Publisher: Oxford University Press   (Total: 412 journals)

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Showing 1 - 200 of 412 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: 61, SJR: 2.196, CiteScore: 5)
Aesthetic Surgery J.     Hybrid Journal   (Followers: 8, SJR: 1.434, CiteScore: 1)
Aesthetic Surgery J. Open Forum     Open Access   (Followers: 1)
African Affairs     Hybrid Journal   (Followers: 74, SJR: 1.869, CiteScore: 2)
Age and Ageing     Hybrid Journal   (Followers: 95, SJR: 1.989, CiteScore: 4)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 21, SJR: 1.376, CiteScore: 3)
American Entomologist     Hybrid Journal   (Followers: 8)
American Historical Review     Hybrid Journal   (Followers: 216, SJR: 0.467, CiteScore: 1)
American J. of Agricultural Economics     Hybrid Journal   (Followers: 54, SJR: 2.113, CiteScore: 3)
American J. of Clinical Nutrition     Hybrid Journal   (Followers: 232, SJR: 3.438, CiteScore: 6)
American J. of Epidemiology     Hybrid Journal   (Followers: 228, SJR: 2.713, CiteScore: 3)
American J. of Health-System Pharmacy     Full-text available via subscription   (Followers: 64, SJR: 0.595, CiteScore: 1)
American J. of Hypertension     Hybrid Journal   (Followers: 29, 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: 11, SJR: 0.116, CiteScore: 0)
American Law and Economics Review     Hybrid Journal   (Followers: 31, SJR: 1.053, CiteScore: 1)
American Literary History     Hybrid Journal   (Followers: 19, 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: 62, 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: 11, SJR: 0.728, CiteScore: 2)
Antibody Therapeutics     Open Access   (Followers: 1)
AoB Plants     Open Access   (Followers: 4, SJR: 1.28, CiteScore: 3)
Applied Economic Perspectives and Policy     Hybrid Journal   (Followers: 18, SJR: 0.858, CiteScore: 2)
Applied Linguistics     Hybrid Journal   (Followers: 66, 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: 20)
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: 58, SJR: 1.871, CiteScore: 3)
Bioinformatics     Hybrid Journal   (Followers: 396, SJR: 6.14, CiteScore: 8)
Biology Methods and Protocols     Open Access   (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: 17, SJR: 1.553, CiteScore: 2)
BJA : British J. of Anaesthesia     Hybrid Journal   (Followers: 234, SJR: 2.115, CiteScore: 3)
BJA Education     Hybrid Journal   (Followers: 69)
Brain     Hybrid Journal   (Followers: 78, SJR: 5.858, CiteScore: 7)
Brain Communications     Open Access   (Followers: 2)
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: 42, 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: 622, SJR: 1.828, CiteScore: 3)
British J. of Social Work     Hybrid Journal   (Followers: 99, 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: 76, SJR: 0.764, CiteScore: 2)
Cambridge J. of Regions, Economy and Society     Hybrid Journal   (Followers: 13, SJR: 2.438, CiteScore: 4)
Cambridge Quarterly     Hybrid Journal   (Followers: 11, SJR: 0.104, CiteScore: 0)
Capital Markets Law J.     Hybrid Journal   (Followers: 3, SJR: 0.222, CiteScore: 0)
Carcinogenesis     Hybrid Journal   (Followers: 2, SJR: 2.135, CiteScore: 5)
Cardiovascular Research     Hybrid Journal   (Followers: 16, SJR: 3.002, CiteScore: 5)
Cerebral Cortex     Hybrid Journal   (Followers: 56, SJR: 3.892, CiteScore: 6)
CESifo Economic Studies     Hybrid Journal   (Followers: 24, 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: 79, SJR: 5.051, CiteScore: 5)
Communication Theory     Hybrid Journal   (Followers: 29, 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: 12, SJR: 0.121, CiteScore: 0)
Contributions to Political Economy     Hybrid Journal   (Followers: 8, 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: 6, 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: 25, SJR: 0.45, CiteScore: 1)
DNA Research     Open Access   (Followers: 6, 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: 124, SJR: 5.161, CiteScore: 3)
Economic Policy     Hybrid Journal   (Followers: 51, SJR: 3.584, CiteScore: 3)
ELT J.     Hybrid Journal   (Followers: 27, SJR: 0.942, CiteScore: 1)
English Historical Review     Hybrid Journal   (Followers: 60, SJR: 0.612, CiteScore: 1)
English: J. of the English Association     Hybrid Journal   (Followers: 23, 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: 28, 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: 23, 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: 7, 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: 239, 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: 23, 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: 31, SJR: 0.702, CiteScore: 1)
European Sociological Review     Hybrid Journal   (Followers: 46, 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: 19, SJR: 1.492, CiteScore: 4)
Fems Microbiology Letters     Hybrid Journal   (Followers: 29, SJR: 0.79, CiteScore: 2)
Fems Microbiology Reviews     Hybrid Journal   (Followers: 38, 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: 26, 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: 2)
Genome Biology and Evolution     Open Access   (Followers: 17, SJR: 2.578, CiteScore: 4)
Geophysical J. Intl.     Hybrid Journal   (Followers: 39, SJR: 1.506, CiteScore: 3)
German History     Hybrid Journal   (Followers: 27, 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: 10, SJR: 1.493, CiteScore: 3)
Health and Social Work     Hybrid Journal   (Followers: 68, 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: 16, SJR: 2.146, CiteScore: 3)
Human Molecular Genetics     Hybrid Journal   (Followers: 11, SJR: 3.555, CiteScore: 5)
Human Reproduction     Hybrid Journal   (Followers: 76, SJR: 2.643, CiteScore: 5)
Human Reproduction Open     Open Access   (Followers: 1)
Human Reproduction Update     Hybrid Journal   (Followers: 18, 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: 59, SJR: 1.591, CiteScore: 3)
ICSID Review : Foreign Investment Law J.     Hybrid Journal   (Followers: 11)
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: 12, SJR: 1.792, CiteScore: 2)
Industrial Law J.     Hybrid Journal   (Followers: 29, 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: 72, 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: 4, SJR: 2.167, CiteScore: 4)
Intl. J. for Quality in Health Care     Hybrid Journal   (Followers: 40, SJR: 1.348, CiteScore: 2)
Intl. J. of Constitutional Law     Hybrid Journal   (Followers: 57, SJR: 0.601, CiteScore: 1)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 292, 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: 21, 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: 38, 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: 55, SJR: 0.297, CiteScore: 1)
J. of Analytical Toxicology     Hybrid Journal   (Followers: 15, 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: 46, SJR: 1.226, 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: 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  [412 journals]
  • Appreciation Professor David Sims Reeves, 1937–2019
    • Authors: Wise R.
      Pages: 1665 - 1666
      PubDate: Sat, 04 Apr 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa088
      Issue No: Vol. 75, No. 7 (2020)
  • COVID-19: a recommendation to examine the effect of hydroxychloroquine in
           preventing infection and progression
    • Authors: Zhou D; Dai S, Tong Q.
      Pages: 1667 - 1670
      Abstract: AbstractA novel coronavirus disease (COVID-19), caused by infection with SARS-CoV-2, has swept across 31 provinces in China and over 40 countries worldwide. The transition from first symptoms to acute respiratory distress syndrome (ARDS) is highly likely to be due to uncontrolled cytokine release. There is an urgent need to identify safe and effective drugs for treatment. Chloroquine (CQ) exhibits a promising inhibitory effect. However, the clinical use of CQ can cause severe side effects. We propose that hydroxychloroquine (HCQ), which exhibits an antiviral effect highly similar to that of CQ, could serve as a better therapeutic approach. HCQ is likely to attenuate the severe progression of COVID-19, inhibiting the cytokine storm by suppressing T cell activation. It has a safer clinical profile and is suitable for those who are pregnant. It is cheaper and more readily available in China. We herein strongly urge that clinical trials are performed to assess the preventive effects of HCQ in both disease infection and progression.
      PubDate: Fri, 20 Mar 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa114
      Issue No: Vol. 75, No. 7 (2020)
  • Indications for the use of highest priority critically important
           antimicrobials in the veterinary sector
    • Authors: Lhermie G; , La Ragione R, et al.
      Pages: 1671 - 1680
      Abstract: AbstractBackgroundAmong the measures taken to preserve the clinical efficacy of highest priority critically important antimicrobials (HP-CIAs), the WHO has recommended avoiding their use in food-producing animals. Little is known regarding the indications for which different antimicrobial classes are used in animals, even in countries where data on antimicrobial use are available.ObjectivesTo outline, in a narrative review, the diseases for which HP-CIAs are used in veterinary medicine, highlighting incongruences with international guidelines and disease conditions where effective alternatives to HP-CIAs are missing.MethodsScientific literature, national reports and expert opinion were used to describe the indications for the use of HP-CIAs in the main food-producing (pigs, cattle and poultry) and companion (horses, dogs and cats) animal species.ResultsThe most common indications for use of HP-CIAs are enteric and respiratory infections in pigs, cattle and poultry, urogenital infections in dogs and cats and respiratory infections in horses. In some instances, no valid and convenient alternatives to colistin and macrolides are available against certain porcine enteric and bovine respiratory pathogens. Effective, legal and convenient alternatives to HP-CIAs are also lacking for managing common infections in cats, for which oral administration is difficult, Rhodococcus equi infections in horses, some enteric and respiratory infections in poultry and MDR infections in all companion animal species.ConclusionsFuture research and stewardship programmes should focus on the disease conditions identified by this review to reduce the use of HP-CIAs in the veterinary sector.
      PubDate: Thu, 02 Apr 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa104
      Issue No: Vol. 75, No. 7 (2020)
  • COVID-19 and the potential long-term impact on antimicrobial resistance
    • Authors: Rawson T; Moore L, Castro-Sanchez E, et al.
      Pages: 1681 - 1684
      Abstract: AbstractThe emergence of the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) has required an unprecedented response to control the spread of the infection and protect the most vulnerable within society. Whilst the pandemic has focused society on the threat of emerging infections and hand hygiene, certain infection control and antimicrobial stewardship policies may have to be relaxed. It is unclear whether the unintended consequences of these changes will have a net-positive or -negative impact on rates of antimicrobial resistance. Whilst the urgent focus must be on controlling this pandemic, sustained efforts to address the longer-term global threat of antimicrobial resistance should not be overlooked.
      PubDate: Wed, 20 May 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa194
      Issue No: Vol. 75, No. 7 (2020)
  • Aztreonam for Neisseria gonorrhoeae: a systematic review and meta-analysis
    • Authors: Barbee L; Golden M.
      Pages: 1685 - 1688
      Abstract: AbstractBackgroundCeftriaxone is the only consistently active antimicrobial agent recommended for the treatment of Neisseria gonorrhoeae. Although some new antimicrobials are in development, the necessity to expand treatment options in the near term may require using older drugs that have not been widely used to treat gonorrhoea.MethodsWe conducted a literature review of clinical trials and case series, published from 1983 to 2017, reporting treatment efficacy results following administration of 1 g aztreonam intramuscularly or IV for uncomplicated gonococcal infections. We summed trial data, stratified by anatomical site of infection, and calculated summary efficacy estimates and 95% CI for each site of infection.ResultsThe 10 identified clinical trials enrolled 678, 38 and 16 individuals with urogenital, rectal and pharyngeal gonorrhoea, respectively. Aztreonam had an efficacy of 98.6% (95% CI: 97.5%–99.4%) for urogenital, 94.7% (95% CI: 82.3%–99.4%) for rectal and 81.3% (95% CI: 54.4%–96.0%) for pharyngeal gonococcal infections.ConclusionsAlthough most clinical trials included in this meta-analysis were conducted >30 years ago, aztreonam appears to have excellent efficacy for urogenital gonorrhoea; its efficacy at extragenital sites remains uncertain.
      PubDate: Tue, 07 Apr 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa108
      Issue No: Vol. 75, No. 7 (2020)
  • Efficacy and safety of colistin loading dose: a meta-analysis
    • Authors: Bellos I; Pergialiotis V, Frountzas M, et al.
