mutation was 12.2% and 34.9% in the total dataset and NNRTI-failing patients (P < 0.001), respectively. In comparison, the prevalence of the common NNRTI mutations V90I, K101E/P, K103N/S, E138A/G/K/Q/R/S, Y181C/I/V and G190A/E/S/Q were higher (8.9%, 7.9%, 28.6%, 12.6%, 14.2% and 8.9%, respectively).ConclusionsThese results suggest that doravirine resistance in antiretroviral-experienced patients generally and specifically among NNRTI-failing patients is lower than resistance to other NNRTIs currently used, confirming its distinguishing resistance pattern.
      PubDate: Fri, 24 Jan 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkz553
      Issue No: Vol. 75, No. 4 (2020)
  • Attributable nephrotoxicity of vancomycin in critically ill patients: a
           marginal structural model study
    • Authors: Arnaud F; Libório A.
      Pages: 1031 - 1037
      Abstract: BackgroundAlthough vancomycin nephrotoxicity is recognizable, critically ill patients have other potential reasons for acute kidney injury (AKI) and determining its attributable nephrotoxic risk in this population can be cumbersome.ObjectivesTo determine the risk of AKI attributable to vancomycin, controlling for baseline and time-dependent confounders.MethodsTime-fixed and daily time-varying variables were extracted from a large public database. The exposures analysed were: (i) IV vancomycin; (ii) serum trough level greater than 15 and 20 mg/L; and (iii) concomitant exposure to vancomycin and piperacillin/tazobactam or other antipseudomonal β-lactams. Censoring and exposure inverse probability of treatment weighting were calculated. Marginal structural models were plotted to evaluate AKI, severe AKI (stage 2/3) and need of renal replacement therapy (RRT).ResultsA total of 26 865 patients were included; 19.7% received vancomycin during ICU stay. After adjusting for fixed and time-variable confounders, vancomycin exposure was associated with AKI (HR = 1.24, 95% CI = 1.09–1.38), but not with severe AKI or need of RRT (HR = 1.05, 95% CI = 0.91–1.23 and HR = 0.97, 95% CI = 0.74–1.29, respectively). A serum trough level greater than 20 mg/L was associated with AKI (HR = 1.90, 95% CI = 1.52–2.30) and severe AKI (HR = 1.69, 95% CI = 1.31–2.19), but showed no statistically significant association with need of RRT (HR = 1.48, 95% CI = 0.92–2.56). The vancomycin + piperacillin/tazobactam combination was not associated with a greater risk than vancomycin alone.ConclusionsThe attributable nephrotoxicity of vancomycin in critically ill patients is significantly lower than previously suggested and severe AKI is related to vancomycin only when trough serum levels are greater than 20 mg/L.
      PubDate: Mon, 06 Jan 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkz520
      Issue No: Vol. 75, No. 4 (2020)
  • Retrospective multicentre matched cohort study comparing safety and
           efficacy outcomes of intermittent-infusion versus continuous-infusion
    • Authors: Ma N; Walker S, Elligsen M, et al.
      Pages: 1038 - 1046
      Abstract: BackgroundPatients with good renal function receiving intermittent-infusion vancomycin (IIV) may require total daily doses ≥4 g to achieve trough concentrations of 15–20 mg/L, increasing the risk of vancomycin-associated nephrotoxicity. Continuous-infusion vancomycin (CIV) may be associated with a lower risk of vancomycin-associated nephrotoxicity compared with IIV, but studies comparing safety of both dosing strategies are lacking.ObjectivesTo compare the risk of nephrotoxicity with CIV versus IIV when target concentration ranges were the same with both dosing modalities.MethodsA retrospective multicentre matched cohort study of admitted patients between 1 January 2010 and 31 December 2016 was completed. Adult patients who received ≥48 h of vancomycin with at least one steady-state vancomycin concentration were eligible. The primary outcome was to compare the rates of nephrotoxic risk and renal injury, defined by the RIFLE criteria, between CIV and IIV.ResultsOf 2136 patients who received vancomycin during the study period, 146 CIV patients were eligible and matched to 146 IIV patients. After adjustment of potential confounders, CIV was found to have a lower odds of developing nephrotoxic risk (OR 0.42, 95% CI 0.21–0.98, P = 0.025) and renal injury (OR 0.19, 95% CI 0.05–0.59, P = 0.004).ConclusionsCIV is associated with a lower odds of nephrotoxicity compared with IIV when targeting the same concentration range and should be an alternative dosing strategy for patients who will receive prolonged therapy or require >4 g/day to achieve therapeutic levels.
