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Publisher: Oxford University Press   (Total: 370 journals)

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Showing 1 - 200 of 370 Journals sorted alphabetically
Acta Biochimica et Biophysica Sinica     Hybrid Journal   (Followers: 6, SJR: 0.881, h-index: 38)
Adaptation     Hybrid Journal   (Followers: 8, SJR: 0.111, h-index: 4)
Aesthetic Surgery J.     Hybrid Journal   (Followers: 6, SJR: 1.538, h-index: 35)
African Affairs     Hybrid Journal   (Followers: 57, SJR: 1.512, h-index: 46)
Age and Ageing     Hybrid Journal   (Followers: 82, SJR: 1.611, h-index: 107)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 15, SJR: 0.935, h-index: 80)
American Entomologist     Full-text available via subscription   (Followers: 6)
American Historical Review     Hybrid Journal   (Followers: 129, SJR: 0.652, h-index: 43)
American J. of Agricultural Economics     Hybrid Journal   (Followers: 41, SJR: 1.441, h-index: 77)
American J. of Epidemiology     Hybrid Journal   (Followers: 157, SJR: 3.047, h-index: 201)
American J. of Hypertension     Hybrid Journal   (Followers: 18, SJR: 1.397, h-index: 111)
American J. of Jurisprudence     Hybrid Journal   (Followers: 15)
American J. of Legal History     Full-text available via subscription   (Followers: 4, SJR: 0.151, h-index: 7)
American Law and Economics Review     Hybrid Journal   (Followers: 26, SJR: 0.824, h-index: 23)
American Literary History     Hybrid Journal   (Followers: 12, SJR: 0.185, h-index: 22)
Analysis     Hybrid Journal   (Followers: 24)
Annals of Botany     Hybrid Journal   (Followers: 35, SJR: 1.912, h-index: 124)
Annals of Occupational Hygiene     Hybrid Journal   (Followers: 26, SJR: 0.837, h-index: 57)
Annals of Oncology     Hybrid Journal   (Followers: 47, SJR: 4.362, h-index: 173)
Annals of the Entomological Society of America     Full-text available via subscription   (Followers: 8, SJR: 0.642, h-index: 53)
Annals of Work Exposures and Health     Hybrid Journal  
AoB Plants     Open Access   (Followers: 4, SJR: 0.78, h-index: 10)
Applied Economic Perspectives and Policy     Hybrid Journal   (Followers: 19, SJR: 0.884, h-index: 31)
Applied Linguistics     Hybrid Journal   (Followers: 51, SJR: 1.749, h-index: 63)
Applied Mathematics Research eXpress     Hybrid Journal   (Followers: 1, SJR: 0.779, h-index: 11)
Arbitration Intl.     Full-text available via subscription   (Followers: 21)
Arbitration Law Reports and Review     Hybrid Journal   (Followers: 12)
Archives of Clinical Neuropsychology     Hybrid Journal   (Followers: 27, SJR: 0.96, h-index: 71)
Aristotelian Society Supplementary Volume     Hybrid Journal   (Followers: 2, SJR: 0.102, h-index: 20)
Arthropod Management Tests     Hybrid Journal   (Followers: 2)
Astronomy & Geophysics     Hybrid Journal   (Followers: 47, SJR: 0.144, h-index: 15)
Behavioral Ecology     Hybrid Journal   (Followers: 47, SJR: 1.698, h-index: 92)
Bioinformatics     Hybrid Journal   (Followers: 236, SJR: 4.643, h-index: 271)
Biology Methods and Protocols     Hybrid Journal  
Biology of Reproduction     Full-text available via subscription   (Followers: 9, SJR: 1.646, h-index: 149)
Biometrika     Hybrid Journal   (Followers: 19, SJR: 2.801, h-index: 90)
BioScience     Hybrid Journal   (Followers: 28, SJR: 2.374, h-index: 154)
Bioscience Horizons : The National Undergraduate Research J.     Open Access   (Followers: 1, SJR: 0.213, h-index: 9)
Biostatistics     Hybrid Journal   (Followers: 16, SJR: 1.955, h-index: 55)
BJA : British J. of Anaesthesia     Hybrid Journal   (Followers: 141, SJR: 2.314, h-index: 133)
BJA Education     Hybrid Journal   (Followers: 66, SJR: 0.272, h-index: 20)
Brain     Hybrid Journal   (Followers: 61, SJR: 6.097, h-index: 264)
Briefings in Bioinformatics     Hybrid Journal   (Followers: 45, SJR: 4.086, h-index: 73)
Briefings in Functional Genomics     Hybrid Journal   (Followers: 4, SJR: 1.771, h-index: 50)
British J. for the Philosophy of Science     Hybrid Journal   (Followers: 33, SJR: 1.267, h-index: 38)
British J. of Aesthetics     Hybrid Journal   (Followers: 25, SJR: 0.217, h-index: 18)
British J. of Criminology     Hybrid Journal   (Followers: 510, SJR: 1.373, h-index: 62)
British J. of Social Work     Hybrid Journal   (Followers: 79, SJR: 0.771, h-index: 53)
British Medical Bulletin     Hybrid Journal   (Followers: 7, SJR: 1.391, h-index: 84)
British Yearbook of Intl. Law     Hybrid Journal   (Followers: 27)
Bulletin of the London Mathematical Society     Hybrid Journal   (Followers: 3, SJR: 1.474, h-index: 31)
Cambridge J. of Economics     Hybrid Journal   (Followers: 56, SJR: 0.957, h-index: 59)
Cambridge J. of Regions, Economy and Society     Hybrid Journal   (Followers: 9, SJR: 1.067, h-index: 22)
Cambridge Quarterly     Hybrid Journal   (Followers: 10, SJR: 0.1, h-index: 7)
Capital Markets Law J.     Hybrid Journal  
Carcinogenesis     Hybrid Journal   (Followers: 2, SJR: 2.439, h-index: 167)
Cardiovascular Research     Hybrid Journal   (Followers: 11, SJR: 2.897, h-index: 175)
Cerebral Cortex     Hybrid Journal   (Followers: 39, SJR: 4.827, h-index: 192)
CESifo Economic Studies     Hybrid Journal   (Followers: 16, SJR: 0.501, h-index: 19)
Chemical Senses     Hybrid Journal   (Followers: 1, SJR: 1.436, h-index: 76)
Children and Schools     Hybrid Journal   (Followers: 6, SJR: 0.211, h-index: 18)
Chinese J. of Comparative Law     Hybrid Journal   (Followers: 3)
Chinese J. of Intl. Law     Hybrid Journal   (Followers: 21, SJR: 0.737, h-index: 11)
Chinese J. of Intl. Politics     Hybrid Journal   (Followers: 8, SJR: 1.238, h-index: 15)
Christian Bioethics: Non-Ecumenical Studies in Medical Morality     Hybrid Journal   (Followers: 11, SJR: 0.191, h-index: 8)
Classical Receptions J.     Hybrid Journal   (Followers: 17, SJR: 0.1, h-index: 3)
Clinical Infectious Diseases     Hybrid Journal   (Followers: 58, SJR: 4.742, h-index: 261)
Clinical Kidney J.     Open Access   (Followers: 4, SJR: 0.338, h-index: 19)
Community Development J.     Hybrid Journal   (Followers: 24, SJR: 0.47, h-index: 28)
Computer J.     Hybrid Journal   (Followers: 7, SJR: 0.371, h-index: 47)
Conservation Physiology     Open Access   (Followers: 2)
Contemporary Women's Writing     Hybrid Journal   (Followers: 11, SJR: 0.111, h-index: 3)
Contributions to Political Economy     Hybrid Journal   (Followers: 6, SJR: 0.313, h-index: 10)
Critical Values     Full-text available via subscription  
Current Legal Problems     Hybrid Journal   (Followers: 25)
Current Zoology     Full-text available via subscription   (SJR: 0.999, h-index: 20)
Database : The J. of Biological Databases and Curation     Open Access   (Followers: 11, SJR: 1.068, h-index: 24)
Digital Scholarship in the Humanities     Hybrid Journal   (Followers: 12)
Diplomatic History     Hybrid Journal   (Followers: 18, SJR: 0.296, h-index: 22)
DNA Research     Open Access   (Followers: 4, SJR: 2.42, h-index: 77)
Dynamics and Statistics of the Climate System     Open Access   (Followers: 3)
Early Music     Hybrid Journal   (Followers: 14, SJR: 0.124, h-index: 11)
Economic Policy     Hybrid Journal   (Followers: 54, SJR: 2.052, h-index: 52)
ELT J.     Hybrid Journal   (Followers: 25, SJR: 1.26, h-index: 23)
English Historical Review     Hybrid Journal   (Followers: 46, SJR: 0.311, h-index: 10)
English: J. of the English Association     Hybrid Journal   (Followers: 13, SJR: 0.144, h-index: 3)
Environmental Entomology     Full-text available via subscription   (Followers: 11, SJR: 0.791, h-index: 66)
Environmental Epigenetics     Open Access   (Followers: 1)
Environmental History     Hybrid Journal   (Followers: 25, SJR: 0.197, h-index: 25)
EP-Europace     Hybrid Journal   (Followers: 2, SJR: 2.201, h-index: 71)
Epidemiologic Reviews     Hybrid Journal   (Followers: 10, SJR: 3.917, h-index: 81)
ESHRE Monographs     Hybrid Journal  
Essays in Criticism     Hybrid Journal   (Followers: 15, SJR: 0.1, h-index: 6)
European Heart J.     Hybrid Journal   (Followers: 47, SJR: 6.997, h-index: 227)
European Heart J. - Cardiovascular Imaging     Hybrid Journal   (Followers: 9, SJR: 2.044, h-index: 58)
European Heart J. - Cardiovascular Pharmacotherapy     Full-text available via subscription   (Followers: 1)
European Heart J. - Quality of Care and Clinical Outcomes     Hybrid Journal  
European Heart J. Supplements     Hybrid Journal   (Followers: 8, SJR: 0.152, h-index: 31)
European J. of Cardio-Thoracic Surgery     Hybrid Journal   (Followers: 8, SJR: 1.568, h-index: 104)
European J. of Intl. Law     Hybrid Journal   (Followers: 149, SJR: 0.722, h-index: 38)
European J. of Orthodontics     Hybrid Journal   (Followers: 4, SJR: 1.09, h-index: 60)
European J. of Public Health     Hybrid Journal   (Followers: 22, SJR: 1.284, h-index: 64)
European Review of Agricultural Economics     Hybrid Journal   (Followers: 12, SJR: 1.549, h-index: 42)
European Review of Economic History     Hybrid Journal   (Followers: 27, SJR: 0.628, h-index: 24)
European Sociological Review     Hybrid Journal   (Followers: 39, SJR: 2.061, h-index: 53)
Evolution, Medicine, and Public Health     Open Access   (Followers: 11)
Family Practice     Hybrid Journal   (Followers: 12, SJR: 1.048, h-index: 77)
Fems Microbiology Ecology     Hybrid Journal   (Followers: 8, SJR: 1.687, h-index: 115)
Fems Microbiology Letters     Hybrid Journal   (Followers: 20, SJR: 1.126, h-index: 118)
Fems Microbiology Reviews     Hybrid Journal   (Followers: 25, SJR: 7.587, h-index: 150)
Fems Yeast Research     Hybrid Journal   (Followers: 13, SJR: 1.213, h-index: 66)
Foreign Policy Analysis     Hybrid Journal   (Followers: 21, SJR: 0.859, h-index: 10)
Forestry: An Intl. J. of Forest Research     Hybrid Journal   (Followers: 16, SJR: 0.903, h-index: 44)
Forum for Modern Language Studies     Hybrid Journal   (Followers: 6, SJR: 0.108, h-index: 6)
French History     Hybrid Journal   (Followers: 30, SJR: 0.123, h-index: 10)
French Studies     Hybrid Journal   (Followers: 19, SJR: 0.119, h-index: 7)
French Studies Bulletin     Hybrid Journal   (Followers: 10, SJR: 0.102, h-index: 3)
Gastroenterology Report     Open Access   (Followers: 2)
Genome Biology and Evolution     Open Access   (Followers: 10, SJR: 3.22, h-index: 39)
Geophysical J. Intl.     Hybrid Journal   (Followers: 31, SJR: 1.839, h-index: 119)
German History     Hybrid Journal   (Followers: 25, SJR: 0.437, h-index: 13)
GigaScience     Open Access   (Followers: 3)
Global Summitry     Hybrid Journal  
Glycobiology     Hybrid Journal   (Followers: 14, SJR: 1.692, h-index: 101)
Health and Social Work     Hybrid Journal   (Followers: 46, SJR: 0.505, h-index: 40)
Health Education Research     Hybrid Journal   (Followers: 12, SJR: 0.814, h-index: 80)
Health Policy and Planning     Hybrid Journal   (Followers: 21, SJR: 1.628, h-index: 66)
Health Promotion Intl.     Hybrid Journal   (Followers: 20, SJR: 0.664, h-index: 60)
History Workshop J.     Hybrid Journal   (Followers: 27, SJR: 0.313, h-index: 20)
Holocaust and Genocide Studies     Hybrid Journal   (Followers: 23, SJR: 0.115, h-index: 13)
Human Molecular Genetics     Hybrid Journal   (Followers: 9, SJR: 4.288, h-index: 233)
Human Reproduction     Hybrid Journal   (Followers: 79, SJR: 2.271, h-index: 179)
Human Reproduction Update     Hybrid Journal   (Followers: 19, SJR: 4.678, h-index: 128)
Human Rights Law Review     Hybrid Journal   (Followers: 58, SJR: 0.7, h-index: 21)
ICES J. of Marine Science: J. du Conseil     Hybrid Journal   (Followers: 54, SJR: 1.233, h-index: 88)
ICSID Review     Hybrid Journal   (Followers: 9)
ILAR J.     Hybrid Journal   (Followers: 1, SJR: 1.099, h-index: 51)
IMA J. of Applied Mathematics     Hybrid Journal   (SJR: 0.329, h-index: 26)
IMA J. of Management Mathematics     Hybrid Journal   (Followers: 2, SJR: 0.351, h-index: 20)
IMA J. of Mathematical Control and Information     Hybrid Journal   (Followers: 2, SJR: 0.661, h-index: 28)
IMA J. of Numerical Analysis - advance access     Hybrid Journal   (SJR: 2.032, h-index: 44)
Industrial and Corporate Change     Hybrid Journal   (Followers: 8, SJR: 1.37, h-index: 81)
Industrial Law J.     Hybrid Journal   (Followers: 29, SJR: 0.184, h-index: 15)
Information and Inference     Free  
Integrative and Comparative Biology     Hybrid Journal   (Followers: 8, SJR: 1.911, h-index: 90)
Interacting with Computers     Hybrid Journal   (Followers: 10, SJR: 0.529, h-index: 59)
Interactive CardioVascular and Thoracic Surgery     Hybrid Journal   (Followers: 4, SJR: 0.743, h-index: 35)
Intl. Affairs     Hybrid Journal   (Followers: 51, SJR: 1.264, h-index: 53)
Intl. Data Privacy Law     Hybrid Journal   (Followers: 27)
Intl. Health     Hybrid Journal   (Followers: 4, SJR: 0.835, h-index: 15)
Intl. Immunology     Hybrid Journal   (Followers: 3, SJR: 1.613, h-index: 111)
Intl. J. for Quality in Health Care     Hybrid Journal   (Followers: 32, SJR: 1.593, h-index: 69)
Intl. J. of Constitutional Law     Hybrid Journal   (Followers: 59, SJR: 0.613, h-index: 19)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 126, SJR: 4.381, h-index: 145)
Intl. J. of Law and Information Technology     Hybrid Journal   (Followers: 3, SJR: 0.247, h-index: 8)
Intl. J. of Law, Policy and the Family     Hybrid Journal   (Followers: 28, SJR: 0.307, h-index: 15)
Intl. J. of Lexicography     Hybrid Journal   (Followers: 8, SJR: 0.404, h-index: 18)
Intl. J. of Low-Carbon Technologies     Open Access   (Followers: 1, SJR: 0.457, h-index: 12)
Intl. J. of Neuropsychopharmacology     Open Access   (Followers: 3, SJR: 1.69, h-index: 79)
Intl. J. of Public Opinion Research     Hybrid Journal   (Followers: 8, SJR: 0.906, h-index: 33)
Intl. J. of Refugee Law     Hybrid Journal   (Followers: 32, SJR: 0.231, h-index: 21)
Intl. J. of Transitional Justice     Hybrid Journal   (Followers: 13, SJR: 0.833, h-index: 12)
Intl. Mathematics Research Notices     Hybrid Journal   (Followers: 1, SJR: 2.052, h-index: 42)
Intl. Political Sociology     Hybrid Journal   (Followers: 30, SJR: 1.339, h-index: 19)
Intl. Relations of the Asia-Pacific     Hybrid Journal   (Followers: 17, SJR: 0.539, h-index: 17)
Intl. Studies Perspectives     Hybrid Journal   (Followers: 7, SJR: 0.998, h-index: 28)
Intl. Studies Quarterly     Hybrid Journal   (Followers: 36, SJR: 2.184, h-index: 68)
Intl. Studies Review     Hybrid Journal   (Followers: 17, SJR: 0.783, h-index: 38)
ISLE: Interdisciplinary Studies in Literature and Environment     Hybrid Journal   (Followers: 1, SJR: 0.155, h-index: 4)
ITNOW     Hybrid Journal   (Followers: 2, SJR: 0.102, h-index: 4)
J. of African Economies     Hybrid Journal   (Followers: 15, SJR: 0.647, h-index: 30)
J. of American History     Hybrid Journal   (Followers: 39, SJR: 0.286, h-index: 34)
J. of Analytical Toxicology     Hybrid Journal   (Followers: 13, SJR: 1.038, h-index: 60)
J. of Antimicrobial Chemotherapy     Hybrid Journal   (Followers: 17, SJR: 2.157, h-index: 149)
J. of Antitrust Enforcement     Hybrid Journal   (Followers: 1)
J. of Applied Poultry Research     Hybrid Journal   (Followers: 3, SJR: 0.563, h-index: 43)
J. of Biochemistry     Hybrid Journal   (Followers: 43, SJR: 1.341, h-index: 96)
J. of Chromatographic Science     Hybrid Journal   (Followers: 16, SJR: 0.448, h-index: 42)
J. of Church and State     Hybrid Journal   (Followers: 11, SJR: 0.167, h-index: 11)
J. of Competition Law and Economics     Hybrid Journal   (Followers: 34, SJR: 0.442, h-index: 16)
J. of Complex Networks     Hybrid Journal   (Followers: 1, SJR: 1.165, h-index: 5)
J. of Conflict and Security Law     Hybrid Journal   (Followers: 12, SJR: 0.196, h-index: 15)
J. of Consumer Research     Full-text available via subscription   (Followers: 41, SJR: 4.896, h-index: 121)
J. of Crohn's and Colitis     Hybrid Journal   (Followers: 9, SJR: 1.543, h-index: 37)
J. of Cybersecurity     Hybrid Journal   (Followers: 3)
J. of Deaf Studies and Deaf Education     Hybrid Journal   (Followers: 8, SJR: 0.69, h-index: 36)
J. of Design History     Hybrid Journal   (Followers: 15, SJR: 0.166, h-index: 14)
J. of Economic Entomology     Full-text available via subscription   (Followers: 6, SJR: 0.894, h-index: 76)
J. of Economic Geography     Hybrid Journal   (Followers: 34, SJR: 2.909, h-index: 69)
J. of Environmental Law     Hybrid Journal   (Followers: 23, SJR: 0.457, h-index: 20)
J. of European Competition Law & Practice     Hybrid Journal   (Followers: 19)
J. of Experimental Botany     Hybrid Journal   (Followers: 14, SJR: 2.798, h-index: 163)
J. of Financial Econometrics     Hybrid Journal   (Followers: 21, SJR: 1.314, h-index: 27)
J. of Global Security Studies     Hybrid Journal   (Followers: 2)
J. of Heredity     Hybrid Journal   (Followers: 3, SJR: 1.024, h-index: 76)
J. of Hindu Studies     Hybrid Journal   (Followers: 7, SJR: 0.186, h-index: 3)
J. of Hip Preservation Surgery     Open Access  
J. of Human Rights Practice     Hybrid Journal   (Followers: 20, SJR: 0.399, h-index: 10)
J. of Infectious Diseases     Hybrid Journal   (Followers: 40, SJR: 4, h-index: 209)
J. of Insect Science     Open Access   (Followers: 9, SJR: 0.388, h-index: 31)