      Pages: 1689 - 1698
      Abstract: AbstractObjectivesColistin represents a polypeptide used for the treatment of MDR microorganisms, although the optimal dosing strategy is under investigation. The present meta-analysis aims to determine whether the administration of a colistin loading dose in patients receiving high-dose maintenance regimens changes the rates of treatment success and the risk of nephrotoxicity.MethodsMedline, Scopus, CENTRAL, and Google Scholar were systematically searched from inception to 18 November 2019. Studies were considered eligible if they reported clinical outcomes among patients receiving high-dose colistin therapy with and without the administration of a loading dose. Meta-analysis was performed by fitting a random-effects model.ResultsEight (three prospective and five retrospective cohort) studies were included, comprising 1115 patients. The administration of a colistin loading dose was associated with significantly higher microbiological [risk ratio (RR) = 1.23, 95% CI = 1.10–1.39] but not clinical (RR = 1.04, 95% CI = 0.87–1.24) success. No significant associations were calculated for nephrotoxicity (RR = 1.31, 95% CI = 0.90–1.91) and mortality (RR = 1.03, 95% CI = 0.82–1.29) risk. The results remained stable after adjustments for small sample size, credibility ceilings, publication bias and risk of bias.ConclusionsObservational evidence suggests that the administration of a colistin loading dose in patients receiving high maintenance dosage regimens is significantly associated with higher rates of microbiological response, but does not change clinical cure, mortality or nephrotoxicity risk. The dosing regimen that would provide the optimal balance between treatment efficacy and safety needs to be determined by future randomized controlled trials.
      PubDate: Sat, 14 Mar 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa064
      Issue No: Vol. 75, No. 7 (2020)
  • Molecular and functional analysis of the novel cfr(D) linezolid resistance
           gene identified in Enterococcus faecium
    • Authors: Guerin F; Sassi M, Dejoies L, et al.
      Pages: 1699 - 1703
      Abstract: AbstractObjectivesTo characterize the novel cfr(D) gene identified in an Enterococcus faecium clinical isolate (15-307.1) collected from France.MethodsThe genome of 15-307.1 was entirely sequenced using a hybrid approach combining short-read (MiSeq, Illumina) and long-read (GridION, Oxford Nanopore Technologies) technologies in order to analyse in detail the genetic support and environment of cfr(D). Transfer of linezolid resistance from 15-307.1 to E. faecium BM4107 was attempted by filter-mating experiments. The recombinant plasmid pAT29Ωcfr(D), containing cfr(D) and its own promoter, was transferred to E. faecium HM1070, Enterococcus faecalis JH2-2 and Escherichia coli AG100A.ResultsAs previously reported, 15-307.1 belonged to ST17 and was phenotypically resistant to linezolid (MIC, 16 mg/L), vancomycin and teicoplanin. A hybrid sequencing approach confirmed the presence of several resistance genes including vanA, optrA and cfr(D). Located on a 103 kb plasmid, cfr(D) encoded a 357 amino acid protein, which shared 64%, 64%, 48% and 51% amino acid identity with Cfr, Cfr(B), Cfr(C) and Cfr(E), respectively. Both optrA and cfr(D) were successfully co-transferred to E. faecium BM4107. When expressed in E. faecium HM1070 and E. faecalis JH2-2, pAT29Ωcfr(D) did not confer any resistance, whereas it was responsible for an expected PhLOPSA resistance phenotype in E. coli AG100A. Analysis of the genetic environment of cfr(D) showed multiple IS1216 elements, putatively involved in its mobilization.ConclusionsCfr(D) is a novel member of the family of 23S rRNA methyltransferases. While only conferring a PhLOPSA resistance phenotype when expressed in E. coli, enterococci could constitute an unknown reservoir of cfr(D).
      PubDate: Sat, 11 Apr 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa125
      Issue No: Vol. 75, No. 7 (2020)
  • Linezolid resistance in Enterococcus faecium and Enterococcus faecalis
           from hospitalized patients in Ireland: high prevalence of the MDR genes
           optrA and poxtA in isolates with diverse genetic backgrounds
    • Authors: Egan S; Shore A, O’Connell B, et al.
      Pages: 1704 - 1711
      Abstract: AbstractObjectivesTo investigate the prevalence of the optrA, poxtA and cfr linezolid resistance genes in linezolid-resistant enterococci from Irish hospitals and to characterize associated plasmids.MethodsOne hundred and fifty-four linezolid-resistant isolates recovered in 14 hospitals between June 2016 and August 2019 were screened for resistance genes by PCR. All isolates harbouring resistance genes, and 20 without, underwent Illumina MiSeq WGS. Isolate relatedness was assessed using enterococcal whole-genome MLST. MinION sequencing (Oxford Nanopore) and hybrid assembly were used to resolve genetic environments/plasmids surrounding resistance genes.ResultsoptrA and/or poxtA were identified in 35/154 (22.7%) isolates, the highest prevalence reported to date. Fifteen isolates with diverse STs harboured optrA only; one Enterococcus faecium isolate harboured optrA (chromosome) and poxtA (plasmid). Seven Enterococcus faecalis and one E. faecium harboured optrA on a 36 331 bp plasmid with 100% identity to the previously described optrA-encoding conjugative plasmid pE349. Variations around optrA were also observed, with optrA located on plasmids in five isolates and within the chromosome in three isolates. Nine E. faecium and 10 E. faecalis harboured poxtA, flanked by IS1216E, within an identical 4001 bp region on plasmids exhibiting 72.9%–100% sequence coverage to a 21 849 bp conjugative plasmid. E. faecalis isolates belonged to ST480, whereas E. faecium isolates belonged to diverse STs. Of the remaining 119 linezolid-resistant isolates without linezolid resistance genes, 20 investigated representatives all harboured the G2576T 23S RNA gene mutation associated with linezolid resistance.ConclusionsThis high prevalence of optrA and poxtA in diverse enterococcal lineages in Irish hospitals indicates significant selective pressure(s) for maintenance.
      PubDate: Wed, 04 Mar 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa075
      Issue No: Vol. 75, No. 7 (2020)
  • Association between vancomycin-resistant Enterococcus faecium colonization
           and subsequent infection: a retrospective WGS study
    • Authors: Rubin I; Pedersen M, Mollerup S, et al.
      Pages: 1712 - 1715
      Abstract: AbstractBackgroundSince 2012, the incidence of vancomycin-resistant Enterococcus faecium (VREfm) has increased dramatically in Copenhagen and vanA E. faecium has become endemic and polyclonal.ObjectivesTo examine whether a patient with a positive VRE clinical sample had the same VREfm in a preceding screening sample (within 60 days).MethodsWe performed a 30 month retrospective study. From our laboratory information system (LIS), we identified all patients with an invasive VREfm isolate and a VREfm rectal screening isolate within 60 days before infection. VREfm pairs (screening isolate and invasive isolate) were whole-genome sequenced. All isolates were analysed using SeqSphere and core-genome MLST (cgMLST) types were determined. We examined all isolates for the presence of the three most dominant vanA plasmids in the Capital Region of Denmark. Two novel vanA plasmids were closed by Nanopore/Illumina sequencing.ResultsWe found a total of 19 VREfm pairs. Of these, 13 patients had pairs with matching cgMLST types and vanA plasmids and a median number of 6 days from identification of carriage to clinical infection. One patient had a pair with non-matching cgMLST types but matching vanA plasmids and 24 days between identification of carriage to clinical infection. Five patients had pairs with non-matching cgMLST types and non-matching vanA plasmids and a median number of 18 days from identification of carriage to clinical infection.ConclusionsOf our 19 pairs, 13 were a match regarding cgMLST types (68%) and 1 more (5%) had matching vanA plasmids. Infection was thus preceded by colonization with the same isolates in 13 out of 19 patients. The five mismatches (26%) could be explained by the longer interval between colonization and infection.
      PubDate: Tue, 03 Mar 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa074
      Issue No: Vol. 75, No. 7 (2020)
  • Challenges in interpretation of WGS and epidemiological data to
           investigate nosocomial transmission of vancomycin-resistant Enterococcus
           faecium in an endemic region: incorporation of patient movement network
           and admission screening
    • Authors: Eichel V; Klein S, Bootsveld C, et al.
      Pages: 1716 - 1721
      Abstract: AbstractObjectivesVRE are listed, by the WHO, among the leading resistant pathogens causing greatest public concern; hence the spread and transmission of VRE, especially in hospitalized patients, need to be monitored. Despite the advancements in typing methods since the implementation of WGS for outbreak investigations, data interpretation, especially for vancomycin-resistant Enterococcus faecium (VREfm) in an endemic setting, remains challenging. In this study we explored the potential added benefit of incorporating patient movement data and admission screening to accurately estimate the magnitude of an outbreak.MethodsWe sequenced 73 VREfm isolates from patients with bacteraemia (n = 43) and rectal colonization (n = 30/32). Genetic relatedness was determined by SNP distance (≤10) between isolates. Patient movements were visualized in a movement network, along with contact intensity and rectal colonization status prior to infection onset.ResultsST117, ST80 and ST203 were the predominant STs in our study population. Forty-four percent (18/41) of VREfm bacteraemia cases were of endogenous origin. SNP analysis of infection and colonization isolates revealed nine clonal groups. Eighty-six percent (37/43) of the patients were visualized in a transmission network due to spatiotemporal overlap. Nineteen out of 43 (44%) belonged to five transmission clusters. Incorporation of prior colonization status revealed that transmission was very likely in only 63% (12/19) of patients in these transmission clusters.DiscussionAlthough interpretation of WGS data is challenging, incorporation of patient movement data and colonization status by admission screening of high-risk patients may provide additional resolution when interpreting the magnitude of an outbreak in an endemic setting.
      PubDate: Fri, 15 May 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa122
      Issue No: Vol. 75, No. 7 (2020)
  • Bacterial population kinetics in heteroresistant Mycobacterium
           tuberculosis harbouring rare resistance-conferring mutations in gyrA and
           rpoB imply an epistatic interaction of mutations in a pre-XDR-TB patient
    • Authors: Yoshida S; Iwamoto T, Arikawa K, et al.
      Pages: 1722 - 1725
      Abstract: AbstractObjectivesBacterial population kinetics of strains harbouring drug resistance-conferring mutations within a patient often show cryptic resistance in clinical practice. We report a case that showed emergence and dominance of Mycobacterium tuberculosis with uncommon rpoB and gyrA mutations, followed by an rpoC compensatory mutation, during treatment.MethodsA pre-XDR-TB patient showed heteroresistance to rifampicin and levofloxacin during treatment as a result of intermittent self-cessation. WGS was applied to investigate intra-host strain composition using five pairs of isolates from sputum samples.ResultsThe subclone in this study possessed rare mutations conferring resistance to rifampicin (rpoB V170F) and levofloxacin (gyrA S91P) and it rapidly outcompeted other subclones during treatment that included levofloxacin but not rifampicin (<7 days). The high-probability compensatory mutation rpoC V483A also emerged and became dominant subsequent to the rpoB V170F mutation.ConclusionsTo the best of our knowledge, this is the first case showing the emergence of such a rare variant that dominated the population within a patient during treatment of TB.
      PubDate: Fri, 17 Apr 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa109
      Issue No: Vol. 75, No. 7 (2020)
  • Genomic characterization of 16S rRNA methyltransferase-producing
           Escherichia coli isolates from the Parisian area, France
    • Authors: Caméléna F; Morel F, Merimèche M, et al.
      Pages: 1726 - 1735
      Abstract: AbstractBackgroundThe resistance to all aminoglycosides (AGs) conferred by 16S rRNA methyltransferase enzymes (16S-RMTases) is a major public health concern.ObjectivesTo characterize the resistance genotype, its genetic environment and plasmid support, and the phylogenetic relatedness of 16S-RMTase-producing Escherichia coli from France.MethodsWe screened 137 E. coli isolates resistant to all clinically relevant AGs from nine Parisian hospitals for 16S-RMTases. WGS was performed on clinical isolates with high-level AG resistance (MIC ≥256 mg/L) and their transformants.ResultsThirty of the 137 AG-resistant E. coli produced 16S-RMTases: 11 ArmA, 18 RmtB and 1 RmtC. The 16S-RMTase producers were also resistant to third-generation cephalosporins (90% due to a blaCTX-M gene), co-trimoxazole, fluoroquinolones and carbapenems (blaNDM and blaVIM genes) in 97%, 83%, 70% and 10% of cases, respectively. Phylogenomic diversity was high in ArmA producers, with 10 different STs, but a similar genetic environment, with the Tn1548 transposon carried by a plasmid closely related to pCTX-M-3 in 6/11 isolates. Conversely, RmtB producers belonged to 12 STs, the most frequent being ST405 and ST complex (STc) 10 (four and four isolates, respectively). The rmtB gene was carried by IncF plasmids in 10 isolates and was found in different genetic environments. The rmtC gene was carried by the pNDM-US plasmid.ConclusionsArmA and RmtB are the predominant 16S-RMTases in France, but their spread follows two different patterns: (i) dissemination of a conserved genetic support carrying armA in E. coli with high levels of genomic diversity; and (ii) various genetic environments surrounding rmtB in clonally related E. coli.