      PubDate: Thu, 09 Jan 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkz531
      Issue No: Vol. 75, No. 4 (2020)
  • The impact of an automated antibiotic stewardship intervention for the
           management of Staphylococcus aureus bacteraemia utilizing the electronic
           health record
    • Authors: Brotherton A; Rab S, Kandiah S, et al.
      Pages: 1054 - 1060
      Abstract: BackgroundStaphylococcus aureus bacteraemia (SAB) management bundles have been shown to improve performance measures and clinical outcomes. SAB bundles often require direct intervention by infectious diseases (ID) physicians or antibiotic stewardship programme (ASP) members or pharmacists. The purpose of this study was to evaluate an automated, real-time ASP intervention utilizing clinical decision support (CDS) in the electronic health record (EHR) for the management of SAB.MethodsA retrospective, single-centre quasi-experimental study of hospitalized patients with known SAB was conducted. The intervention was the implementation of a hard-stop best practice advisory (BPA) alert that would prompt physicians to use an electronic order set, on identification of SAB, with management recommendations, including ID consultation. The primary outcome was overall adherence to six institutional ASP SAB bundle elements. Secondary outcomes included both clinical and process outcomes.ResultsA total of 227 patients were included, 111 in the pre-intervention and 116 in the post-intervention period. Completion of all six bundle elements improved by 27.2% in the post-intervention group (29.7% versus 56.9%, P < 0.001). BPA activation and order-set utilization occurred in 95.7% and 57.8% in the post-intervention group, respectively. Composite outcome of 30 day mortality or 90 day readmission with SAB complication decreased in the post-intervention group by 9.6% (24.3% versus 14.7%, P = 0.092).ConclusionsOptimization of CDS within the EHR, using real-time BPA alert and order set, demonstrated an immediate, sustainable intervention that improved adherence to institutional performance measures for SAB management without direct prospective audit with intervention and feedback.
      PubDate: Mon, 13 Jan 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkz518
      Issue No: Vol. 75, No. 4 (2020)
  • An analysis of antibiotic prescribing practices for enteric bacterial
           infections within FoodNet Canada sentinel sites
    • Authors: Dougherty B; Finley R, Marshall B, et al.
      Pages: 1061 - 1067
      Abstract: ObjectivesUnderstanding the current state of antibiotic treatment guidelines and prescribing practices for bacterial enteric infections is critical to inform antibiotic stewardship initiatives. This study aims to add to the current understanding through three objectives: (i) to identify and summarize published treatment guidelines for bacterial enteric infections; (ii) to describe observed antibiotic prescribing practices for bacterial enteric infections across three sentinel sites in Canada; and (iii) to assess concordance between observed antibiotic prescribing and treatment guidelines.MethodsAn environmental scan of treatment guidelines for bacterial enteric infections was conducted and recommendations were collated. A descriptive analysis of cases of bacterial enteric illnesses captured in FoodNet Canada’s sentinel site surveillance system between 2010 and 2018 was performed. Antibiotic-use data were self-reported by cases via an enhanced questionnaire.ResultsTen treatment guidelines were identified in the environmental scan. There was substantial variation between guidelines for both when to prescribe antibiotics and which antibiotics were recommended. Of the 5877 cases of laboratory-confirmed bacterial enteric illness in the three sites, 49% of cases reported having received an antibiotic prescription. Of particular significance was the finding that 21% of verotoxigenic Escherichia coli cases received a prescription. Of the 17 antibiotics recommended in the guidelines, 14 were used in practice. In addition to these, 18 other antibiotics not included in any of the guidelines reviewed were also prescribed.ConclusionsOur study suggests that a substantial proportion of enteric bacterial infections in Canada are prescribed antibiotics. These findings highlight the need to standardize treatment guidelines for enteric illnesses and could be used to inform future stewardship programme development.