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Journal Cover Journal of Antimicrobial Chemotherapy
  [SJR: 2.157]   [H-I: 149]   [17 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0305-7453 - ISSN (Online) 1460-2091
   Published by Oxford University Press Homepage  [370 journals]
  • Dr George N. Rolinson, 16 March 1926–8 December 2016
    • Authors: Geddes AM.
      First page: 1847
      PubDate: 2017-03-13
      DOI: 10.1093/jac/dkx075
       
  • Revisiting the mutant prevention concentration to guide dosing in
           childhood tuberculosis
    • Authors: Jaganath D; Schaaf H, Donald PR.
      First page: 1848
      Abstract: The mutant prevention concentration (MPC) is a well-known concept in the chemotherapy of many bacterial infections, but is seldom considered in relation to tuberculosis (TB) treatment, as the required concentrations are generally viewed as unachievable without undue toxicity. Early studies revealed single mutations conferring high MICs of first- and second-line anti-TB agents; however, the growing application of genomics and quantitative drug susceptibility testing in TB suggests a wide range of MICs often determined by specific mutations and strain type. In paediatric TB, pharmacokinetic studies indicate that despite increasing dose recommendations, a proportion of children still do not achieve adult-derived targets. When considering the next stage in anti-TB drug dosing and the introduction of novel therapies for children, we suggest consideration of MPC and its incorporation into pharmacokinetic studies to more accurately determine appropriate concentration targets in children, to restrict the growth of resistant mutants and better manage drug-resistant TB.
      PubDate: 2017-03-09
      DOI: 10.1093/jac/dkx051
       
  • Antibiotic exposure in neonates and early adverse outcomes: a systematic
           review and meta-analysis
    • Authors: Esaiassen E; Fjalstad J, Juvet L, et al.
      First page: 1858
      Abstract: Objectives: To systematically review and meta-analyse the relationship between antibiotic exposure in neonates and the following early adverse outcomes: necrotizing enterocolitis (NEC), invasive fungal infections (IFIs) and/or death.Methods: Data sources were PubMed, Embase, Medline and the Cochrane Database (to December 2016), supplemented by manual searches of reference lists. Randomized controlled trials (RCTs) and observational studies were included if they provided data on different categories of antibiotic exposures (yes versus no, long versus short duration, and/or broad- versus narrow-spectrum regimens) and the risk of developing NEC, IFI and/or death in the neonatal period. Two reviewers extracted data and evaluated the risk of bias using the Cochrane Handbook, adapted to include observational studies. When appropriate, meta-analyses were conducted using the random-effect model.Results: We identified 9 RCTs and 38 observational studies. The quality of the majority of studies was poor to moderate. There was a significant association between prolonged antibiotic exposure and an increased risk of NEC in five observational studies (5003 participants) and/or risk of death in five observational studies (13 534 participants). Eleven of 15 studies with data on broad- versus narrow-spectrum regimens reported an increased risk of IFI after broad-spectrum antibiotic exposure, in particular with third-generation cephalosporins and carbapenems. Meta-analysis was limited by few and old RCTs, insufficient sample sizes and diversity of antibiotic exposure and outcomes reported.Conclusions: Prolonged antibiotic exposure in uninfected preterm infants is associated with an increased risk of NEC and/or death, and broad-spectrum antibiotic exposure is associated with an increased risk of IFI.
      PubDate: 2017-03-24
      DOI: 10.1093/jac/dkx088
       