      PubDate: Thu, 16 Apr 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa105
      Issue No: Vol. 75, No. 7 (2020)
  • Characterization of Klebsiella pneumoniae isolates from a
           mother–child cohort in Madagascar
    • Authors: Rakotondrasoa A; Passet V, Herindrainy P, et al.
      Pages: 1736 - 1746
      Abstract: AbstractObjectivesTo define characteristics of Klebsiella pneumoniae isolated from carriage and infections in mothers and their neonates belonging to a paediatric cohort in Madagascar.MethodsA total of 2000 mothers and their 2001 neonates were included. For each mother, vaginal and stool samples were collected at the birth. Additionally, upon suspicion of infection, samples were collected from suspected infected body sites in 121 neonates. Genomic sequences of all isolated K. pneumoniae were used for phylogenetic analyses and to investigate the genomic content of antimicrobial resistance genes, virulence genes and plasmid replicon types.ResultsFive percent (n = 101) of mothers were K. pneumoniae positive. Of 251 collected K. pneumoniae isolates, 102 (40.6%) were from mothers and 149 (59.3%) were from neonates. A total of 49 (19.5%; all from infants except 1) isolates were from infected body sites. MLST identified 108 different STs distributed over the six K. pneumoniae phylogroups Kp1 to Kp6. We found 65 (25.8%) ESBL producers and a total of 101 (40.2%) MDR isolates. The most common ESBL gene was blaCTX-M-15 (in 99.3% of isolates expressing ESBL). One isolate co-harboured blaCTX-M-15 and blaNDM-1 genes. Three isolates from infected body sites belonged to hypervirulent-associated ST23 (n = 1) and ST25 (n = 2). We observed two cases of mother-to-child transmission and sustained K. pneumoniae carriage was identified in 10 neonates, with identical isolates observed longitudinally over the course of 18 to 115 days.ConclusionsThis study revealed substantial genetic diversity and a high rate of antimicrobial resistance among K. pneumoniae isolated from both carriage and infections in Madagascar.
      PubDate: Fri, 17 Apr 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa107
      Issue No: Vol. 75, No. 7 (2020)
  • RNA markers for ultra-rapid molecular antimicrobial susceptibility testing
           in fluoroquinolone-treated Klebsiella pneumoniae
    • Authors: Yang X; Hashemi M, Andini N, et al.
      Pages: 1747 - 1755
      Abstract: AbstractObjectivesTraditional antimicrobial susceptibility testing (AST) is growth dependent and time-consuming. With rising rates of drug-resistant infections, a novel diagnostic method is critically needed that can rapidly reveal a pathogen’s antimicrobial susceptibility to guide appropriate treatment. Recently, RNA sequencing has been identified as a powerful diagnostic tool to explore transcriptional gene expression and improve AST.MethodsRNA sequencing was used to investigate the potential of RNA markers for rapid molecular AST using Klebsiella pneumoniae and ciprofloxacin as a model. Downstream bioinformatic analysis was applied for optimal marker selection. Further validation on 11 more isolates of K. pneumoniae was performed using quantitative real-time PCR.ResultsFrom RNA sequencing, we identified RNA signatures that were induced or suppressed following exposure to ciprofloxacin. Significant shifts at the transcript level were observed as early as 10 min after antibiotic exposure. Lastly, we confirmed marker expression profiles with concordant MIC results from traditional culture-based AST and validated across 11 K. pneumoniae isolates. recA, coaA and metN transcripts harbour the most sensitive susceptibility information and were selected as our top markers.ConclusionsOur results suggest that RNA signature is a promising approach to AST development, resulting in faster clinical diagnosis and treatment of infectious disease. This approach is potentially applicable in other models including other pathogens exposed to different classes of antibiotics.
      PubDate: Thu, 19 Mar 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa078
      Issue No: Vol. 75, No. 7 (2020)
  • Global clonal spread of mcr-3-carrying MDR ST34 Salmonella enterica
           serotype Typhimurium and monophasic 1,4,[5],12:i:− variants from
           clinical isolates
    • Authors: Sun R; Ke B, Fang L, et al.
      Pages: 1756 - 1765
      Abstract: AbstractObjectivesTo investigate the prevalence and transmission of mcr-3 among Salmonella enterica serotype Typhimurium and 1,4,[5],12:i:−.MethodsA total of 4724 clinical Salmonella isolates were screened for the presence of mcr-3 in China during 2014–19. The clonal relationship of the mcr-3-positive isolates and their plasmid contents and complete sequence were also characterized based on WGS data from the Illumina and MinION platforms.ResultsWe identified 10 mcr-3-positive isolates, and all were MDR, mostly resistant to colistin, cefotaxime, ciprofloxacin, doxycycline and florfenicol. mcr-3 was co-present with blaCTX-M-55-qnrS1 on hybrid ST3-IncC-FII conjugatable plasmids (n = 6) and an ST3-IncC non-conjugatable plasmid (n = 1) and embedded into a pCHL5009T-like IncFII plasmid on the Salmonella chromosome (n = 3). Four distinctive genetic contexts surrounded mcr-3 and all but one were closely related to each other and to the corresponding region of IncFII plasmid pCHL5009T. IS15DI was most likely the vehicle for integration of mcr-3-carrying IncFII plasmids into ST3-IncC plasmids and the chromosome and for shaping the MDR regions. In addition, a phylogenetic tree based on the core genome revealed a unique Salmonella lineage (≤665 SNPs) that contained these 10 mcr-3-positive isolates and another 38 (33 from patients) mcr-3-positive Salmonella from five countries. In particular, most of the 51 mcr-3-positive isolates belonged to ST34 and harboured diverse antibiotic resistance genes (ARGs), including mcr-3-blaCTX-M-55-qnrS1, and possessed similar ARG profiles.ConclusionsOur findings revealed global clonal spread of MDR ST34 Salmonella from clinical isolates co-harbouring mcr-3 with blaCTX-M-55 and qnrS1 and a flexibility of mcr-3 co-transmittance with other ARGs mediated by mobile genetic elements.
      PubDate: Fri, 10 Apr 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa115
      Issue No: Vol. 75, No. 7 (2020)
  • Impact of the first-line treatment shift from
           dihydroartemisinin/piperaquine to artesunate/mefloquine on Plasmodium
           vivax drug susceptibility in Cambodia
    • Authors: Roesch C; Mairet-Khedim M, Kim S, et al.
      Pages: 1766 - 1771
      Abstract: AbstractBackgroundCambodia is the epicentre of the emergence of Plasmodium falciparum drug resistance. Much less is known regarding the drug susceptibility of the co-endemic Plasmodium vivax. Only in vitro drug assays can determine the parasite’s intrinsic susceptibility, but these are challenging to implement for P. vivax and rarely performed.ObjectivesTo evaluate the evolution of Cambodian P. vivax susceptibility to antimalarial drugs and determine their association with putative markers of drug resistance.MethodsIn vitro response to three drugs used in the past decade in Cambodia was measured for 52 clinical isolates from Eastern Cambodia collected between 2015 and 2018 and the sequence and copy number variation of their pvmdr1 and pvcrt genes were analysed. pvmdr1 polymorphism was also determined for an additional 250 isolates collected in Eastern Cambodia between 2014 and 2019.ResultsAmong the 52 cryopreserved isolates tested, all were susceptible to the three drugs, with overall median IC50s of 16.1 nM (IQR 11.4–22.3) chloroquine, 3.4 nM (IQR 2.1–5.0) mefloquine and 4.6 nM (IQR 2.7–7.0) piperaquine. A significant increase in chloroquine and piperaquine susceptibility was observed between 2015 and 2018, unrelated to polymorphisms in pvcrt and pvmdr1. Susceptibility to mefloquine was significantly lower in parasites with a single mutation in pvmdr1 compared with isolates with multiple mutations. The proportion of parasites with this single mutation genotype increased between 2014 and 2019.ConclusionsP. vivax with decreased susceptibility to mefloquine is associated with the introduction of mefloquine-based treatment during 2017–18.
      PubDate: Tue, 24 Mar 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa092
      Issue No: Vol. 75, No. 7 (2020)
  • Development and validation of a UHPLC-MS/MS method for quantification of
           the prodrug remdesivir and its metabolite GS-441524: a tool for clinical
           pharmacokinetics of SARS-CoV-2/COVID-19 and Ebola virus disease
    • Authors: Avataneo V; de Nicolò A, Cusato J, et al.
      Pages: 1772 - 1777
      Abstract: AbstractBackgroundRemdesivir has received significant attention for its potential application in the treatment of COVID-19, caused by SARS-CoV-2. Remdesivir has already been tested for Ebola virus disease treatment and found to have activity against SARS and MERS coronaviruses. The remdesivir core contains GS-441524, which interferes with RNA-dependent RNA polymerases alone. In non-human primates, following IV administration, remdesivir is rapidly distributed into PBMCs and converted within 2 h to the active nucleoside triphosphate form, while GS-441524 is detectable in plasma for up to 24 h. Nevertheless, remdesivir pharmacokinetics and pharmacodynamics in humans are still unexplored, highlighting the need for a precise analytical method for remdesivir and GS-441524 quantification.ObjectivesThe validation of a reliable UHPLC-MS/MS method for remdesivir and GS-441524 quantification in human plasma.MethodsRemdesivir and GS-441524 standards and quality controls were prepared in plasma from healthy donors. Sample preparation consisted of protein precipitation, followed by dilution and injection into the QSight 220 UHPLC-MS/MS system. Chromatographic separation was obtained through an Acquity HSS T3 1.8 μm, 2.1 × 50 mm column, with a gradient of water and acetonitrile with 0.05% formic acid. The method was validated using EMA and FDA guidelines.ResultsAnalyte stability has been evaluated and described in detail. The method successfully fulfilled the validation process and it was demonstrated that, when possible, sample thermal inactivation could be a good choice in order to improve biosafety.ConclusionsThis method represents a useful tool for studying remdesivir and GS-441524 clinical pharmacokinetics, particularly during the current COVID-19 outbreak.
      PubDate: Sun, 03 May 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa152
      Issue No: Vol. 75, No. 7 (2020)
  • Identification of gp120 polymorphisms in HIV-1 B subtype potentially
           associated with resistance to fostemsavir
    • Authors: Bouba Y; Berno G, Fabeni L, et al.
      Pages: 1778 - 1786
      Abstract: AbstractObjectivesWe evaluated natural resistance to the new antiretroviral fostemsavir and its potential association with other HIV-1 gp120 polymorphisms.MethodsA total of 1997 HIV-1 B subtype gp120 sequences from the Los Alamos HIV Database were analysed for mutation prevalence at fostemsavir resistance-associated positions and potential association with other gp120 polymorphisms. The role of each fostemsavir resistance-related position and the correlated gp120 mutations, both in protein stability and in reducing the binding affinity between antibody and/or T cell lymphocyte epitopes and the MHC molecules, was estimated.ResultsThe prevalence of fostemsavir resistance mutations was as follows: L116Q (0.05%), S375H/M/T (0.55%/1.35%/17.73%, the latter being far less relevant in determining resistance), M426L (7.56%), M434I (4.21%) and M475I (1.65%). Additionally, the M426R polymorphism had a prevalence of 16.32%. A significantly higher prevalence in X4 viruses versus R5 viruses was found only for S375M (0.69% versus 3.93%, P = 0.009) and S375T (16.60% versus 22.11%, P = 0.030). Some fostemsavirv resistance positions positively and significantly correlated with specific gp120 polymorphisms: S375T with I371V; S375M with L134W, I154V and I323T; M475I with K322A; and M426R with G167N, K192T and S195N. The topology of the dendrogram suggested the existence of three distinct clusters (bootstrap ≥0.98) involving these fostemsavir resistance mutations and gp120 polymorphisms. Interestingly, all clustered mutations are localized in class I/II-restricted T cell/antibody epitopes, suggesting a potential role in immune HIV escape.ConclusionsA low prevalence of known fostemsavir resistance mutations was found in the HIV-1 B subtype. The detection of novel HIV-1 gp120 polymorphisms potentially relevant for fostemsavir resistance deserves new in-depth in vitro investigations.