      PubDate: Mon, 20 Jan 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkz525
      Issue No: Vol. 75, No. 4 (2020)
  • Rapid detection and characterization of tet(X4)-positive Escherichia coli
           strains with nanopore sequencing
    • Authors: Li R; Lu X, Liu Z, et al.
      Pages: 1068 - 1070
      Abstract: Sir,
      PubDate: Mon, 13 Jan 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkz528
      Issue No: Vol. 75, No. 4 (2020)
  • Prevalence and mechanisms of azole resistance in clinical isolates of
           Aspergillus section Fumigati species in a Canadian tertiary care centre,
           2000 to 2013
    • Authors: Parent-Michaud M; Dufresne P, Fournier E, et al.
      Pages: 849 - 858
      Abstract: ObjectivesAzole resistance among Aspergillus fumigatus isolates is a growing concern worldwide. Induction of mutations during azole therapy, environment-acquired mutations caused by azole fungicides and intrinsic resistance of cryptic Fumigati species all contribute to the burden of resistance. However, there is a lack of data in Canada on this emerging threat.MethodsTo gain insights into the magnitude and mechanisms of resistance, a 14 year collection of Aspergillus section Fumigati comprising 999 isolates from 807 patients at a Montreal hospital was screened for azole resistance, and resistance mechanisms were investigated with the combined use of genome sequencing, 3D modelling and phenotypic efflux pump assays.ResultsOverall azole resistance was low (4/807 patients; 0.5%). A single azole-resistant A. fumigatus sensu stricto strain, isolated from a patient with pulmonary aspergillosis, displayed efflux-pump-mediated resistance. Three patients were colonized or infected with azole-resistant cryptic Fumigati species (one Aspergillus thermomutatus, one Aspergillus lentulus and one Aspergillus turcosus). Evidence is presented that azole resistance is efflux-pump-mediated in the A. turcosus isolate, but not in the A. lentulus and A. thermomutatus isolates.ConclusionsAzole resistance is rare in our geographic area and currently driven by cryptic Fumigati species. Continued surveillance of emergence of resistance is warranted.
      PubDate: Tue, 31 Dec 2019 00:00:00 GMT
      DOI: 10.1093/jac/dkz534
      Issue No: Vol. 75, No. 4 (2019)
  • Constitutive expression of the cryptic vanGCd operon promotes vancomycin
           resistance in Clostridioides difficile clinical isolates
    • Authors: Shen W; Deshpande A, Hevener K, et al.
      Pages: 859 - 867
      Abstract: ObjectivesTo describe, for the first time (to the best of our knowledge), the genetic mechanisms of vancomycin resistance in clinical isolates of Clostridioides difficile ribotype 027.MethodsClinical isolates and laboratory mutants were analysed: genomically to identify resistance mutations; by transcriptional analysis of vanGCd, the vancomycin resistance operon encoding lipid II d-alanine-d-serine that is less bound by vancomycin than native lipid II d-alanine-d-alanine; by imaging of vancomycin binding to cell walls; and for changes in vancomycin bactericidal activity and autolysis.ResultsVancomycin-resistant laboratory mutants and clinical isolates acquired mutations to the vanSR two-component system that regulates vanGCd. The substitutions impaired VanSR’s function, resulting in constitutive transcription of vanGCd. Resistance was reversed by silencing vanG, encoding d-alanine-d-serine ligase in the vanGCd operon. In resistant cells, vancomycin was less bound to the cell wall septum, the site where vancomycin interacts with lipid II. Vancomycin’s bactericidal activity was reduced against clinical isolates and laboratory mutants (64 and ≥1024 mg/L, respectively) compared with WT strains (4 mg/L). Truncation of the potassium transporter TrkA occurred in laboratory mutants, which were refractory to autolysis, accounting for their survival in high drug concentrations.ConclusionsRibotype 027 evolved first-step resistance to vancomycin by constitutively expressing vanGCd, which is otherwise silent. Experimental evolutions and bactericidal assays show that ribotype 027 can acquire mutations to drastically enhance its tolerance to vancomycin. Thus, further epidemiological studies are warranted to examine the extent to which vancomycin resistance impacts clinical outcomes and the potential for these strains to evolve higher-level resistance, which would be devastating.
