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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: 9, SJR: 0.111, h-index: 4)
Aesthetic Surgery J.     Hybrid Journal   (Followers: 6, SJR: 1.538, h-index: 35)
African Affairs     Hybrid Journal   (Followers: 59, SJR: 1.512, h-index: 46)
Age and Ageing     Hybrid Journal   (Followers: 85, SJR: 1.611, h-index: 107)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 17, SJR: 0.935, h-index: 80)
American Entomologist     Full-text available via subscription   (Followers: 6)
American Historical Review     Hybrid Journal   (Followers: 148, 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: 171, 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: 6, SJR: 0.151, h-index: 7)
American Law and Economics Review     Hybrid Journal   (Followers: 27, SJR: 0.824, h-index: 23)
American Literary History     Hybrid Journal   (Followers: 12, SJR: 0.185, h-index: 22)
Analysis     Hybrid Journal   (Followers: 23)
Annals of Botany     Hybrid Journal   (Followers: 35, SJR: 1.912, h-index: 124)
Annals of Occupational Hygiene     Hybrid Journal   (Followers: 28, SJR: 0.837, h-index: 57)
Annals of Oncology     Hybrid Journal   (Followers: 50, 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: 52, 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: 20)
Arbitration Law Reports and Review     Hybrid Journal   (Followers: 13)
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)
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Behavioral Ecology     Hybrid Journal   (Followers: 51, SJR: 1.698, h-index: 92)
Bioinformatics     Hybrid Journal   (Followers: 274, 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: 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: 16, SJR: 1.955, h-index: 55)
BJA : British J. of Anaesthesia     Hybrid Journal   (Followers: 156, SJR: 2.314, h-index: 133)
BJA Education     Hybrid Journal   (Followers: 65, SJR: 0.272, h-index: 20)
Brain     Hybrid Journal   (Followers: 63, 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: 35, SJR: 1.267, h-index: 38)
British J. of Aesthetics     Hybrid Journal   (Followers: 27, SJR: 0.217, h-index: 18)
British J. of Criminology     Hybrid Journal   (Followers: 547, SJR: 1.373, h-index: 62)
British J. of Social Work     Hybrid Journal   (Followers: 85, 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: 59, SJR: 0.957, h-index: 59)
Cambridge J. of Regions, Economy and Society     Hybrid Journal   (Followers: 10, SJR: 1.067, h-index: 22)
Cambridge Quarterly     Hybrid Journal   (Followers: 11, SJR: 0.1, h-index: 7)
Capital Markets Law J.     Hybrid Journal   (Followers: 1)
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: 43, 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: 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: 9, 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: 24, SJR: 0.1, h-index: 3)
Clinical Infectious Diseases     Hybrid Journal   (Followers: 60, 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: 8, 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: 5, SJR: 0.313, h-index: 10)
Critical Values     Full-text available via subscription  
Current Legal Problems     Hybrid Journal   (Followers: 26)
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: 11, SJR: 1.068, h-index: 24)
Digital Scholarship in the Humanities     Hybrid Journal   (Followers: 13)
Diplomatic History     Hybrid Journal   (Followers: 20, 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: 15, SJR: 0.124, h-index: 11)
Economic Policy     Hybrid Journal   (Followers: 37, 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: 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: 28, 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: 16, SJR: 0.1, h-index: 6)
European Heart J.     Hybrid Journal   (Followers: 50, 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: 8, SJR: 1.568, h-index: 104)
European J. of Intl. Law     Hybrid Journal   (Followers: 168, 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: 23, SJR: 1.284, h-index: 64)
European Review of Agricultural Economics     Hybrid Journal   (Followers: 11, 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: 41, 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: 9, SJR: 1.687, h-index: 115)
Fems Microbiology Letters     Hybrid Journal   (Followers: 21, SJR: 1.126, h-index: 118)
Fems Microbiology Reviews     Hybrid Journal   (Followers: 26, 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: 22, 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: 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: 12, SJR: 3.22, h-index: 39)
Geophysical J. Intl.     Hybrid Journal   (Followers: 34, SJR: 1.839, h-index: 119)
German History     Hybrid Journal   (Followers: 26, 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: 51, 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: 21, 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: 27, 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: 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: 17, SJR: 4.678, h-index: 128)
Human Rights Law Review     Hybrid Journal   (Followers: 61, 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: 11)
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: 1, 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: 7, SJR: 1.37, h-index: 81)
Industrial Law J.     Hybrid Journal   (Followers: 32, 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: 5, SJR: 0.743, h-index: 35)
Intl. Affairs     Hybrid Journal   (Followers: 52, 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: 34, SJR: 1.593, h-index: 69)
Intl. J. of Constitutional Law     Hybrid Journal   (Followers: 60, SJR: 0.613, h-index: 19)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 149, SJR: 4.381, h-index: 145)
Intl. J. of Law and Information Technology     Hybrid Journal   (Followers: 4, SJR: 0.247, h-index: 8)
Intl. J. of Law, Policy and the Family     Hybrid Journal   (Followers: 29, 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: 9, SJR: 0.906, h-index: 33)
Intl. J. of Refugee Law     Hybrid Journal   (Followers: 34, 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: 31, SJR: 1.339, h-index: 19)
Intl. Relations of the Asia-Pacific     Hybrid Journal   (Followers: 18, 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: 40, SJR: 2.184, h-index: 68)
Intl. Studies Review     Hybrid Journal   (Followers: 18, 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: 44, 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: 13, 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: 17, 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: 36, 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: 43, SJR: 4.896, h-index: 121)
J. of Crohn's and Colitis     Hybrid Journal   (Followers: 10, SJR: 1.543, h-index: 37)
J. of Cybersecurity     Hybrid Journal   (Followers: 3)
J. of Deaf Studies and Deaf Education     Hybrid Journal   (Followers: 9, SJR: 0.69, h-index: 36)
J. of Design History     Hybrid Journal   (Followers: 16, 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: 24, SJR: 0.457, h-index: 20)
J. of European Competition Law & Practice     Hybrid Journal   (Followers: 20)
J. of Experimental Botany     Hybrid Journal   (Followers: 14, 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: 4)
J. of Heredity     Hybrid Journal   (Followers: 4, 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: 39, 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]   [13 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]
  • Acknowledgement to referees
    • Abstract: The Editors of the Journal of Antimicrobial Chemotherapy are most grateful to the following for their assistance with the assessment of manuscripts over the last year.
      PubDate: 2017-11-21
  • Impact of baseline plasma HIV-1 RNA and time to virological suppression on
           virological rebound according to first-line antiretroviral regimen
    • Authors: Raffi F; Hanf M, Ferry T, et al.
      Abstract: J Antimicrob Chemother 2017; 72: 3425–3434
      PubDate: 2017-10-07
  • Efficacy and safety of delafloxacin compared with vancomycin plus
           aztreonam for acute bacterial skin and skin structure infections: a Phase
           3, double-blind, randomized study
    • Authors: Pullman J; Gardovskis J, Farley B, et al.