  • Adverse drug reactions during drug-resistant TB treatment in high HIV
           prevalence settings: a systematic review and meta-analysis
    • Authors: Schnippel K; Firnhaber C, Berhanu R, et al.
      First page: 1871
      Abstract: Objectives: To estimate the prevalence of adverse drug reactions or events (ADR) during drug-resistant TB (DR-TB) treatment in the context of settings with high HIV prevalence (at least 20% of patients).Methods: We conducted a systematic review and meta-analysis of articles in PubMed and Scopus. Pooled proportions of patients experiencing adverse events and relative risk with 95% CI were calculated.Results: The search yielded 24 studies, all observational cohorts. Ten reported on the number of patients experiencing ADR and were included in the meta-analysis representing 2776 study participants of whom 1943 were known to be HIV infected (70.0%). An average of 83% (95% CI: 82%–84%) of patients experienced one or more ADR. Among the seven articles (n = 664 study participants) with information on occurrence of severe ADR, 24% (95% CI: 21%–27%) of patients experienced at least one severe ADR during drug-resistant TB treatment. Sixteen of the 24 studies analysed the relative risk of ADR by HIV infection, nine of which found no statistically significant association between HIV infection and occurrence of drug-related ADR. There was insufficient information to disaggregate risk by concomitant treatment with HIV antiretrovirals or by immunosuppression (CD4 count).Conclusions: No randomized clinical trials were found for WHO-recommended treatment of drug-resistant TB treatment where at least 20% of the cohort was coinfected with HIV. Nearly all patients (83%) experience ADR during DR-TB treatment. While no significant association between ADR and HIV coinfection was found, further research is needed to determine whether concomitant antiretrovirals or immunosuppression increases the risks for HIV-infected patients.
      PubDate: 2017-04-16
      DOI: 10.1093/jac/dkx107
       
  • Secondary use of data from hospital electronic prescribing and pharmacy
           systems to support the quality and safety of antimicrobial use: a
           systematic review
    • Authors: Micallef C; Chaudhry NT, Holmes AH, et al.
      First page: 1880
      Abstract: Background: Electronic prescribing (EP) and electronic hospital pharmacy (EHP) systems are increasingly common. A potential benefit is the extensive data in these systems that could be used to support antimicrobial stewardship, but there is little information on how such data are currently used to support the quality and safety of antimicrobial use.Objectives: To summarize the literature on secondary use of data (SuD) from EP and EHP systems to support quality and safety of antimicrobial use, to describe any barriers to secondary use and to make recommendations for future work in this field.Methods: We conducted a systematic search within four databases; we included original research studies that were (1) based on SuD from hospital EP or EHP systems and (2) reported outcomes relating to quality and/or safety of antimicrobial use and/or qualitative findings relating to SuD in this context.Results: Ninety-four full-text articles were obtained; 14 met our inclusion criteria. Only two described interventions based on SuD; seven described SuD to evaluate other antimicrobial stewardship interventions and five described descriptive or exploratory studies of potential applications of SuD. Types of data used were quantitative antibiotic usage data (n = 9 studies), dose administration data (n = 4) and user log data from an electronic dashboard (n = 1). Barriers included data access, data accuracy and completeness, and complexity when using data from multiple systems or hospital sites.Conclusions: The literature suggests that SuD from EP and EHP systems is potentially useful to support or evaluate antimicrobial stewardship activities; greater system functionality would help to realize these benefits.
      PubDate: 2017-03-22
      DOI: 10.1093/jac/dkx082
       
  • Cross-resistance to lincosamides, streptogramins A and pleuromutilins in
           Streptococcus agalactiae isolates from the USA
    • Authors: Hawkins PA; Law CS, Metcalf BJ, et al.
      First page: 1886
      Abstract: Background:Streptococcus agalactiae (Group B Streptococcus, GBS) is a leading cause of meningitis, sepsis and pneumonia in neonates in the United States. GBS also causes invasive disease in older infants, pregnant women, children and young adults with underlying medical conditions, and older adults. Resistance to lincosamides in the absence of erythromycin resistance is rare in GBS, but has been previously reported in clinical isolates, both on its own or in combination with resistance to streptogramins A and pleuromutilins (L/LSA/LSAP phenotypes).Objectives: To retrospectively screen the Active Bacterial Core surveillance (ABCs) GBS isolate collection for these phenotypes in order to identify the causal genetic determinants and determine whether their frequency is increasing.Methods: Based on MIC data, 65 (0.31%) isolates susceptible to erythromycin (MIC ≤0.25 mg/L) and non-susceptible to clindamycin (MIC ≥0.5 mg/L) were identified among 21 186 GBS isolates. Genomic DNA was extracted and WGS was performed. The presence of 10 genes previously associated with LSA resistance was investigated by read mapping.Results: Forty-nine (75%) isolates carried the lsa(C) gene and expressed the LSAP phenotype, and 12 (18%) carried both the lnu(B) and lsa(E) genes and expressed the LSAP phenotype. The four remaining isolates were negative for all determinants investigated.Conclusions: While the overall observed frequency of these phenotypes among our GBS isolates was quite low (0.31%), this frequency has increased in recent years. To the best of our knowledge, this is the first time the LSAP phenotype has been reported among GBS isolates from the USA.
      PubDate: 2017-03-13
      DOI: 10.1093/jac/dkx077
       
  • Double mutation in DNA gyrase confers moxifloxacin resistance and
           decreased fitness of Mycobacterium smegmatis
    • Authors: Luo T; Yuan J, Peng X, et al.
      First page: 1893
      Abstract: Objectives: Ofloxacin and moxifloxacin are the most commonly used fluoroquinolones (FQs) for the treatment of tuberculosis. As a new generation FQ, moxifloxacin has been recommended for the treatment of ofloxacin-resistant TB. However, the mechanism by which ofloxacin-resistant Mycobacterium tuberculosis further gains resistance to moxifloxacin remains unclear.Methods: We used Mycobacterium smegmatis as a model for studying FQ resistance in M. tuberculosis. Moxifloxacin-resistant M. smegmatis was selected in vitro based on strains with primary ofloxacin resistance. The gyrA and gyrB genes of the resistant strains were sequenced to identify resistance-associated mutations. An in vitro competition assay was applied to explore the influence of gyrA/gyrB mutations on bacterial fitness. Finally, we evaluated the clinical relevance of our findings by analysing the WGS data of 1984 globally collected M. tuberculosis strains.Results: A total of 57 moxifloxacin-resistant M. smegmatis strains based on five ofloxacin-resistant strains were obtained. Sequencing results revealed that all moxifloxacin-resistant strains harboured second-step mutations in gyrA or gyrB. The relative fitnesses of the double-mutation strains varied from 0.65 to 0.93 and were mostly lower than those of their mono-mutation parents. From the genomic data, we identified 37 clinical M. tuberculosis strains harbouring double mutations in gyrA and/or gyrB and 36 of them carried at least one low-level FQ-resistance mutation.Conclusions: Double mutation in DNA gyrase leads to moxifloxacin resistance and decreased fitness in M. smegmatis. Under current dosing of moxifloxacin, double mutations mainly happened in M. tuberculosis strains with primary low-level resistance mutations.
      PubDate: 2017-04-06
      DOI: 10.1093/jac/dkx110
       
  • Examination of bedaquiline- and linezolid-resistant Mycobacterium
           tuberculosis isolates from the Moscow region
    • Authors: Zimenkov DV; Nosova Eu, Kulagina EV, et al.
      First page: 1901
      Abstract: Objectives: To study the isolates with acquired resistance to bedaquiline and linezolid that were obtained from patients enrolled in a clinical study of a novel therapy regimen for drug-resistant TB in Moscow, Russia.Methods: Linezolid resistance was detected using MGIT 960 with a critical concentration of 1 mg/L. The MIC of bedaquiline was determined using the proportion method. To identify genetic determinants of resistance, sequencing of the mmpR (Rv0678), atpE, atpC, pepQ, Rv1979c, rrl, rplC and rplD loci was performed.Results: A total of 85 isolates from 27 patients with acquired resistance to linezolid and reduced susceptibility to bedaquiline (MIC ≥0.06 mg/L) were tested. Most mutations associated with a high MIC of bedaquiline were found in the mmpR gene. We identified for the first time two patients whose clinical isolates had substitutions D28N and A63V in AtpE, which had previously been found only in in vitro-selected strains. Several patients had isolates with elevated MICs of bedaquiline prior to treatment; four of them also bore mutations in mmpR, indicating the presence of some hidden factors in bedaquiline resistance acquisition. The C154R substitution in ribosomal protein L3 was the most frequent in the linezolid-resistant strains. Mutations in the 23S rRNA gene (g2294a and g2814t) associated with linezolid resistance were also found in two isolates. Heteroresistance was identified in ∼40% of samples, which reflects the complex nature of resistance acquisition.Conclusions: The introduction of novel drugs into treatment must be accompanied by continuous phenotypic susceptibility testing and the analysis of genetic determinants of resistance.
      PubDate: 2017-04-06
      DOI: 10.1093/jac/dkx094
       
  • RCH51, a multiply antibiotic-resistant Acinetobacter baumannii ST103IP
           isolate, carries resistance genes in three plasmids, including a novel
           potentially conjugative plasmid carrying oxa235 in transposon Tn 6252
    • Authors: Hamidian M; Nigro SJ, Hartstein RM, et al.
      First page: 1907
      Abstract: Objectives: To determine the identity and context of genes conferring antibiotic resistance in a sporadic multiply antibiotic-resistant Acinetobacter baumannii recovered at Royal Children’s Hospital, Brisbane.Methods: The antibiotic resistance phenotype for 23 antibiotics was determined using disc diffusion or MIC determination. The whole-genome sequence of RCH51 was determined using the Illumina HiSeq platform. Antibiotic resistance determinants were identified using ResFinder. Plasmids were recovered by transformation.Results: Isolate RCH51 belongs to the uncommon STs ST103IP (7-3-2-1-7-1-4) and ST514OX (1-52-29-28-18-114-7). It was found to be resistant to sulfamethoxazole, tetracycline, gentamicin, tobramycin and kanamycin and also exhibited reduced susceptibility to imipenem (MIC 2 mg/L) and meropenem (MIC 6 mg/L). RCH51 carries the oxa235, sul2, floR, aadB and tet39 resistance genes, all located on plasmids. The largest of the three plasmids, pRCH51-3, is 52 789 bp and carries oxa235 in the ISAba1-bounded transposon Tn6252, as well as sul2 and floR. pRCH51-3 represents a new A. baumannii plasmid family that is potentially conjugative as it contains several genes predicted to encode transfer functions. However, conjugation of pRCH51-3 was not detected. The aadB and tet39 resistance genes were each found in small plasmids identical to the known plasmids pRAY*-v1 and pRCH52-1, respectively.Conclusions: The resistance gene complement of RCH51 was found in three plasmids. pRCH51-3, which carries the oxa235, sul2 and floR resistance genes, represents a new, potentially conjugative A. baumannii plasmid type.
      PubDate: 2017-03-13
      DOI: 10.1093/jac/dkx069
       