      PubDate: Tue, 24 Dec 2019 00:00:00 GMT
      DOI: 10.1093/jac/dkz513
      Issue No: Vol. 75, No. 4 (2019)
  • Candida albicans enhances meropenem tolerance of Pseudomonas aeruginosa in
           a dual-species biofilm
    • Authors: Alam F; Catlow D, Di Maio A, et al.
      Pages: 925 - 935
      Abstract: BackgroundPseudomonas aeruginosa is an opportunistic bacterium that infects the airways of cystic fibrosis patients, surfaces of surgical and burn wounds, and indwelling medical devices. Patients are prone to secondary fungal infections, with Candida albicans being commonly co-isolated with P. aeruginosa. Both P. aeruginosa and C. albicans are able to form extensive biofilms on the surfaces of mucosa and medical devices.ObjectivesTo determine whether the presence of C. albicans enhances antibiotic tolerance of P. aeruginosa in a dual-species biofilm.MethodsSingle- and dual-species biofilms were established in microtitre plates and the survival of each species was measured following treatment with clinically relevant antibiotics. Scanning electron microscopy and confocal microscopy were used to visualize biofilm structure.ResultsC. albicans enhances P. aeruginosa biofilm tolerance to meropenem at the clinically relevant concentration of 5 mg/L. This effect is specific to biofilm cultures and is dependent upon C. albicans extracellular matrix polysaccharides, mannan and glucan, with C. albicans cells deficient in glycosylation structures not enhancing P. aeruginosa tolerance to meropenem.ConclusionsWe propose that fungal mannan and glucan secreted into the extracellular matrix of P. aeruginosa/C. albicans dual-species biofilms play a central role in enhancing P. aeruginosa tolerance to meropenem, which has direct implications for the treatment of coinfected patients.
      PubDate: Sun, 22 Dec 2019 00:00:00 GMT
      DOI: 10.1093/jac/dkz514
      Issue No: Vol. 75, No. 4 (2019)
  • Stigmasterol as a potential biomarker for amphotericin B resistance in
           Leishmania donovani
    • Authors: Bansal R; Sen S, Muthuswami R, et al.
      Pages: 942 - 950
      Abstract: BackgroundLeishmania donovani, a protozoan parasite, is the primary causative agent for visceral leishmaniasis. Toxicity and increased resistance to existing drugs have led to an urgent need for identifying new drugs and drug targets. Understanding the risks and mechanisms of resistance is of great importance. Amphotericin B (AmB) is a polyene antimicrobial, the mainstay therapy for visceral leishmaniasis in several parts of India.ObjectivesIn the present study, we established a line of AmB-resistant L. donovani promastigotes in vitro and demonstrated the molecular basis of resistance to AmB.MethodsAmB-resistant promastigotes were generated and characterized to evaluate the mechanism of resistance to AmB. We examined the sterol composition of the promastigotes and the axenic amastigotes derived from the WT and AmB-resistant promastigotes. The role of the plant-like C-22 desaturase responsible for stigmasterol production was also evaluated in the AmB-resistant strain.ResultsThe IC50 for resistant cells was four times higher than for the WT. AmB-resistant promastigotes showed an increase in the conversion of β-sitosterol into stigmasterol. The presence of higher amounts of stigmasterol in resistant promastigotes, as well as in axenic amastigotes, signifies its role in AmB resistance in Leishmania. The resistant strain showed reduced infectivity in vitro.ConclusionsWe have elucidated the mode of action and resistance mechanisms to the drug. However, further work is required to validate the potential role of stigmasterol in resistance and to help develop a diagnostic kit that can assist in diagnosing potentially resistant lines in the field.
      PubDate: Mon, 30 Dec 2019 00:00:00 GMT
      DOI: 10.1093/jac/dkz515
      Issue No: Vol. 75, No. 4 (2019)
  • Transmission potential of paromomycin-resistant Leishmania infantum and
           Leishmania donovani
    • Authors: Hendrickx S; Van Bockstal L, Aslan H, et al.
