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Publisher: Oxford University Press   (Total: 372 journals)

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Showing 1 - 200 of 372 Journals sorted alphabetically
Acta Biochimica et Biophysica Sinica     Hybrid Journal   (Followers: 5, 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: 65, SJR: 1.512, h-index: 46)
Age and Ageing     Hybrid Journal   (Followers: 86, SJR: 1.611, h-index: 107)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 18, SJR: 0.935, h-index: 80)
American Entomologist     Full-text available via subscription   (Followers: 6)
American Historical Review     Hybrid Journal   (Followers: 143, SJR: 0.652, h-index: 43)
American J. of Agricultural Economics     Hybrid Journal   (Followers: 39, SJR: 1.441, h-index: 77)
American J. of Epidemiology     Hybrid Journal   (Followers: 166, SJR: 3.047, h-index: 201)
American J. of Hypertension     Hybrid Journal   (Followers: 25, SJR: 1.397, h-index: 111)
American J. of Jurisprudence     Hybrid Journal   (Followers: 18)
American J. of Legal History     Full-text available via subscription   (Followers: 9, SJR: 0.151, h-index: 7)
American Law and Economics Review     Hybrid Journal   (Followers: 28, SJR: 0.824, h-index: 23)
American Literary History     Hybrid Journal   (Followers: 15, SJR: 0.185, h-index: 22)
Analysis     Hybrid Journal   (Followers: 21)
Annals of Botany     Hybrid Journal   (Followers: 35, SJR: 1.912, h-index: 124)
Annals of Occupational Hygiene     Hybrid Journal   (Followers: 29, SJR: 0.837, h-index: 57)
Annals of Oncology     Hybrid Journal   (Followers: 48, 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: 17, SJR: 0.884, h-index: 31)
Applied Linguistics     Hybrid Journal   (Followers: 55, 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: 19)
Arbitration Law Reports and Review     Hybrid Journal   (Followers: 13)
Archives of Clinical Neuropsychology     Hybrid Journal   (Followers: 30, SJR: 0.96, h-index: 71)
Aristotelian Society Supplementary Volume     Hybrid Journal   (Followers: 3, SJR: 0.102, h-index: 20)
Arthropod Management Tests     Hybrid Journal   (Followers: 2)
Astronomy & Geophysics     Hybrid Journal   (Followers: 46, SJR: 0.144, h-index: 15)
Behavioral Ecology     Hybrid Journal   (Followers: 51, SJR: 1.698, h-index: 92)
Bioinformatics     Hybrid Journal   (Followers: 281, 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: 20, SJR: 2.801, h-index: 90)
BioScience     Hybrid Journal   (Followers: 30, 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: 17, SJR: 1.955, h-index: 55)
BJA : British J. of Anaesthesia     Hybrid Journal   (Followers: 159, SJR: 2.314, h-index: 133)
BJA Education     Hybrid Journal   (Followers: 64, SJR: 0.272, h-index: 20)
Brain     Hybrid Journal   (Followers: 68, SJR: 6.097, h-index: 264)
Briefings in Bioinformatics     Hybrid Journal   (Followers: 43, SJR: 4.086, h-index: 73)
Briefings in Functional Genomics     Hybrid Journal   (Followers: 3, 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: 26, SJR: 0.217, h-index: 18)
British J. of Criminology     Hybrid Journal   (Followers: 577, SJR: 1.373, h-index: 62)
British J. of Social Work     Hybrid Journal   (Followers: 86, 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: 30)
Bulletin of the London Mathematical Society     Hybrid Journal   (Followers: 4, SJR: 1.474, h-index: 31)
Cambridge J. of Economics     Hybrid Journal   (Followers: 61, 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: 9, SJR: 0.1, h-index: 7)
Capital Markets Law J.     Hybrid Journal   (Followers: 2)
Carcinogenesis     Hybrid Journal   (Followers: 2, SJR: 2.439, h-index: 167)
Cardiovascular Research     Hybrid Journal   (Followers: 12, SJR: 2.897, h-index: 175)
Cerebral Cortex     Hybrid Journal   (Followers: 44, SJR: 4.827, h-index: 192)
CESifo Economic Studies     Hybrid Journal   (Followers: 17, SJR: 0.501, h-index: 19)
Chemical Senses     Hybrid Journal   (Followers: 1, SJR: 1.436, h-index: 76)
Children and Schools     Hybrid Journal   (Followers: 5, SJR: 0.211, h-index: 18)
Chinese J. of Comparative Law     Hybrid Journal   (Followers: 4)
Chinese J. of Intl. Law     Hybrid Journal   (Followers: 22, 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: 10, SJR: 0.191, h-index: 8)
Classical Receptions J.     Hybrid Journal   (Followers: 25, SJR: 0.1, h-index: 3)
Clinical Infectious Diseases     Hybrid Journal   (Followers: 62, SJR: 4.742, h-index: 261)
Clinical Kidney J.     Open Access   (Followers: 3, SJR: 0.338, h-index: 19)
Community Development J.     Hybrid Journal   (Followers: 27, SJR: 0.47, h-index: 28)
Computer J.     Hybrid Journal   (Followers: 9, SJR: 0.371, h-index: 47)
Conservation Physiology     Open Access   (Followers: 2)
Contemporary Women's Writing     Hybrid Journal   (Followers: 9, SJR: 0.111, h-index: 3)
Contributions to Political Economy     Hybrid Journal   (Followers: 5, SJR: 0.313, h-index: 10)
Critical Values     Full-text available via subscription  
Current Legal Problems     Hybrid Journal   (Followers: 27)
Current Zoology     Full-text available via subscription   (Followers: 1, SJR: 0.999, h-index: 20)
Database : The J. of Biological Databases and Curation     Open Access   (Followers: 8, SJR: 1.068, h-index: 24)
Digital Scholarship in the Humanities     Hybrid Journal   (Followers: 13)
Diplomatic History     Hybrid Journal   (Followers: 19, SJR: 0.296, h-index: 22)
DNA Research     Open Access   (Followers: 5, SJR: 2.42, h-index: 77)
Dynamics and Statistics of the Climate System     Open Access   (Followers: 3)
Early Music     Hybrid Journal   (Followers: 15, SJR: 0.124, h-index: 11)
Economic Policy     Hybrid Journal   (Followers: 39, SJR: 2.052, h-index: 52)
ELT J.     Hybrid Journal   (Followers: 25, SJR: 1.26, h-index: 23)
English Historical Review     Hybrid Journal   (Followers: 51, SJR: 0.311, h-index: 10)
English: J. of the English Association     Hybrid Journal   (Followers: 14, 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: 3)
Environmental History     Hybrid Journal   (Followers: 26, SJR: 0.197, h-index: 25)
EP-Europace     Hybrid Journal   (Followers: 2, SJR: 2.201, h-index: 71)
Epidemiologic Reviews     Hybrid Journal   (Followers: 9, SJR: 3.917, h-index: 81)
ESHRE Monographs     Hybrid Journal  
Essays in Criticism     Hybrid Journal   (Followers: 16, SJR: 0.1, h-index: 6)
European Heart J.     Hybrid Journal   (Followers: 54, SJR: 6.997, h-index: 227)
European Heart J. - Cardiovascular Imaging     Hybrid Journal   (Followers: 8, 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: 7, SJR: 0.152, h-index: 31)
European J. of Cardio-Thoracic Surgery     Hybrid Journal   (Followers: 9, SJR: 1.568, h-index: 104)
European J. of Intl. Law     Hybrid Journal   (Followers: 169, 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: 20, SJR: 1.284, h-index: 64)
European Review of Agricultural Economics     Hybrid Journal   (Followers: 9, SJR: 1.549, h-index: 42)
European Review of Economic History     Hybrid Journal   (Followers: 28, SJR: 0.628, h-index: 24)
European Sociological Review     Hybrid Journal   (Followers: 40, SJR: 2.061, h-index: 53)
Evolution, Medicine, and Public Health     Open Access   (Followers: 10)
Family Practice     Hybrid Journal   (Followers: 14, SJR: 1.048, h-index: 77)
Fems Microbiology Ecology     Hybrid Journal   (Followers: 10, SJR: 1.687, h-index: 115)
Fems Microbiology Letters     Hybrid Journal   (Followers: 22, SJR: 1.126, h-index: 118)
Fems Microbiology Reviews     Hybrid Journal   (Followers: 27, SJR: 7.587, h-index: 150)
Fems Yeast Research     Hybrid Journal   (Followers: 14, SJR: 1.213, h-index: 66)
Foreign Policy Analysis     Hybrid Journal   (Followers: 23, SJR: 0.859, h-index: 10)
Forestry: An Intl. J. of Forest Research     Hybrid Journal   (Followers: 14, 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: 32, SJR: 0.123, h-index: 10)
French Studies     Hybrid Journal   (Followers: 20, 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: 11, SJR: 3.22, h-index: 39)
Geophysical J. Intl.     Hybrid Journal   (Followers: 34, SJR: 1.839, h-index: 119)
German History     Hybrid Journal   (Followers: 22, SJR: 0.437, h-index: 13)
GigaScience     Open Access   (Followers: 3)
Global Summitry     Hybrid Journal   (Followers: 1)
Glycobiology     Hybrid Journal   (Followers: 14, SJR: 1.692, h-index: 101)
Health and Social Work     Hybrid Journal   (Followers: 54, SJR: 0.505, h-index: 40)
Health Education Research     Hybrid Journal   (Followers: 13, SJR: 0.814, h-index: 80)
Health Policy and Planning     Hybrid Journal   (Followers: 24, SJR: 1.628, h-index: 66)
Health Promotion Intl.     Hybrid Journal   (Followers: 21, SJR: 0.664, h-index: 60)
History Workshop J.     Hybrid Journal   (Followers: 28, SJR: 0.313, h-index: 20)
Holocaust and Genocide Studies     Hybrid Journal   (Followers: 26, SJR: 0.115, h-index: 13)
Human Molecular Genetics     Hybrid Journal   (Followers: 8, SJR: 4.288, h-index: 233)
Human Reproduction     Hybrid Journal   (Followers: 72, SJR: 2.271, h-index: 179)
Human Reproduction Update     Hybrid Journal   (Followers: 17, SJR: 4.678, h-index: 128)
Human Rights Law Review     Hybrid Journal   (Followers: 60, SJR: 0.7, h-index: 21)
ICES J. of Marine Science: J. du Conseil     Hybrid Journal   (Followers: 51, SJR: 1.233, h-index: 88)
ICSID Review     Hybrid Journal   (Followers: 12)
ILAR J.     Hybrid Journal   (Followers: 2, 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   (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: 10, SJR: 1.37, h-index: 81)
Industrial Law J.     Hybrid Journal   (Followers: 34, SJR: 0.184, h-index: 15)
Information and Inference     Free  
Integrative and Comparative Biology     Hybrid Journal   (Followers: 7, 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: 6, SJR: 0.743, h-index: 35)
Intl. Affairs     Hybrid Journal   (Followers: 56, SJR: 1.264, h-index: 53)
Intl. Data Privacy Law     Hybrid Journal   (Followers: 30)
Intl. Health     Hybrid Journal   (Followers: 5, SJR: 0.835, h-index: 15)
Intl. Immunology     Hybrid Journal   (Followers: 3, SJR: 1.613, h-index: 111)
Intl. J. for Quality in Health Care     Hybrid Journal   (Followers: 33, SJR: 1.593, h-index: 69)
Intl. J. of Constitutional Law     Hybrid Journal   (Followers: 63, SJR: 0.613, h-index: 19)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 178, SJR: 4.381, h-index: 145)
Intl. J. of Law and Information Technology     Hybrid Journal   (Followers: 5, SJR: 0.247, h-index: 8)
Intl. J. of Law, Policy and the Family     Hybrid Journal   (Followers: 30, SJR: 0.307, h-index: 15)
Intl. J. of Lexicography     Hybrid Journal   (Followers: 10, SJR: 0.404, h-index: 18)
Intl. J. of Low-Carbon Technologies     Open Access   (Followers: 1, SJR: 0.457, h-index: 12)
Intl. J. of Neuropsychopharmacology     Open Access   (Followers: 3, SJR: 1.69, h-index: 79)
Intl. J. of Public Opinion Research     Hybrid Journal   (Followers: 9, SJR: 0.906, h-index: 33)
Intl. J. of Refugee Law     Hybrid Journal   (Followers: 35, SJR: 0.231, h-index: 21)
Intl. J. of Transitional Justice     Hybrid Journal   (Followers: 12, 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: 35, SJR: 1.339, h-index: 19)
Intl. Relations of the Asia-Pacific     Hybrid Journal   (Followers: 22, SJR: 0.539, h-index: 17)
Intl. Studies Perspectives     Hybrid Journal   (Followers: 9, SJR: 0.998, h-index: 28)
Intl. Studies Quarterly     Hybrid Journal   (Followers: 42, SJR: 2.184, h-index: 68)
Intl. Studies Review     Hybrid Journal   (Followers: 20, 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: 1, 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: 45, 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: 14, SJR: 2.157, h-index: 149)
J. of Antitrust Enforcement     Hybrid Journal   (Followers: 1)
J. of Applied Poultry Research     Hybrid Journal   (Followers: 4, SJR: 0.563, h-index: 43)
J. of Biochemistry     Hybrid Journal   (Followers: 41, SJR: 1.341, h-index: 96)
J. of Burn Care & Research     Full-text available via subscription   (Followers: 9, SJR: 0.713, h-index: 57)
J. of Chromatographic Science     Hybrid Journal   (Followers: 18, 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: 35, 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: 13, 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: 17, 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: 24, SJR: 2.909, h-index: 69)
J. of Environmental Law     Hybrid Journal   (Followers: 21, SJR: 0.457, h-index: 20)
J. of European Competition Law & Practice     Hybrid Journal   (Followers: 20)
J. of Experimental Botany     Hybrid Journal   (Followers: 13, SJR: 2.798, h-index: 163)
J. of Financial Econometrics     Hybrid Journal   (Followers: 22, SJR: 1.314, h-index: 27)
J. of Global Security Studies     Hybrid Journal   (Followers: 5)
J. of Heredity     Hybrid Journal   (Followers: 3, SJR: 1.024, h-index: 76)
J. of Hindu Studies     Hybrid Journal   (Followers: 8, SJR: 0.186, h-index: 3)
J. of Hip Preservation Surgery     Open Access  
J. of Human Rights Practice     Hybrid Journal   (Followers: 16, SJR: 0.399, h-index: 10)
J. of Infectious Diseases     Hybrid Journal   (Followers: 40, SJR: 4, h-index: 209)