      PubDate: Wed, 11 Mar 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa073
      Issue No: Vol. 75, No. 7 (2020)
  • The effect of N-acetylcysteine in a combined antibiofilm treatment against
           antibiotic-resistant Staphylococcus aureus
    • Authors: Manoharan A; Das T, Whiteley G, et al.
      Pages: 1787 - 1798
      Abstract: AbstractBackgroundThe WHO declared Staphylococcus aureus as a ‘pathogen of high importance’ in 2017. One-fifth of all bloodstream-related infections in Australia and 12 000 cases of bacteraemia in the UK (2017–18) were caused by the MRSA variant. To address the need for novel therapies, we investigated several permutations of an innovative combination therapy containing N-acetylcysteine (NAC), an antibiotic and an enzyme of choice in eradicating MRSA and MSSA biofilms.MethodsBiofilm viability (resazurin assay) and colony count methods were used to investigate the effect of NAC, antibiotics and enzymes on S. aureus biofilm disruption and killing. The effects of NAC and enzymes on the polysaccharide content of biofilm matrices were analysed using the phenol/sulphuric acid method and the effect of NAC on DNA cleavage was determined using the Qubit fluorometer technique. Changes in biofilm architecture when subjected to NAC and enzymes were visualized using confocal laser scanning microscopy (CLSM).ResultsNAC alone displayed bacteriostatic effects when tested on planktonic bacterial growth. Combination treatments containing 30 mM NAC resulted in ≥90% disruption of biofilms across all MRSA and MSSA strains with a 2–3 log10 decrease in cfu/mL in treated biofilms. CLSM showed that NAC treatment drastically disrupted S. aureus biofilm architecture. There was also reduced polysaccharide production in MRSA biofilms in the presence of NAC.ConclusionsOur results indicate that inclusion of NAC in a combination treatment is a promising strategy for S. aureus biofilm eradication. The intrinsic acidity of NAC was identified as key to maximum biofilm disruption and degradation of matrix components.
      PubDate: Sun, 03 May 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa093
      Issue No: Vol. 75, No. 7 (2020)
  • A multicentre study to optimize echinocandin susceptibility testing of
           Aspergillus species with the EUCAST methodology and a broth microdilution
           colorimetric method
    • Authors: Meletiadis J; Siopi M, Kanioura L, et al.
      Pages: 1799 - 1806
      Abstract: AbstractBackgroundThe determination of the minimal effective concentration (MEC) of echinocandins against Aspergillus species is subjective, time consuming and has been associated with very major errors.MethodsThe MECs/MICs of 40 WT [10 each of Aspergillus fumigatus species complex (SC), Aspergillus flavus SC, Aspergillus terreus SC and Aspergillus niger SC] and 4 non-WT A. fumigatus isolates were determined with EUCAST E.Def 9.3.1 read microscopically, macroscopically, spectrophotometrically and colorimetrically in three centres. The optimal conditions for spectrophotometric (single- versus multi-point readings) and colorimetric (XTT/menadione concentration and stability, incubation time) methods were evaluated in preliminary studies using different cut-offs for the determination of macroscopic, spectrophotometric and colorimetric MIC endpoints compared with the microscopically determined MEC. Inter-centre and inter-method essential (within one 2-fold dilution) agreement (EA) and categorical agreement (CA) were determined.ResultsBoth macroscopic and spectrophotometric endpoint readings showed poor inter-centre EA (53%–66%) and low CA (41%–88%) in distinguishing WT from non-WT A. fumigatus SC isolates, while significant differences compared with the microscopic MECs were observed for all echinocandins (EA 6%–54%). For the colorimetric method, the optimal conditions were 400 mg/L XTT/6.25 μΜ menadione, incubation for 1–2 h until the drug-free control reached an absorbance at 450/630 nm of >0.8 and use of 50% inhibition of XTT conversion as a cut-off for all species and echinocandins. All non-WT isolates had high XTT MICs >1 mg/L, whereas the overall inter-centre EA and CA were 72%–89% and 100%, respectively.ConclusionsThe XTT colorimetric assay improved the antifungal susceptibility testing of echinocandins against Aspergillus spp., reliably detecting non-WT isolates.
      PubDate: Fri, 24 Apr 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa102
      Issue No: Vol. 75, No. 7 (2020)
  • Multicentre validation of a EUCAST method for the antifungal
           susceptibility testing of microconidia-forming dermatophytes
    • Authors: Arendrup M; Jørgensen K, Guinea J, et al.
      Pages: 1807 - 1819
      Abstract: AbstractObjectivesTerbinafine resistance is increasingly reported in Trichophyton, rendering susceptibility testing particularly important in non-responding cases. We performed a multicentre evaluation of six EUCAST-based methods.MethodsTen laboratories susceptibility tested terbinafine, itraconazole, voriconazole and amorolfine against a blinded panel of 38 terbinafine WT and target gene mutant isolates. E.Def 9.3.1 modifications included: medium with/without addition of chloramphenicol and cycloheximide (CC), incubation at 25°C to 28°C for 5–7 days and three MIC endpoints [visually and spectrophotometrically (90%/50% inhibition)], generating 7829 MICs. Quality control (QC) strains were Aspergillus flavus ATCC 204304 and CNM-CM1813. Eyeball, ECOFFinder (where ECOFF stands for epidemiological cut-off) and derivatization WT upper limits (WT-ULs), very major errors (VMEs; mutants with MICs ≤WT-ULs) and major errors (MEs; WT isolates with MICs >WT-ULs) were determined.ResultsMICs fell within the QC ranges for ATCC 204304/CNM-CM1813 for 100%/96% (voriconazole) and 84%/84% (itraconazole), respectively. Terbinafine MICs fell within 0.25–1 mg/L for 96%/92%, suggesting high reproducibility. Across the six methods, the number of terbinafine MEs varied from 2 to 4 (2.6%–5.2%) for Trichophyton rubrum and from 0 to 2 (0%–2.0%) for Trichophyton interdigitale. Modes for WT and mutant populations were at least seven 2-fold dilutions apart in all cases. Excluding one I121M/V237I T. rubrum mutant and two mixed WT/mutant T. interdigitale specimens, the numbers of VMEs were as follows: T. rubrum: CC visual, 1/67 (1.5%); CC spectrophotometric 90% inhibition, 3/59 (5.1%); and CC spectrophotometric 50% inhibition, 1/67 (1.5%); and T. interdigitale: none. Voriconazole and amorolfine MICs were quite uniform, but trailing growth complicated determination of itraconazole visual and spectrophotometric 90% inhibition MIC.ConclusionsAlthough none of the laboratories was experienced in dermatophyte testing, error rates were low. We recommend the CC spectrophotometric 50% inhibition method and provide QC ranges and WT-ULs for WT/non-WT classification.
      PubDate: Fri, 17 Apr 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa111
      Issue No: Vol. 75, No. 7 (2020)
  • Azithromycin susceptibility testing for Salmonella enterica isolates:
           discordances in results using MIC gradient strips
    • Authors: Goldblatt J; Ward A, Yusuf M, et al.
      Pages: 1820 - 1823
      Abstract: AbstractBackgroundAzithromycin resistance is emerging in typhoidal Salmonella. Confirmation of azithromycin MIC is the most frequent antibiotic susceptibility request made to the Gastrointestinal Bacteria Reference Unit (GBRU) laboratory in England by local diagnostic laboratories.Objectives(i) Determine concordance between local diagnostic and reference laboratory estimations of azithromycin MIC by gradient strip in Salmonella enterica serovars Typhi and Paratyphi. (ii) Consider causes of variation.MethodsIsolates from patients with enteric fever attending a central London hospital between May 2011 and April 2019 were tested for azithromycin susceptibility using gradient strips, according to EUCAST methodology. Matched local diagnostic and reference laboratory estimations of azithromycin and ciprofloxacin (as a comparator) MICs were included; concordance in estimations was examined.ResultsLocal diagnostic laboratory readings overestimated azithromycin MIC values compared with the reference laboratory, resulting in poor concordance in susceptibility/resistance attribution (concordant susceptibility interpretation in 8/19, κ = 0). In contrast, ciprofloxacin MIC estimation demonstrated superior concordance (concordant susceptibility interpretation in 16/17, κ = 0.85). None of the isolates was resistant to azithromycin at the reference laboratory and no known genes associated with azithromycin resistance were detected in any isolate using WGS.ConclusionsOverestimation of azithromycin resistance is likely to be due to difficulty in interpreting the point of intersection of the ‘trailing edge’ with the gradient strip, used to determine MIC. We advise local diagnostic laboratories to review their experience and consider adopting a ‘second reader’ system to mitigate this.
      PubDate: Sat, 28 Mar 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa097
      Issue No: Vol. 75, No. 7 (2020)
  • Antimicrobial susceptibility of Clostridioides difficile isolated from
           diarrhoeal stool specimens of Canadian patients: summary of results from
           the Canadian Clostridioides difficile (CAN-DIFF) surveillance study from
           2013 to 2017
    • Authors: Karlowsky J; Adam H, Baxter M, et al.
      Pages: 1824 - 1832
      Abstract: AbstractObjectivesTo summarize data generated by the Canadian Clostridioides difficile (CAN-DIFF) surveillance study from 2013 to 2017.MethodsIsolates of C. difficile (n = 2158) were cultured from toxin-positive diarrhoeal stool specimens submitted by eight hospital laboratories to a coordinating laboratory. Antimicrobial susceptibility testing was performed according to the CLSI agar dilution method (M11, 2018). Isolate ribotypes were determined using an international, standardized, high-resolution capillary gel-based electrophoresis protocol.ResultsOf the 2158 isolates of C. difficile, 2133 (98.8%) had vancomycin MICs ≤2 mg/L [i.e. were vancomycin susceptible (EUCAST breakpoint tables, v 9.0, 2019) or WT (CLSI M100, 29th edition, 2019)]. Fidaxomicin MICs were lower than those of all other agents tested (MIC90, 0.5 mg/L); however, one isolate with a fidaxomicin MIC of >8 mg/L was identified. Metronidazole MICs ranged from 0.12 to 4 mg/L; all isolates were metronidazole susceptible by the CLSI breakpoint (≤8 mg/L) compared with 96.8% susceptible by the EUCAST breakpoint (≤2 mg/L). In total, 182 different ribotypes were identified from 2013 to 2017. The most common ribotypes identified were 027 (19.3% of isolates) and 106 (8.2%). Ribotype 027 isolates were frequently moxifloxacin resistant (87.3% of isolates) and MDR (48.6%), associated with vancomycin (10/25, 40.0%) and metronidazole (58/69, 84.1%) resistance and from patients aged ≥80 years. The prevalence of ribotype 027 decreased significantly (P < 0.0001) from 2013 (27.5%) to 2017 (9.0%) and was replaced by increases in ribotype 106 (P = 0.0003) and multiple less common ribotypes.ConclusionsPeriodic surveillance is required to monitor clinical isolates of C. difficile for changes to in vitro susceptibility testing profiles and ribotype evolution.
      PubDate: Wed, 15 Apr 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa118
      Issue No: Vol. 75, No. 7 (2020)
  • In vitro activity of sulbactam/durlobactam against clinical isolates of
           Acinetobacter baumannii collected in China
    • Authors: Yang Q; Xu Y, Jia P, et al.