      Abstract: BackgroundDelafloxacin is an investigational anionic fluoroquinolone in development for oral or intravenous administration for the treatment of infections caused by Gram-positive (including MRSA), Gram-negative, atypical and anaerobic organisms.ObjectivesTo establish the non-inferiority of delafloxacin compared with vancomycin plus aztreonam for the treatment of acute bacterial skin and skin structure infections and to compare the safety of the two antimicrobials.Patients and methodsA Phase 3, multicentre, randomized, double-blind, active-controlled study with 660 patients compared delafloxacin 300 mg or vancomycin 15 mg/kg plus aztreonam 2 g each administered twice daily intravenously for 5–14 days. Non-inferiority was evaluated by objective response (≥20% erythema reduction) at 48–72 h after initiation of study drug, investigator subjective assessment of outcome and microbiological responses. Clinical Trials Registration: NCT01811732. EudraCT number: 2012-001767-71.ResultsIn the ITT analysis set, the objective response was 78.2% in the delafloxacin arm and 80.9% in the vancomycin/aztreonam arm (mean treatment difference, −2.6%; 95% CI, −8.78% to 3.57%). Investigator-assessed cure was similar between the two groups at follow-up (52.0% versus 50.5%) and late follow-up (70.4% versus 66.6%). Bacterial eradication of MRSA was 100% and 98.5% in the delafloxacin group and the vancomycin/aztreonam group, respectively. Frequency of treatment-emergent adverse events in the delafloxacin and vancomycin/aztreonam groups was similar. Treatment-emergent adverse events leading to study drug discontinuation were higher in the vancomycin/aztreonam group compared with the delafloxacin group (4.3% versus 0.9%).ConclusionsDelafloxacin, an anionic fluoroquinolone, was statistically non-inferior to vancomycin/aztreonam at 48–72 h following the start of therapy and was well tolerated as monotherapy in the treatment of acute bacterial skin and skin structure infections.
      PubDate: 2017-10-05
  • National disparities in the relationship between antimicrobial resistance
           and antimicrobial consumption in Europe: an observational study in 29
           countries—authors’ response
    • Authors: McDonnell L; Armstrong D, Ashworth M, et al.
      Abstract: Sir,
      PubDate: 2017-10-04
  • Multicentre validation of 4-well azole agar plates as a screening method
           for detection of clinically relevant azole-resistant Aspergillus fumigatus
    • Authors: Arendrup M; Verweij P, Mouton J, et al.
      Abstract: ObjectivesAzole-resistant Aspergillus fumigatus is emerging worldwide. Reference susceptibility testing methods are technically demanding and no validated commercial susceptibility tests for moulds currently exist. In this multicentre study a 4-well azole-containing screening agar method was evaluated using clinically relevant isolates.MethodsForty WT and 39 cyp51A mutant A. fumigatus [G54 (n = 10), M220 (n = 10), TR34/L98H (n = 9) and TR46/Y121F/T289A (n = 10)] were tested individually and as simulated mixed samples (sampling 4 WT and 1 mutant colonies). EUCAST MICs were determined following E.Def 9.3. In-house and commercial 4-well plates containing agars supplemented with 4 mg/L itraconazole, 1 mg/L voriconazole, 0.5 mg/L posaconazole and no antifungal, respectively, were evaluated. Growth was scored (0–3) by two independent observers in three laboratories. Inter-plate, inter-observer, essential and categorical agreement, sensitivity and specificity were calculated.ResultsCYP51A genotype and antifungal compound-specific MICs and growth patterns were documented. The inter-observer agreement was excellent with 86%–99% identical scores (range 80%–100%) for both plates. The qualitative agreement (no growth versus growth) was excellent (median 95%–100%, range 87%–100%, overall). The overall sensitivity and specificity for the 4-well plate (no growth versus growth) was 99% (range 97%–100%) and 99% (95%–100%), respectively. The sensitivity for simulated WT/mutant specimens was 94% (range 83%–100%) for the WT-TR34/L98H combination, but 100% for the WT/G54W combination. The performance remained unchanged using only itraconazole- and voriconazole-containing agars, but was lower for the other combinations.ConclusionsImplementation of the 4-well screening plate in routine laboratories will allow easy and reliable detection of the most common azole-resistant A. fumigatus.
      PubDate: 2017-10-04
  • Pharmacodynamics of fosfomycin against ESBL- and/or
           carbapenemase-producing Enterobacteriaceae
    • Authors: Fransen F; Hermans K, Melchers M, et al.
      Abstract: BackgroundThe increase in antibiotic resistance in Gram-negative bacteria and the limited therapeutic options due to the shortage of new antibiotics have increased the interest of the ‘old’ antibiotic fosfomycin in the treatment of infections. However, there are contradictory reports on the pharmacodynamics of and emergence of resistance to fosfomycin.MethodsTime–kill assays were performed with 11 ESBL-positive and 3 ESBL-negative strains, exposing the bacteria to 2-fold static concentrations from 0.125× to 32× MIC. The sigmoid maximum effect (Emax) model was fitted to the time–kill curve data. Amplification of resistance over time was evaluated under various conditions of selective pressure by plating on 16× MIC plates.ResultsFosfomycin was bactericidal for all strains within 8 h. Using the Emax model, no significant differences between strains were observed for the pharmacodynamic parameters. However, the large variation in Hill slope factors for Escherichia coli of 0.87 up to 4.02 indicates that the killing behaviour appears to be more time dependent for some strains but concentration dependent for others. In the fosfomycin-exposed cultures under low and high selective pressure (≥2× MIC) the median resistance proportions between the resistant and total population increased from ≤2 × 10−6 (T = 0 h) to 0.652–0.899 (T = 24 h). Resistance appeared stable after repeated subculturing.ConclusionsKilling behaviour of fosfomycin does not only differ between species but also within species and may have an impact on the design of optimal dosing regimens. Although fosfomycin was bactericidal against all strains (re)growth of resistant subpopulations occurred relatively fast. This may limit the use of fosfomycin as a single drug therapy.
      PubDate: 2017-10-04
  • Pharmacokinetics and safety results from the Phase 3 randomized,
           open-label, study of intravenous posaconazole in patients at risk of
           invasive fungal disease
    • Authors: Cornely O; Robertson M, Haider S, et al.
      Abstract: J Antimicrob Chemother 2017; 72: 3406–3413
      PubDate: 2017-10-03
  • Carbapenem-resistant Citrobacter spp. isolated in Spain from 2013 to 2015
           produced a variety of carbapenemases including VIM-1, OXA-48, KPC-2, NDM-1
           and VIM-2
    • Authors: Arana D; Ortega A, González-Barberá E, et al.
      Abstract: ObjectivesThere is little information about carbapenemase-producing (CP) Citrobacter spp. We studied the molecular epidemiology and microbiological features of CP Citrobacter spp. isolates collected in Spain (2013–15).MethodsIn total, 119 isolates suspected of being CP by the EUCAST screening cut-off values were analysed. Carbapenemases and ESBLs were characterized using PCR and sequencing. The genetic relationship among Citrobacter freundii isolates was studied by PFGE.ResultsOf the 119 isolates, 63 (52.9%) produced carbapenemases, of which 37 (58.7%) produced VIM-1, 20 (31.7%) produced OXA-48, 12 (19%) produced KPC-2, 2 (3.2%) produced NDM-1 and 1 (1.6%) produced VIM-2; 9 C. freundii isolates co-produced VIM-1 plus OXA-48. Fourteen isolates (22.2%) also carried ESBLs: 8 CTX-M-9 plus SHV-12, 2 CTX-M-9, 2 SHV-12 and 2 CTX-M-15. Fifty-seven isolates (90.5%) were C. freundii, 4 (6.3%) were Citrobacter koseri, 1 (1.6%) was Citrobacter amalonaticus and 1 (1.6%) was Citrobacter braakii. By EUCAST breakpoints, eight (12.7%) of the CP isolates were susceptible to the four carbapenems tested. In the 53 CP C. freundii analysed by PFGE, a total of 44 different band patterns were observed. Four PFGE clusters were identified: cluster 1 included eight isolates co-producing VIM-1 and OXA-48; blaVIM-1 was carried in a class 1 integron (intI–blaVIM-1–aacA4–dfrB1–aadA1–catB2–qacEΔ1/sul1) and blaOXA-48 was carried in a Tn1999.2 transposon.ConclusionsWe observed the clonal and polyclonal spread of CP Citrobacter spp. across several Spanish geographical areas. Four species of Citrobacter spp. produced up to five carbapenemase types, including co-production of VIM-1 plus OXA-48. Some CP Citrobacter spp. isolates were susceptible to the four carbapenems tested, a finding with potential clinical implications.