      Pages: 951 - 957
      Abstract: ObjectivesFormer studies demonstrated quick selection of paromomycin resistance for Leishmania infantum and Leishmania donovani accompanied by increased fitness. The present study aimed to interpret these findings in an epidemiological context by comparing infection of WT and experimentally derived paromomycin-resistant strains in the sand fly vector.MethodsDepending on the Leishmania species, Lutzomyia longipalpis and Phlebotomus perniciosus or Phlebotomus argentipes sand flies were artificially infected with procyclic promastigotes of WT and paromomycin-resistant L. infantum (MHOM/FR/96/LEM3323-cl4) or L. donovani (MHOM/NP/03/BPK275/0-cl18). The infection rate and gut/stomodeal valve colonization were determined to monitor parasite phenotypic behaviour within the vector. The impact of the previously described gain of fitness in the vertebrate host on infectivity for the vector was assessed by feeding L. longipalpis on Syrian golden hamsters heavily infected with either WT or paromomycin-resistant parasites.ResultsWT and paromomycin-resistant Leishmania of both species behaved similarly in terms of infection and parasite location within the studied sand fly species. Blood feeding on infected hamsters did not reveal differences in acquisition of WT and paromomycin-resistant parasites, despite the higher organ burdens observed for the paromomycin-resistant strain. Strains remained resistant after passage in the vector.ConclusionsAlthough paromomycin-resistant parasites show an increased parasite fitness in vitro and in laboratory rodents, the intrinsic infection potential of paromomycin-resistant parasites remains unaltered in the sand fly. Of importance is the fact that paromomycin-resistant Leishmania are able to complete development in the natural vectors and produce stomodeal infection with metacyclic forms, which clearly suggests their potential to spread and circulate in nature.
      PubDate: Mon, 30 Dec 2019 00:00:00 GMT
      DOI: 10.1093/jac/dkz517
      Issue No: Vol. 75, No. 4 (2019)
  • Evaluation of phthalazinone phosphodiesterase inhibitors with improved
           activity and selectivity against Trypanosoma cruzi
    • Authors: De Araújo J; da Silva P, Batista M, et al.
      Pages: 958 - 967
      Abstract: BackgroundChagas’ disease, caused by the protozoan parasite Trypanosoma cruzi, needs urgent alternative therapeutic options as the treatments currently available display severe limitations, mainly related to efficacy and toxicity.ObjectivesAs phosphodiesterases (PDEs) have been claimed as novel targets against T. cruzi, our aim was to evaluate the biological aspects of 12 new phthalazinone PDE inhibitors against different T. cruzi strains and parasite forms relevant for human infection.MethodsIn vitro trypanocidal activity of the inhibitors was assessed alone and in combination with benznidazole. Their effects on parasite ultrastructural and cAMP levels were determined. PDE mRNA levels from the different T. cruzi forms were measured by quantitative reverse transcription PCR.ResultsFive TcrPDEs were found to be expressed in all parasite stages. Four compounds displayed strong effects against intracellular amastigotes. Against bloodstream trypomastigotes (BTs), three were at least as potent as benznidazole. In vitro combination therapy with one of the most active inhibitors on both parasite forms (NPD-040) plus benznidazole demonstrated a quite synergistic profile (xΣ FICI = 0.58) against intracellular amastigotes but no interaction (xΣ FICI = 1.27) when BTs were assayed. BTs treated with NPD-040 presented disrupted Golgi apparatus, a swollen flagellar pocket and signs of autophagy. cAMP measurements of untreated parasites showed that amastigotes have higher ability to efflux this second messenger than BTs. NPD-001 and NPD-040 increase the intracellular cAMP content in both BTs and amastigotes, which is also released into the extracellular milieu.ConclusionsThe findings demonstrate the potential of PDE inhibitors as anti-T. cruzi drug candidates.
      PubDate: Fri, 20 Dec 2019 00:00:00 GMT
      DOI: 10.1093/jac/dkz516
      Issue No: Vol. 75, No. 4 (2019)
  • Impact of bacterial species and baseline resistance on fosfomycin efficacy
           in urinary tract infections
    • Authors: Abbott I; Dekker J, van Gorp E, et al.