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Journal Cover Journal of Antimicrobial Chemotherapy
  [SJR: 2.157]   [H-I: 149]   [14 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  [372 journals]
  • Reducing inappropriate prescribing of antibiotics in English primary care:
           evidence and outlook
    • Authors: Davies S.
      Abstract: Antibiotics are indispensable for treating bacterial infections, but their effectiveness is threatened by the emergence and spread of antibacterial resistance. Antibiotics are unique among drugs since the more they are used, the less effective they become because bacterial resistance is likely to develop. In response to this threat, the UK government aims to reduce inappropriate antibiotic prescribing in humans by 50% by 2020. A team at Public Health England has found that at least 20% of antibiotic prescriptions in primary care in England were inappropriate, which, if correct, implies that antibiotic prescribing nationally needs to be reduced by 10% by 2020. These data are published in five articles in a Supplement to JAC entitled Appropriateness of antibiotic prescribing in English primary care. Inappropriate prescribing was found in every general practice included in the analyses so each one should attempt to reduce unnecessary prescriptions, not just high-prescribing practices. An ambition of 10% reduction in antibiotic prescriptions seems attainable when compared with the reduction targets of other European countries. The need for substantial improvements in data quality that are necessary to further safeguard this precious resource is also highlighted by the authors in this Supplement.
      PubDate: Tue, 27 Feb 2018 00:00:00 GMT
       
  • Prevalence of and factors associated with MDR Neisseria gonorrhoeae in
           England and Wales between 2004 and 2015: analysis of annual
           cross-sectional surveillance surveys
    • Authors: Clifton S; Bolt H, Mohammed H, et al.
      Abstract: ObjectivesTo describe trends in prevalence, susceptibility profile and risk factors for MDR Neisseria gonorrhoeae (MDR-NG) in England and Wales.MethodsIsolates from 16 242 gonorrhoea episodes at sexual health clinics within the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) underwent antimicrobial susceptibility testing. MDR-NG was defined as resistance to ceftriaxone, cefixime or azithromycin, plus at least two of penicillin, ciprofloxacin and spectinomycin. Trends in resistance are presented for 2004–15; prevalence and logistic regression analyses for MDR-NG cover the period of the most recent treatment guideline (ceftriaxone plus azithromycin), 2011–15.ResultsBetween 2004 and 2015, the proportion of N. gonorrhoeae isolates fully susceptible to all antimicrobial classes fell from 80% to 46%, with the proportion resistant to multiple (two or more) classes increasing from 7.3% to 17.5%. In 2011–15, 3.5% of isolates were MDR-NG, most of which were resistant to cefixime (100% in 2011, decreasing to 36.9% in 2015) and/or azithromycin (4.2% in 2011, increasing to 84.3% in 2015). After excluding azithromycin-resistant isolates, modal azithromycin MICs were higher in MDR versus non-MDR isolates (0.5 versus 0.125 mg/L), with similar results for ceftriaxone (modal MICs 0.03 versus ≤0.002 mg/L). After adjustment for confounders, MDR-NG was more common among isolates from heterosexual men, although absolute differences in prevalence were small [4.6% versus 3.3% (MSM) and 2.5% (women)].ConclusionsN. gonorrhoeae is becoming less susceptible to available antimicrobials. Since 2011, a minority of isolates were MDR-NG; however, MICs of azithromycin or ceftriaxone (first-line therapies) for many of these were elevated. These findings highlight the importance of continued antimicrobial stewardship for gonorrhoea.
      PubDate: Tue, 30 Jan 2018 00:00:00 GMT
       
  • Exploring colistin pharmacodynamics against Klebsiella pneumoniae: a need
           to revise current susceptibility breakpoints
    • Authors: Tsala M; Vourli S, Georgiou P, et al.
      Abstract: ObjectivesBecause the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of colistin against Enterobacteriaceae are not well explored, we studied the activity of colistin against K. pneumoniae in an in vitro PK/PD model simulating different dosing regimens.MethodsThree clinical isolates of K. pneumoniae with MICs of 0.5, 1 and 4 mg/L were tested in an in vitro PK/PD model following a dose-fractionation design over a period of 24 h. A high and low inoculum of 107 and 104 cfu/mL with and without a heteroresistant subpopulation, respectively, were used. PK/PD indices associated with colistin activity were explored and Monte Carlo analysis was performed in order to determine the PTA for achieving a bactericidal effect (2 log kill).ResultsThe fAUC/MIC (R2 = 0.64–0.68) followed by fCmax/MIC (R2 = 0.55–0.63) best described colistin’s 24 h log10 cfu/mL reduction for both low and high inocula. Dosing regimens with fCmax/MIC ≥6 were always associated with a bactericidal effect (P = 0.0025). However, at clinically achievable concentrations, usually below fCmax/MIC = 6, an fAUC/MIC ≥25 was more predictive of a bactericidal effect. Using a dosing regimen of 9 MU/day, the PTA for this pharmacodynamic target was 100%, 5%–70% and 0%, for isolates with MICs of ≤0.5, 1 and ≥2 mg/L, respectively. Dosing regimens that aim for a trough level of 1 mg/L achieve coverage of strains up to 0.5 mg/L (target trough/MIC = 2 mg/L).ConclusionsCharacterization of the pharmacodynamics of colistin against Enterobacteriaceae in an in vitro model of infection indicates that a revision of current susceptibility breakpoints is needed. Therapeutic drug monitoring of colistin to achieve pharmacodynamic targets in individual patients is highly recommended.
      PubDate: Thu, 25 Jan 2018 00:00:00 GMT
       