      PubDate: 2017-09-27
  • Detection of optrA in the African continent (Tunisia) within a mosaic
           Enterococcus faecalis plasmid from urban wastewaters
    • Authors: Freitas A; Elghaieb H, León-Sampedro R, et al.
      Abstract: ObjectivesOxazolidinone resistance is a serious limitation in the treatment of MDR Enterococcus infections. Plasmid-mediated oxazolidinone resistance has been strongly linked to animals where the use of phenicols might co-select resistance to both antibiotic families. Our goal was to assess the diversity of genes conferring phenicol/oxazolidinone resistance among diverse enterococci and to characterize the optrA genetic environment.MethodsChloramphenicol-resistant isolates (>16 mg/L, n = 245) from different sources (hospitals/healthy humans/wastewaters/animals) in Portugal, Angola and Tunisia (1996–2016) were selected. Phenicol (eight cat variants, fexA, fexB) or phenicol + oxazolidinone [cfr, cfr(B), optrA] resistance genes were searched for by PCR. Susceptibility (disc diffusion/microdilution), filter mating, stability of antibiotic resistance (500 bacterial generations), plasmid typing (S1-PFGE/hybridization), MLST and WGS (Illumina-HiSeq) were performed for optrA-positive isolates.ResultsResistance to phenicols (n = 181, 74%) and phenicols + oxazolidinones (n = 2, 1%) was associated with the presence of cat(A-8) (40%, predominant in hospitals and swine), cat(A-7) (29%, predominant in poultry and healthy humans), cat(A-9) (2%), fexB (2%) and fexA + optrA (1%). fexA and optrA genes were co-located in a transferable plasmid (pAF379, 72 918 bp) of two ST86 MDR Tunisian Enterococcus faecalis (wastewaters) carrying several putative virulence genes. MICs of chloramphenicol, linezolid and tedizolid were stably maintained at 64, 4 and 1 mg/L, respectively. The chimeric pAF379 comprised relics of genetic elements from different Gram-positive bacteria and origins (human/porcine).ConclusionsTo the best of our knowledge, we report the first detection of optrA in an African country (Tunisia) within a transferable mosaic plasmid of different origins. Its identification in isolates from environmental sources is worrisome and alerts for the need of a concerted global surveillance on the occurrence and spread of optrA.
      PubDate: 2017-09-26
  • Patient-specific modelling of regional tobramycin concentration levels in
           airways of patients with cystic fibrosis: can we dose once daily'
    • Authors: Bos A; Mouton J, van Westreenen M, et al.
      Abstract: BackgroundInhaled tobramycin is important in the treatment of Pseudomonas aeruginosa (Pa) infections in cystic fibrosis (CF). However, despite its use it fails to attenuate the clinical progression of CF lung disease. The bactericidal efficacy of tobramycin is known to be concentration-dependent and hence changing the dosing regimen from a twice-daily (q12h) inhalation to a once-daily (q24h) inhaled double dose could improve treatment outcomes.ObjectivesTo predict local concentrations of nebulized tobramycin in the airways of patients with CF, delivered with the small airway-targeting Akita® system or standard PARI-LC® Plus system, with different inspiratory flow profiles.MethodsComputational fluid dynamic (CFD) methods were applied to patient-specific airway models reconstructed from chest CT scans. The following q12h and q24h dosing regimens were evaluated: Akita® (150 and 300 mg) and PARI-LC® Plus (300 and 600 mg). Site-specific concentrations were calculated.ResultsTwelve CT scans from patients aged 12–17 years (median = 15.7) were selected. Small airway concentrations were 762–2999 mg/L for the q12h dosing regimen and 1523–5997 mg/L for the q24h dosing regimen, well above the MIC for WT Pa strains. Importantly, the q24h regimen appeared to be more suitable than the q12h regimen against more resistant Pa strains and the inhibitory effects of sputum on tobramycin activity.ConclusionsCFD modelling showed that high concentrations of inhaled tobramycin are indeed delivered to the airways, with the Akita® system being twice as efficient as the PARI-LC® system. Ultimately, the q24h dosing regimen appears more effective against subpopulations with high MICs (i.e. more resistant strains).
      PubDate: 2017-09-23
  • Comment on: National disparities in the relationship between antimicrobial
           resistance and antimicrobial consumption in Europe: an observational study
           in 29 countries
    • Authors: Pulcini C.
      Abstract: Sir,
      PubDate: 2017-09-18
  • Identification of a novel transposon-associated phosphoethanolamine
           transferase gene, mcr-5 , conferring colistin resistance in d -tartrate
           fermenting Salmonella enterica subsp. enterica serovar Paratyphi B
    • Authors: Borowiak M; Fischer J, Hammerl J, et al.
      Abstract: ObjectivesPlasmid-mediated mobilized colistin resistance is currently known to be caused by phosphoethanolamine transferases termed MCR-1, MCR-2, MCR-3 and MCR-4. However, this study focuses on the dissection of a novel resistance mechanism in mcr-1-, mcr-2- and mcr-3-negative d-tartrate fermenting Salmonella enterica subsp. enterica serovar Paratyphi B (Salmonella Paratyphi B dTa+) isolates with colistin MIC values >2 mg/L.MethodsA selected isolate from the strain collection of the German National Reference Laboratory for Salmonella was investigated by WGS and bioinformatical analysis to identify novel phosphoethanolamine transferase genes involved in colistin resistance. Subsequently PCR screening, S1-PFGE and DNA-DNA hybridization were performed to analyse the prevalence and location of the identified mcr-5 gene. Cloning and transformation experiments in Escherichia coli DH5α and Salmonella Paratyphi B dTa+ control strains were carried out and the activity of MCR-5 was determined in vitro by MIC testing.ResultsIn this study, we identified a novel phosphoethanolamine transferase in 14 mcr-1-, mcr-2- and mcr-3-negative Salmonella Paratyphi B dTa+ isolates with colistin MIC values >2 mg/L that were received during 2011–13. The respective gene, further termed as mcr-5 (1644 bp), is part of a 7337 bp transposon of the Tn3 family and usually located on related multi-copy ColE-type plasmids. Interestingly, in one isolate an additional subclone with a chromosomal location of the mcr-5 transposon was observed.ConclusionsOur findings suggest that the transfer of colistin-resistance-mediating phosphoethanolamine transferase genes from bacterial chromosomes to mobile genetic elements has occurred in multiple independent events raising concern regarding their variety, prevalence and impact on public health.