      Pages: 1833 - 1839
      Abstract: AbstractBackgroundDurlobactam is a broad-spectrum inhibitor of class A, C and D β-lactamases. Sulbactam is a generic β-lactam most commonly used as a β-lactamase inhibitor in combination with ampicillin; however, it has a unique property in that it has selective intrinsic activity against Acinetobacter baumannii. Currently, there is widespread resistance caused by multiple β-lactamases including class A carbapenemases and class C and class D enzymes. The addition of durlobactam to sulbactam restores in vitro activity against MDR A. baumannii that possess multiple β-lactamases.ObjectivesPreviously, susceptibility data for sulbactam/durlobactam were limited to isolates from patients in Western countries. This study was undertaken to determine the activity of sulbactam/durlobactam against A. baumannii isolated from patients in mainland China.MethodsNine hundred and eighty-two recent A. baumannii clinical isolates were collected from 22 sites across mainland China during 2016–18. The isolates were collected from lower respiratory tract, intra-abdominal, urinary tract and skin and skin structure infections. The in vitro activities of sulbactam/durlobactam and comparators were determined by broth microdilution.ResultsThe addition of durlobactam restored the activity of sulbactam against the majority of the strains tested. The MIC90 of sulbactam/durlobactam was 2 mg/L for all A. baumannii, compared with 64 mg/L for sulbactam alone. The MIC90 of sulbactam/durlobactam of 2 mg/L remained unchanged for 831 carbapenem-resistant isolates. Colistin was the only comparator with comparable activity (MIC90 = 1 mg/L).ConclusionsThis study demonstrated the potential utility of sulbactam/durlobactam for the treatment of infections caused by A. baumannii in China.
      PubDate: Sun, 19 Apr 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa119
      Issue No: Vol. 75, No. 7 (2020)
  • Activity of cefiderocol against high-risk clones of multidrug-resistant
           Enterobacterales, Acinetobacter baumannii, Pseudomonas aeruginosa and
           Stenotrophomonas maltophilia
    • Authors: Delgado-Valverde M; Conejo M, Serrano L, et al.
      Pages: 1840 - 1849
      Abstract: AbstractBackgroundCefiderocol is a novel siderophore cephalosporin, developed for activity against MDR Gram-negative bacilli (MDR-GNB).ObjectivesTo assess the in vitro antibacterial activity of cefiderocol against a collection of MDR-GNB clinical isolates from hospitals in southern Spain.MethodsTwo hundred and thirty-one isolates of successful clones were tested: 125 Enterobacterales (121 ESBL- and/or carbapenemase-producing Klebsiella pneumoniae and 4 carbapenemase-producing Enterobacter cloacae), 80 Acinetobacter baumannii, 6 Pseudomonas aeruginosa and 20 Stenotrophomonas maltophilia. Ceftolozane/tazobactam, ceftazidime, ceftazidime/avibactam, cefepime, aztreonam, meropenem, amikacin, ciprofloxacin, colistin and tigecycline were used as comparators against Enterobacterales, P. aeruginosa and A. baumannii. Minocycline, levofloxacin and trimethoprim/sulfamethoxazole were studied against S. maltophilia instead of aztreonam, ciprofloxacin and cefepime. MICs were determined by broth microdilution according to CLSI guidelines. MIC determination was performed in CAMHB for all antimicrobials except cefiderocol, where iron-depleted CAMHB was used.ResultsCefiderocol showed potent in vitro activity against the isolates analysed. MIC50 and MIC90 values were in the ranges 0.125–8 mg/L and 0.5–8 mg/L, respectively, and 98% of isolates were inhibited at ≤4 mg/L. Only five isolates showed cefiderocol MICs of >4 mg/L: three ST2/OXA-24/40-producing A. baumannii, one ST114/VIM-1-producing E. cloacae and one ST114/VIM-1 + OXA-48-producing E. cloacae. All KPC-3-producing K. pneumoniae were susceptible to cefiderocol, even those resistant to ceftazidime/avibactam. P. aeruginosa isolates showed cefiderocol MICs of <4 mg/L, including those resistant to ceftolozane/tazobactam. S. maltophilia isolates displayed cefiderocol MICs of <4 mg/L, including those resistant to levofloxacin and/or trimethoprim/sulfamethoxazole.ConclusionsCefiderocol showed excellent activity against MDR-GNB, including carbapenem-resistant isolates, and was the most active antimicrobial tested against this collection.
      PubDate: Sat, 11 Apr 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa117
      Issue No: Vol. 75, No. 7 (2020)
  • In vitro activity of the novel β-lactamase inhibitor taniborbactam
           (VNRX-5133), in combination with cefepime or meropenem, against MDR
           Gram-negative bacterial isolates from China
    • Authors: Wang X; Zhao C, Wang Q, et al.
      Pages: 1850 - 1858
      Abstract: AbstractObjectivesTo evaluate in vitro activity of the novel β-lactamase boronate inhibitor taniborbactam (VNRX-5133) combined with cefepime or meropenem against 500 urinary Gram-negative bacilli.MethodsCefepime/taniborbactam and 14 comparators were tested by broth microdilution or agar dilution methods. A total of 450 Enterobacteriaceae and 50 Pseudomonas aeruginosa were selected from 2017 to 2019 based on different β-lactamase-producing or resistance phenotypes. For carbapenem-non-susceptible isolates, the modified carbapenem inactivation method (mCIM), EDTA-CIM (eCIM) and amplification of carbapenemase genes were performed. For NDM-producing isolates and those with cefepime/taniborbactam MICs >8 mg/L, the MICs of meropenem/taniborbactam and/or mutations in PBP3 were investigated.ResultsTaniborbactam improved cefepime activity with the same efficiency as avibactam improved ceftazidime activity against 66 KPC-2 producers, 30 non-carbapenemase-producing carbapenem-non-susceptible Enterobacteriaceae and 28 meropenem-susceptible P. aeruginosa. However, cefepime/taniborbactam exhibited more potent activity than ceftazidime/avibactam against 56 ESBL-producing, 61 AmpC-producing, 32 ESBL and AmpC co-producing, 87 NDM-producing and 21 MBL-producing Enterobacteriaceae predicted by phenotypic mCIM and eCIM, 82 Enterobacteriaceae that were susceptible to all tested β-lactams and 22 carbapenem-non-susceptible P. aeruginosa. A four-amino acid ‘INYR’ or ‘YRIN’ insertion, with or without a one/two-amino acid mutation in PBP3, may have caused cefepime/taniborbactam MICs >8 mg/L among 96.6% (28/29) of the NDM-5-producing Escherichia coli, which accounted for the majority of isolates with cefepime/taniborbactam MICs >8 mg/L (76.1%, 35/46).ConclusionsTaniborbactam’s superior breadth of activity, when paired with cefepime or meropenem, suggests these β-lactam/β-lactamase inhibitor combinations could be promising candidates for treating urinary tract infections caused by ESBL and/or AmpC, KPC or NDM-producing Enterobacteriaceae or P. aeruginosa.
      PubDate: Tue, 10 Mar 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa053
      Issue No: Vol. 75, No. 7 (2020)
  • In vitro activity of ceftazidime/avibactam and comparators against
           Gram-negative bacterial isolates collected from Latin American centres
           between 2015 and 2017
    • Authors: Stone G; Ponce-de-Leon A.
      Pages: 1859 - 1873
      Abstract: AbstractObjectivesWe report the in vitro activity of ceftazidime/avibactam and comparators against 7729 Enterobacterales isolates and 2053 Pseudomonas aeruginosa isolates collected from six Latin American countries between 2015 and 2017.MethodsA central reference laboratory performed antimicrobial susceptibility testing using broth microdilution panels according to CLSI guidelines. The presence of β-lactamases was confirmed using multiplex PCR assays.ResultsSusceptibility rates among Enterobacterales were highest for ceftazidime/avibactam (99.3%, MIC90 = 0.5 mg/L), meropenem (95.4%, MIC90 = 0.12 mg/L) and amikacin (93.5%, MIC90 = 8 mg/L). High susceptibility rates were observed for ceftazidime/avibactam in all six countries. The majority of carbapenemase-positive isolates among Enterobacterales (N = 366, 4.7%) were susceptible to ceftazidime/avibactam (86.9%), colistin (76.8%) and amikacin (60.9%); MBL-positive isolates (N = 49, 0.6%) were susceptible only to colistin (79.6%), with a minority susceptible to amikacin (49.0%), aztreonam and levofloxacin (both 30.6%). Highest rates of susceptibility among P. aeruginosa isolates were for colistin (99.2%) and ceftazidime/avibactam (86.6%), with rates of susceptibility to all other agents being <80.0%. MDR P. aeruginosa isolates (N = 712, 34.7%) had a high rate of susceptibility to colistin (98.9%); the rate of susceptibility to ceftazidime/avibactam was 61.4% and <50.0% to all other comparator agents. A total of 235 (11.4%) isolates of P. aeruginosa were carbapenemase positive and 148 (7.2%) were MBL positive; both subsets had high rates of susceptibility to colistin (98.3% and 100%, respectively).ConclusionsCeftazidime/avibactam susceptibility rates in Latin American countries are stable and high; ceftazidime/avibactam can be an appropriate treatment for patients with infections caused by Enterobacterales or P. aeruginosa and for whom treatment options may be limited.
      PubDate: Sat, 11 Apr 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa089
      Issue No: Vol. 75, No. 7 (2020)
  • In vitro synergy of ceftolozane/tazobactam in combination with fosfomycin
           or aztreonam against MDR Pseudomonas aeruginosa
    • Authors: Cuba G; Rocha-Santos G, Cayô R, et al.
      Pages: 1874 - 1878
      Abstract: AbstractObjectivesCarbapenem-resistant Pseudomonas aeruginosa (CR-PSA) imposes great limitations on empirical therapeutic choices, which are further complicated by metallo-β-lactamase production. This study evaluated in vitro antimicrobial synergy of ceftolozane/tazobactam in combination with aztreonam and fosfomycin against MDR PSA.MethodsMICs were determined by broth microdilution and gradient strips. The effect of ceftolozane/tazobactam+aztreonam and ceftolozane/tazobactam+fosfomycin combinations were tested against 27 MDR PSA isolates carrying blaSPM-1 (n = 13), blaIMP (n = 4), blaVIM (n = 3), blaGES-1 (n = 2) and blaCTX-M-like (n = 2), and 3 isolates with no acquired β-lactamase production detected by gradient diffusion strip crossing (GDSC). Six genetically unrelated SPM-1-producing isolates were also evaluated by time–kill analysis (TKA).ResultsAll CR-PSA isolates harbouring blaSPM-1, blaGES-1 and blaIMP-1 were categorized as resistant to ceftolozane/tazobactam, meropenem and fosfomycin, with 70% being susceptible to aztreonam. Synergism for ceftolozane/tazobactam+fosfomycin and ceftolozane/tazobactam+aztreonam combinations was observed for 88.9% (24/27) and 18.5% (5/27) of the isolates by GDSC, respectively. A 3- to 9-fold reduction in ceftolozane/tazobactam MICs was observed, depending on the combination. Ceftolozane/tazobactam+fosfomycin was synergistic by TKA against one of six SPM-1-producing isolates, with additional non-synergistic bacterial density reduction for another isolate. Aztreonam peak concentrations alone demonstrated a ≥3 log10 cfu/mL reduction against all six isolates, but all strains were within the susceptible range for the drug. No antagonism was observed.ConclusionsIn the context of increasing CR-PSA and the genetic diversity of resistance mechanisms, new combinations and stewardship strategies may need to be explored in the face of increasingly difficult to treat pathogens.
      PubDate: Thu, 02 Apr 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa095
      Issue No: Vol. 75, No. 7 (2020)
  • Efficacy of single and multiple oral doses of fosfomycin against
           Pseudomonas aeruginosa urinary tract infections in a dynamic in vitro
           bladder infection model
    • Authors: Abbott I; van Gorp E, Wijma R, et al.