  • Impact of antiretroviral resistance and virological failure on HIV-1
           informational entropy
    • Authors: Lima E; Piqueira J, Camargo M, et al.
      Abstract: ObjectivesThe present study investigated the relationship between genomic variability and resistance of HIV-1 sequences in protease (PR) and reverse transcriptase (RT) regions of the pol gene. In addition, we analysed the resistance among 651 individuals presenting antiretroviral virological failure, from 2009 to 2011, in the state of São Paulo, Brazil.MethodsThe genomic variability was quantified by using informational entropy methods and the relationship between resistance and replicative fitness, as inferred by the residual viral load and CD4+ T cell count.ResultsThe number of antiretroviral schemes is related to the number of resistance mutations in the HIV-1 PR (α = 0.2511, P = 0.0003, R2 = 0.8672) and the RT (α = 0.7892, P = 0.0001, R2 = 0.9141). Increased informational entropy rate is related to lower levels of HIV-1 viral loads (α = −0.0121, P = 0.0471, R2 = 0.7923), lower levels of CD4+ T cell counts (α = −0.0120, P = 0.0335, R2 = 0.8221) and a higher number of antiretroviral resistance-related mutations.ConclusionsLess organized HIV genomes as inferred by higher levels of informational entropy relate to less competent host immune systems, lower levels of HIV replication and HIV genetic evolution as a consequence of antiretroviral resistance.
      PubDate: Tue, 23 Jan 2018 00:00:00 GMT
       
  • Two decades of blaVIM-2-producing Pseudomonas aeruginosa dissemination: an
           interplay between mobile genetic elements and successful clones
    • Authors: Botelho J; Grosso F, Quinteira S, et al.
      Abstract: ObjectivesInformation on clonal lineages and genetic platforms involved in the mobilization of carbapenemases between Pseudomonas aeruginosa strains in Portugal is scarce. Here, we outline the genetic drivers contributing to the occurrence of blaVIM-2-producing P. aeruginosa over two decades.MethodsA collection of carbapenem-resistant P. aeruginosa clinical isolates (n = 263, 1995–2014) was screened for carbapenemase production by Blue-Carba and PCR. Antimicrobial susceptibility testing was performed according to EUCAST and clonal analysis by MLST. Nine isolates representing different integrons and STs were selected for WGS, followed by bioinformatics.ResultsTwenty-seven blaVIM-2-producing P. aeruginosa belonging to 10 STs were identified, with ST179 and ST111 being the most prevalent and persistent clones. blaVIM-2 was associated with seven class I integrons frequently co-harbouring aminoglycoside resistance genes. In58 was commonly identified, followed by derivatives and In100. blaVIM-2-harbouring transposons of the Tn3 and Tn402 families were linked to different plasmids or integrative conjugative elements of the clc family.ConclusionsThe dissemination of blaVIM-2 carrying integrons is associated with a complex interplay between different mobile genetic elements, including the overlooked integrative conjugative elements, and successful spread of particular clones.
      PubDate: Tue, 23 Jan 2018 00:00:00 GMT
       
  • Automated annotation of mobile antibiotic resistance in Gram-negative
           bacteria: the Multiple Antibiotic Resistance Annotator (MARA) and database
           
    • Authors: Partridge S; Tsafnat G.
      Abstract: BackgroundMultiresistance in Gram-negative bacteria is often due to acquisition of several different antibiotic resistance genes, each associated with a different mobile genetic element, that tend to cluster together in complex conglomerations. Accurate, consistent annotation of resistance genes, the boundaries and fragments of mobile elements, and signatures of insertion, such as DR, facilitates comparative analysis of complex multiresistance regions and plasmids to better understand their evolution and how resistance genes spread.ObjectivesTo extend the Repository of Antibiotic resistance Cassettes (RAC) web site, which includes a database of ‘features’, and the Attacca automatic DNA annotation system, to encompass additional resistance genes and all types of associated mobile elements.MethodsAntibiotic resistance genes and mobile elements were added to RAC, from existing registries where possible. Attacca grammars were extended to accommodate the expanded database, to allow overlapping features to be annotated and to identify and annotate features such as composite transposons and DR.ResultsThe Multiple Antibiotic Resistance Annotator (MARA) database includes antibiotic resistance genes and selected mobile elements from Gram-negative bacteria, distinguishing important variants. Sequences can be submitted to the MARA web site for annotation. A list of positions and orientations of annotated features, indicating those that are truncated, DR and potential composite transposons is provided for each sequence, as well as a diagram showing annotated features approximately to scale.ConclusionsThe MARA web site (http://mara.spokade.com) provides a comprehensive database for mobile antibiotic resistance in Gram-negative bacteria and accurately annotates resistance genes and associated mobile elements in submitted sequences to facilitate comparative analysis.
      PubDate: Tue, 23 Jan 2018 00:00:00 GMT
       
  • Antibiotic resistance in Timor-Leste: a systematic review of evidence
    • Authors: Tebano G; la Martire G, Sarmento N, et al.
      Abstract: Sir,
      PubDate: Mon, 22 Jan 2018 00:00:00 GMT
       
  • Physiologically based pharmacokinetic modelling prediction of the effects
           of dose adjustment in drug–drug interactions between levonorgestrel
           contraceptive implants and efavirenz-based ART
    • Authors: Roberts O; Rajoli R, Back D, et al.
      Abstract: BackgroundHIV-positive women receiving efavirenz-based ART and levonorgestrel contraceptive implants are at risk of low levonorgestrel exposure and unintended pregnancy.ObjectivesTo investigate clinically applicable dose-adjustment strategies to overcome the known drug–drug interaction (DDI) between levonorgestrel and efavirenz, using a physiologically based pharmacokinetic (PBPK) modelling-based approach.MethodsA PBPK model was qualified against clinical data to predict levonorgestrel plasma concentrations when standard-dose (150 mg) levonorgestrel implants were administered alone (control group), as well as when standard-dose or increased-dose (300 mg) levonorgestrel implants were coadministered with either 600 or 400 mg of efavirenz.ResultsNo difference was seen between in vivo clinical and PBPK-model-simulated levonorgestrel plasma concentrations (P > 0.05). Simulated levonorgestrel plasma concentrations were ∼50% lower at 48 weeks post-implant-placement in virtual individuals receiving standard-dose levonorgestrel with either 600 or 400 mg of efavirenz compared with the control group (efavirenz:control geometric mean ratio = 0.42 and 0.49, respectively). Conversely, increased-dose levonorgestrel in combination with either 600 or 400 mg of efavirenz was sufficient to restore levonorgestrel concentrations to levels similar to those observed in the 150 mg levonorgestrel control group 48 weeks post-implant-placement (efavirenz:control geometric mean ratio = 0.86 and 1.03, respectively).ConclusionsThese results suggest that the clinically significant DDI between efavirenz and levonorgestrel is likely to persist despite efavirenz dose reduction, whereas dose escalation of implantable levonorgestrel may represent a successful clinical strategy to circumvent efavirenz–levonorgestrel DDIs and will be of use to inform clinical trial design to assess coadministration of efavirenz and levonorgestrel implants.
      PubDate: Mon, 22 Jan 2018 00:00:00 GMT
       
  • Decreased darunavir concentrations during once-daily co-administration
           with maraviroc and raltegravir: OPTIPRIM-ANRS 147 trial
    • Authors: Pressiat C; Hirt D, Treluyer J, et al.
      Abstract: BackgroundThe OPTIPRIM-ANRS 147 trial compared intensive combination ART (darunavir/ritonavir, tenofovir disoproxil fumarate/emtricitabine, raltegravir and maraviroc) started early during primary HIV-1 infection with standard tritherapy with darunavir/ritonavir, tenofovir disoproxil fumarate and emtricitabine. From month 6 to 18, the percentage of viral load values <50 copies/mL was lower in the pentatherapy arm than in the tritherapy arm. Here we compared antiretroviral drug concentrations between the two arms. MethodsPlasma samples were collected from 50 patients at various times after drug administration. A Bayesian approach based on published population pharmacokinetic models was used to estimate residual drug concentrations (Ctrough) and exposures (AUC) in each patient. A mixed linear regression model was then used to compare the AUC and Ctrough values of each drug used in both groups.ResultsPublished models adequately described our data and could be used to predict Ctrough and AUC. No significant difference in tenofovir disoproxil fumarate, emtricitabine and ritonavir parameters was found between the two arms. However, darunavir Ctrough and AUC were significantly lower in the pentatherapy arm than in the tritherapy arm (P = 0.03 and P = 0.04, respectively).ConclusionsAdding maraviroc and raltegravir to darunavir-based tritherapy decreased darunavir concentrations. Compliance issues, maraviroc–darunavir interaction and raltegravir–darunavir interaction were suspected and may affect the kinetics of viral decay during pentatherapy. A specific pharmacokinetic interaction study is needed to explore the interactions between darunavir and maraviroc and raltegravir.
      PubDate: Mon, 22 Jan 2018 00:00:00 GMT
       
  • A multiplex lateral flow immunoassay for the rapid identification of NDM-,
           KPC-, IMP- and VIM-type and OXA-48-like carbapenemase-producing
           Enterobacteriaceae
    • Authors: Boutal H; Vogel A, Bernabeu S, et al.
      Abstract: ObjectivesThe global spread of carbapenemase-producing Enterobacteriaceae represents a substantial challenge in clinical practice and rapid and reliable detection of these organisms is essential. The aim of this study was to develop and validate a lateral flow immunoassay (Carba5) for the detection of the five main carbapenemases (KPC-, NDM-, VIM- and IMP-type and OXA-48-like).MethodsCarba5 was retrospectively and prospectively evaluated using 296 enterobacterial isolates from agar culture. An isolated colony was suspended in extraction buffer and then loaded on the manufactured Carba5.ResultsAll 185 isolates expressing a carbapenemase related to one of the Carba5 targets were correctly and unambiguously detected in <15 min. All other isolates gave negative results except those producing OXA-163 and OXA-405, which are considered low-activity carbapenemases. No cross-reaction was observed with non-targeted carbapenemases, ESBLs, AmpCs or oxacillinases (OXA-1, -2, -9 and -10). Overall, this assay reached 100% sensitivity and 95.3% (retrospectively) to 100% (prospectively) specificity.ConclusionsCarba5 is efficient, rapid and easy to implement in the routine workflow of a clinical microbiology laboratory for confirmation of the five main carbapenemases encountered in Enterobacteriaceae.
      PubDate: Mon, 22 Jan 2018 00:00:00 GMT
       