      PubDate: 2017-09-18
  • Evaluation of minor groove binders (MGBs) as novel anti-mycobacterial
           agents and the effect of using non-ionic surfactant vesicles as a delivery
           system to improve their efficacy
    • Authors: Hlaka L; Rosslee M, Ozturk M, et al.
      Abstract: ObjectivesThe slow development of major advances in drug discovery for the treatment of Mycobacterium tuberculosis (Mtb) infection suggests a compelling need for evaluation of more effective drug therapies against TB. New classes of drugs are constantly being evaluated for anti-mycobacterial activity with currently a very limited number of new drugs approved for TB treatment. Minor groove binders (MGBs) have previously revealed promising antimicrobial activity against various infectious agents; however, they have not yet been screened against Mtb.MethodsThe mycobactericidal activity of 96 MGB compounds against Mtb was determined using an H37Rv-GFP microplate assay. MGB hits were screened for their intracellular mycobactericidal efficacy against the clinical Beijing Mtb strain HN878 in bone-marrow-derived macrophages using standard cfu counting. Cell viability was assessed by CellTiter-Blue assays. Selected MGBs were encapsulated into non-ionic surfactant vesicles (NIVs) for drug delivery system evaluation.ResultsH37Rv-GFP screening yielded a hit-list of seven compounds at an MIC99 of between 0.39 and 1.56 μM. MGB-362 and MGB-364 displayed intracellular mycobactericidal activity against Mtb HN878 at an MIC50 of 4.09 and 4.19 μM, respectively, whilst being non-toxic. Subsequent encapsulation into NIVs demonstrated a 1.6- and 2.1-fold increased intracellular mycobacterial activity, similar to that of rifampicin when compared with MGB-alone formulation.ConclusionsMGB anti-mycobacterial activities together with non-toxic properties indicate that MGB compounds constitute an important new class of drug/chemical entity, which holds promise in future anti-TB therapy. Furthermore, the ability of NIVs to better deliver entrapped MGB compounds to an intracellular Mtb infection suggests further preclinical evaluation is warranted.
      PubDate: 2017-09-18
  • Optimal cure rate by personalized HCV regimens in real-life: a
           proof-of-concept study
    • Authors: Cento V; Aragri M, Teti E, et al.
      Abstract: BackgroundPretreatment evaluation of HCV-infected patients is a complex interplay between multiple clinical and viral parameters, leading to a tailored approach that may bring real-life sustained virological response (SVR) rates close to 98%–99%.ObjectivesAs proof-of-concept, we evaluated the efficacy of all-oral direct-acting antiviral (DAA) regimens in patients whose personalization included pre-therapy evaluation of natural resistance-associated substitutions (RASs), in addition to international guideline recommendations.MethodsOne hundred and thirty-one patients who started a first-line all-oral DAA regimen between April 2015 and December 2016 were tested for baseline NS3 and NS5A RASs by Sanger sequencing. SVR12 was defined as HCV-RNA undetectability 12 weeks after treatment discontinuation.ResultsCompatibly with a real-life context, 74.0% (97 of 131) of patients presented ≥2 pretreatment risk factors for failure to achieve SVR12 (infection by GT-1a/GT-3a; cirrhosis; previous treatment experience; HCV-RNA ≥800 000 IU/mL) and 33.6% had ≥3 risk factors. Natural RASs were frequently detected (32.1% prevalence), with substantial prevalence of NS5A RASs (15.3%), mostly represented by Y93H in GT-1b (3 of 36, 8.3%) and GT-3a (3 of 25, 12.0%) and F28C in GT-2c (2 of 11, 18.2%). Overall, personalized treatment led to 100% SVR12, even in those patients for whom treatment strategy was either strengthened (by ribavirin inclusion and/or duration increase) or simplified (by ribavirin exclusion and/or duration reduction), thanks to baseline RAS evaluation.ConclusionsEven with newer DAA regimens, an integrated interpretation of clinical and virological pretreatment parameters, including natural RASs, may play a relevant role in bringing SVR rates close to the highest achievable. Treatment tailoring can be foreseen in ‘hard-to-treat’ patients, but also in ‘easy’ patients with favourable indicators, whereby a simplification/shortening of recommended regimens can be indicated.
      PubDate: 2017-09-18
  • Impact of amoxicillin resistance on the efficacy of amoxicillin-containing
           regimens for Helicobacter pylori eradication: analysis of five randomized
    • Authors: Chen M; Wu M, Chen C, et al.
      Abstract: BackgroundThe impact of amoxicillin resistance on the efficacy of regimens containing amoxicillin for Helicobacter pylori eradication remains unknown.ObjectivesTo investigate whether the efficacy of an amoxicillin-containing regimen is affected by amoxicillin resistance and to identify the optimal breakpoint for amoxicillin resistance.MethodsThis was a pooled analysis of five randomized trials conducted in Taiwan from 2007 to 2016. Patients who received amoxicillin-containing regimens were recruited. MICs were determined by agar dilution testing. Meta-analysis was performed to assess the risk ratio of eradication failure in amoxicillin-resistant strains compared with susceptible strains of seven different regimens. We performed further the pooled analysis and logistic regression in patients treated with clarithromycin triple therapy to identify the optimal breakpoint for amoxicillin resistance. ResultsA total of 2339 patients with available amoxicillin MICs were enrolled. Meta-analysis showed that the presence of amoxicillin resistance was consistently associated with increased risk of treatment failure of amoxicillin-containing regimens at different breakpoints (risk ratio: 1.41, 95% CI 1.12–1.78, P = 0.004 when the cut-off was 0.5 mg/L). The heterogeneity was low (I2 = 0%, P = 0.615). Pooled analysis also showed that amoxicillin resistance was an independent risk factor for treatment failure of clarithromycin triple therapy at different breakpoints. The best correlation was observed when the breakpoint of amoxicillin resistance was ≥0.125 mg/L (kappa coefficient 0.298), at which the resistance rate was 11.1% (110 of 990).ConclusionsThe efficacies of amoxicillin-containing regimens are affected by amoxicillin resistance and the optimal breakpoint MIC is ≥ 0.125 mg/L.
      PubDate: 2017-09-18
  • Trends and patterns in antibiotic prescribing among out-of-hours primary
           care providers in England, 2010–14
    • Authors: Edelstein M; Agbebiyi A, Ashiru-Oredope D, et al.