  • A combination of mecillinam and amoxicillin/clavulanate can restore
           susceptibility of high-level TEM-1-producing Escherichia coli to
           mecillinam
    • Authors: Birgy A; Delecourt M, Geslain G, et al.
      First page: 1911
      Abstract: Objectives: Mecillinam is recommended in France as a first-line treatment for lower urinary tract infections, due to the large increase in resistance of Escherichia coli to other oral treatments, such as co-trimoxazole or fluoroquinolones, its limited impact on faecal microbiota and its stability in the presence of numerous β-lactamases. However, we recently identified several mecillinam-resistant E. coli isolates with a high-level expression penicillinase (HEP) phenotype that merit further study.Patients and methods: We studied two isogenic clinical isolates from one patient (one susceptible to mecillinam and one resistant to mecillinam) by WGS to determine the mechanism of mecillinam resistance and compared it with other mecillinam-resistant E. coli. We evaluated the synergistic combination of amoxicillin/clavulanate and mecillinam using a simple test, suitable for daily laboratory practice, to determine the MIC of this combination.Results: We showed that the presence of an SNP in the promoter of the plasmidic TEM-1 β-lactamase gene is sufficient to confer resistance to mecillinam. This mechanism was present in 67% of HEP-phenotype E. coli tested. Combining mecillinam with amoxicillin/clavulanate abolished resistance, with an MIC compatible with clinical use. This association was not sensitive to the inoculum effect, in contrast to mecillinam alone.Conclusions: An HEP phenotype can confer mecillinam resistance in vitro. This resistance is abolished, regardless of the inoculum, by combining mecillinam with amoxicillin/clavulanate, and can be easily tested in the laboratory. This combination may be used as an oral relay treatment of non-complicated pyelonephritis due to multiresistant E. coli strains.
      PubDate: 2017-03-27
      DOI: 10.1093/jac/dkx087
       
  • Occurrence and molecular characteristics of ESBL/AmpC-producing
           Escherichia coli in faecal samples from horses in an equine clinic
    • Authors: Apostolakos I; Franz E, van Hoek AM, et al.
      First page: 1915
      Abstract: Objectives: To investigate the occurrence and characteristics of ESBL/AmpC-producing Escherichia coli in faecal samples from horses at one equine clinic in the Netherlands.Methods: A total of 91 horses, including residents and patients, were sampled. ESBL/AmpC-producing E. coli were identified by a combination disc diffusion test. Phylogenetic groups and MLST were determined. ESBL/AmpC genes were analysed using PCR and sequencing. Plasmids were characterized by transformation and PCR-based replicon typing. Subtyping of plasmids was done by plasmid MLST.Results: At least one E. coli isolate with a confirmed ESBL/AmpC gene was found in samples from 76 horses (84%). Although phylogenetic group B1 E. coli blaCTX-M-1 predominated, a diverse E. coli population was found, indicating that clonal nosocomial spread was not the only reason for the high occurrence found. MLST analysis revealed the presence of 47 E. coli STs, organized in four clusters of genetically related strains. ST10, ST641, ST1079 and ST1250 were most commonly found. With regard to the genes, blaCTX-M-1 was most prevalent (n = 91), followed by blaCTX-M-2 (n = 26). The most frequently found plasmid type was IncHI1, but plasmids belonging to the IncF, IncI1 and IncN groups were also identified.Conclusions: A high occurrence of ESBL-producing E. coli in faecal samples was found among horses in an equine clinic and the variety of STs, ESBL genes and plasmid types suggests nosocomial transmission. ESBL E. coli can cause difficult-to-treat infections in horses and prudent use of antimicrobials is warranted. A further assessment of the risks of transmission to persons in close contact with horses, such as caretakers or veterinarians, is crucial.
      PubDate: 2017-03-13
      DOI: 10.1093/jac/dkx072
       
  • WGS-based surveillance of third-generation cephalosporin-resistant
           Escherichia coli from bloodstream infections in Denmark
    • Authors: Roer L; Hansen F, Thomsen M, et al.
      First page: 1922
      Abstract: Objectives: To evaluate a genome-based surveillance of all Danish third-generation cephalosporin-resistant Escherichia coli (3GC-R Ec) from bloodstream infections between 2014 and 2015, focusing on horizontally transferable resistance mechanisms.Methods: A collection of 552 3GC-R Ec isolates were whole-genome sequenced and characterized by using the batch uploader from the Center for Genomic Epidemiology (CGE) and automatically analysed using the CGE tools according to resistance profile, MLST, serotype and fimH subtype. Additionally, the phylogenetic relationship of the isolates was analysed by SNP analysis.Results: The majority of the 552 isolates were ESBL producers (89%), with blaCTX-M-15 being the most prevalent (50%) gene, followed by blaCTX-M-14 (14%), blaCTX-M-27 (11%) and blaCTX-M-101 (5%). ST131 was detected in 50% of the E. coli isolates, with the remaining isolates belonging to 73 other STs, including globally disseminated STs (e.g. ST10, ST38, ST58, ST69 and ST410). Five of the bloodstream isolates were carbapenemase producers, carrying blaOXA-181 (3) and blaOXA-48 (2). Phylogenetic analysis revealed 15 possible national outbreaks during the 2 year period, one caused by a novel ST131/blaCTX-M-101 clone, here observed for the first time in Denmark. Additionally, the analysis revealed three individual cases with possible persistence of closely related clones collected more than 13 months apart.Conclusions: Continuous WGS-based national surveillance of 3GC-R Ec, in combination with more detailed epidemiological information, can improve the ability to follow the population dynamics of 3GC-R Ec, thus allowing for the detection of potential outbreaks and the effects of changing treatment regimens in the future.
      PubDate: 2017-03-22
      DOI: 10.1093/jac/dkx092
       
  • High ceftazidime hydrolysis activity and porin OmpK35 deficiency
           contribute to the decreased susceptibility to ceftazidime/avibactam in
           KPC-producing Klebsiella pneumoniae
    • Authors: Shen Z; Ding B, Ye M, et al.
      First page: 1930
      Abstract: Objectives: To investigate mechanisms for the decreased susceptibility to ceftazidime/avibactam in KPC-producing Klebsiella pneumoniae (KPC-KP).Methods: A total of 24 isolates, 8 each with ceftazidime/avibactam MICs of 4–8, 1–2 and ≤0.5 mg/L, were randomly selected from 214 clinical isolates of KPC-KP, and the β-lactamase hydrolysis activity and porin expression profiles were determined. Plasmid profile and relative expression and copy number of the blaKPC gene were also analysed.Results: Ceftazidime/avibactam MIC50 and MIC90 were 2 and 4 mg/L, respectively, for the 214 KPC-KP isolates. The hydrolysis activities of nitrocefin and ceftazidime in both of the ceftazidime/avibactam MIC 4–8 and 1–2 mg/L groups were significantly higher than those of the MIC ≤0.5 mg/L group, while the hydrolysis activities were 4–4.6-fold higher in the MIC 4–8 mg/L group than in the other two groups when 4 mg/L avibactam was added. The relative expression and copy number of the blaKPC gene in the MIC 4–8 mg/L group were 4.2–4.8-fold higher than in the other two groups. Meanwhile, SDS-PAGE showed that all isolates in the two groups with MIC ≥1 mg/L lacked OmpK35, which had either an early frameshift with a premature stop codon (n = 15, ST11) or overexpression of the negative regulation genes, micF and ompR (n = 1, ST15), whereas OmpK35 and OmpK36 could both be observed in all isolates with MIC ≤0.5 mg/L.Conclusions: Decreased ceftazidime/avibactam susceptibility in KPC-KP clinical isolates is caused by high ceftazidime hydrolysis activity and OmpK35 porin deficiency and the majority of isolates belong to ST11.
      PubDate: 2017-03-15
      DOI: 10.1093/jac/dkx066
       
  • WGS to predict antibiotic MICs for Neisseria gonorrhoeae
    • Authors: Eyre DW; De Silva D, Cole K, et al.
      First page: 1937
      Abstract: BackgroundTracking the spread of antimicrobial-resistant Neisseria gonorrhoeae is a major priority for national surveillance programmes.ObjectivesWe investigate whether WGS and simultaneous analysis of multiple resistance determinants can be used to predict antimicrobial susceptibilities to the level of MICs in N. gonorrhoeae.MethodsWGS was used to identify previously reported potential resistance determinants in 681 N. gonorrhoeae isolates, from England, the USA and Canada, with phenotypes for cefixime, penicillin, azithromycin, ciprofloxacin and tetracycline determined as part of national surveillance programmes. Multivariate linear regression models were used to identify genetic predictors of MIC. Model performance was assessed using leave-one-out cross-validation.ResultsOverall 1785/3380 (53%) MIC values were predicted to the nearest doubling dilution and 3147 (93%) within ±1 doubling dilution and 3314 (98%) within ±2 doubling dilutions. MIC prediction performance was similar across the five antimicrobials tested. Prediction models included the majority of previously reported resistance determinants. Applying EUCAST breakpoints to MIC predictions, the overall very major error (VME; phenotypically resistant, WGS-prediction susceptible) rate was 21/1577 (1.3%, 95% CI 0.8%–2.0%) and the major error (ME; phenotypically susceptible, WGS-prediction resistant) rate was 20/1186 (1.7%, 1.0%–2.6%). VME rates met regulatory thresholds for all antimicrobials except cefixime and ME rates for all antimicrobials except tetracycline. Country of testing was a strongly significant predictor of MIC for all five antimicrobials.ConclusionsWe demonstrate a WGS-based MIC prediction approach that allows reliable MIC prediction for five gonorrhoea antimicrobials. Our approach should allow reasonably precise prediction of MICs for a range of bacterial species.
      PubDate: 2017-03-10
      DOI: 10.1093/jac/dkx067
       
  • Evaluation of the AID carbapenemase line probe assay for rapid detection
           and identification of carbapenemase genes in Gram-negative bacilli
    • Authors: Bloemberg GV; Braun-Kiewnick A, Tedrup J, et al.
      First page: 1948
      Abstract: Objectives: This study evaluated the AID carbapenemase line probe assay (LPA) for the detection and identification of carbapenem resistance genes in Enterobacteriaceae and other Gram-negative bacilli (GNB) using bacterial cultures and DNA extracts directly from patient urine samples.Methods: The AID carbapenemase LPA detects 13 different carbapenemase genes. Test probe accuracy was verified for using clinical Enterobacteriaceae isolates harbouring blaKPC, blaVIM, blaNDM, blaGIM, blaAIM, blaSPM, blaIMP and blaOXA-48 and a well-characterized set of Escherichia coli DH5α strains transformed with the vector plasmid pUC57-kan harbouring blaBIC, blaSIM, blaDIM, blaIMI-3, blaIMI-1 and blaNMC-A. Sensitivity and specificity was determined by testing 151 clinical GNB strains previously characterized for the production of carbapenemase activity and carbapenemase genes. Direct detection of carbapenemase genes using the LPA was determined using 299 clinical urine specimens. Analytical sensitivity for detection in urine was determined by testing serial dilutions of blaKPC and blaNDM in clinical Klebsiella pneumoniae strains.Results: All carbapenemase gene probes showed 100% accuracy without cross-reactions. Sensitivity and specificity of the LPA using clinical isolates was 100% for each. Analytical sensitivity for detection of blaKPC and blaNDM in urine was 101–102 cfu. The LPA detected carbapenemase genes in 20 urines, which were confirmed in 12 samples by conventional multiplex PCR. Remarkably, 0 of the 20 urines grew carbapenemase-suspicious GNB applying EUCAST recommendations.Conclusions: The AID carbapenemase LPA is an accurate, sensitive and easy-to-use test for the detection and identification of carbapenemase genes, which can readily be implemented in any diagnostic laboratory.
      PubDate: 2017-04-11
      DOI: 10.1093/jac/dkx100
       