      Pages: 1879 - 1888
      Abstract: AbstractObjectivesWe used a dynamic bladder infection in vitro model with synthetic human urine (SHU) to examine fosfomycin exposures to effectively kill, or prevent emergence of resistance, among Pseudomonas aeruginosa isolates.MethodsDynamic urinary fosfomycin concentrations after 3 g oral fosfomycin were simulated, comparing single and multiple (daily for 7 days) doses. Pharmacodynamic response of 16 P. aeruginosa (MIC range 1 to >1024 mg/L) were examined. Baseline disc diffusion susceptibility, broth microdilution MIC and detection of heteroresistance were assessed. Pathogen kill and emergence of resistance over 72 h following a single dose, and over 216 h following daily dosing for 7 days, were investigated. The fAUC0–24/MIC associated with stasis and 1, 2 and 3 log10 kill were determined.ResultsPre-exposure high-level resistant (HLR) subpopulations were detected in 11/16 isolates after drug-free incubation in the bladder infection model. Five of 16 isolates had >2 log10 kill after single dose, reducing to 2/16 after seven doses. Post-exposure HLR amplification occurred in 8/16 isolates following a single dose and in 11/16 isolates after seven doses. Baseline MIC ≥8 mg/L with an HLR subpopulation predicted post-exposure emergence of resistance following the multiple doses. A PK/PD target of fAUC0–24/MIC >5000 was associated with 3 log10 kill at 72 h and 7 day-stasis.ConclusionsSimulated treatment of P. aeruginosa urinary tract infections with oral fosfomycin was ineffective, despite exposure to high urinary concentrations and repeated daily doses for 7 days. Emergence of resistance was observed in the majority of isolates and worsened following prolonged therapy. Detection of a baseline resistant subpopulation predicted treatment failure.
      PubDate: Sun, 03 May 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa127
      Issue No: Vol. 75, No. 7 (2020)
  • Inhaled tigecycline is effective against Mycobacterium abscessus in vitro
           and in vivo
    • Authors: Pearce C; Ruth M, Pennings L, et al.
      Pages: 1889 - 1894
      Abstract: AbstractBackgroundMycobacterium abscessus causes chronic pulmonary infections. Owing to its resistance to most classes of antibiotics, treatment is complex and cure rates are only 45%. Tigecycline is active against M. abscessus, but severe toxicity and the need for IV administration limit its use.ObjectivesTo assess the potential of inhaled tigecycline as a treatment for M. abscessus pulmonary disease, by measuring its efficacy in a mouse model of chronic M. abscessus pulmonary disease, establishing the intracellular activity of tigecycline against M. abscessus in human macrophages and measuring the activity of tigecycline in the sputum of cystic fibrosis patients.MethodsWe infected GM-CSF knockout mice with M. abscessus by intrapulmonary aerosol. Infected mice were treated with tigecycline in 0.25, 1.25 and 2.5 mg doses, by inhalation, or untreated, for 28 days. Tigecycline was added to human peripheral blood-derived macrophages infected with M. abscessus to assess its intracellular activity. We performed a time–kill kinetics experiment of tigecycline against M. abscessus with and without sputum of cystic fibrosis patients.ResultsInhaled tigecycline proved highly effective against M. abscessus in GM-CSF knockout mice. The effect was dose dependent. Tigecycline showed potent activity against M. abscessus in macrophages and retained most of its activity in the presence of sputum of cystic fibrosis patients.ConclusionsInhaled tigecycline may represent a viable treatment option for M. abscessus pulmonary disease, where treatment outcomes are currently very poor. A stable and safe formulation is required to proceed to further pharmacodynamic studies and ultimately clinical trials.
      PubDate: Wed, 15 Apr 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa110
      Issue No: Vol. 75, No. 7 (2020)
  • Repositioning rafoxanide to treat Gram-negative bacilli infections
    • Authors: Miró-Canturri A; Ayerbe-Algaba R, Villodres Á, et al.
      Pages: 1895 - 1905
      Abstract: AbstractObjectivesRepurposing drugs provides a new approach to the fight against MDR Gram-negative bacilli (MDR-GNB). Rafoxanide, a veterinary antihelminthic drug, has shown antibacterial activity in vitro against Gram-positive bacteria. We aimed to analyse the in vitro and in vivo efficacy of rafoxanide in combination with colistin against colistin-susceptible (Col-S) and colistin-resistant (Col-R) GNB.MethodsA collection of Col-S and Col-R Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae were used. Chequerboard and time–kill curve analyses were performed to determine the synergy between rafoxanide and colistin. Changes in membrane structure and permeability were analysed using transmission electron microscopy and fluorescence assays. A murine peritoneal sepsis model using Col-R strains of these pathogens was performed to study the efficacy of rafoxanide (10 mg/kg/24 h, IV), colistimethate sodium (CMS) (20 mg/kg/8 h, intraperitoneally) and rafoxanide (10 mg/kg/24 h, IV) plus CMS (20 mg/kg/8 h, intraperitoneally) for 72 h.ResultsRafoxanide showed MICs ≥256 mg/L for all Col-S and Col-R strains. Chequerboard and time–kill curve analyses showed that rafoxanide (1 mg/L) is more synergistic with colistin against Col-R than Col-S strains. Col-R, but not Col-S, strains treated with rafoxanide demonstrated higher membrane permeabilization. Transmission electron microscopy visualization confirmed that Col-R strains suffer morphological changes. In the murine peritoneal sepsis model with Col-R strains, rafoxanide plus CMS, compared with CMS alone, increased mouse survival to 53.8% and 73.3%, and reduced bacterial loads in tissues and blood between 2.34 and 4.99 log10 cfu/g or mL, respectively.ConclusionsRafoxanide repurposing, as monotherapy and in combination with CMS, may address the urgent need for new treatments for infections caused by MDR-GNB.
      PubDate: Thu, 02 Apr 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa103
      Issue No: Vol. 75, No. 7 (2020)
  • Efficacy of continuous versus intermittent administration of
           nanoformulated benznidazole during the chronic phase of Trypanosoma cruzi
           Nicaragua infection in mice
    • Authors: Rial M; Arrúa E, Natale M, et al.
      Pages: 1906 - 1916
      Abstract: AbstractBackgroundBenznidazole and nifurtimox are effective drugs used to treat Chagas’ disease; however, their administration in patients in the chronic phase of the disease is still limited, mainly due to their limited efficacy in the later chronic stage of the disease and to the adverse effects related to these drugs.ObjectivesTo evaluate the effect of low doses of nanoformulated benznidazole using a chronic model of Trypanosoma cruzi Nicaragua infection in C57BL/6J mice.MethodsNanoformulations were administered in two different schemes: one daily dose for 30 days or one dose every 7 days, 13 times.ResultsBoth treatment schemes showed promising outcomes, such as the elimination of parasitaemia, a reduction in the levels of T. cruzi-specific antibodies and a reduction in T. cruzi-specific IFN-γ-producing cells, as well as an improvement in electrocardiographic alterations and a reduction in inflammation and fibrosis in the heart compared with untreated T. cruzi-infected animals. These results were also compared with those from our previous work on benznidazole administration, which was shown to be effective in the same chronic model.ConclusionsIn this experimental model, intermittently administered benznidazole nanoformulations were as effective as those administered continuously; however, the total dose administered in the intermittent scheme was lower, indicating a promising therapeutic approach to Chagas’ disease.
      PubDate: Fri, 10 Apr 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa101
      Issue No: Vol. 75, No. 7 (2020)
  • Developmental population pharmacokinetics–pharmacodynamics and dosing
           optimization of cefoperazone in children
    • Authors: Shi H; Wang K, Wang R, et al.
      Pages: 1917 - 1924
      Abstract: AbstractObjectivesTo evaluate the population pharmacokinetics of cefoperazone in children and establish an evidence-based dosing regimen using a developmental pharmacokinetic–pharmacodynamic approach in order to optimize cefoperazone treatment.MethodsA model-based, open-label, opportunistic-sampling pharmacokinetic study was conducted in China. Blood samples from 99 cefoperazone-treated children were collected and quantified by HPLC/MS. NONMEM software was used for population pharmacokinetic–pharmacodynamic analysis. This study was registered at (NCT03113344).ResultsA two-compartment model with first-order elimination agreed well with the experimental data. Covariate analysis showed that current body weight had a significant effect on the pharmacokinetics of cefoperazone. Monte Carlo simulation showed that for bacteria for which cefoperazone has an MIC of 0.5 mg/L, 78.1% of hypothetical children treated with ‘40 mg/kg/day, q8h, IV drip 3 h’ would reach the pharmacodynamic target. For bacteria for which cefoperazone has an MIC of 8 mg/L, 88.4% of hypothetical children treated with 80 mg/kg/day (continuous infusion) would reach the treatment goal. A 160 mg/kg/day (continuous infusion) regimen can cover bacteria for which cefoperazone has an MIC of 16 mg/L. Nevertheless, even if using the maximum reported dose of 160 mg/kg/day (continuous infusion), the ratio of hypothetical children reaching the treatment target was only 9.9% for bacteria for which cefoperazone has an MIC of 32 mg/L.ConclusionsFor cefoperazone, population pharmacokinetics were evaluated in children and an appropriate dosing regimen was developed based on developmental pharmacokinetics–pharmacodynamics. The dose indicated in the instructions (20–160 mg/kg/day) can basically cover the clinically common bacteria for which cefoperazone has an MIC of ≤16 mg/L. However, for bacteria for which the MIC is >16 mg/L, cefoperazone is not a preferred choice.
      PubDate: Wed, 04 Mar 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa071
      Issue No: Vol. 75, No. 7 (2020)
  • Characteristics of drug resistance in HIV-1 CRF55_01B from ART-experienced
           patients in Guangdong, China
    • Authors: Lan Y; Xin R, Cai W, et al.
      Pages: 1925 - 1931
      Abstract: AbstractBackgroundHIV-1 acquired drug resistance (ADR) has become a critical clinical and public health issue. Recently, HIV-1 CRF55_01B has been found more frequently in the MSM population.ObjectiveTo investigate the characteristics of HIV-1 drug resistance mutations (DRMs) and the extent of changes in drug susceptibility among ART-experienced CRF55_01B-infected adults of Guangdong.MethodsADR was tested for immediately in CRF55_01B-infected patients with virological failure. Demographic and epidemiological information was collected. DRMs and antiretroviral susceptibility were interpreted using the Stanford University HIV Drug Resistance Database HIVdb program.ResultsOverall, 162 (4.78%) CRF55_01B isolates were identified from 2013 to 2018. Among DRMs, M184V (43.83%) was the most frequent NRTI DRM, followed by K65R (23.46%), and V179E (98.77%) was the most frequent NNRTI DRM, followed by K103N (47.53%) and Y181C (14.81%). According to the HIVdb program, 79.01% of the CRF55_01B-infected patients carried mutations conferring low-level or higher drug resistance to any of the three classes of ART drugs. Among PI DRMs, only one mutation affording low-level resistance to nelfinavir was found (0.62%). Among NRTI DRMs, a high proportion of high-level resistance to lamivudine (58.64%) and emtricitabine (58.02%) was found. As regards NNRTIs, more than 75% of patients carried efavirenz and nevirapine DRMs. The percentages of high-level resistance were 70.99%, 63.58%, 22.22%, 17.90% and 4.32% for nevirapine, efavirenz, rilpivirine, doravirine and etravirine, respectively.ConclusionsHigh frequencies of DRMs and resistance were observed among CRF55_01B-infected patients failing ART in Guangdong, and interventions may be considered to minimize ecological contributions to ART.
      PubDate: Thu, 16 Apr 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa116
      Issue No: Vol. 75, No. 7 (2020)
  • High level of pre-treatment and acquired HIV drug resistance in Honduras:
           a nationally representative survey, 2016–17
    • Authors: Girón-Callejas A; García-Morales C, Mendizabal-Burastero R, et al.