      Abstract: ObjectivesAntimicrobial resistance is a global threat, increasing morbidity and mortality. In England, publicly funded clinical commissioning groups (CCGs) commission out-of-hours (OOH) primary care services outside daytime hours. OOH consultations represent 1% of in-hours general practice (GP) consultations. Antibiotic prescriptions increased 32% in non-GP community services between 2010 and 2013. We describe OOH antibiotic prescribing patterns and trends between 2010 and 2014.MethodsWe: estimated the proportion of CCGs with OOH data available; described and compared antibiotic prescribing by volume of prescribed items, seasonality and trends in GP and OOH, using linear regression; and compared the proportion of broad-spectrum to total antibiotic prescriptions in OOHs with their respective CCGs in terms of seasonality and trends, using binomial regression.ResultsData were available for 143 of 211 (68%) CCGs. OOH antibiotic prescription volume represented 4.5%–5.4% of GP prescription volume and was stable over time (P = 0.37). The proportion of broad-spectrum antibiotic prescriptions increased in OOH when it increased in the CCG they operated in (regression coefficient 0.98; 95% CI 0.96–0.99). Compared with GP, the proportion of broad-spectrum antibiotic prescriptions in OOH was higher but decreased both in GP and OOH (−0.57%, 95% CI − 0.54% to − 0.6% and −0.76%, 95% CI − 0.59% to − 0.93% per year, respectively).ConclusionsOOH proportionally prescribed more antibiotics than GPs although we could not comment on prescribing appropriateness. OOH prescribing volume was stable over time, and followed GP seasonal patterns. OOH antibiotic prescribing reflected the CCGs they operated in but with relatively more broad-spectrum antibiotics than in-hours GP. Understanding factors influencing prescribing in OOH will enable the development of tailored interventions promoting optimal prescribing in this setting.
      PubDate: 2017-09-18
  • Modelling of mycobacterial load reveals bedaquiline’s
           exposure–response relationship in patients with drug-resistant TB
    • Authors: Svensson E; Karlsson M.
      Abstract: BackgroundBedaquiline has been shown to reduce time to sputum culture conversion (SCC) and increase cure rates in patients with drug-resistant TB, but the influence of drug exposure remains uncharacterized.ObjectivesTo investigate whether an exposure–response relationship could be characterized by making better use of the existing information on pharmacokinetics and longitudinal measurements of mycobacterial load.MethodsQuantitative culture data in the form of time to positivity (TTP) in mycobacterial growth indicator tubes obtained from a randomized placebo-controlled Phase IIb registration trial were examined using non-linear mixed-effects methodology. The link to individual bedaquiline exposures and other patient characteristics was evaluated.ResultsThe developed model included three simultaneously fitted components: a longitudinal representation of mycobacterial load in patients, a probabilistic component for bacterial presence in sputum samples, and a time-to-event model for TTP. Data were described adequately, and time to SCC was well predicted. Individual bedaquiline exposure was found to significantly affect the decline in mycobacterial load. Consequently, the proportion of patients without SCC at week 20 is expected to decrease from 25% (95% CI 20%–31%) without bedaquiline to 17% (95% CI 13%–21%), 12% (95% CI 8%–16%) and 7% (95% CI 4%–11%), respectively, with half the median, median and double the median bedaquiline exposure observed in patients with standard dosing. Baseline bacterial load and level of drug resistance were other important predictors.ConclusionsTo our knowledge, this is the first successful description of bedaquiline’s exposure–response relationship and may be used when considering dose optimization. Characterization of this relationship was possible by integrating quantitative information in existing clinical data using novel models.
      PubDate: 2017-09-13
  • Identification of novel mutations associated with cycloserine resistance
           in Mycobacterium tuberculosis
    • Authors: Chen J; Zhang S, Cui P, et al.
      Abstract: Objectivesd-Cycloserine is an important second-line drug used to treat MDR- and XDR-TB. However, the mechanisms of resistance to d-cycloserine are not well understood. Here we investigated the molecular basis of d-cycloserine resistance using in vitro-isolated resistant mutants.MethodsMycobacterium tuberculosis H37Rv was subjected to mutant selection on 7H11 agar plates containing varying concentrations of d-cycloserine. A total of 18 d-cycloserine-resistant mutants were isolated and subjected to WGS. The identified mutations associated with d-cycloserine resistance were confirmed by PCR and Sanger sequencing.ResultsWe identified mutations in 16 genes that are associated with d-cycloserine resistance. Interestingly, we found mutations only in alr (rv3423c) encoding alanine racemase, but not in other known d-cycloserine resistance-associated genes such as ddl, cycA or ald. Instead, we identified 13 new genes [rv0059, betP (rv0917), rv0221, rv1403c, rv1683, rv1726, gabD2 (rv1731), rv2749, sugI (rv3331), hisC2 (rv3772), the 5′ intergenic region of rv3345c and rv1435c, and the 3′ region of rv0759c] that had solo mutations associated with d-cycloserine resistance. Our findings indicate that the mechanisms of d-cycloserine resistance are more complex than previously thought and involve genes participating in different cellular functions such as lipid metabolism, methyltransferase, the stress response and transport systems.ConclusionsNew mutations in diverse genes associated with d-cycloserine resistance have been identified that shed new light on the mechanisms of action and resistance of d-cycloserine. Future studies are needed to verify these findings in clinical strains so that molecular detection of d-cycloserine resistance for improved treatment of MDR-TB can be developed.
      PubDate: 2017-09-12
  • Enteric microbiome profiles during a randomized Phase 2 clinical trial of
           surotomycin versus vancomycin for the treatment of Clostridium difficile
    • Authors: Cannon K; Byrne B, Happe J, et al.
      Abstract: ObjectivesThe effects of surotomycin (CB-183,315, MK-4261), a bactericidal cyclic lipopeptide, and vancomycin, the current standard-of-care for Clostridium difficile infection (CDI), on intestinal pathogens and microbiota were evaluated parallel to a Phase 2 randomized, double-blind clinical trial.MethodsThe single-centre cohort included 26 patients receiving surotomycin [125 or 250 mg twice daily (n = 9 each)] or oral vancomycin [125 mg four times daily (n = 8)] for 10 days. Faecal samples were collected at days 0–42 to quantify both C. difficile by conventional culture and the major components of the microbiome by quantitative PCR.ResultsSurotomycin 250 mg twice daily or vancomycin 125 mg four times daily reduced faecal C. difficile counts from ∼105–107 log10 cfu/g at baseline to ≤ 102 cfu/g by days 4–10 of treatment. Day 10 counts of C. difficile in 3/9 patients receiving surotomycin 125 mg twice daily remained detectable, including one patient who failed to achieve clinical cure. Bacteroidetes and Prevotella mean counts increased 0.7 log10 or remained unchanged with surotomycin 125 and 250 mg twice daily, respectively, whereas vancomycin reduced counts by 2.5–3.2 log10 (P < 0.02). Vancomycin reduced Firmicutes counts by 2.5–2.8 log10; surotomycin moderately suppressed these microbes in a dose-dependent manner.ConclusionsIn this Phase 2 trial substudy, compared with vancomycin 125 mg four times daily, surotomycin 250 mg twice daily is as active in vivo against C. difficile, but was more sparing of microbiota. Surotomycin is no longer in development due to failed Phase 3 efficacy results.
      PubDate: 2017-09-12
  • Comparison of phenotypic and WGS-derived antimicrobial resistance profiles
           of enteroaggregative Escherichia coli isolated from cases of diarrhoeal
           disease in England, 2015–16
    • Authors: Do Nascimento V; Day M, Doumith M, et al.