  • Prospective evaluation of the OKN K- SeT assay, a new multiplex
           immunochromatographic test for the rapid detection of OXA-48-like, KPC and
           NDM carbapenemases
    • Authors: Glupczynski Y; Jousset A, Evrard S, et al.
      First page: 1955
      Abstract: Objectives: There is an urgent need for accurate and fast diagnostic tests capable of identifying carbapenemase producers. Here, we assessed the performance of a new multiplex lateral flow assay (OKN K-SeT) for the rapid detection of OXA-48-like, KPC and NDM carbapenemase-producing Enterobacteriaceae from culture colonies.Methods: Two hundred collection isolates with characterized β-lactamase content and 183 non-duplicate consecutive isolates referred to two National Reference Centres over a 2 month period in 2016 were used to evaluate the OKN K-SeT assay.Results: The assay correctly detected all 42 OXA-48-like-, 27 KPC- and 30 NDM-producing isolates from the collection panel, including 7 isolates that co-produced NDM and OXA-181 carbapenemases. No cross-reactivity was observed with non-targeted carbapenemases (n = 41) or with non-carbapenemase producers (n = 60). Prospectively, all OXA-48-like (n = 69), KPC (n = 9) and NDM (n = 19) carbapenemase-producing Enterobacteriaceae isolates were correctly detected, while 11 carbapenemase producers not targeted by the assay went undetected [VIM (n = 8) and OXA-23/OXA-58-like (n = 3)]. Overall, the sensitivity and specificity of the assay were 100%.Conclusions: The OKN assay is efficient, rapid and easy to implement in the workflow of a clinical microbiology laboratory for the confirmation of OXA-48, NDM and KPC carbapenemases. This test represents a powerful diagnostic tool as it enables the rapid detection of the most clinically important carbapenemases without the need for more costly and less frequently available molecular assays.
      PubDate: 2017-03-22
      DOI: 10.1093/jac/dkx089
       
  • A new rapid resazurin-based microdilution assay for antimicrobial
           susceptibility testing of Neisseria gonorrhoeae
    • Authors: Foerster S; Desilvestro V, Hathaway LJ, et al.
      First page: 1961
      Abstract: Objectives: Rapid, cost-effective and objective methods for antimicrobial susceptibility testing of Neisseria gonorrhoeae would greatly enhance surveillance of antimicrobial resistance. Etest, disc diffusion and agar dilution methods are subjective, mostly laborious for large-scale testing and take ∼24 h. We aimed to develop a rapid broth microdilution assay using resazurin (blue), which is converted into resorufin (pink fluorescence) in the presence of viable bacteria.Methods: The resazurin-based broth microdilution assay was established using 132 N. gonorrhoeae strains and the antimicrobials ceftriaxone, cefixime, azithromycin, spectinomycin, ciprofloxacin, tetracycline and penicillin. A regression model was used to estimate the MICs. Assay results were obtained in ∼7.5 h.Results: The EC50 of the dose–response curves correlated well with Etest MIC values (Pearson’s r = 0.93). Minor errors resulting from misclassifications of intermediate strains were found for 9% of the samples. Major errors (susceptible strains misclassified as resistant) occurred for ceftriaxone (4.6%), cefixime (3.3%), azithromycin (0.6%) and tetracycline (0.2%). Only one very major error was found (a ceftriaxone-resistant strain misclassified as susceptible). Overall the sensitivity of the assay was 97.1% (95% CI 95.2–98.4) and the specificity 78.5% (95% CI 74.5–82.9).Conclusions: A rapid, objective, high-throughput, quantitative and cost-effective broth microdilution assay was established for gonococci. For use in routine diagnostics without confirmatory testing, the specificity might remain suboptimal for ceftriaxone and cefixime. However, the assay is an effective low-cost method to evaluate novel antimicrobials and for high-throughput screening, and expands the currently available methodologies for surveillance of antimicrobial resistance in gonococci.
      PubDate: 2017-04-19
      DOI: 10.1093/jac/dkx113
       
  • The novel oral glucan synthase inhibitor SCY-078 shows in vitro activity
           against sessile and planktonic Candida spp.
    • Authors: Marcos-Zambrano L; Gómez-Perosanz M, Escribano P, et al.
      First page: 1969
      Abstract: Objectives: We studied the antifungal activity of SCY-078 (an orally bioavailable 1,3-β-d-glucan synthesis inhibitor), micafungin and fluconazole against the planktonic and sessile forms of 178 Candida and non-Candida isolates causing fungaemia in patients recently admitted to a large European hospital.Methods: The in vitro activity of SCY-078, micafungin and fluconazole against the planktonic form of the isolates was assessed using EUCAST EDef 7.3 and CLSI M27-A3. Antibiofilm activity was assessed using the XTT reduction assay.Results: SCY-078 and micafungin showed potent in vitro activity against Candida and non-Candida isolates. The in vitro activity of both drugs was similar, but SYC-078 displayed significantly lower MIC values than micafungin against Candida parapsilosis and non-Candida isolates, whereas micafungin displayed significantly lower MIC values for the remaining species (P <0.001). In contrast, SCY-078 and micafungin showed essentially the same activity against the biofilms with the exception of Candida glabrata, in which the micafungin sessile MIC values were significantly lower (P <0.001). These observations were confirmed by assessing biofilm structure by scanning electron microscopy after antifungal treatment.Conclusions: Our study showed that the high in vitro activity of SCY-078 against invasive Candida isolates in both sessile and planktonic forms is comparable to that of micafungin.
      PubDate: 2017-04-26
      DOI: 10.1093/jac/dkx010
       
  • Dihydroorotate dehydrogenase inhibitor F901318 has potent in vitro
           activity against Scedosporium species and Lomentospora prolificans
    • Authors: Wiederhold NP; Law D, Birch M.
      First page: 1977
      Abstract: Background:Scedosporium species and Lomentospora prolificans are increasing causes of invasive infections in immunocompromised hosts and many isolates are resistant to available antifungals. Our objective was to assess the in vitro potency of F901318, a member of the orotomide class of antifungals, against Scedosporium species and L. prolificans.Methods: The in vitro potency of F901318 was evaluated against 66 Scedosporium and 7 L. prolificans clinical isolates using the CLSI M38-A2 reference standard. Scedosporium species included Scedosporium apiospermum (n = 43), Scedosporium aurantiacum (n = 6), Scedosporium dehoogii (n = 2) and Scedosporium boydii (n = 15). Positive comparators included amphotericin B, caspofungin, posaconazole and voriconazole.Results: Against S. apiospermum and S. boydii F901318 geometric mean MICs/MECs (0.079 and 0.046 mg/L, respectively) were significantly lower than those observed with amphotericin (3.404 and 5.595 mg/L), posaconazole (1.937 and 1.823 mg/L), voriconazole (0.784 and 0.630 mg/L) and caspofungin (5.703 and 7.639 mg/L) (P < 0.001). Against S. aurantiacum and S. dehoogii the F901318 MIC range (0.12–0.5 mg/L) was also lower than those for the other antifungals (0.5 to >8 mg/L). F901318 also maintained activity against L. prolificans isolates (range 0.12–0.25 mg/L) in contrast to other antifungals, of which none demonstrated in vitro activity.Conclusions: F901318 demonstrated potent in vitro activity against Scedosporium species and L. prolificans. This activity was maintained against isolates that had significantly reduced susceptibility to the other antifungals. Further studies are warranted to evaluate the in vivo efficacy of F901318 against Scedosporium species and L. prolificans.
      PubDate: 2017-03-15
      DOI: 10.1093/jac/dkx065
       
  • In vitro evaluation of different antimicrobial combinations against
           carbapenemase-producing Klebsiella pneumoniae : the activity of the
           double-carbapenem regimen is related to meropenem MIC value
    • Authors: Oliva AA; Scorzolini LL, Cipolla AA, et al.
      First page: 1981
      Abstract: Objectives and methods: We evaluated the in vitro activity of different antimicrobial combinations with and without colistin against 39 carbapenem-resistant Klebsiella pneumoniae (CR-Kp) strains (colistin + meropenem/doripenem, colistin + tigecycline, colistin + rifampicin, gentamicin + meropenem, gentamicin + tigecycline and the double-carbapenem regimen meropenem + ertapenem) using the chequerboard method. The triple combination colistin + meropenem + tigecycline was also tested. In addition, killing studies were performed for meropenem + ertapenem.Results: Gentamicin-based combinations showed a high level of synergy. Meropenem + ertapenem was synergic in 12/39 (30.7%) of the strains, whereas based on killing studies 1 × MIC meropenem + 1 × MIC ertapenem and 2 × MIC meropenem + 1 × MIC ertapenem combinations were bactericidal and synergic at 24 h [mean area under the bactericidal curve (AUBC) 54.9 ± 26.1 and 44.2 ± 15.3 compared with 1 × MIC meropenem (134.5 ± 40.1) and 2 × MIC meropenem (126.4 ± 5.4), respectively, P < 0.0001]. When the results were stratified according to meropenem MIC, we found that the degree of synergy significantly increased for isolates with lower meropenem (and not ertapenem) MICs, up to an MIC of 128 mg/L. Among colistin-containing combinations, synergy was observed in 18/39 (46.1%), 33/34 (97%), 24/39 (61.5%) and 17/39 (43.5%) of the strains for colistin + meropenem, colistin + rifampicin, colistin + tigecycline and colistin + doripenem, respectively, including colistin-resistant strains. Colistin + meropenem + tigecycline at subinhibitory concentrations resulted in the absence of growth of 37/39 strains (94.8%).Conclusions: Our in vitro data suggest that colistin might be a valid therapeutic option against CR-Kp, even in the presence of colistin resistance, whereas the double-carbapenem regimen represents a viable option when colistin is not recommended, especially if the meropenem MIC is ≤ 128 mg/L. Since traditional antimicrobial susceptibility reports are not sufficiently informative for clinicians, synergy testing as well as actual meropenem MIC evaluation should always be performed in the case of CR-Kp infections.
      PubDate: 2017-03-22
      DOI: 10.1093/jac/dkx084
       
  • Pharmacodynamics of colistin and fosfomycin: a ‘treasure trove’
           combination combats KPC-producing Klebsiella pneumoniae
    • Authors: Zhao M; Bulman ZP, Lenhard JR, et al.
      First page: 1985
      Abstract: Objectives: KPC-producing Klebsiella pneumoniae are an emerging public health problem around the globe. We defined the combinatorial pharmacodynamics and ability to suppress resistance of two ‘old’ antibiotics, fosfomycin and colistin, in time–kill experiments and hollow-fibre infection models (HFIM).Methods: Two KPC-2-producing K. pneumoniae isolates were used: one susceptible to both colistin and fosfomycin (KPC 9A: MICcolistin 0.25 mg/L and MICfosfomycin ≤8 mg/L) and the other resistant to colistin and susceptible to fosfomycin (KPC 5A: MICcolistin 64 mg/L and MICfosfomycin 32 mg/L). Time–kill experiments assessed an array of colistin and fosfomycin concentrations against both isolates. Colistin and fosfomycin pharmacokinetics from critically ill patients were simulated in the HFIM to define the pharmacodynamic activity of humanized regimens over 5 days against KPC 9A.Results: In time–kill experiments, synergy was demonstrated for all colistin/fosfomycin combinations containing >8 mg/L fosfomycin against the double-susceptible KPC strain, 9A. Synergy versus KPC strain 5A was only achieved at the highest concentrations of colistin (4 mg/L) and fosfomycin (512 mg/L) at 48 h. In the HFIM, colistin or fosfomycin monotherapies resulted in rapid proliferation of resistant subpopulations; KPC 9A regrew by 24 h. In contrast to the monotherapies, the colistin/fosfomycin combination resulted in a rapid 6.15 log10 cfu/mL reduction of KPC 9A by 6 h and complete suppression of resistant subpopulations until 120 h.Conclusions: Colistin and fosfomycin may represent an important treatment option for KPC-producing K. pneumoniae otherwise resistant to traditional antibiotics.
      PubDate: 2017-04-21
      DOI: 10.1093/jac/dkx070
       