  • It is time to give social research a voice to tackle antimicrobial
           resistance'
    • Authors: Haenssgen M; Charoenboon N, Khine Zaw Y.
      Abstract: Sir,
      PubDate: Thu, 18 Jan 2018 00:00:00 GMT
       
  • What to expect and when: benznidazole toxicity in chronic Chagas’
           disease treatment
    • Authors: Aldasoro E; Posada E, Requena-Méndez A, et al.
      Abstract: BackgroundBenznidazole is one of the two most effective antiparasitic drugs for Chagas’ disease treatment. However, knowledge about its toxicity profile is mostly based on post-marketing observational studies.ObjectivesOur study combines data from two prospective clinical trials designed to assess the safety of the drug newly produced by ELEA Laboratories (Abarax®).MethodsEligible participants were selected using a consecutive sampling strategy in the CINEBENZ and BIOMARCHA studies between 2013 and 2016 (EUDRACT 2011-002900-34 and 2012-002645-38, respectively, and clinicaltrials.gov NCT01755403 and NCT01755377, respectively). Enrolled subjects received treatment with 5 mg/kg/day benznidazole orally in two divided doses for 8 weeks and were followed up fortnightly.ResultsWe observed 305 adverse reactions in 85 of 99 participants (85.9%). Each patient had a median of three adverse reactions, 89.5% were mild and the median duration was 12 days. Most adverse reactions appeared in the first month of treatment except arthritis and peripheral neuropathy. Twenty-six patients did not complete treatment: 2 were withdrawn, 1 for ectopic pregnancy and 1 for epilepsy relapse due to cysticercosis; 2 were lost to follow-up; and 22 were owing to adverse reactions, two of them severe. We observed some unexpected adverse reactions that have not been described previously, such as psychiatric symptoms, erectile dysfunction, menstrual cycle alterations and lung infiltration.ConclusionsThere is a very high frequency of adverse reactions to benznidazole. Most adverse reactions are mild, but the treatment burden is significant and unexpected reactions are not rare. Severe reactions are uncommon, but they can be life-threatening. Further studies are necessary to optimize treatment.
      PubDate: Tue, 16 Jan 2018 00:00:00 GMT
       
  • Are infection specialists recommending short antibiotic treatment
           durations' An ESCMID international cross-sectional survey
    • Authors: Macheda G; Dyar O, Luc A, et al.
      Abstract: ObjectivesTo evaluate the current practice and the willingness to shorten the duration of antibiotic therapy among infection specialists.MethodsInfection specialists giving at least weekly advice on antibiotic prescriptions were invited to participate in an online cross-sectional survey between September and December 2016. The questionnaire included 15 clinical vignettes corresponding to common clinical cases with favourable outcomes; part A asked about the antibiotic treatment duration they would usually advise to prescribers and part B asked about the shortest duration they were willing to recommend.ResultsWe included 866 participants, mostly clinical microbiologists (22.8%, 197/863) or infectious diseases specialists (58.7%, 507/863), members of an antibiotic stewardship team in 73% (624/854) of the cases, coming from 58 countries on all continents. Thirty-six percent of participants (271/749) already advised short durations of antibiotic therapy (compared with the literature) to prescribers for more than half of the vignettes and 47% (312/662) chose shorter durations in part B compared with part A for more than half of the vignettes. Twenty-two percent (192/861) of the participants declared that their regional/national guidelines expressed durations of antibiotic therapy for a specific clinical situation as a fixed duration as opposed to a range and in the multivariable analysis this was associated with respondents advising short durations for more than half of the vignettes (adjusted OR 1.5, P = 0.02).ConclusionsThe majority of infection specialists currently do not advise the shortest possible duration of antibiotic therapy to prescribers. Promoting short durations among these experts is urgently needed.
      PubDate: Tue, 16 Jan 2018 00:00:00 GMT
       
  • Genetic characterization of a VanG-type vancomycin-resistant Enterococcus
           faecium clinical isolate
    • Authors: Sassi M; Guérin F, Lesec L, et al.
      Abstract: ObjectivesTo characterize, phenotypically and genotypically, the first Enterococcus faecium clinical isolate harbouring a vanG operon.MethodsThe antibiotic resistance profile of E. faecium 16-346 was determined and its whole genome sequenced using PacBio technology. Attempts to transfer vancomycin resistance by filter mating were performed and the inducibility of expression of the vanG operon was studied by reverse-transcription quantitative PCR (RT-qPCR) in the presence or absence of subinhibitory concentrations of vancomycin.ResultsE. faecium 16-346 was resistant to rifampicin (MIC >4 mg/L), erythromycin (MIC >4 mg/L), tetracycline (MIC >16 mg/L) and vancomycin (MIC 8 mg/L), but susceptible to teicoplanin (MIC 0.5 mg/L). The strain harboured the vanG operon in its chromosome, integrated in a 45.5 kb putative mobile genetic element, similar to that of Enterococcus faecalis BM4518. We were unable to transfer vancomycin resistance from E. faecium 16-346 to E. faecium BM4107 and E. faecalis JH2-2. Lastly, transcription of the vanG gene was inducible by vancomycin.ConclusionsThis is, to the best of our knowledge, the first report of a VanG-type vancomycin-resistant strain of E. faecium. Despite the alarm pulled because of the therapeutic problems caused by VRE, our work shows that new resistant loci can still be found in E. faecium.
      PubDate: Tue, 16 Jan 2018 00:00:00 GMT
       
  • Evaluation of the rapid carbapenem inactivation method (rCIM): a
           phenotypic screening test for carbapenemase-producing Enterobacteriaceae
    • Authors: Muntean M; Muntean A, Gauthier L, et al.
      Abstract: ObjectivesFast and accurate diagnostic tests to identify carbapenemase-producing Enterobacteriaceae (CPE) are mandatory for proper antimicrobial therapy and implementing infection control measures. Here, we have developed a rapid Carbapenem Inactivation Method (rCIM) for CPE detection.MethodsThe rCIM consists of the incubation of a potential carbapenemase producer with meropenem discs and use of the resulting supernatant to challenge a susceptible indicator strain. Growth of the indicator strain is monitored using a nephelometer. The performances of the rCIM were compared with the CIM and Carba NP tests using a collection of 113 well-characterized carbapenem-resistant enterobacterial isolates, including 85 carbapenemase producers and 28 non-carbapenemase producers. In addition, rCIM was compared with the Carba NP test and PCR sequencing in a prospective analysis of 101 carbapenem-resistant enterobacterial isolates addressed to the French National Reference Center for Antimicrobial Resistance in July 2017.Results and discussionThe rCIM correctly identified 84/85 carbapenemase producers and 28/28 non-carbapenemase producers, yielding a sensitivity of 99% and a specificity of 100%, slightly higher than the CIM and Carba NP test. In the prospective validation study, the rCIM showed a sensitivity and specificity of 97% and 95%, respectively. Two cephalosporinase-hyperproducing Enterobacter cloacae gave false-positive results, whereas an IMI-17-producing Enterobacter asburiae gave a false-negative result. The result was, however, positive when the isolate was grown on selective antibiotic-containing media.ConclusionsThe rCIM is a rapid (less than 3 h), cheap and accurate test for the detection of CPEs, which can be implemented in low-resource settings, making it a useful tool for microbiology laboratories.
      PubDate: Tue, 16 Jan 2018 00:00:00 GMT
       
  • Phenotypic analysis of HIV-1 E157Q integrase polymorphism and impact on
           virological outcome in patients initiating an integrase inhibitor-based
           regimen
    • Authors: Charpentier C; Malet I, Andre-Garnier E, et al.
      Abstract: ObjectivesTo assess the phenotypic susceptibility of the E157Q polymorphism in HIV-1 integrase (IN) and the virological outcome of patients infected with E157Q-mutated virus initiating an IN inhibitor (INI)-based regimen.MethodsThis was a multicentre study assessing IN sequences from INI-naive patients among 17 French HIV clinical centres. E157Q site-directed mutants in pNL4.3 and pCRF02_AG contexts were assessed in a recombinant phenotypic assay.ResultsPrevalence of the E157Q polymorphism was 2.7% among 8528 IN sequences from INI-naive patients and its distribution was 1.7%, 5.6% and 2.2% in B, CRF02_AG and various non-B subtypes, respectively. Thirty-nine INI-naive patients with E157Q-mutated virus initiated an INI-based regimen. Among them, 15 had a viral load (VL) <50 copies/mL at initiation and virological suppression was maintained during the first year of follow-up in all but two exhibiting a viral blip. Twenty-four patients had a VL > 50 copies/mL at the time of INI-based regimen initiation. Among them eight were receiving a first-line regimen and the only two patients who did not reach VL < 50 copies/mL at week 24 were receiving elvitegravir. The 16 remaining patients were ART experienced in virological failure with drug-resistant viruses displaying several virological outcomes independently of the genotypic susceptibility score. Phenotypic analyses showed a fold change in EC50 of 0.6, 0.9 and 1.9 for raltegravir, dolutegravir and elvitegravir, respectively, in a subtype B context, and 1.1, 1.9 and 2.4 for raltegravir, dolutegravir and elvitegravir, respectively, in a CRF02_AG context.ConclusionsAssessment of virological response in 39 patients initiating an INI-based regimen with E157Q-mutated virus, in combination with phenotypic analysis, suggests that particular attention should be paid to antiretroviral-naive patients and dolutegravir should be preferentially used in these patients.
      PubDate: Fri, 12 Jan 2018 00:00:00 GMT
       