      Pages: 988 - 996
      Abstract: ObjectivesTo assess the antibacterial effects of a single 3 g oral fosfomycin dose on Escherichia coli and Klebsiella pneumoniae clinical isolates within a dynamic bladder infection model.MethodsAn in vitro model simulating dynamic urinary fosfomycin concentrations was used. Target fosfomycin exposure (Cmax = 1984 mg/L and Tmax = 7.5 h) was validated by LC-MS/MS. Pharmacodynamic responses of 24 E. coli and 20 K. pneumoniae clinical isolates were examined (fosfomycin MIC ≤0.25–128 mg/L). Mutant prevention concentration (MPC), fosfomycin heteroresistance, fosfomycin resistance genes and fosA expression were examined. Pathogen kill and emergence of high-level resistance (HLR; MIC >1024 mg/L) were quantified.ResultsFollowing fosfomycin exposure, 20 of 24 E. coli exhibited reductions in bacterial counts below the lower limit of quantification without regrowth, despite baseline fosfomycin MICs up to 128 mg/L. Four E. coli regrew (MIC = 4–32 mg/L) with HLR population replacement. At baseline, these isolates had detectable HLR subpopulations and MPC >1024 mg/L. All E. coli isolates were fosA negative. In contrast, 17 of 20 K. pneumoniae regrew post exposure, 6 with emergence of HLR (proportion = 0.01%–100%). The three isolates without regrowth did not have a detectable HLR subpopulation after dynamic drug-free incubation. All K. pneumoniae had MPC >1024 mg/L and were fosA positive. WGS analysis and fosA expression failed to predict fosfomycin efficacy.ConclusionsE. coli and K. pneumoniae isolates demonstrate discrepant responses to a single fosfomycin dose in a dynamic bladder infection in vitro model. Treatment failure against E. coli was related to an HLR subpopulation, not identified by standard MIC testing. Activity against K. pneumoniae appeared limited, regardless of MIC testing, due to universal baseline heteroresistance.
      PubDate: Tue, 24 Dec 2019 00:00:00 GMT
      DOI: 10.1093/jac/dkz519
      Issue No: Vol. 75, No. 4 (2019)
  • Identification of hospitalized patients with community-acquired infection
           in whom treatment guidelines do not apply: a validated model
    • Authors: Cardoso T; Rodrigues P, Nunes C, et al.
      Pages: 1047 - 1053
      Abstract: ObjectivesTo develop and validate a clinical model to identify patients admitted to hospital with community-acquired infection (CAI) caused by pathogens resistant to antimicrobials recommended in current CAI treatment guidelines.MethodsInternational prospective cohort study of consecutive patients admitted with bacterial infection. Logistic regression was used to associate risk factors with infection by a resistant organism. The final model was validated in an independent cohort.ResultsThere were 527 patients in the derivation and 89 in the validation cohort. Independent risk factors identified were: atherosclerosis with functional impairment (Karnofsky index <70) [adjusted OR (aOR) (95% CI) = 2.19 (1.41–3.40)]; previous invasive procedures [adjusted OR (95% CI) = 1.98 (1.28–3.05)]; previous colonization with an MDR organism (MDRO) [aOR (95% CI) = 2.67 (1.48–4.81)]; and previous antimicrobial therapy [aOR (95% CI) = 2.81 (1.81–4.38)]. The area under the receiver operating characteristics (AU-ROC) curve (95% CI) for the final model was 0.75 (0.70–0.79). For a predicted probability ≥22% the sensitivity of the model was 82%, with a negative predictive value of 85%. In the validation cohort the sensitivity of the model was 96%. Using this model, unnecessary broad-spectrum therapy would be recommended in 30% of cases whereas undertreatment would occur in only 6% of cases.ConclusionsFor patients hospitalized with CAI and none of the following risk factors: atherosclerosis with functional impairment; previous invasive procedures; antimicrobial therapy; or MDRO colonization, CAI guidelines can safely be applied. Whereas, for those with some of these risk factors, particularly if more than one, alternative antimicrobial regimens should be considered.
      PubDate: Tue, 24 Dec 2019 00:00:00 GMT
      DOI: 10.1093/jac/dkz521
      Issue No: Vol. 75, No. 4 (2019)
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