  • Studying the effect of administration route and treatment dose on the
           selection of enrofloxacin resistance in commensal Escherichia coli in
           broilers
    • Authors: Chantziaras I; Smet A, Haesebrouck F, et al.
      First page: 1991
      Abstract: Objectives: Factors potentially contributing to fluoroquinolone resistance selection in commensal Escherichia coli strains in poultry were studied through a series of in vivo experiments. The effect of the initial prevalence of enrofloxacin resistance in the E. coli gut microbiota, effect of the bacterial fitness of the enrofloxacin-resistant strain and effect of treatment with enrofloxacin (effect of dose and effect of route of administration) were assessed.Methods: Four in vivo studies with broiler chickens were performed. Right after hatching, the chicks were inoculated with either a bacteriologically fit or a bacteriologically non-fit fluoroquinolone-resistant strain as either a minority or the majority of the total E. coli population. Six days later, the chicks were treated for three consecutive days either orally or parenterally and using three different doses (under-, correct- and over-dose) of enrofloxacin. The faecal shedding of E. coli strains was quantified by plating on agar plates either supplemented or not supplemented with enrofloxacin. Linear mixed models were used to assess the effect of the aforementioned variables on the selection of enrofloxacin resistance.Results: The factors that significantly contributed were treatment (P < 0.001), bacterial fitness of the resistant donor strain (P < 0.001), administration route (P = 0.052) and interactions between bacterial fitness and administration route (P < 0.001).Conclusions: In the currently used models, fluoroquinolone resistance selection was influenced by treatment, bacterial fitness of the inoculation strain and administration route. The use of oral treatment seems to select more for fluoroquinolone resistance, particularly in the model where a non-fit strain was used for inoculation.
      PubDate: 2017-04-16
      DOI: 10.1093/jac/dkx104
       
  • Dose optimization of piperacillin/tazobactam in critically ill children
    • Authors: De Cock PG; van Dijkman SC, de Jaeger A, et al.
      First page: 2002
      Abstract: Objectives: To characterize the population pharmacokinetics of piperacillin and tazobactam in critically ill infants and children, in order to develop an evidence-based dosing regimen.Patients and methods: This pharmacokinetic study enrolled patients admitted to the paediatric ICU for whom intravenous piperacillin/tazobactam (8:1 ratio) was indicated (75 mg/kg every 6 h based on piperacillin). Piperacillin/tazobactam concentrations were measured by an LC–MS/MS method. Pharmacokinetic data were analysed using non-linear mixed effects modelling.Results: Piperacillin and tazobactam blood samples were collected from 47 patients (median age 2.83 years; range 2 months to 15 years). Piperacillin and tazobactam disposition was best described by a two-compartment model that included allometric scaling and a maturation function to account for the effect of growth and age. Mean clearance estimates for piperacillin and tazobactam were 4.00 and 3.01 L/h for a child of 14 kg. Monte Carlo simulations showed that an intermittent infusion of 75 mg/kg (based on piperacillin) every 4 h over 2 h, 100 mg/kg every 4 h given over 1 h or a loading dose of 75 mg/kg followed by a continuous infusion of 300 mg/kg/24 h were the minimal requirements to achieve the therapeutic targets for piperacillin (60% fT>MIC >16 mg/L).Conclusions: Standard intermittent dosing regimens do not ensure optimal piperacillin/tazobactam exposure in critically ill patients, thereby risking treatment failure. The use of a loading dose followed by a continuous infusion is recommended for treatment of severe infections in children >2 months of age.
      PubDate: 2017-04-06
      DOI: 10.1093/jac/dkx093
       
  • Activity of faropenem with and without rifampicin against Mycobacterium
           tuberculosis : evaluation in a whole-blood bactericidal activity trial
    • Authors: Gurumurthy M; Verma R, Naftalin CM, et al.
      First page: 2012
      Abstract: Background: Faropenem has in vitro activity against Mycobacterium tuberculosis (Mtb) and shows synergy with rifampicin. We tested this in a whole-blood bactericidal activity (WBA) trial.Methods: We randomized healthy volunteers to receive a single oral dose of faropenem (600 mg) with amoxicillin/clavulanic acid (500/125 mg) (n = 8), rifampicin (10 mg/kg) (n = 14) or the combination rifampicin + faropenem + amoxicillin/clavulanic acid (n = 14). Blood was drawn at intervals to 8 h post-dose. Drug levels were measured using LC–tandem MS. WBA was measured by inoculating blood samples with Mtb and estimating the change in bacterial cfu after 72 h. Trial registration: ClinicalTrials.gov (NCT02393586).Results: There was no activity in the faropenem + amoxicillin/clavulanic acid group (cumulative WBA 0.02 Δlog cfu; P = 0.99 versus zero change). There was a suggestion of a trend favouring the rifampicin + faropenem + amoxicillin/clavulanic acid group at 8 h (cumulative WBA −0.19 ± 0.03 and −0.26 ± 0.03 Δlog cfu in the rifampicin and rifampicin + faropenem + amoxicillin/clavulanic acid groups, respectively; P = 0.180), which was significant in the first hour post-dose (P = 0.032). Faropenem Cmax and AUC were 5.4 mg/L and 16.2 mg·h/L, respectively, and MIC for Mtb H37Rv was 5–10 mg/L.Conclusions: Faropenem is not active when used alone, possibly due to inadequate plasma levels relative to MIC. However, there was a suggestion of modest synergy with rifampicin that may merit further testing in clinical trials.
      PubDate: 2017-03-18
      DOI: 10.1093/jac/dkx081
       
  • Markers of gut dysfunction do not explain low rifampicin bioavailability
           in HIV-associated TB
    • Authors: Vinnard C; Ravimohan S, Tamuhla N, et al.
      First page: 2020
      Abstract: Background: Rifampicin is the key drug responsible for sterilizing activities in the first-line TB treatment regimen. Damage to the gut during acute and chronic HIV infection may inhibit drug absorptive capacity. We sought to test the hypothesis that markers of intestinal damage, bacterial translocation and systemic immune activation would relate to rifampicin bioavailability among HIV/TB patients.Patients and methods: We conducted a prospective cohort study of rifampicin pharmacokinetics in HIV/TB patients in Gaborone, Botswana. We performed two intensively sampled pharmacokinetic visits, before and after ART initiation. Non-linear mixed-effects modelling was performed to determine whether variability in markers of gut damage, microbial translocation or systemic immune activation contributed to variability in rifampicin bioavailability before and after the initiation of ART.Results: We enrolled 40 HIV/TB patients in the first pharmacokinetic visit and 24 patients returned for the second pharmacokinetic visit after initiating ART. Low rifampicin exposure, as defined by the maximum serum concentration, was observed in 40% of patients prior to initiating ART and 46% of patients after initiating ART. In the non-linear mixed-effects model, we did not observe significant covariate effects of markers of gut damage, microbial translocation or immune activation on rifampicin bioavailability before and after ART initiation.Discussion: Markers of intestinal damage, microbial translocation and systemic immune activation did not explain variability in rifampicin bioavailability. The a priori identification of HIV/TB patients at risk for low rifampicin concentrations remains a challenge, supporting a role for therapeutic drug monitoring during HIV/TB therapy.
      PubDate: 2017-05-02
      DOI: 10.1093/jac/dkx111
       
  • Prevention of TB using rifampicin plus isoniazid reduces nevirapine
           concentrations in HIV-exposed infants
    • Authors: McIlleron H; Denti P, Cohn S, et al.
      First page: 2028
      Abstract: Background: Newborns of HIV-infected mothers are given daily doses of nevirapine to prevent HIV-1 acquisition. Infants born to mothers with TB should also receive TB preventive therapy. TB preventive regimens include isoniazid for 6 months or rifampicin plus isoniazid for 3 months (RH preventive therapy). The effect of concomitant RH preventive therapy on nevirapine concentrations in infants is unknown.Patients and methods: Tshepiso was a prospective case–control cohort study of pregnant HIV-infected women with and without TB whose newborn infants received standard doses of nevirapine for HIV prophylaxis. Infants born to mothers with TB also received RH preventive therapy. Infant plasma nevirapine concentrations were measured at 1 and 6 weeks. The effects of RH preventive therapy on nevirapine disposition were investigated in a population pharmacokinetic model.Results: Of 164 infants undergoing pharmacokinetic sampling, 46 received RH preventive therapy. After adjusting for weight using allometric scaling, the model estimated a 33% reduction in nevirapine trough concentrations with RH preventive therapy compared with TB-unexposed infants not receiving concomitant rifampicin and a 30% decline in trough concentrations in a typical infant between day 7 and 35 post-partum.Conclusions: Rifampicin-based TB preventative treatment reduces nevirapine concentrations significantly in HIV-exposed infants. Although the nevirapine exposures required to prevent HIV acquisition in breastfeeding infants are undefined, given the potential risks associated with underdosing nevirapine in this setting, it is prudent to avoid rifampicin-based preventive therapy in HIV-exposed children receiving prophylactic nevirapine.
      PubDate: 2017-04-16
      DOI: 10.1093/jac/dkx112
       
  • Once-daily atazanavir/cobicistat and darunavir/cobicistat exposure over
           72 h post-dose in plasma, urine and saliva: contribution to drug
           pharmacokinetic knowledge
    • Authors: Elliot ER; Amara A, Pagani N, et al.
      First page: 2035
      Abstract: Background: We investigated the pharmacokinetics (PK) of atazanavir/cobicistat and darunavir/cobicistat once daily over 72 h following drug intake cessation in plasma, saliva and urine.Methods: Healthy volunteers received a fixed-dose combination of 300/150 mg of atazanavir/cobicistat once daily for 10 days, followed by a 10 day washout period and then a fixed-dose combination of 800/150 mg of darunavir/cobicistat once daily for 10 days. Full PK profiles were assessed for each phase for 72 h following day 10 and parameters determined to the last measurable concentration in plasma, saliva and urine by non-compartmental methods.Results: Sixteen subjects completed the study. Geometric mean (GM) terminal elimination half-life values to 72 h of atazanavir and darunavir were 6.77 and 6.35 h, respectively. All subjects had atazanavir concentrations above the suggested minimum effective concentration of 150 ng/mL 24 h post-dose and 14/16 subjects had concentrations higher than this target at 30 h post-dose (GM of 759 and 407 ng/mL, respectively). Thirteen out of 16 subjects had darunavir concentrations higher than the target of 550 ng/mL at 24 h post-dose and 5/16 subjects had concentrations higher than the target at 30 h post-dose (GM of 1033 and 382 ng/mL, respectively). Cobicistat half-life to 72 h was 4.21 h with atazanavir and 3.62 h with darunavir. GM values 24 h after the observed dose (C24) for atazanavir and darunavir were 141 and 43 ng/mL, respectively, in saliva and 24857 and 11878 ng/mL, respectively, in urine. Concentration decay in saliva/urine mirrored plasma concentrations for both drugs.Conclusions: Different concentration decay patterns were seen for atazanavir and darunavir, which may be partially explained by cobicistat half-life (longer with atazanavir than darunavir). For the first time, we also measured drug PK forgiveness in saliva and urine, which represent easier markers of adherence.
      PubDate: 2017-04-12
      DOI: 10.1093/jac/dkx108
       
  • Bone mineral density reductions after tenofovir disoproxil fumarate
           initiation and changes in phosphaturia: a secondary analysis of ACTG
           A5224s
    • Authors: Gupta SK; Yeh E, Kitch DW, et al.
      First page: 2042
      Abstract: Background: It is unknown if the greater reductions in bone mineral density (BMD) associated with initiation of tenofovir disoproxil fumarate compared with abacavir in previously untreated HIV-infected participants in the ACTG A5224s clinical trial were associated with potentially worsening tenofovir-related phosphaturia.Methods: We correlated changes in BMD at the hip and spine with changes in phosphaturia [transtubular reabsorption of phosphorus (TRP) and tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR)] from entry through week 96 in those initiating tenofovir (n = 134) versus abacavir (n = 135) with efavirenz or atazanavir/ritonavir in A5224s. We also correlated changes in BMD with tenofovir AUC measured between weeks 4 and 24.Results: Changes in TRP and TmP/GFR through week 96 between the tenofovir and abacavir arms were not significantly different (both P ≥ 0.70) and did not differ with use of efavirenz versus atazanavir/ritonavir. There were no significant correlations between changes in either TRP or TmP/GFR and with either hip or spine BMD in the tenofovir arms. Tenofovir AUC was significantly correlated with changes in hip BMD, but not spine BMD, at week 24 (r = −0.22, P = 0.028) and week 48 (r = −0.26, P = 0.010), but not at week 96 (r = −0.14, P = 0.18).Conclusions: Changes in phosphaturia were not different between the tenofovir and abacavir arms in A5224s. Changes in hip and spine BMD with tenofovir were not related to changes in phosphaturia. However, tenofovir exposure was weakly associated with changes in hip BMD through week 48.
      PubDate: 2017-03-20
      DOI: 10.1093/jac/dkx076
       