  • Impact of antibiotic stewardship programmes in Asia: a systematic review
           and meta-analysis
    • Authors: Lee C; Cowling B, Feng S, et al.
      Abstract: BackgroundThe use of antibiotic stewardship programmes (ASPs) is increasing in Asia, but their effectiveness in reducing antibiotic consumption and their impact on clinical outcomes is not known.ObjectivesTo determine the impact of ASPs conducted in Asia on the consumption of antibiotics and on patients’ clinical outcomes.MethodsWe systematically searched the Embase and Medline (PubMed) databases for studies that compared antibiotic consumption or clinical outcomes of patients in an Asian hospital or clinic with an ASP (intervention) with those in a similar setting without an ASP (control). Meta-analyses of all-cause mortality and hospital-acquired infection (HAI) were performed using random-effects models.ResultsThe search identified 77 studies of which 22 and 19 reported antibiotic usage and cost, respectively. Among these, 20 (91%) studies reported reduced antibiotic usage and 19 (100%) reported cost savings in the intervention group. Duration of antibiotic therapy was reduced in six of seven studies in association with an ASP. Rates of all-cause mortality and HAI were not significantly different between the intervention and control groups. However, mortality rates were significantly improved by ASPs using drug monitoring, while HAI rates were also improved by ASPs that included infection control or hand hygiene programmes.ConclusionsIn Asia, ASPs reduce antibiotic consumption in hospital and clinic settings and do not worsen clinical outcomes. The findings strongly support the broad implementation of antimicrobial stewardship interventions in hospital and clinic settings in Asia.
      PubDate: Thu, 11 Jan 2018 00:00:00 GMT
       
  • Development and impact of a massive open online course (MOOC) for
           antimicrobial stewardship
    • Authors: Sneddon J; Barlow G, Bradley S, et al.
      Abstract: BackgroundThe University of Dundee and the BSAC developed a massive open online course (MOOC) to address the global need for education to support antimicrobial stewardship in low- and middle-income countries.MethodsAn interactive course, Antimicrobial Stewardship: Managing Antibiotic Resistance, was developed and delivered via the FutureLearn© platform. The course ran over four 6 week periods during 2015 and 2016 supported by educators and was evaluated via data on uptake and feedback from learners on impact on clinical practice.ResultsIn total, 32 944 people, 70% of them healthcare professionals, from 163 countries joined the course from Europe (49%), Asia (16%), Africa (13%), North America (9%), Australia (8%) and South America (5%). Between 33% and 37% of joiners in each run completed at least one step in any week of the course and 219 participants responded to a post-course survey. The course was rated good or excellent by 208 (95%) of the participants, and 83 (38%) intended to implement stewardship interventions in their own setting. A follow-up survey 6 months later suggested that 49% had implemented such interventions.ConclusionsThe MOOC has addressed a global learning need by providing education free at the point of access, and learning from its development will help others embarking upon similar educational solutions. Initial quantitative and qualitative feedback suggests it has engaged participants and complements traditional educational methods. Measuring its real impact on clinical practice remains a challenge. The FutureLearn© platform offers flexibility for MOOCs to be sustainable through modification to remove educator facilitation but maintain active participant discussion.
      PubDate: Wed, 10 Jan 2018 00:00:00 GMT
       
  • Emergence of blaCTX-M-55 associated with fosA, rmtB and mcr gene variants
           in Escherichia coli from various animal species in France
    • Authors: Lupo A; Saras E, Madec J, et al.
      Abstract: ObjectivesIn Asian countries, blaCTX-M-55 is the second most common ESBL-encoding gene. blaCTX-M-55 frequently co-localizes with fosA and rmtB genes on epidemic plasmids, which remain sporadic outside Asia. During 2010–13, we investigated CTX-M-55-producing Escherichia coli isolates and their co-resistance to fosfomycin, aminoglycosides, fluoroquinolones and colistin as part of a global survey of ESBLs in animals in France.MethodsblaCTX-M-55, fosA, rmtB and plasmidic quinolone and colistin resistance genes were characterized by PCR, sequencing and hybridization experiments. Plasmids were classified according to their incompatibility groups and subtypes. Genotyping was performed by MLST and repetitive extragenic palindromic sequence-based PCR.ResultsTwenty-one E. coli isolates from bovines (n = 16), dogs (n = 2), horses (n = 2) and a monkey harboured blaCTX-M-55, were MDR and belonged to ST744 (n = 9) and 10 other clones. blaCTX-M-55 was mostly located on IncF (n = 19), but also on IncI1 (n = 2) plasmids. On IncF33:A1:B1 plasmids, blaCTX-M-55 co-localized with the rmtB and aac(6′)-Ib genes and in one isolate with the fosA3 allele. Ten IncF46:A-:B20 plasmids, which were found in different clones from unrelated animals, also carried the mcr-3 gene. blaCTX-M-55-carrying IncF18:A-:B1 plasmids were found in different animal species from distinct locations and periods, and one additionally carried the fosA4 gene. One isolate harboured the mcr-1 gene, which did not co-localize with blaCTX-M-55.ConclusionsA large diversity of E. coli clones and plasmid types supported the spread of blaCTX-M-55, together with atypical resistance genes, in various animal species in France. fosA and rmtB genes are emerging among animals in Europe and this issue is of concern for public health.
      PubDate: Wed, 10 Jan 2018 00:00:00 GMT
       
  • A multicentre study of antifungal susceptibility patterns among 350
           Candida auris isolates (2009–17) in India: role of the ERG11 and FKS1
           genes in azole and echinocandin resistance
    • Authors: Chowdhary A; Prakash A, Sharma C, et al.
      Abstract: BackgroundCandida auris has emerged globally as an MDR nosocomial pathogen in ICU patients.ObjectivesWe studied the antifungal susceptibility of C. auris isolates (n = 350) from 10 hospitals in India collected over a period of 8 years. To investigate azole resistance, ERG11 gene sequencing and expression profiling was conducted. In addition, echinocandin resistance linked to mutations in the C. auris FKS1 gene was analysed.MethodsCLSI antifungal susceptibility testing of six azoles, amphotericin B, three echinocandins, terbinafine, 5-flucytosine and nystatin was conducted. Screening for amino acid substitutions in ERG11 and FKS1 was performed.ResultsOverall, 90% of C. auris were fluconazole resistant (MICs 32 to ≥64 mg/L) and 2% and 8% were resistant to echinocandins (≥8 mg/L) and amphotericin B (≥2 mg/L), respectively. ERG11 sequences of C. auris exhibited amino acid substitutions Y132 and K143 in 77% (n = 34/44) of strains that were fluconazole resistant whereas WT genotypes, i.e. without substitutions at these positions, were observed in isolates with low fluconazole MICs (1–2 mg/L) suggesting that these substitutions confer a phenotype of resistance to fluconazole similar to that described for Candida albicans. No significant expression of ERG11 was observed, although expression was inducible in vitro with fluconazole exposure. Echinocandin resistance was linked to a novel mutation S639F in FKS1 hot spot region I.ConclusionsOverall, 25% and 13% of isolates were MDR and multi-azole resistant, respectively. The most common resistance combination was azoles and 5-flucytosine in 14% followed by azoles and amphotericin B in 7% and azoles and echinocandins in 2% of isolates.
      PubDate: Tue, 09 Jan 2018 00:00:00 GMT
       
  • TGF-β-mediated NADPH oxidase 4-dependent oxidative stress promotes
           colistin-induced acute kidney injury
    • Authors: Jeong B; Park S, Cho S, et al.
      Abstract: BackgroundColistin (polymyxin E) is an important constituent of the polymyxin class of cationic polypeptide antibiotics. Intrarenal oxidative stress can contribute to colistin-induced nephrotoxicity. Nicotinamide adenine dinucleotide 3-phosphate oxidases (Noxs) are important sources of reactive oxygen species. Among the various types of Noxs, Nox4 is predominantly expressed in the kidney.ObjectivesWe investigated the role of Nox4 and benefit of Nox4 inhibition in colistin-induced acute kidney injury using in vivo and in vitro models.MethodsHuman proximal tubular epithelial (HK-2) cells were treated with colistin with or without NOX4 knockdown, or GKT137831 (most specific Nox1/4 inhibitor). Effects of Nox4 inhibition on colistin-induced acute kidney injury model in Sprague–Dawley rats were examined.ResultsNox4 expression in HK-2 cells significantly increased following colistin exposure. SB4315432 (transforming growth factor-β1 receptor I inhibitor) significantly inhibited Nox4 expression in HK-2 cells. Knockdown of NOX4 transcription reduced reactive oxygen species production, lowered the levels of pro-inflammatory markers (notably mitogen-activated protein kinases) implicated in colistin-induced nephrotoxicity and attenuated apoptosis by altering Bax and caspase 3/7 activity. Pretreatment with GKT137831 replicated these effects mediated by downregulation of mitogen-activated protein kinase activities. In a rat colistin-induced acute kidney injury model, administration of GKT137831 resulted in attenuated colistin-induced acute kidney injury as indicated by attenuated impairment of glomerulus function, preserved renal structures, reduced expression of 8-hydroxyguanosine and fewer apoptotic cells.ConclusionsCollectively, these findings identify Nox4 as a key source of reactive oxygen species responsible for kidney injury in colistin-induced nephrotoxicity and highlight a novel potential way to treat drug-related nephrotoxicity.
      PubDate: Tue, 09 Jan 2018 00:00:00 GMT
       
  • In vivo daptomycin efficacy against experimental vancomycin-resistant
           Enterococcus faecium endocarditis
    • Authors: Reissier S; Saleh-Mghir A, Guerin F, et al.
      Abstract: ObjectivesDaptomycin has become a first-line therapeutic option for vancomycin-resistant Enterococcus faecium infective endocarditis (IE). Although high doses (≥8 mg/kg) are often recommended, optimal doses, particularly for strains with MICs close to the susceptibility breakpoint (4 mg/L), are still debated.MethodsDaptomycin efficacy at doses equivalent to 8 mg/kg daptomycin (DAP8) and 12 mg/kg daptomycin (DAP12) in humans was evaluated in a rabbit model of aortic valve IE induced by 108 cfu of E. faecium reference strain Aus0004 (daptomycin MIC = 2 mg/L) or its in vitro mutant strain Mut4 (daptomycin MIC = 4 mg/L). Treatment began 48 h post-inoculation and lasted 5 days.ResultsWith Aus0004, the median log10 cfu/g of vegetations was significantly lower after DAP8 and DAP12 versus controls [6.05 (n = 12) and 2.15 (n = 10) versus 9.14 (n = 11), respectively; P < 0.001], with DAP12 being more effective than DAP8 concerning vegetation bacterial load (P < 0.001) and percentages of sterile vegetations (100% versus 0%, respectively; P < 0.001). Daptomycin-resistant Aus0004 mutants were detected in 8.3% of DAP8-treated vegetations. With Mut4, the median log10 cfu/g of vegetations was significantly lower after DAP8 and DAP12 versus controls [7.7 (n = 11) and 6.95 (n = 10) versus 9.59 (n = 11), respectively; P = 0.001 and P = 0.002], without any between-dose difference, but no vegetation was sterile. Moreover, 7 of 11 (63.6%) and 7 of 9 (77.8%) vegetations contained resistant mutants after DAP8 and DAP12, respectively.ConclusionsDAP12 was the most successful strategy against IE due to a WT E. faecium strain (daptomycin MIC = 2 mg/L). To treat IE strains with MIC = 4 mg/L, DAP8 or DAP12 monotherapy was poorly effective with the risk of resistant mutant emergence. Reassessment of the daptomycin susceptibility breakpoint for enterococci seems necessary.
      PubDate: Tue, 09 Jan 2018 00:00:00 GMT
       