      Pages: 1932 - 1942
      Abstract: AbstractBackgroundPre-treatment HIV drug resistance (HIVDR) to NNRTIs has consistently increased in low-/middle-income countries during the last decade.ObjectivesTo estimate the prevalence of pre-treatment HIVDR and acquired HIVDR among persons living with HIV (PLHIV) on ART for 12 ± 3 months (ADR12) and ≥48 months (ADR48) in Honduras.Patients and methodsA nationwide cross-sectional survey with a two-stage cluster sampling was conducted from October 2016 to November 2017. Twenty-two of 54 total ART clinics representing >90% of the national cohort of adults on ART were included. HIVDR was assessed for protease and reverse transcriptase Sanger sequences using the Stanford HIVdb tool.ResultsA total of 729 PLHIV were enrolled; 26.3% (95% CI 20.1%–33.5%) ART initiators reported prior exposure to antiretrovirals. Pre-treatment HIVDR prevalence was 26.9% (95% CI 20.2%–34.9%) to any antiretroviral and 25.9% (19.2%–33.9%) to NNRTIs. NNRTI pre-treatment HIVDR was higher in ART initiators with prior exposure to antiretrovirals (P = 0.001). Viral load (VL) suppression rate was 89.7% (85.1%–93.0%) in ADR12 and 67.9% (61.7%–73.6%) in ADR48. ADR12 to any drug among PLHIV with VL ≥1000 copies/mL was 86.1% (48.9%–97.6%); 67.1% (37.4%–87.5%) had HIVDR to both NNRTIs and NRTIs, and 3.8% (0.5%–25.2%) to PIs. ADR48 was 92.0% (86.8%–95.3%) to any drug; 78.1% (66.6%–86.5%) to both NNRTIs and NRTIs, and 7.3% (1.8%–25.1%) to PIs.ConclusionsThe high prevalence of NNRTI pre-treatment HIVDR observed in Honduras warrants consideration of non-NNRTI-based first-line regimens for ART initiation. Programmatic improvements in HIVDR monitoring and adherence support may also be considered.
      PubDate: Fri, 17 Apr 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa100
      Issue No: Vol. 75, No. 7 (2020)
  • Characterization of viral rebounds on dual etravirine/raltegravir
           maintenance therapy (ANRS-163 ETRAL trial)
    • Authors: Soulie C; Assoumou L, Abdi B, et al.
      Pages: 1943 - 1949
      Abstract: AbstractBackgroundThe ANRS-163 ETRAL trial, a switch study to an etravirine 200 mg/raltegravir 400 mg twice-daily regimen in 165 patients with HIV-1 infection, showed durable efficacy until Week 96. The aim of this work was to investigate in detail the virological rebounds (VRs), defined as at least one plasma HIV viral load (VL) >50 copies/mL.MethodsQuantification of HIV-DNA level was assessed at baseline, Week 48 and Week 96 (n = 157). VLs were measured in seminal plasma at Week 48 (n = 26). Genotypic resistance testing by ultra-deep sequencing (UDS) for reverse transcriptase (RT) and integrase regions was performed at baseline and at the time of VR.ResultsIn this study, 19 patients experienced VR, with 2 patients having virological failure (VF; two consecutive VLs >50 copies/mL). For the first patient with VF, UDS detected minority resistant variants only in RT (K103N, 9.6%; Y181C, 4.9%) at baseline. Some RT variants became dominant at VF (K101E, 86.3%; Y181C, 100.0%; G190A, 100.0%) and others emerged in integrase (Y143C, 2.4%; Q148R, 6.2%; N155H, 18.8%). For the second patient with VF, neither RT nor integrase mutations were detected at baseline and VF. Median HIV-DNA level was similar at baseline, Week 48 and Week 96 (2.17, 2.06 and 2.11 log10 copies/106 cells, respectively). Only one patient had a detectable seminal HIV VL (505 copies/mL).ConclusionsThe dual etravirine/raltegravir regimen as maintenance therapy was effective and the emergence of mutations in cases of VF was similar to that seen in other dual-regimen studies. No HIV-DNA level modification was evidenced by Week 96.
      PubDate: Tue, 07 Apr 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa090
      Issue No: Vol. 75, No. 7 (2020)
  • Effectiveness of dolutegravir-based antiretroviral treatment for HIV-2
           infection: retrospective observational study from Western India
    • Authors: Pujari S; Patel A, Gaikwad S, et al.
      Pages: 1950 - 1954
      Abstract: AbstractBackgroundData on the use of dolutegravir for treatment of HIV-2 infection are limited.ObjectivesTo assess the effectiveness of dolutegravir in people living with HIV-2 (PLHIV-2).MethodsA retrospective chart review was performed in two clinics in Western India. PLHIV-2 initiated on dolutegravir-based regimens were included. Response to treatment in both treatment-naive (TN) and treatment-experienced (TE; substitution and not in the context of failure) was assessed by CD4 counts and HIV-2 viral load (VL) in a proportion of individuals. The primary objective was to assess immunological effectiveness (absence of a drop in absolute CD4 counts by more than 30% of baseline). Change in absolute CD4 counts was assessed by fitting a mixed-effects model.ResultsSixty-two PLHIV-2 treated with dolutegravir were included. The immunological effectiveness rates (95% CI) were 91.9% (82.4%–96.5%), 92% (81.1%–96.8%) and 91.6% (64.6%–98.5%) amongst all, TE and TN individuals, respectively. Median change in absolute CD4 counts at 6, 12 and 18 months were +29 cells/mm3, +101 cells/mm3 and +72 cells/mm3, respectively. The virological effectiveness rates (HIV-2 VL <100 copies/mL) (95% CI) for all, TE and TN individuals were 88.8% (74.6%–95%), 89.6% (73.6%–96.4%) and 85.7% (48.6%–97.4%), respectively. Three clinical events were documented: spinal tuberculosis, relapsed non-Hodgkin’s lymphoma and herpes simplex virus retinitis. One individual reported self-limiting somnolence.ConclusionsDolutegravir was well tolerated and associated with immunological, virological and clinical effectiveness in both TN and TE PLHIV-2 in a large cohort from Western India. Dolutegravir-based ART is an excellent option for treatment of individuals with HIV-2 infection.
      PubDate: Sat, 11 Apr 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa112
      Issue No: Vol. 75, No. 7 (2020)
  • Effectiveness of boosted darunavir plus rilpivirine in patients with
           long-lasting HIV-1 infection: DARIL study
    • Authors: Navarro J; González-Cordón A, Casado J, et al.
      Pages: 1955 - 1960
      Abstract: AbstractBackgroundThe combination of boosted darunavir plus rilpivirine, once daily, could be a convenient, effective and well-tolerated two-drug regimen to achieve HIV suppression in HIV-infected patients.MethodsMulticentre, retrospective cohort study in nine hospitals in Spain. All HIV-infected subjects starting boosted darunavir plus rilpivirine were included, irrespective of their viral load (VL). The primary objective was the percentage of patients with VL <50 copies/mL at 48 weeks. Secondary objectives included changes in CD4+ cell count, lipid profile and renal function.ResultsEighty-one of 84 patients reached Week 48. Fifty-nine (70.2%) patients had VL <50 copies/mL at baseline and the rest had a median VL of 202 (IQR 98–340) copies/mL. Subjects had a median of 21 years of infection with six prior regimens. The main reasons for starting boosted darunavir plus rilpivirine were simplification (44%), kidney or bone toxicity (28.6%) and virological failure (17.9%). Historical genotypes from 47 patients showed 41 (87.2%) patients with NRTI RAMs, 21 (44.7%) with NNRTI RAMs, 12 (25.5%) with primary PI RAMs and 7 (14.9%) with integrase strand transfer inhibitor (INSTI) RAMs. One patient had low-level resistance to boosted darunavir and five patients had some resistance to rilpivirine. At 48 weeks, 71 (87.7%) patients had VL <50 copies/mL. According to undetectable or detectable baseline VL, effectiveness was 91.1% or 80%, respectively. There were four virological failures with no emergence of new RAMs. Three of these patients resuppressed viraemia while maintaining the same regimen.ConclusionsThe combination of boosted darunavir plus rilpivirine has shown good effectiveness and tolerability in this cohort of pretreated patients with a long-lasting HIV infection, exposure to multiple antiretroviral regimens and prior HIV resistance.
      PubDate: Thu, 05 Mar 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa072
      Issue No: Vol. 75, No. 7 (2020)
  • Grazoprevir/elbasvir for the immediate treatment of recently acquired HCV
           genotype 1 or 4 infection in MSM
    • Authors: Boyd A; Miailhes P, Chas J, et al.
      Pages: 1961 - 1968
      Abstract: AbstractBackgroundIn Europe, increases in HCV infection have been observed over the last two decades in MSM, making them a key population for recently acquired HCV. Alternative combinations of direct-acting antiviral agents against early HCV infection need to be assessed.Patients and methodsIn this pilot trial, MSM with recently acquired genotype 1 or 4 HCV infection were prospectively included and received 8 weeks of oral grazoprevir 100 mg and elbasvir 50 mg in a fixed-dose combination administered once daily. The primary endpoint was sustained virological response evaluated 12 weeks after the end of treatment (EOT) (SVR12). Secondary endpoints were the virological characterization of failures, the quality of life before, during and after treatment and the rate of reinfection.ResultsIn a 15 month period, 30 patients were enrolled, all of whom were MSM. Of the 29 patients completing follow-up, 28 (96%, 95% CI = 82%–99%) achieved SVR12. One patient interrupted follow-up (suicide) but had undetectable plasma HCV RNA at EOT. One patient with suboptimal adherence confirmed by plasma drug monitoring relapsed and developed NS3, NS5A and NS5B resistance-associated substitutions (V36M, M28V and S556G). The most common adverse events related to study drug were diarrhoea (n = 4, 13%), insomnia (n = 2, 7%) and fatigue (n = 2, 7%), although no patient discontinued treatment. No HIV RNA breakthrough was reported in the 28 patients with HIV coinfection. At Week 48, reinfection was diagnosed in three patients.ConclusionsOur data support the use of grazoprevir/elbasvir for immediate treatment against HCV in order to reduce HCV transmission in MSM.
      PubDate: Sun, 19 Apr 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa091
      Issue No: Vol. 75, No. 7 (2020)
  • Antiretroviral concentrations in the presence and absence of valproic acid
    • Authors: Calcagno A; Cusato J, Ferrara M, et al.
      Pages: 1969 - 1971
      Abstract: AbstractObjectivesAn unexpected drug–drug interaction has been recently reported between dolutegravir, an HIV integrase inhibitor, and valproic acid. Despite there being several potential underlying mechanisms, plasma protein displacement has been suggested. The aim of this study was to assess plasma concentrations of several antiretrovirals when administered with or without valproic acid.MethodsWe performed a therapeutic drug monitoring registry analysis and identified patients concomitantly taking antiretrovirals and valproic acid and without clinical affecting conditions or interacting drugs.ResultsOne hundred and thirty-four patients were identified. Median (IQR) age and BMI were 49.7 years (45–56) and 23.4 kg/m2 (20.8–26.3) and 78 were male (58.2%). Despite small groups, we observed no major effect on antiretroviral exposure, even when considering highly protein-bound compounds (such as etravirine), with the exception of dolutegravir trough concentrations [median (IQR) = 132 ng/mL (62–227) in individuals on valproic acid versus 760 ng/mL (333–1407) in those not receiving valproic acid].ConclusionsValproic acid does not have a major effect on antiretrovirals other than dolutegravir. The mechanism of this unexpected drug–drug interaction may be the combination of protein displacement, reduced absorption and CYP3A4 induction.
      PubDate: Wed, 25 Mar 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa094
      Issue No: Vol. 75, No. 7 (2020)
  • Real-life management of drug–drug interactions between
           antiretrovirals and statins
    • Authors: Courlet P; Livio F, Alves Saldanha S, et al.
      Pages: 1972 - 1980
      Abstract: AbstractBackgroundPIs cause drug–drug interactions (DDIs) with most statins due to inhibition of drug-metabolizing enzymes and/or the hepatic uptake transporter OATP1B1, which may alter the pharmacodynamic (PD) effect of statins.ObjectivesTo assess the management of DDIs between antiretrovirals (ARVs) and statins in people living with HIV (PLWH) considering statin plasma concentrations, compliance with dosing recommendations and achievement of lipid targets.MethodsPLWH of the Swiss HIV Cohort Study were eligible if they received a statin concomitantly with ARVs. HDL, total cholesterol (TC) and statin plasma concentration were measured during follow-up visits. Individual non-HDL and TC target values were set using the Framingham score and the 2018 European AIDS Clinical Society recommendations.ResultsData were analysed for rosuvastatin (n = 99), atorvastatin (n = 92), pravastatin (n = 46) and pitavastatin (n = 21). Rosuvastatin and atorvastatin underdosing frequently led to suboptimal PD response. Insufficient lipid control was observed with PIs despite high atorvastatin concentrations, likely explained by inhibition of OATP1B1 resulting in less statin uptake in the liver. Target lipid values were more often achieved with unboosted integrase inhibitors due to both their favourable DDI profiles and neutral effect on lipids. Insufficient lipid control was common with pravastatin and pitavastatin regardless of co-administered ARVs and despite using maximal recommended statin doses. The latter suggests lower efficacy compared with rosuvastatin or atorvastatin.ConclusionsSuboptimal management of DDIs with statin underdosing was observed in 29% of prescriptions. Integrase inhibitor-based regimens and/or treatment with rosuvastatin or atorvastatin should be favoured in patients with refractory dyslipidaemia.