      Abstract: ObjectivesPhenotypic and genotypic methods for the detection of antimicrobial resistance (AMR) in enteroaggregative Escherichia coli (EAEC) were compared and evaluated.MethodsWGS data from 155 isolates of EAEC isolated between June 2015 and December 2016 were mapped to genes known to be associated with phenotypic AMR.ResultsPhenotypic and genotypic testing of 155 isolates against 10 antimicrobial classes resulted in a total of 25 (1.6%) discordant results of a possible 1550 isolate/antimicrobial combinations. Twenty-three of the mismatches were observed in streptomycin or sulphonamide resistance profiles. These discrepancies were associated with either insertions or truncations in the genes predicted to confer resistance, or in their promotors, rendering them non-functional, or with the presence of aadA variants associated with reduced expression. The most common resistances detected were to ampicillin (56.1%), the sulphonamides (49.7%) and trimethoprim (48.4%). The presence of CTX-M ESBL variants and/or acquired AmpC was detected in 87 of 155 (56.1%) isolates and 18 of 155 (11.6%) isolates were resistant to ciprofloxacin. Eighty-eight (56.8%) isolates were MDR.ConclusionsPhenotypic and genome-derived AMR comparisons showed good correlation for EAEC. A better understanding of the role of allelic variants, specific gene combinations and promoter/attenuator mechanisms in the phenotypic manifestation will improve our ability to provide a robust interpretation of the data for surveillance purposes and, ultimately, in the clinical setting.
      PubDate: 2017-09-11
  • Pharmacodynamics of nitrofurantoin at different pH levels against
           pathogens involved in urinary tract infections
    • Authors: Fransen F; Melchers M, Lagarde C, et al.
      Abstract: BackgroundUrinary tract infections are among the most common human infections. Due to the progressive increase in ESBL-producing bacteria and the unavailability of new antibiotics, re-evaluation of ‘old’ antibiotics is needed. However, the pharmacodynamics of nitrofurantoin under variable pH conditions are poorly understood. We determined the pharmacodynamic properties of nitrofurantoin at different pH levels using time–kill assays.MethodsTime–kill assays were performed at four pH levels (5.5, 6.5, 7.5 and 8.5), exposing the bacteria to 2-fold increasing concentrations from 0.125 to 32 times the MIC. Seven ESBL-positive and two ESBL-negative strains (MICs 8–32 mg/L) were used. The Δlog10 cfu/mL values at 6 and 24 h were plotted against each log10-transformed concentration and analysed with non-linear regression analysis using the sigmoid maximum effect model with variable slope. Geometric means normalized by the MIC of the EC50, stasis and 1 and 3 log10 cfu/mL kill were calculated.ResultsMinimum bactericidal effects differed significantly by species and pH level. At pH 5.5–6.5 bactericidal effects were observed at ≥ 0.5 × MIC for Escherichia coli and Enterobacter cloacae. At pH 8.5 only the two highest concentrations were considered bactericidal. Strong pH-dependent pharmacodynamic output parameters were observed in 6 h and especially 24 h modelling. At 24 h, pH 5.5–6.5 for E. coli and Klebsiella pneumoniae required significantly lower nitrofurantoin concentrations compared with pH 7.5 or 8.5. Although for E. cloacae similar strong decreasing trends were visible with decreasing pH, none of the tested pharmacodynamic parameters was significant.ConclusionsNitrofurantoin bactericidal activity against Enterobacteriaceae significantly increases at lower pH levels. Bactericidal activity of nitrofurantoin may be overestimated or underestimated, which may have implications for therapy and the interpretation of clinical breakpoints.
      PubDate: 2017-09-11
  • Pharmacodynamics of teicoplanin against MRSA
    • Authors: Ramos-Martín V; Johnson A, McEntee L, et al.
      Abstract: ObjectivesThe overall study aim was to identify the relevant preclinical teicoplanin pharmacokinetic (PK)/pharmacodynamic (PD) indices to predict efficacy and suppression of resistance in MRSA infection.MethodsA hollow-fibre infection model and a neutropenic murine thigh infection model were developed. The PK/PD data generated were modelled using a non-parametric population modelling approach with Pmetrics. The posterior Bayesian estimates derived were used to study the exposure–effect relationships. Monte Carlo simulations from previously developed population PK models in adults and children were conducted to explore the probability of target attainment (PTA) for teicoplanin dosage regimens against the current EUCAST WT susceptibility range.ResultsThere was a concentration-dependent activity of teicoplanin in both the in vitro and in vivo models. A total in vivo AUC/MIC of 610.4 (total AUC of 305.2 mg·h/L) for an MRSA strain with an MIC of 0.5 mg/L was needed for efficacy (2 log10 cell kill) against a total bacterial population. A total AUC/MIC ratio of ∼1500 (total AUC of ∼750 mg·h/L) was needed to suppress the emergence of resistance. The PTA analyses showed that adult and paediatric patients receiving a standard regimen were only successfully treated for the in vivo bactericidal target if the MIC was ≤0.125 mg/L in adults and ≤0.064 mg/L in children.ConclusionsThis study improves our understanding of teicoplanin PD against MRSA and defines an in vivo AUC/MIC target for efficacy and suppression of resistance. Additional studies are needed to further corroborate the PK/PD index in a variety of infection models and in patients.
      PubDate: 2017-09-11
  • Serum levels, safety and tolerability of new formulation SUBA-itraconazole
           prophylaxis in patients with haematological malignancy or undergoing
           allogeneic stem cell transplantation
    • Authors: Lindsay J; Sandaradura I, Wong K, et al.
      Abstract: ObjectivesTo assess therapeutic levels, safety and tolerability of a novel formulation SUBA-itraconazole (where SUBA stands for SUper BioAvailability) when compared with conventional itraconazole liquid when used as antifungal prophylaxis in patients undergoing allogeneic HSCT or in haematological malignancy patients with an intermediate/high risk of invasive fungal infection (IFI).MethodsThis was a single-institution, prospective cohort study using a historical control group as the comparator.ResultsA total of 57 patients were assessed: 27 in the SUBA-itraconazole cohort and 30 in the liquid itraconazole cohort. Therapeutic concentrations were achieved significantly more quickly in the SUBA-itraconazole group: median of 6 (95% CI 5–11) days versus 14 (95% CI 12–21) days in the liquid itraconazole group (P < 0.0001). At day 10, therapeutic concentrations were achieved in 69% (95% CI 44%–81%) of the SUBA-itraconazole group versus 21% (95% CI 7%–33%) of the liquid itraconazole group (P < 0.0001). The mean trough serum concentrations at steady-state of SUBA-itraconazole were significantly higher, with less interpatient variability [1577 ng/mL, coefficient of variation (CV) 35%] versus liquid itraconazole (1218 ng/mL, CV 60%) (P < 0.001). There were two (7.4%) treatment failures in the SUBA-itraconazole group, both due to cessation of therapy for mucositis, compared with seven (23.3%) treatment failures in the liquid itraconazole group, due to subtherapeutic levels (five), mucositis (one) and gastrointestinal intolerance (one) (P = 0.096).ConclusionsThe use of the SUBA-itraconazole formulation was associated with more rapid attainment of therapeutic levels with less interpatient variability compared with conventional liquid itraconazole when used as IFI prophylaxis in allogeneic HSCT or intermediate-/high-IFI risk haematological malignancy patients.
      PubDate: 2017-09-11
  • High incidence of pandrug-resistant Acinetobacter baumannii isolates
           collected from patients with ventilator-associated pneumonia in Greece,
           Italy and Spain as part of the MagicBullet clinical trial
    • Authors: Nowak J; Zander E, Stefanik D, et al.