  • Continued propagation of the CRF19_cpx variant among HIV-positive MSM
           patients in Spain
    • Authors: Pérez-Parra S; Álvarez M, Fernandez-Caballero J, et al.
      Abstract: ObjectivesThe HIV-1 CRF19_cpx genetic form has been recently associated with greater pathogenicity. We used CoRIS, a national cohort of 31 reference hospitals in Spain, to investigate the current epidemiological situation of this variant in Spain.Patients and methodsWe analysed 4734 naive HIV-1-positive patients diagnosed during the 2007–15 period with an available pol gene sequence in the CoRIS resistance database. HIV-1 CRF19_cpx was ascribed through REGA3.0 and confirmed by a phylogenetic analysis. We analysed the presence of the transmission clusters of HIV-1 CRF19_cpx by maximum likelihood [with the randomized accelerated maximum likelihood (RAxML) program] and the time to the most recent common ancestor using Bayesian inference (BEAST, v. 1.7.5).ResultsNineteen patients were infected with CRF19_cpx: all were male, they had a mean age of 42.9 years (95% CI: 36.4–52.5 years), the majority were MSM [n = 18 (95%)] and of Spanish nationality [n = 16 (84.2%)] and they had high CD4+ T cell counts (∼415 cells/mm3). Fifteen patients were grouped into four different transmission clusters: two clusters (two patients each) grouped the patients from Valencia and another cluster grouped one patient from Madrid and another from Seville. We found a larger cluster that grouped nine patients from southern Spain (Malaga and Seville), of which six presented mutation G190A. We estimated the origin of all the transmission clusters to take place between 2009 and 2010.ConclusionsWe demonstrate that this variant has spread in Spain in recent years among young HIV-positive MSM and we note a recent expansion in southern Spain in patients who carry mutation G190A. We alert healthcare managers to enhance preventive measures to prevent the continuous spread of HIV-1 CRF19_cpx.
      PubDate: Mon, 08 Jan 2018 00:00:00 GMT
       
  • The effect of measuring serum doxycycline concentrations on clinical
           outcomes during treatment of chronic Q fever
    • Authors: van Roeden S; Bleeker-Rovers C, Kampschreur L, et al.
      Abstract: BackgroundFirst choice treatment for chronic Q fever is doxycycline plus hydroxychloroquine. Serum doxycycline concentration (SDC) >5 μg/mL has been associated with a favourable serological response, but the effect on clinical outcomes is unknown.ObjectivesTo assess the effect of measuring SDC during treatment of chronic Q fever on clinical outcomes.MethodsWe performed a retrospective cohort study, to assess the effect of measuring SDC on clinical outcomes in patients treated with doxycycline and hydroxychloroquine for chronic Q fever. Primary outcome was the first disease-related event (new complication or chronic Q fever-related mortality); secondary outcomes were all-cause mortality and PCR-positivity. Multivariable analysis was performed with a Cox proportional hazards model, with shared-frailty terms for different hospitals included.ResultsWe included 201 patients (mean age 68 years, 83% male): in 167 patients (83%) SDC was measured, 34 patients (17%) were treated without SDC measurement. First SDC was >5 μg/mL in 106 patients (63%), all with 200 mg doxycycline daily. In patients with SDC measured, dosage was adjusted in 41% (n = 68), concerning an increase in 64 patients. Mean SDC was 4.1 μg/mL before dosage increase, and 5.9 μg/mL afterwards. SDC measurement was associated with a lower risk for disease-related events (HR 0.51, 95% CI 0.26–0.97, P = 0.04), but not with all-cause mortality or PCR-positivity.ConclusionsSDC measurement decreases the risk for disease-related events, potentially through more optimal dosing or improved compliance. We recommend measurement of SDC and striving for SDC >5 μg/mL and <10 μg/mL during treatment of chronic Q fever.
      PubDate: Mon, 08 Jan 2018 00:00:00 GMT
       
  • Probable vancomycin-induced myasthenic crisis: a case report
    • Authors: Nguyen C; Nanfro J.
      Abstract: Sir,
      PubDate: Fri, 05 Jan 2018 00:00:00 GMT
       
  • Benznidazole treatment safety: the Médecins Sans Frontières experience
           in a large cohort of Bolivian patients with Chagas’ disease—authors’
           response
    • Authors: Sperandio da Silva G; Mediano M, Hasslocher-Moreno A, et al.
      Abstract: Sir,
      PubDate: Thu, 04 Jan 2018 00:00:00 GMT
       
  • Plasma and breast milk pharmacokinetics of emtricitabine, tenofovir and
           lamivudine using dried blood and breast milk spots in nursing African
           mother–infant pairs
    • Authors: Waitt C; Olagunju A, Nakalema S, et al.
      Abstract: BackgroundBreast milk transfer of first-line ART from mother to infant is not fully understood.ObjectivesTo determine the concentrations of lamivudine, emtricitabine and tenofovir in maternal blood, breast milk and infant blood from breastfeeding mother–infant pairs.MethodsIntensive pharmacokinetic sampling of maternal dried blood spots (DBS), dried breast milk spots (DBMS) and infant DBS from 30 Ugandan and 29 Nigerian mothers receiving first-line ART and their infants was conducted. DBS and DBMS were collected pre-dose and at 5–6 timepoints up to 12 h following observed dosing. Infant DBS were sampled twice during this period. Lamivudine, emtricitabine and tenofovir were quantified using LC-MS/MS, with non-compartmental analysis to calculate key pharmacokinetic parameters.ResultsPeak concentrations in breast milk from women taking lamivudine and emtricitabine occurred later than in plasma (4–8 h compared with 2 h for lamivudine and 2–4 h for emtricitabine). Consequently, the milk-to-plasma (M:P) ratio of lamivudine taken once daily was 0.95 (0.82–1.15) for AUC0–12, whereas for AUC12–20 this was 3.04 (2.87–4.16). Lamivudine was detectable in 36% (14/39) of infants [median 17.7 (16.3–22.7) ng/mL]. For 200 mg of emtricitabine once daily, the median M:P ratio was 3.01 (2.06–3.38). Three infants (19%) had measurable emtricitabine [median 18.5 (17.6–20.8) ng/mL]. For 300 mg of tenofovir once daily, the median M:P ratio was 0.015 (0–0.03) and no infant had measurable tenofovir concentrations.ConclusionsEmtricitabine and lamivudine accumulate in breast milk and were detected in breastfeeding infants. In contrast, tenofovir penetrates the breast milk to a small degree, but is undetectable in breastfeeding infants.
      PubDate: Thu, 04 Jan 2018 00:00:00 GMT
       
  • Antimicrobial usage in German acute care hospitals: results of the third
           national point prevalence survey and comparison with previous national
           point prevalence surveys
    • Authors: Aghdassi S; Gastmeier P, Piening B, et al.
      Abstract: ObjectivesPrevious point prevalence surveys (PPSs) revealed the potential for improving antimicrobial usage (AU) in German acute care hospitals. Data from the 2016 German national PPS on healthcare-associated infections and AU were used to evaluate efforts in antimicrobial stewardship (AMS).MethodsA national PPS in Germany was organized by the German National Reference Centre for Surveillance of Nosocomial Infections in 2016 as part of the European PPS initiated by the ECDC. The data were collected in May and June 2016. Results were compared with data from the PPS 2011.ResultsA total of 218 hospitals with 64 412 observed patients participated in the PPS 2016. The prevalence of patients with AU was 25.9% (95% CI 25.6%–26.3%). No significant increase or decrease in AU prevalence was revealed in the group of all participating hospitals. Prolonged surgical prophylaxis was found to be common (56.1% of all surgical prophylaxes on the prevalence day), but significantly less prevalent than in 2011 (P < 0.01). The most frequently administered antimicrobial groups were penicillins plus β-lactamase inhibitors (BLIs) (23.2%), second-generation cephalosporins (12.9%) and fluoroquinolones (11.3%). Significantly more penicillins plus BLIs and fewer second-generation cephalosporins and fluoroquinolones were used in 2016. Overall, an increase in the consumption of broad-spectrum antimicrobials was noted. For 68.7% of all administered antimicrobials, the indication was documented in the patient notes.ConclusionsThe current data reaffirm the points of improvement that previous data identified and reveal that recent efforts in AMS in German hospitals require further intensification.
      PubDate: Thu, 04 Jan 2018 00:00:00 GMT
       
  • Serious neuropsychiatric adverse effects related to interaction between
           itraconazole and darunavir/ritonavir in an HIV-infected patient with
           cerebral histoplasmosis
    • Authors: Le Meur L; Tantet C, Lê M, et al.
      Abstract: Sir,
      PubDate: Mon, 25 Dec 2017 00:00:00 GMT
       