      PubDate: Thu, 02 Apr 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa099
      Issue No: Vol. 75, No. 7 (2020)
  • Voriconazole: an audit of hospital-based dosing and monitoring and
           evaluation of the predictive performance of a dose-prediction software
    • Authors: Chaudhri K; Stocker S, Williams K, et al.
      Pages: 1981 - 1984
      Abstract: AbstractBackgroundTherapeutic drug monitoring (TDM) is recommended to guide voriconazole therapy.ObjectivesTo determine compliance of hospital-based voriconazole dosing and TDM with the Australian national guidelines and evaluate the predictive performance of a one-compartment population pharmacokinetic voriconazole model available in a commercial dose-prediction software package.MethodsA retrospective audit of voriconazole therapy at an Australian public hospital (1 January to 31 December 2016) was undertaken. Data collected included patient demographics, dosing history and plasma concentrations. Concordance of dosing and TDM with Australian guidelines was assessed. Observed concentrations were compared with those predicted by dose-prediction software. Measures of bias (mean prediction error) and precision (mean squared prediction error) were calculated.ResultsAdherence to dosing guidelines for 110 courses of therapy (41% for prophylaxis and 59% for invasive fungal infections) was poor, unless oral formulation guidelines recommended a 200 mg dose, the most commonly prescribed dose (56% of prescriptions). Plasma voriconazole concentrations were obtained for 82% (90/110) of courses [median of 3 (range: 1–27) obtained per course]. A minority (27%) of plasma concentrations were trough concentrations [median concentration: 1.5 mg/L (range: <0.1 to >5.0 mg/L)]. Of trough concentrations, 57% (58/101) were therapeutic, 37% (37/101) were subtherapeutic and 6% (6/101) were supratherapeutic. The dose-prediction software performed well, with acceptable bias and precision of 0.09 mg/L (95% CI −0.08 to 0.27) and 1.32 (mg/L)2 (95% CI 0.96–1.67), respectively.ConclusionsVoriconazole dosing was suboptimal based on published guidelines and TDM results. Dose-prediction software could enhance TDM-guided therapy.
      PubDate: Sat, 11 Apr 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa098
      Issue No: Vol. 75, No. 7 (2020)
  • Fluoroquinolone resistance in Escherichia coli isolates after exposure to
           non-fluoroquinolone antibiotics: a retrospective case–control study
    • Authors: Chaname Pinedo L; Bruyndonckx R, Catry B, et al.
      Pages: 1985 - 1992
      Abstract: AbstractObjectivesTo investigate whether prior exposure to non-fluoroquinolone antibiotics increases the risk of fluoroquinolone resistance in Escherichia coli.MethodsThis was a secondary analysis of data collected retrospectively in a case–control study linking microbiological test results (isolated bacteria and their susceptibility) of urine samples routinely collected from primary, secondary and tertiary care patients in Belgium with information on prior antibiotic use at the patient level up to 1 year previously.ResultsIn urine samples from 6125 patients, 7204 E. coli isolates were retrieved [1949 fluoroquinolone-resistant isolates (cases) and 5255 fluoroquinolone-susceptible isolates (controls)]. After adjusting for potential confounders (including fluoroquinolone use) and correcting for multiple testing there were lower odds of fluoroquinolone resistance in E. coli isolates after exposure to cefazolin (OR = 0.65; 95% CI = 0.52–0.81; P = 0.00014) and higher odds after exposure to trimethoprim/sulfamethoxazole (OR = 1.56; 95% CI = 1.23–1.97; P =0.00020) or nitrofurantoin (OR = 1.50; 95% CI = 1.23–1.84; P =0.000083). A sensitivity analysis excluding samples with antibiotic use during the 6 months prior to the sampling date confirmed the higher odds of fluoroquinolone resistance after exposure to trimethoprim/sulfamethoxazole and nitrofurantoin.ConclusionsAssuming no residual confounding or other biases, this study suggests that exposure to non-fluoroquinolone antibiotics, i.e. trimethoprim/sulfamethoxazole and nitrofurantoin, might be causally related to fluoroquinolone resistance in E. coli isolates from urinary samples. Future prospective research is needed to confirm non-fluoroquinolone antibiotics as potential drivers of fluoroquinolone resistance.
      PubDate: Tue, 12 May 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa128
      Issue No: Vol. 75, No. 7 (2020)
  • Oral fosfomycin use for pyelonephritis and complicated urinary tract
           infections: a 1 year review of outcomes and prescribing habits in a large
           municipal healthcare system
    • Authors: Hatlen T; Flor R, Nguyen M, et al.
      Pages: 1993 - 1997
      Abstract: AbstractBackgroundThe rising incidence of MDR uropathogens has driven increased use of oral fosfomycin for treatment of complicated urinary tract infections (cUTIs). However, there are limited data to support its use for cUTI, especially pyelonephritis.MethodsWe performed a retrospective review of all oral fosfomycin prescriptions between 1 January and 31 December 2017 in the Los Angeles County Department of Health Service system, the second largest US municipal health system. We examined demographics, clinical characteristics, adverse events and 30 day treatment success for patients with cUTI. Follow-up urine cultures till 31 December 2018 were examined for emergence of fosfomycin resistance.ResultsOf 154 patients prescribed fosfomycin, 99 (64%) had cUTI. Of these, 39 (39%) had lower tract, 37 (37%) pyelonephritis and 23 (23%) non-pyelonephritis upper tract cUTI. Escherichia coli ESBL producers were the predominant pathogens (73%). Of the 63 patients with 30 day follow-up, 49 (78%) had clinical success, including 16/20 (80%) treated for pyelonephritis. Treatment failure was associated with male sex (P < 0.01), urological abnormalities (P = 0.05), non-E. coli cUTI (P = 0.03) and receipt of <25% IV therapy prior to fosfomycin switch (P = 0.03). Of patients prescribed fosfomycin (n = 154), fosfomycin-resistant E. coli were found in 9/64 (14%) of the patients with follow-up urine cultures >30 days after initial treatment.ConclusionsDespite the lack of data supporting its use, we found that most patients receiving oral fosfomycin off-label for cUTI, including pyelonephritis, had clinical success. However, emergence of subsequent resistance warrants caution. Prospective comparative studies should be done to better evaluate oral fosfomycin use for cUTI.
      PubDate: Fri, 17 Apr 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa126
      Issue No: Vol. 75, No. 7 (2020)
  • Development and evaluation of a national gentamicin and vancomycin quality
           improvement programme
    • Authors: Semple Y; Bennie M, Sneddon J, et al.
      Pages: 1998 - 2003
      Abstract: AbstractBackgroundScottish Antimicrobial Prescribing Group (SAPG) recommendations to reduce broad-spectrum antimicrobial use led to an increase in gentamicin and vancomycin prescribing. In 2009, SAPG introduced national guidance to standardize dosage regimens, reduce calculation errors and improve the monitoring of these antibiotics. Studies conducted in 2010 and 2011 identified limitations in guideline implementation.ObjectivesTo develop, implement and assess the long-term impact of quality improvement (QI) resources to support gentamicin and vancomycin prescribing, administration and monitoring.MethodsNew resources, comprising revised guidelines, online and mobile app dose calculators, educational material and specialized prescribing and monitoring charts were developed in collaboration with antimicrobial specialists and implemented throughout Scotland during 2013–16. An online survey in 2017 evaluated the use of these resources and a before (2011) and after (2018) point prevalence study assessed their impact.ResultsAll 12 boards who responded to the survey (80%) were using the guidance, electronic calculators and gentamicin prescription chart; 8 used a vancomycin chart. The percentage of patients who received the recommended gentamicin dose increased from 44% to 89% (OR 10.99, 95% CI = 6.37–18.95) between 2011 and 2018. For vancomycin, the correct loading dose increased from 50% to 85% (OR = 5.69, CI = 2.76–11.71) and the correct maintenance dose from 55% to 90% (OR = 7.17, CI = 3.01–17.07).ConclusionsThis study demonstrated improvements in the national prescribing of gentamicin and vancomycin through the development and coordinated implementation of a range of QI resources and engagement with local and national multidisciplinary teams.
      PubDate: Sat, 11 Apr 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa096
      Issue No: Vol. 75, No. 7 (2020)
  • Emergence of OXA-232-producing hypervirulent Klebsiella pneumoniae ST23
           causing neonatal sepsis
    • Authors: Mukherjee S; Naha S, Bhadury P, et al.
      Pages: 2004 - 2006
      Abstract: Sir,
      PubDate: Tue, 10 Mar 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa080
      Issue No: Vol. 75, No. 7 (2020)
  • OXA-48 carbapenemase-producing Salmonella enterica serovar Kentucky ST198
           isolated from Saudi Arabia
    • Authors: Alghoribi M; Desin T, Alswaji A, et al.
      Pages: 2006 - 2008
      Abstract: Sir,
      PubDate: Tue, 10 Mar 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa077
      Issue No: Vol. 75, No. 7 (2020)
  • Detection of multidrug- and colistin-resistant Salmonella Choleraesuis
           causing bloodstream infection
    • Authors: dos Santos C; Cunha M, Bertani A, et al.
      Pages: 2009 - 2010
      Abstract: Sir,
      PubDate: Tue, 10 Mar 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa076
      Issue No: Vol. 75, No. 7 (2020)
  • Evaluation of five carbapenemase detection assays for Enterobacteriaceae
           harbouring blaKPC variants associated with ceftazidime/avibactam
    • Authors: Gaibani P; Lombardo D, Foschi C, et al.
      Pages: 2010 - 2013
      Abstract: Sir,
      PubDate: Tue, 17 Mar 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa079
      Issue No: Vol. 75, No. 7 (2020)
  • Favipiravir, an antiviral for COVID-19'
    • Authors: Coomes E; Haghbayan H.
      Pages: 2013 - 2014
      Abstract: Sir,
      PubDate: Sun, 17 May 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa171
      Issue No: Vol. 75, No. 7 (2020)
  • COVID-19 infection also occurs in patients taking hydroxychloroquine
    • Authors: Lahouati M; Mériglier E, Martin L, et al.
      Pages: 2014 - 2015
      Abstract: Sir,
      PubDate: Sun, 17 May 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa193
      Issue No: Vol. 75, No. 7 (2020)
  • Comment on: COVID-19: a recommendation to examine the effect of
           hydroxychloroquine in preventing infection and progression
    • Authors: Fung K; Chan P.
      Pages: 2016 - 2017
      Abstract: Sir,
      PubDate: Sun, 03 May 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa169
      Issue No: Vol. 75, No. 7 (2020)
  • Comment on: Gross national income and antibiotic resistance in invasive
           isolates: analysis of the top-ranked antibiotic-resistant bacteria on the
           2017 WHO priority list
    • Authors: Aarestrup F; van Bunnik B.
      Pages: 2017 - 2018
      Abstract: Sir,
      PubDate: Thu, 23 Jan 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkz551
      Issue No: Vol. 75, No. 7 (2020)
  • Gross national income and antibiotic resistance in invasive isolates:
           analysis of the top-ranked antibiotic-resistant bacteria on the 2017 WHO
           priority list—authors’ response
    • Authors: Savoldi A; Carrara E, Tacconelli E.
      Pages: 2018 - 2018
      Abstract: Sir,
      PubDate: Wed, 27 May 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa203
      Issue No: Vol. 75, No. 7 (2020)
  • Erratum to: In vitro activity of the novel β-lactamase inhibitor
           taniborbactam (VNRX-5133), in combination with cefepime or meropenem,
           against MDR Gram-negative bacterial isolates from China
    • Authors: Wang X; Zhao C, Wang Q, et al.
      Pages: 2019 - 2019
      Abstract: J Antimicrob Chemother 2020; 75: 1850–8
      PubDate: Sun, 26 Apr 2020 00:00:00 GMT
      DOI: 10.1093/jac/dkaa132
      Issue No: Vol. 75, No. 7 (2020)
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