      Abstract: ObjectivesTo investigate the molecular epidemiology, antimicrobial susceptibility and carbapenem resistance determinants of Acinetobacter baumannii isolates from respiratory tract samples of patients diagnosed with ventilator-associated pneumonia (VAP) who were enrolled in the MagicBullet clinical trial.MethodsA. baumannii isolates were prospectively cultured from respiratory tract samples from 65 patients from 15 hospitals in Greece, Italy and Spain. Susceptibility testing was performed by broth microdilution. Carbapenem resistance determinants were identified by PCR and sequencing. Molecular epidemiology was investigated using rep-PCR (DiversiLab) and international clones (IC) were identified using our in-house database.ResultsOf 65 isolates, all but two isolates (97%) were resistant to imipenem and these were always associated with an acquired carbapenemase, OXA-23 (80%), OXA-40 (4.6%), OXA-58 (1.5%) or OXA-23/58 (1.5%). Resistance to colistin was 47.7%. Twenty-two isolates were XDR, and 20 isolates were pandrug-resistant (PDR). The majority of isolates clustered with IC2 (n = 54) with one major subtype comprising isolates from 12 hospitals in the three countries, which included 19 XDR and 16 PDR isolates.ConclusionsCarbapenem resistance rates were very high in A. baumannii recovered from patients with VAP. Almost half of the isolates were colistin resistant, and 42 (64.6%) isolates were XDR or PDR. Rep-PCR confirmed IC2 is the predominant clonal lineage in Europe and suggests the presence of an epidemic XDR/PDR A. baumannii clone that has spread in Greece, Italy and Spain. These data highlight the difficulty in empirical treatment of patients with A. baumannii VAP in centres with a high prevalence of carbapenem-resistant A. baumannii.
      PubDate: 2017-09-08
  • Multiclonal emergence of levofloxacin-resistant group B Streptococcus ,
    • Authors: Wu C; Lai J, Huang I, et al.
      Abstract: ObjectivesThis study investigated the trend in antimicrobial resistance among group B Streptococcus (GBS) from a national surveillance programme in Taiwan and delineated characteristics of and factors associated with levofloxacin-resistant isolates.MethodsClinical isolates of all sample types and patient groups were collected from multiple hospitals biennially between 2002 and 2012. Susceptibilities to different antibiotics were determined by broth microdilution. Molecular studies of levofloxacin-resistant isolates included serotyping, PFGE, mutations in the QRDRs and MLST.ResultsA total of 1559 isolates were tested and all remained susceptible to penicillin, cephalosporins, meropenem and vancomycin. However, levofloxacin resistance increased from 2.2% (range 0%–3.3%) in 2002–06 to 6.2% (5.9%–7.5%) in 2008–12 (P = 0.016). Among the 88 levofloxacin-resistant isolates, the majority (79.5%) had the GyrA(S81L)+ParC(S79F/Y) double mutations and most (54.5%) were also resistant to clindamycin, erythromycin and tetracycline. The predominant genotype of the levofloxacin-resistant isolates was ST19/serotype III (43.2%). Four previously unreported genotypes, ST1 and its single-locus variants (ST920 and ST922)/serotype VI (28.4%) and ST1/serotype II (18.2%), were found to have circulated locally. Serotype III isolates were predominately from urine and female genital tract specimens and <65-year-old adult outpatients, while serotype II and VI isolates were mostly from respiratory and urine samples and >65-year-old inpatients. Multivariate analysis revealed that elderly age and respiratory samples were independent factors associated with levofloxacin resistance.ConclusionsMulticlonal emergence and dissemination of levofloxacin-resistant GBS isolates occurred in healthcare and community settings in Taiwan. Continuous molecular-level surveillance is important to detect new epidemic trends.
      PubDate: 2017-09-06
  • Effects of different resistance mechanisms on susceptibility to different
           classes of antibiotics in Klebsiella pneumoniae strains: a strategic
           system for the screening and activity testing of new antibiotics
    • Authors: Tsai Y; Liou C, Chang F, et al.
      Abstract: ObjectivesA strategic system for the screening and testing of new antibiotics was created to facilitate the development of antibiotics that are robustly effective against MDR bacteria.MethodsIn-frame deletion, site-directed mutagenesis and plasmid transformation were used to generate genetically engineered strains with various resistance mechanisms from a fully susceptible clinical isolate of Klebsiella pneumoniae. Antimicrobial susceptibility testing and a mouse infection model were used to test antibiotics against these strains in vitro and in vivo, respectively.ResultsA total of 193 strains, including 29 strains with chromosome-mediated resistance, 33 strains with plasmid-mediated resistance and 131 strains with a combination of both resistance mechanisms were constructed; these strains covered resistance to β-lactams, quinolones, aminoglycosides, tetracyclines, folate pathway inhibitors and other antibiotics. MICs for all strains were tested, and the effects of genetic modifications on increasing the MICs were assessed. Ceftazidime and cefotaxime were used to assess the correlation between antibacterial activities in vitro and in vivo. Against a K. pneumoniae strain with blaOXA-48, ceftazidime had a lower MIC (0.5 mg/L) than cefotaxime (2 mg/L). Ceftazidime had an ED50 of 30 mg/kg, and no mice survived treatment with the same dose of cefotaxime. A positive correlation was observed between these in vitro and in vivo results.ConclusionsThe system developed here could reduce the considerable time required to evaluate the effectiveness of new antibiotics against MDR bacteria, particularly in the early stages of drug development. This system could also be expanded as new resistance mechanisms emerge.
      PubDate: 2017-09-06
  • AmpC β-lactamase induction by avibactam and relebactam
    • Authors: Livermore D; Jamrozy D, Mushtaq S, et al.
      Abstract: BackgroundDiazabicyclooctanes, e.g. avibactam and relebactam, are a new class of β-lactamase inhibitors. Their spectrum includes AmpC enzymes, but it is important to understand whether they also induce these enzymes.MethodsLevels of ampC mRNA were measured by RT–PCR during 4 h of exposure of Enterobacter cloacae, Citrobacter freundii and Pseudomonas aeruginosa (n = 5 strains per species) to avibactam, relebactam and cefoxitin at 0, 1, 4 and 32 mg/L. The method had low precision compared with conventional specific-activity-based induction assays, which are impracticable for inhibitors. Accordingly, induction was only considered to be significant if induction ratios >10 were found at two consecutive time intervals, with ‘strong induction’ if one or more of these ratios was >100.ResultsCefoxitin, as expected, gave concentration-dependent induction for all strains, with strong induction for 13/15. At the other extreme, relebactam caused no significant induction for any strain. Avibactam gave strain-variable results, with strong concentration-dependent induction for 2/5 E. cloacae and 2/5 P. aeruginosa, but little or no induction for the other strains, including all the C. freundii strains.ConclusionsAvibactam, but not relebactam, had some strain-variable ability to induce AmpC enzymes, though at concentrations (32 mg/L) above those reached in the patient.
      PubDate: 2017-09-06
  • Intraosteoblastic activity of daptomycin in combination with oxacillin and
           ceftaroline against MSSA and MRSA
    • Authors: Dupieux C; Trouillet-Assant S, Camus C, et al.