  • Antimicrobial activity of oritavancin and comparator agents when tested
           against Gram-positive bacterial isolates causing infections in cancer
           patients (2014–16)
    • Authors: Pfaller M; Sader H, Castanheira M, et al.
      Abstract: ObjectivesThe in vitro activity of oritavancin was assessed against clinically relevant Gram-positive pathogens causing infections in cancer patients in European and US hospitals.MethodsA total of 1357 Gram-positive cocci (GPC) were included. Isolates were predominantly from bloodstream infections (54.6%). The most frequently isolated GPC were Staphylococcus aureus (43.6%), CoNS (14.4%) and Enterococcus spp. (22.0%).ResultsOritavancin (99.8% susceptible) showed modal MIC, MIC50 and MIC90 results of 0.015, 0.015–0.03 and 0.06 mg/L, respectively, when tested against S. aureus, regardless of methicillin susceptibility or geographical region. CoNS isolates from the USA demonstrated an MIC90 of oritavancin (MIC90, 0.12 mg/L) that was slightly higher than that for isolates from European countries (MIC90 0.06 mg/L). Oritavancin inhibited all Enterococcus faecalis and Enterococcus faecium, including VRE, at ≤ 0.25 mg/L. Oritavancin exhibited MIC50 results of 0.03 and 0.008–0.015 mg/L when tested against isolates of β-haemolytic streptococci and viridans group streptococci, respectively, regardless of geographical region.ConclusionsOritavancin had potent activity in vitro against this contemporary collection of European and US GPC isolates from cancer patients.
      PubDate: Mon, 25 Dec 2017 00:00:00 GMT
       
  • Carbapenem-resistant Acinetobacter baumannii ST294 harbouring the OXA-72
           carbapenemase from a captive grey parrot
    • Authors: Klotz P; Jacobmeyer L, Stamm I, et al.
      Abstract: Sir,
      PubDate: Thu, 21 Dec 2017 00:00:00 GMT
       
  • Proline-rich antimicrobial peptides show a long-lasting post-antibiotic
           effect on Enterobacteriaceae and Pseudomonas aeruginosa
    • Authors: Holfeld L; Knappe D, Hoffmann R.
      Abstract: BackgroundProline-rich antimicrobial peptides (PrAMPs) represent a promising class of potential therapeutics to treat multiresistant infections. They inhibit bacterial protein translation at the 70S ribosome by either blocking the peptide-exit tunnel (oncocin type) or trapping release factors (apidaecin type).ObjectivesBesides direct concentration-dependent antibacterial effects, the post-antibiotic effect (PAE) is the second most important criterion of antimicrobial pharmacodynamics to be determined in vitro. Here, PAEs of 10 PrAMPs and three antibiotics against three Escherichia coli strains, Klebsiella pneumoniae ATCC 10031 and Pseudomonas aeruginosa ATCC 27853 were studied after 1 h of exposure.MethodsA robust high-throughput screening to determine PAEs was established, i.e. liquid handling by a 96-channel pipetting system and continuous incubation and absorbance measurement in a microplate reader.ResultsProlonged PAEs (≥4 h) were detected for all peptides at their MIC values against all strains; PAEs were even >10 h for Api88, Api137, Bac7(1-60) and A3-APO. The PAEs increased further at 4 × MIC. Aminoglycosides gentamicin and kanamycin usually showed lower PAEs (≤4 h) at MIC, but PAEs increased to > 10 h at 4 × MIC. Bacteriostatic chloramphenicol exhibited the shortest PAEs (<4 h).ConclusionsThe PAEs of PrAMPs studied against Enterobacteriaceae and P. aeruginosa for the first time were typically 4-fold stronger than for conventional antibiotics. Together with their fast and irreversible uptake by bacteria, the observed prolonged PAE of PrAMPs helps to explain their high in vivo efficacy despite unfavourable pharmacokinetics.
      PubDate: Thu, 21 Dec 2017 00:00:00 GMT
       
  • Antimicrobial susceptibilities of clinical Legionella longbeachae isolates
    • Authors: Isenman H; Anderson T, Chambers S, et al.
      Abstract: Sir,
      PubDate: Tue, 19 Dec 2017 00:00:00 GMT
       
  • Clinical outcomes after combination treatment with ceftazidime/avibactam
           and aztreonam for NDM-1/OXA-48/CTX-M-15-producing Klebsiella pneumoniae
           infection
    • Authors: Shaw E; Rombauts A, Tubau F, et al.
      Abstract: Sir,
      PubDate: Tue, 19 Dec 2017 00:00:00 GMT
       
  • Genetic correlates of clarithromycin susceptibility among isolates of the
           Mycobacterium abscessus group and the potential clinical applicability of
           a PCR-based analysis of erm(41)
    • Authors: Carvalho N; Pavan F, Sato D, et al.
      Abstract: ObjectivesTo define the genetic basis of clarithromycin resistance among isolates of the Mycobacterium abscessus group (MAG).MethodsWe analysed 133 isolates identified as MAG. Species identification was confirmed by sequencing the rpoB gene. Clarithromycin susceptibility testing was performed according to CLSI recommendations, with an extended 14 day incubation. Known resistance genotypes of erm(41) and rrl were identified by sequencing; the presence of deletions in erm(41) was detected by PCR.ResultsThe 133 MAG isolates included 82 M. abscessus, 27 Mycobacterium massiliense and 24 Mycobacterium bolletii. After the 3 day incubation, only five isolates demonstrated clarithromycin resistance (R); after 14 days of extended incubation, an additional 92 exhibited inducible resistance (IR), with the remaining being susceptible (S). The distribution of susceptibility phenotypes varied among the species. Among M. abscessus isolates, 11% were S, 84% IR and 5% R; among M. bolletii isolates, 96% were IR and 4% R; and among M. massiliense isolates 100% were S. Sequencing of rrl identified only a single isolate with the A2058G mutation. Deletions in erm(41) were present in 30 susceptible isolates; among the remaining 103 isolates, 97 were R or IR (sensitivity, 83%; specificity, 100%; positive predictive value, 100%; negative predictive value, 94%). Among the six susceptible isolates without deletions, all carried the erm(41) T28C point mutation.ConclusionsA significant proportion of MAG isolates demonstrate inducible resistance to clarithromycin that is only detectable with an extended 14 day incubation. Further, the majority of clarithromycin-susceptible MAG isolates have characteristic deletions in erm(41) that can rapidly and reliably be detected by a simple PCR.
      PubDate: Mon, 18 Dec 2017 00:00:00 GMT
       
  • Antibacterial activity of ceftolozane/tazobactam alone and in combination
           with other antimicrobial agents against MDR Pseudomonas aeruginosa
    • Authors: Monogue M; Nicolau D.
      Abstract: ObjectivesBroad-spectrum antimicrobial resistance in Pseudomonas aeruginosa (PSA) isolates is a growing concern as our therapeutic options have become significantly limited. Although ceftolozane/tazobactam (C/T) has been shown to be highly active against MDR PSA pathogens, combination regimens are often employed in real-world settings. To assist the clinical decision-making process regarding the selection of combination antibiotics and dosages for this pathogen, we performed time–kill studies assessing clinical free peak and trough C/T concentrations alone and in combination with eight anti-pseudomonal agents against four clinical MDR PSA isolates.MethodsTime–kill analyses were performed over 24 h in duplicate using C/T concentrations reflective of the free peak concentrations of a 3 g dose every 8 h (q8h; 120/25.2 mg/L) and the peak and trough of a 1.5 g q8h dose (60/12.6 and 7.5/1.6 mg/L) in humans. The activity of C/T 120, 60 and 7.5 mg/L alone and C/T 7.5 mg/L in combination with free peak and trough concentrations of clinical doses for cefepime, ciprofloxacin, colistin, aztreonam, meropenem, piperacillin/tazobactam, fosfomycin and amikacin was tested for all isolates.ResultsC/T 3 and 1.5 g q8h peak concentrations demonstrated killing against the MDR PSA. Colistin and fosfomycin were synergistic with C/T as dual therapy and triple therapy regimens.ConclusionsAs a result of escalating resistance, PSA is an increasingly challenging pathogen in the clinical setting. Our findings aid in the identification of novel treatment options using achievable drug exposures for the treatment of MDR PSA.
      PubDate: Mon, 18 Dec 2017 00:00:00 GMT
       
  • Population pharmacokinetics of total and unbound teicoplanin
           concentrations and dosing simulations in patients with haematological
           malignancy
    • Authors: Byrne C; Parton T, McWhinney B, et al.
      Abstract: ObjectivesTo develop a pharmacokinetic model describing total and unbound teicoplanin concentrations in patients with haematological malignancy and to perform Monte Carlo simulations to evaluate target attainment of unbound trough concentrations with various dose regimens.MethodsThis was a hospital-based clinical trial (EudraCT 2013-004535-72). The dosing regimen was 600/800 mg q12h for three doses then 600/800 mg daily. Serial total and unbound teicoplanin concentrations were collected. Maximum protein binding was estimated from serum albumin concentration. Population pharmacokinetic analyses and Monte Carlo simulations were conducted using Pmetrics®. Target total and unbound trough concentrations were ≥20 and ≥1.5 mg/L, respectively.ResultsThirty adult patients were recruited with a mean (SD) bodyweight of 69.1 (15.8) kg, a mean (SD) CLCR of 72 (41) mL/min and a median (IQR) serum albumin concentration of 29 (4) g/L. A three-compartment complex binding pharmacokinetic model best described the concentration–time data. Total and unbound teicoplanin concentrations were related by serum albumin concentration and a dissociation constant. CLCR and bodyweight were supported as covariates for CL and volume of the central compartment, respectively. Dosing simulations showed that high CLCR was associated with reduced probability of achieving target total and unbound trough concentrations. Low serum albumin concentration was associated with a reduced probability of attaining target total but not unbound trough concentrations. A method to estimate the unbound teicoplanin concentration from the measured total concentration at different serum albumin concentration was demonstrated.ConclusionsStandard teicoplanin dosing regimens should be used with caution in patients with haematological malignancy. Bodyweight, CLCR and serum albumin concentration are important considerations for appropriate dosing.
      PubDate: Mon, 18 Dec 2017 00:00:00 GMT
       
  • Colistin- and carbapenem-resistant Klebsiella pneumoniae carrying mcr-1
           and blaOXA-48 isolated at a paediatric hospital in Vietnam
    • Authors: Berglund B; Hoang N, Tärnberg M, et al.
      Abstract: Sir,
      PubDate: Fri, 15 Dec 2017 00:00:00 GMT
       