  • Variable endothelial cell function restoration after initiation of two
           antiretroviral regimens in HIV-infected individuals
    • Authors: Echeverría PP; Gómez-Mora EE, Roura SS, et al.
      First page: 2049
      Abstract: Background: The effect of ART on endothelial cell function is incompletely characterized.Methods: We performed a 24 week prospective, case–control and comparative pilot study of ART-naive HIV-infected patients who started a darunavir- or rilpivirine-based regimen, matched with non-HIV-infected volunteers, to compare changes at week 24 from baseline in levels of circulating endothelial cells (CECs), endothelial progenitor cells (EPCs) and circulating angiogenic cells, as well as changes in immune-activation markers.Results: The study population comprised 24 HIV-infected patients and 24 non-infected volunteers. Both HIV groups completely suppressed viraemia. HIV-infected patients had higher levels of activation markers than the control group in CD8 T cells at baseline; these decreased after 24 weeks of treatment, but without reaching the levels of the control group. No statistical differences in immune activation were seen between the darunavir and rilpivirine groups. Levels of CECs were higher and levels of EPCs and circulating angiogenic cells were lower in HIV-infected patients than in the control group, although these parameters were similar between the darunavir group and the control group, but not the rilpivirine group, at week 24. An unfavourable association was observed between rilpivirine, age and increased number of CECs.Conclusions: Restoration of circulating levels of EPCs and CECs in darunavir-treated patients was greater than in those treated with rilpivirine, suggesting ongoing endothelial repair mechanisms.
      PubDate: 2017-03-22
      DOI: 10.1093/jac/dkx074
       
  • Evolution of blood-associated HIV-1 DNA levels after 48 weeks of switching
           to atazanavir/ritonavir+lamivudine dual therapy versus continuing triple
           therapy in the randomized AtLaS-M trial
    • Authors: Lombardi F; Belmonti S, Quiros-Roldan E, et al.
      First page: 2055
      Abstract: Objectives: The AtLaS-M randomized trial showed that in patients with HIV-1 RNA <50 copies/mL on atazanavir/ritonavir + two NRTIs, switching to a dual therapy with atazanavir/ritonavir+lamivudine had superior efficacy as compared with continuing the previous triple therapy. This substudy was designed to evaluate at 48 weeks the impact of the dual therapy versus the three-drug atazanavir/ritonavir-based therapy on the HIV-1 cellular reservoir as reflected by the quantification of blood-associated HIV-1 DNA levels.Methods: In a representative subset of 201 of 266 randomized patients (104 in the dual-therapy arm and 97 in the triple-therapy arm) total HIV-1 DNA levels in whole blood at baseline and after 48 weeks and factors associated with the HIV-1 DNA levels were evaluated.Results: The mean baseline HIV-1 DNA levels (2.47 log10 copies/106 leucocytes) were comparable between arms. A significant mean decrease between baseline and week 48 was observed: −0.069 log10 copies/106 leucocytes in the dual-therapy arm (P = 0.046) and −0.078 in the triple-therapy arm (P = 0.011); the mean difference between arms was −0.009 (P = 0.842). Nadir CD4 count was inversely correlated with baseline HIV-1 DNA (P = 0.009); longer duration of ART and lower nadir CD4 correlated with a less prominent HIV-1 DNA decrease (both P < 0.005). Higher baseline HIV-1 DNA was associated with residual viraemia at week 48 (P = 0.031).Conclusions: When compared with continuing three-drug therapy, atazanavir/ritonavir+lamivudine dual therapy resulted in a similar decline in HIV-1 DNA levels in patients with sustained virological suppression. These data support the safety of this simplified treatment strategy in terms of its effect on the cellular HIV-1 reservoir.
      PubDate: 2017-03-10
      DOI: 10.1093/jac/dkx068
       
  • Switching to second-line ART in relation to mortality in a large Tanzanian
           HIV cohort
    • Authors: Hawkins C; Hertzmark E, Spiegelman D, et al.
      First page: 2060
      Abstract: Objectives: In a large cohort of HIV-infected Tanzanians, we assessed: (i) rates of first-line treatment failure and switches to second-line ART; (ii) the effect of switching to second-line ART on death and loss to follow-up; and (iii) treatment outcomes on second-line ART by regimen.Methods: HIV-1-infected adults (≥15 years) initiated on first-line ART between November 2004 and September 2012, and who remained on initial therapy for at least 24 weeks before switching, were studied. Survival analyses were conducted to examine the effect of second-line ART on mortality and loss to follow-up in: (i) the whole cohort; (ii) all patients eligible for second-line ART by immunological failure (IF) and/or virological failure (VF) criteria; and (iii) patients eligible by VF criteria.Results: In total, 47 296 HIV-infected patients [mean age 37.5 (SD 9.5) years, CD4 175 (SD 158) cells/mm3, 71% female] were included in the analyses. Of these, 1760 (3.7%) patients switched to second-line ART (incidence rate = 1.7/100 person-years). Higher rates of mortality were observed in switchers versus non-switchers in all patients and patients with ART failure using IF/VF criteria. Switching only protected against mortality in patients with ART failure defined virologically and with the highest level of adherence [switching versus non-switching; >95% adherence; adjusted HR = 0.50 (95% CI = 0.26–0.93); P = 0.03].Conclusions: Switching patients to second-line ART may only be beneficial in a select group of patients who are virologically monitored and demonstrate good adherence. Our data emphasize the need for routine viral load monitoring and aggressive adherence interventions in HIV programmes in sub-Saharan Africa.
      PubDate: 2017-04-06
      DOI: 10.1093/jac/dkx098
       
  • Strengthening HIV therapy and care in rural Tanzania affects rates of
           viral suppression
    • Authors: Ntamatungiro AJ; Muri L, Glass TR, et al.
      First page: 2069
      Abstract: Objectives: To assess viral suppression rates, to assess prevalence of acquired HIV drug resistance and to characterize the spectrum of HIV-1 drug resistance mutations (HIV-DRM) in HIV-1-infected patients in a rural Tanzanian HIV cohort.Methods: This was a cross-sectional study nested within the Kilombero and Ulanga Antiretroviral Cohort. Virological failure was defined as HIV-1 RNA ≥50 copies/mL. Risk factors associated with virological failure and with the development of HIV-DRM were assessed using logistic regression.Results: This study included 304 participants with a median time on ART of 3.5 years (IQR = 1.7–5.3 years); 91% were on an NNRTI-based regimen and 9% were on a boosted PI-based regimen. Viral suppression was observed in 277/304 patients (91%). Of the remaining 27 patients, 21 were successfully genotyped and 17/21 (81%) harboured ≥1 clinically relevant HIV-DRM. Of these, 13/17 (76.5%) had HIV-1 plasma viral loads of >1000 copies/mL. CD4 cell count <200 cells/mm3 at the time of recruitment was independently associated with a close to 8-fold increased odds of virological failure [adjusted OR (aOR) = 7.71, 95% CI = 2.86–20.78, P < 0.001] and with a >8-fold increased odds of developing HIV-DRM (aOR = 8.46, 95% CI = 2.48–28.93, P = 0.001).Conclusions: High levels of viral suppression can be achieved in rural sub-Saharan Africa when treatment and care programmes are well managed. In the absence of routine HIV sequencing, the WHO-recommended threshold of 1000 viral RNA copies/mL largely discriminates virological failure secondary to HIV-DRM.
      PubDate: 2017-04-06
      DOI: 10.1093/jac/dkx095
       
  • An association between K65R and HIV-1 subtype C viruses in patients
           treated with multiple NRTIs
    • Authors: Smit E; White E, Clark D, et al.
      First page: 2075
      Abstract: Objectives: HIV-1 subtype C might have a greater propensity to develop K65R mutations in patients with virological failure compared with other subtypes. However, the strong association between viral subtype and confounding factors such as exposure groups and ethnicity affects the calculation of this propensity. We exploited the diversity of viral subtypes within the UK to undertake a direct comparative analysis.Patients and methods: We analysed only sequences with major IAS-defined mutations from patients with virological failure. Prevalence of K65R was related to subtype and exposure to the NRTIs that primarily select for this mutation (tenofovir, abacavir, didanosine and stavudine). A multivariate logistic regression model quantified the effect of subtype on the prevalence of K65R, adjusting for previous and current exposure to all four specified drugs.Results: Subtype B patients (n = 3410) were mostly MSM (78%) and those with subtype C (n = 810) were mostly heterosexual (82%). K65R was detected in 7.8% of subtype B patients compared with 14.2% of subtype C patients. The subtype difference in K65R prevalence was observed irrespective of NRTI exposure and K65R was frequently selected by abacavir, didanosine and stavudine in patients with no previous exposure to tenofovir. Multivariate logistic regression confirmed that K65R was significantly more common in subtype C viruses (adjusted OR = 2.02, 95% CI = 1.55–2.62, P < 0.001).Conclusions: Patients with subtype C HIV-1 have approximately double the frequency of K65R in our database compared with other subtypes. The exact clinical implications of this finding need to be further elucidated.
      PubDate: 2017-04-03
      DOI: 10.1093/jac/dkx091
       
  • Drug resistance mutations in HIV-2 patients failing raltegravir and
           influence on dolutegravir response
    • Authors: Requena S; Treviño A, Cabezas T, et al.
      First page: 2083
      Abstract: Background: A broader extent of amino acid substitutions in the integrase of HIV-2 compared with HIV-1 might enable greater cross-resistance between raltegravir and dolutegravir in HIV-2 infection. Few studies have examined the virological response to dolutegravir in HIV-2 patients that failed raltegravir.Methods: All patients recorded in the HIV-2 Spanish cohort were examined. The integrase coding region was sequenced in viraemic patients. Changes associated with resistance to raltegravir and dolutegravir in HIV-1 were recorded.Results: From 319 HIV-2-infected patients recorded in the HIV-2 Spanish cohort, 53 integrase sequences from 30 individuals were obtained (20 raltegravir naive and 10 raltegravir experienced). Only one secondary mutation (E138A) was found in one of the 20 raltegravir-naive HIV-2 patients. For raltegravir-experienced individuals, the resistance mutation profile in 9 of 10 viraemic patients was as follows: N155H + A153G/S (four); Y143G + A153S (two); Q148R + G140A/S (two); and Y143C + Q91R (one). Of note, all patients with Y143G and N155H developed a rare non-polymorphic mutation at codon 153. Rescue therapy with dolutegravir was given to 5 of these 10 patients. After >6 months on dolutegravir therapy, three patients with baseline N155H experienced viral rebound. In two of them N155H was replaced by Q148K/R and in another by G118R.Conclusions: A wide repertoire of resistance mutations in the integrase gene occur in HIV-2-infected patients failing on raltegravir. Although dolutegravir may allow successful rescue in most HIV-2 raltegravir failures, we report and characterize three cases of dolutegravir resistance in HIV-2 patients, emerging variants Q148K and Q148R and a novel change G118R.
      PubDate: 2017-03-23
      DOI: 10.1093/jac/dkx090
       