  • Characterization of the impact of rpoB mutations on the in vitro and in
           vivo competitive fitness of Clostridium difficile and susceptibility to
           fidaxomicin
    • Authors: Kuehne S; Dempster A, Collery M, et al.
      Abstract: ObjectivesTo establish the role of specific, non-synonymous SNPs in the RNA polymerase β subunit (rpoB) gene in reducing the susceptibility of Clostridium difficile to fidaxomicin and to explore the potential in vivo significance of rpoB mutant strains.MethodsAllelic exchange was used to introduce three different SNPs into the rpoB gene of an erythromycin-resistant derivative (CRG20291) of C. difficile R20291. The genome sequences of the created mutants were determined and each mutant analysed with respect to growth and sporulation rates, toxin A/B production and cytotoxicity against Vero cells, and in competition assays. Their comparative virulence and colonization ability was also assessed in a hamster infection model.ResultsThe MIC of fidaxomicin displayed by three mutants CRG20291-TA, CRG20291-TG and CRG20291-GT was substantially increased (>32, 8 and 2 mg/L, respectively) relative to that of the parent strain (0.25 mg/L). Genome sequencing established that the intended mutagenic substitutions in rpoB were the only changes present. Relative to CRG20291, all mutants had attenuated growth, were outcompeted by the parental strain, had lower sporulation and toxin A/B production capacities, and displayed diminished cytotoxicity. In a hamster model, virulence of all three mutants was significantly reduced compared with the progenitor strain, whereas the degree of caecum colonization was unaltered.ConclusionsOur study demonstrates that particular SNPs in rpoB lead to reduced fidaxomicin susceptibility. These mutations were associated with a fitness cost in vitro and reduced virulence in vivo.
      PubDate: Fri, 15 Dec 2017 00:00:00 GMT
       
  • Comment on: Benznidazole treatment safety: the Médecins Sans Frontières
           experience in a large cohort of Bolivian patients with Chagas’ disease
    • Authors: Novaes R; Gonçalves R.
      Abstract: Sir,
      PubDate: Thu, 14 Dec 2017 00:00:00 GMT
       
  • Genomic analysis reveals different mechanisms of fusidic acid resistance
           in Staphylococcus aureus from Danish atopic dermatitis patients
    • Authors: Edslev S; Clausen M, Agner T, et al.
      Abstract: BackgroundStaphylococcus aureus skin colonization is common in patients with atopic dermatitis (AD) and is associated with risk of skin infections. AD patients therefore often receive antibiotic treatments, including topical treatment with fusidic acid, which have been associated with resistance development.ObjectivesTo examine the prevalence of antibiotic resistance in S. aureus isolated from Danish AD patients, with a primary focus on fusidic acid resistance and the genetic mechanisms that underlie it.MethodsOne hundred and thirty-eight S. aureus isolates collected from lesional skin (n = 54), non-lesional skin (n = 27) and anterior nares (n = 57) from 71 adult AD patients were included in the study. Isolates were tested for susceptibility to 17 selected antibiotics. S. aureus whole-genome sequences were used to examine the genetic determinants of fusidic acid resistance (fusA or fusE mutations or carriage of fusB or fusC genes).ResultsOne hundred and nine isolates (79%) were resistant to at least one of the tested antibiotics, with the most prevalent resistances being to penicillin (55%), fusidic acid (41%) and erythromycin (11%). The primary genetic mechanisms of fusidic acid resistance were carriage of fusC (57%) or mutations in fusA (38%). The most prevalent S. aureus lineage was ST1 (23%). All ST1 isolates carried fusC.ConclusionsS. aureus fusidic acid resistance, caused by either fusA mutations or fusC gene carriage, is a major concern among AD patients. Resistant S. aureus might spread from the patients to the community, indicating the need to reduce the use of fusidic acid in the treatment of AD.
      PubDate: Thu, 14 Dec 2017 00:00:00 GMT
       
  • Atazanavir and darunavir in pregnant women with HIV: evaluation of
           laboratory and clinical outcomes from an observational national study
    • Authors: Floridia M; Masuelli G, Ravizza M, et al.
      Abstract: BackgroundAtazanavir and darunavir represent the main HIV PIs recommended in pregnancy, but comparative data in pregnant women are limited. We assessed the safety and activity profile of these two drugs in pregnancy using data from a national observational study.MethodsWomen with atazanavir or darunavir exposure in pregnancy were evaluated for laboratory measures and main pregnancy outcomes (e.g. preterm delivery, low birthweight, non-elective caesarean section and neonatal gestational age-adjusted birthweight Z-score).ResultsFinal analysis included 500 pregnancies with either atazanavir (n = 409) or darunavir (n = 91) exposure. No differences in pregnancy outcomes, weight gain in pregnancy, drug discontinuations, undetectable HIV-RNA, haemoglobin, ALT, total cholesterol, HDL cholesterol and LDL cholesterol were observed between the two groups. At third trimester, exposure to darunavir was associated with higher levels of plasma triglycerides (median 235.5 versus 179 mg/dL; P = 0.032) and a higher total cholesterol/HDL cholesterol ratio (median 4.03 versus 3.27; P = 0.028) and exposure to atazanavir was associated with higher levels of plasma bilirubin (1.54 versus 0.32 mg/dL; P < 0.001).ConclusionsIn this observational study, the two main HIV PIs currently recommended by perinatal guidelines showed similar safety and activity in pregnancy, with no evidence of differences between the two drugs in terms of main pregnancy outcomes. Based on the minor differences observed in laboratory measures, prescribing physicians might prefer either drug in some particular situations where the different impacts of treatment on lipid profile and bilirubin may have clinical relevance.
      PubDate: Wed, 13 Dec 2017 00:00:00 GMT
       
  • Dolutegravir reshapes the genetic diversity of HIV-1 reservoirs
    • Authors: Gantner P; Lee G, Rey D, et al.
      Abstract: ObjectivesBetter understanding of the dynamics of HIV reservoirs under ART is a critical step to achieve a functional HIV cure. Our objective was to assess the genetic diversity of archived HIV-1 DNA over 48 weeks in blood cells of individuals starting treatment with a dolutegravir-based regimen.MethodsEighty blood samples were prospectively and longitudinally collected from 20 individuals (NCT02557997) including: acutely (n = 5) and chronically (n = 5) infected treatment-naive individuals, as well as treatment-experienced individuals who switched to a dolutegravir-based regimen and were either virologically suppressed (n = 5) or had experienced treatment failure (n = 5). The integrase and V3 loop regions of HIV-1 DNA isolated from PBMCs were analysed by pyrosequencing at baseline and weeks 4, 24 and 48. HIV-1 genetic diversity was calculated using Shannon entropy.ResultsAll individuals achieved or maintained viral suppression throughout the study. A low and stable genetic diversity of archived HIV quasispecies was observed in individuals starting treatment during acute infection. A dramatic reduction of the genetic diversity was observed at week 4 of treatment in the other individuals. In these patients and despite virological suppression, a recovery of the genetic diversity of the reservoirs was observed up to 48 weeks. Viral variants bearing dolutegravir resistance-associated substitutions at integrase position 50, 124, 230 or 263 were detected in five individuals (n = 5/20, 25%) from all groups except those who were ART-failing at baseline. None of these substitutions led to virological failure.ConclusionsThese data demonstrate that the genetic diversity of the HIV-1 reservoir is reshaped following the initiation of a dolutegravir-based regimen and strongly suggest that HIV-1 can continue to replicate despite successful treatment.
      PubDate: Wed, 13 Dec 2017 00:00:00 GMT
       
  • Population pharmacokinetics and probability of target attainment of
           ertapenem administered by subcutaneous or intravenous route in patients
           with bone and joint infection
    • Authors: Goutelle S; Valour F, Gagnieu M, et al.
      Abstract: BackgroundErtapenem is a therapeutic option in patients with Gram-negative bone and joint infection (BJI). The subcutaneous (sc) route of administration is convenient in the outpatient setting and has shown favourable pharmacokinetics (PK), but available data on ertapenem are limited.ObjectivesTo perform population PK analysis and pharmacokinetic/pharmacodynamic (PK/PD) simulation of ertapenem administered by the intravenous (iv) or sc route to patients with BJI.Patients and methodsThis was a retrospective analysis of PK data collected in patients with BJI who received iv or sc ertapenem. Measured ertapenem concentrations were analysed with a non-parametric population approach. Then, simulations were performed based on the final model to investigate the influence of ertapenem route of administration, dosage and renal function on the probability of achieving a pharmacodynamic (PD) target, defined as the percentage of time for which free plasma concentrations of ertapenem remained above the MIC (fT>MIC) of 40%.ResultsForty-six PK profiles (13 with iv and 33 with sc ertapenem) with a total of 133 concentrations from 31 subjects were available for the analysis. A two-compartment model with linear sc absorption and linear elimination best fitted the data. Creatinine clearance was found to significantly influence ertapenem plasma clearance. Simulations showed that twice daily dosing, sc administration and renal impairment were associated with an increase in fT>MIC and target attainment.ConclusionsOur results indicate that 1 g of ertapenem administered twice daily, by the iv or sc route, may optimize ertapenem exposure and achievement of PK/PD targets in patients with BJI.
      PubDate: Wed, 13 Dec 2017 00:00:00 GMT
       
  • Delivering precision antimicrobial therapy through closed-loop control
           systems
    • Authors: Rawson T; O’Hare D, Herrero P, et al.
      Abstract: Sub-optimal exposure to antimicrobial therapy is associated with poor patient outcomes and the development of antimicrobial resistance. Mechanisms for optimizing the concentration of a drug within the individual patient are under development. However, several barriers remain in realizing true individualization of therapy. These include problems with plasma drug sampling, availability of appropriate assays, and current mechanisms for dose adjustment. Biosensor technology offers a means of providing real-time monitoring of antimicrobials in a minimally invasive fashion. We report the potential for using microneedle biosensor technology as part of closed-loop control systems for the optimization of antimicrobial therapy in individual patients.
      PubDate: Mon, 04 Dec 2017 00:00:00 GMT
       
 
 
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