  • Clinical effectiveness of early posaconazole suspension pre-emptive
           therapy in lung transplant recipients: The Alfred’s experience
    • Authors: Jeong W; Snell GI, Levvey BJ, et al.
      First page: 2089
      Abstract: Objectives: This study describes the clinical outcomes and therapeutic drug monitoring (TDM) following posaconazole suspension pre-emptive therapy in lung transplant (LTx) recipients.Methods: This was a single-centre, retrospective cohort study evaluating posaconazole suspension pre-emptive therapy in LTx recipients between January 2009 and December 2015.Results: Forty-two LTx recipients were prescribed posaconazole suspension pre-emptively. Aspergillus fumigatus was the most commonly isolated fungal organism. Of the patients receiving posaconazole suspension as the initial antifungal post-LTx, 93% had eradication of colonization at 6 months after commencing therapy. In contrast, only 61% had eradication of fungal colonization when posaconazole suspension was administered following initial therapy with voriconazole. Posaconazole suspension appeared to be well tolerated, although one case was curtailed following concern about abnormal liver function and another due to nausea/vomiting. TDM was performed in 37 patients. The initial median (IQR) trough plasma concentration (Cmin) following 400 mg twice-daily posaconazole suspension was 0.78 (0.46–1.19) mg/L. Doses beyond 800 mg daily did not appear to result in a higher median CminConclusions: Early initiation of posaconazole suspension pre-emptive therapy in LTx recipients appears to be well tolerated and may potentially afford favourable clinical outcomes.
      PubDate: 2017-03-22
      DOI: 10.1093/jac/dkx085
       
  • Effect of cadexomer iodine on the microbial load and diversity of chronic
           non-healing diabetic foot ulcers complicated by biofilm in vivo
    • Authors: Malone MM; Johani KK, Jensen SO, et al.
      First page: 2093
      Abstract: Objectives: The performance of cadexomer iodine was determined against microbial populations from chronic non-healing diabetic foot ulcers (DFUs) complicated by biofilm in vivo, using molecular, microscopy and zymography methods.Methods: Chronic non-healing DFUs due to suspected biofilm involvement were eligible for enrolment. DNA sequencing and real-time quantitative PCR was used to determine the microbial load and diversity of tissue punch biopsies obtained pre- and post-treatment. Scanning electron microscopy and/or fluorescence in situ hybridization confirmed the presence or absence of biofilm. Zymography was used to determine levels of wound proteases.Results: Seventeen participants were recruited over a 6 month period. Scanning electron microscopy and or fluorescence in situ hybridization confirmed the presence of biofilm in all samples. Eleven participants exhibited log10 reductions in microbial load after treatment (range 1–2 log10) in comparison with six patients who experienced <1 log10 reduction (P = 0.04). Samples were tested for levels of wound proteases pre- and post-treatment. Reductions in the microbial load correlated to reductions in wound proteases pre- and post-treatment (P = 0.03).Conclusions: To the best of our knowledge, this study represents the first in vivo evidence, employing a range of molecular and microscopy techniques, of the ability of cadexomer iodine to reduce the microbial load of chronic non-healing DFUs complicated by biofilm. Further analyses correlating log reductions to optimal duration of therapy and improvements in clinical parameters of wound healing in a larger cohort are required.
      PubDate: 2017-04-10
      DOI: 10.1093/jac/dkx099
       
  • High vancomycin MICs predict the development of infective endocarditis in
           patients with catheter-related bacteraemia due to methicillin-resistant
           Staphylococcus aureus
    • Authors: San-Juan R; Fernández-Ruiz M, Gasch O, et al.
      First page: 2102
      Abstract: Background: It has been suggested that there is an increased risk of treatment failure in episodes of MRSA bloodstream infection (BSI) caused by strains with high vancomycin MICs. However, it is unknown if this phenomenon may also act as a risk factor for the development of infective endocarditis (IE).Methods: We analysed 207 episodes of catheter-related (CR)-BSI recruited from June 2008 to December 2009 within a prospective study on MRSA BSI in 21 Spanish hospitals. Vancomycin susceptibility was centrally tested. The impact of high vancomycin MIC values (≥1.5 mg/L by Etest) on the subsequent development of IE was investigated by Cox regression.Results: High vancomycin MIC values were observed in 46.9% of the isolates. Initial therapy consisted of vancomycin [99 episodes (44.7%)], daptomycin [25 (12.1%)], linezolid [18 (8.7%)] and other antistaphylococcal agents [16 (7.7%)]. Haematogenous complications occurred in 41 patients (19.8%), including 10 episodes complicated by IE. Early (48 h) and late (30 day) all-cause mortality were 3.4% and 25.1%, respectively. High vancomycin MIC isolates were more common among patients that developed IE compared with those free from this complication [90.9% (9/10) versus 44.7% (88/197); P = 0.007]. This association remained significant after adjusting for multiple confounders (including initial antibiotic therapy and catheter removal) in different models (minimum hazard ratio: 9.18; 95% CI: 1.16–72.78; P = 0.036). There were no differences in mortality according to vancomycin MIC values.Conclusions: Decreased susceptibility to vancomycin acted as a predictor of the development of IE complicating MRSA CR-BSI.
      PubDate: 2017-03-31
      DOI: 10.1093/jac/dkx096
       
  • Outcomes of multisite antimicrobial stewardship programme implementation
           with a shared clinical decision support system
    • Authors: Bond SE; Chubaty AJ, Adhikari S, et al.
      First page: 2110
      Abstract: Background: Studies evaluating antimicrobial stewardship programmes (ASPs) supported by computerized clinical decision support systems (CDSSs) have predominantly been conducted in single site metropolitan hospitals.Objectives: To examine outcomes of multisite ASP implementation supported by a centrally deployed CDSS.Methods: An interrupted time series study was conducted across five hospitals in New South Wales, Australia, from 2010 to 2014. Outcomes analysed were: effect of the intervention on targeted antimicrobial use, antimicrobial costs and healthcare-associated Clostridium difficile infection (HCA-CDI) rates. Infection-related length of stay (LOS) and standardized mortality ratios (SMRs) were also assessed.Results: Post-intervention, antimicrobials targeted for increased use rose from 223 to 293 defined daily doses (DDDs)/1000 occupied bed days (OBDs)/month (+32%, P < 0.01). Conversely, antimicrobials targeted for decreased use fell from 254 to 196 DDDs/1000 OBDs/month (−23%; P < 0.01). These effects diminished over time. Antimicrobial costs decreased initially (−AUD$64551/month; P < 0.01), then increased (+AUD$7273/month; P < 0.01). HCA-CDI rates decreased post-intervention (−0.2 cases/10 000 OBDs/month; P < 0.01). Proportional LOS reductions for key infections (respiratory from 4.8 to 4.3 days, P < 0.01; septicaemia 6.8 to 6.1 days, P < 0.01) were similar to background LOS reductions (2.1 to 1.9 days). Similarly, infection-related SMRs (observed/expected deaths) decreased (respiratory from 1.1 to 0.75; septicaemia 1.25 to 0.8; background rate 1.19 to 0.90.Conclusions: Implementation of a collaborative multisite ASP supported by a centrally deployed CDSS was associated with changes in targeted antimicrobial use, decreased antimicrobial costs, decreased HCA-CDI rates, and no observable increase in LOS or mortality. Ongoing targeted interventions are suggested to promote sustainability.
      PubDate: 2017-03-14
      DOI: 10.1093/jac/dkx080
       
  • A mixed-method evaluation of peer-education workshops for school-aged
           children to teach about antibiotics, microbes and hygiene
    • Authors: Young VL; Cole A, Lecky DM, et al.
      First page: 2119
      Abstract: Background: Delivering health topics in schools through peer education is known to be beneficial for all students involved. In this study, we have evaluated a peer-education workshop that aims to educate primary and secondary school students on hygiene, the spread of infection and antibiotics.Methods: Four schools in south-west England, in a range of localities, took part in peer-education workshops, with students completing before, after and knowledge-retention questionnaires. Mixed-effect logistic regression and mixed-effect linear regression were used to analyse the data. Data were analysed by topic, region and peer/non-peer-educator status. Qualitative interviews and focus groups with students and educators were conducted to assess changes in participants’ skills, confidence and behaviour.Results: Qualitative data indicated improvements in peer-educator skills and behaviour, including confidence, team-working and communication. There was a significant improvement in knowledge for all topics covered in the intervention, although this varied by region. In the antibiotics topic, peer-educators’ knowledge increased in the retention questionnaire, whereas non-peer-educators’ knowledge decreased. Knowledge declined in the retention questionnaires for the other topics, although this was mostly not significant.Conclusions: This study indicates that peer education is an effective way to educate young people on important topics around health and hygiene, and to concurrently improve communication skills. Its use should be encouraged across schools to help in the implementation of the National Institute for Health and Care Excellence (NICE) guidance that recommends children are taught in an age-appropriate manner about hygiene and antibiotics.
      PubDate: 2017-03-18
      DOI: 10.1093/jac/dkx083
       
  • Citrobacter braakii carrying plasmid-borne mcr-1 colistin resistance gene
           from ready-to-eat food from a market in the Chaco region of Bolivia
    • Authors: Sennati S; Di Pilato V, Riccobono E, et al.
      First page: 2127
      Abstract: Sir,
      PubDate: 2017-03-15
      DOI: 10.1093/jac/dkx078
       
  • IMI-2 carbapenemase in a clinical Klebsiella variicola isolated in the UK
    • Authors: Hopkins KL; Findlay J, Doumith M, et al.
      First page: 2129
      Abstract: Sir,
      PubDate: 2017-04-03
      DOI: 10.1093/jac/dkx103
       
  • VIM-1-producing Salmonella Infantis isolated from swine and minced pork
           meat in Germany
    • Authors: Borowiak M; Szabo I, Baumann B, et al.
      First page: 2131
      Abstract: Sir,
      PubDate: 2017-03-24
      DOI: 10.1093/jac/dkx101
       
  • Variation in formation of persister cells against colistin in
           Acinetobacter baumannii isolates and its relationship with treatment
           failure
    • Authors: Chung E; Wi Y, Ko K.
      First page: 2133
      Abstract: Sir,
      PubDate: 2017-04-03
      DOI: 10.1093/jac/dkx102
       
  • Correction of myelotoxicity after switch of linezolid to tedizolid for
           prolonged treatments
    • Authors: Khatchatourian LL; Le Bourgeois AA, Asseray NN, et al.
      First page: 2135
      Abstract: Sir,
      PubDate: 2017-03-27
      DOI: 10.1093/jac/dkx097
       
  • Dolutegravir monotherapy in HIV-infected naive patients with an HIV-RNA
           load <100 000 copies/mL: a medium-term follow-up
    • Authors: Lanzafame M; Nicolè S, Gibellini D, et al.
      First page: 2136
      Abstract: Sir,
      PubDate: 2017-04-06
      DOI: 10.1093/jac/dkx109
       
  • Raltegravir plus lamivudine as ‘maintenance therapy’ in suppressed
           HIV-1-infected patients in real-life settings
    • Authors: Cucchetto G; Lanzafame M, Nicolè S, et al.
      First page: 2138
      Abstract: Sir,
      PubDate: 2017-04-16
      DOI: 10.1093/jac/dkx106
       
  • Antimicrobial resistance in Staphylococcus pseudintermedius and the
           molecular epidemiology of methicillin-resistant S. pseudintermedius in
           small animals in Finland
    • Authors: Grönthal T; Eklund M, Thomson K, et al.
      First page: 2141
      Abstract: J Antimicrob Chemother 2017; 72: 1021–30
      PubDate: 2017-03-08
      DOI: 10.1093/jac/dkx086
       
  • Studying the effect of administration route and treatment dose on the
           selection of enrofloxacin resistance in commensal Escherichia coli in
           broilers
    • Authors: Chantziaras I; Smet A, Haesebrouck F, et al.
      First page: 2142
      Abstract: J Antimicrob Chemother 2017; 72: 1991–2001
      PubDate: 2017-05-16
      DOI: 10.1093/jac/dkx162
       
  • Once-daily atazanavir/cobicistat and darunavir/cobicistat exposure over
           72 h post-dose in plasma, urine and saliva: contribution to drug
           pharmacokinetic knowledge
    • Authors: Elliot ER; Amara A, Pagani N, et al.
      First page: 2143
      Abstract: J Antimicrob Chemother 2017; 72: 2035–41
      PubDate: 2017-05-06
      DOI: 10.1093/jac/dkx145
       
 
 
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