      Abstract: BackgroundThe Staphylococcus aureus intracellular reservoir is associated with bone and joint infection (BJI) chronicity. As daptomycin is increasingly prescribed in BJI, strategies for improving its reduced intracellular activity should be promoted.ObjectivesBased on the known in vitro synergy of daptomycin with β-lactams, the aim of the present study was to evaluate the intracellular activity of these combinations in an ex vivo osteoblast infection model.MethodsOsteoblastic cells infected with an MRSA strain or its isogenic MSSA counterpart were incubated for 24 h with daptomycin, oxacillin or ceftaroline alone or in combination using usual intraosseous therapeutic concentrations. Intracellular bacteria were quantified by plating cell lysates. MICs for MSSA and MRSA were determined using the chequerboard method at pH 5 to mimic conditions expected within lysosomes, the foremost S. aureus intracellular location.ResultsDaptomycin failed to reduce the intracellular MSSA inoculum, and was weakly active against MRSA compared with untreated cells (−27.6%; P < 10−3). Oxacillin and ceftaroline revealed significant intracellular activity, including oxacillin against MRSA-infected cells (−43.2%; P < 10−3). The daptomycin/oxacillin combination was significantly more active against intracellular MSSA and MRSA compared with daptomycin and oxacillin alone (−44.4% and −57.2%, respectively; P < 0.05). In contrast, daptomycin/ceftaroline was not more efficient than ceftaroline alone. Interestingly, oxacillin MICs for MRSA decreased in vitro from >256 to 0.023 mg/L when the pH decreased from 7 to 5, and chequerboards showed an additive effect of the daptomycin/oxacillin combination against MRSA at pH 5.ConclusionsIn acidic intracellular conditions, oxacillin enhances daptomycin activity against the intraosteoblastic reservoir of S. aureus, including MRSA.
      PubDate: 2017-09-06
  • Spatiotemporal pharmacodynamics of meropenem- and tobramycin-treated
           Pseudomonas aeruginosa biofilms
    • Authors: Haagensen J; Verotta D, Huang L, et al.
      Abstract: ObjectivesThe selection and dose of antibiotic therapy for biofilm-related infections are based on traditional pharmacokinetic studies using planktonic bacteria. The objective of this study was to characterize the time course and spatial activity of human exposure levels of meropenem and tobramycin against Pseudomonas aeruginosa biofilms grown in an in vitro flow-chamber model.MethodsPharmacokinetic profiles of meropenem and tobramycin used in human therapy were administered to GFP-labelled P. aeruginosa PAO1 grown in flow chambers for 24 or 72 h. Images were acquired using confocal laser scanning microscopy throughout antibiotic treatment. Bacterial biomass was measured using COMSTAT and pharmacokinetic/pharmacodynamic models were fitted using NONMEM7.ResultsMeropenem treatment resulted in more rapid and sustained killing of both the 24 and 72 h PAO1 biofilm compared with tobramycin. Biofilm regrowth after antibiotic treatment occurred fastest with tobramycin. Meropenem preferentially killed subpopulations within the mushroom cap of the biofilms, regardless of biofilm maturity. The spatial killing by tobramycin varied with biofilm maturity. A tobramycin-treated 24 h biofilm resulted in live and dead cells detaching from the biofilm, while treatment of a 72 h biofilm preferentially killed subpopulations on the periphery of the mushroom stalk. Regrowth occurred primarily on the mushroom caps. Combination meropenem and tobramycin therapy resulted in rapid and efficient killing of biofilm cells, with a spatial pattern similar to meropenem alone.ConclusionsSimulated human concentrations of meropenem and tobramycin in young and mature PAO1 biofilms exhibited differences in temporal and spatial patterns of killing and antibiotic tolerance development.
      PubDate: 2017-09-06
  • Impact of baseline plasma HIV-1 RNA and time to virological suppression on
           virological rebound according to first-line antiretroviral regimen
    • Authors: Raffi F; Hanf M, Ferry T, et al.
      Abstract: ObjectivesWe investigated the risk of virological rebound in HIV-1-infected patients achieving virological suppression on first-line combined ART (cART) according to baseline HIV-1 RNA, time to virological suppression and type of regimen.Patients and methodsSubjects were 10 836 adults who initiated first-line cART (two nucleoside or nucleotide reverse transcriptase inhibitors + efavirenz, a ritonavir-boosted protease inhibitor or an integrase inhibitor) from 1 January 2007 to 31 December 2014. Cox proportional hazards models with multiple adjustment and propensity score matching were used to investigate the effect of baseline HIV-1 RNA and time to virological suppression on the occurrence of virological rebound.ResultsDuring 411 436 patient-months of follow-up, risk of virological rebound was higher in patients with baseline HIV-1 RNA ≥100 000 copies/mL versus <100 000 copies/mL, in those achieving virological suppression in > 6 months versus <6 months, and lower with efavirenz or integrase inhibitors than with ritonavir-boosted protease inhibitors. Baseline HIV-1 RNA >100 000 copies/mL was associated with virological rebound for ritonavir-boosted protease inhibitors but not for efavirenz or integrase inhibitors. Time to virological suppression >6 months was strongly associated with virological rebound for all regimens.ConclusionsIn HIV-1-infected patients starting cART, risk of virological rebound was lower with efavirenz or integrase inhibitors than with ritonavir-boosted protease inhibitors. These data, from a very large observational cohort, in addition to the more rapid initial virological suppression obtained with integrase inhibitors, reinforce the positioning of this class as the preferred one for first-line therapy.
      PubDate: 2017-09-06
  • Surotomycin versus vancomycin in adults with Clostridium difficile
           infection: primary clinical outcomes from the second pivotal, randomized,
           double-blind, Phase 3 trial
    • Authors: Daley P; Louie T, Lutz J, et al.
      Abstract: BackgroundThe available treatment options for Clostridium difficile infection (CDI) are limited by high recurrence rates. Surotomycin was a novel bactericidal cyclic lipopeptide in development to treat CDI that demonstrated non-inferiority to vancomycin in a Phase 2 trial.ObjectivesTo assess surotomycin safety and clinical response (non-inferiority versus vancomycin) at the end of treatment (EOT) of CDI. Additionally, to assess surotomycin response over time and sustained response at 30–40 days post-EOT (superiority versus vancomycin).Patients and methodsPatients with CDI were randomized (1:1) to receive twice-daily oral surotomycin 250 mg alternating with twice-daily placebo or four-times-daily oral vancomycin 125 mg for 10 days in this Phase 3, double-blind, multicentre, international trial. Clinical response over time and sustained clinical response were monitored until the end of the trial, through a follow-up period of 30–40 days. Clinical Trial Registration: NCT01598311.ResultsA total of 285 and 292 patients with confirmed CDI were randomized to receive surotomycin and vancomycin, respectively. Surotomycin-associated clinical response at EOT was non-inferior to vancomycin (surotomycin/vancomycin: 83.4%/82.1%; difference 1.4%, 95% CI − 4.9, 7.6). Following treatment with surotomycin, both clinical response over time (stratified log-rank test, P = 0.277) and sustained clinical response (63.3%/59.0%; difference 4.3%, 95% CI − 3.6, 12.2) did not demonstrate superiority versus vancomycin at end of trial. Both treatments were generally well tolerated.ConclusionsSurotomycin demonstrated non-inferiority to vancomycin for CDI clinical response at EOT. Surotomycin did not demonstrate superiority to vancomycin for clinical response over time or sustained clinical response rate.
      PubDate: 2017-09-06
  • Rifampicin potentiation of aminoglycoside activity against cystic fibrosis
           isolates of Pseudomonas aeruginosa
    • Authors: Mikalauskas A; Parkins M, Poole K.
      Abstract: ObjectivesRifampicin potentiates the activity of aminoglycosides (AGs) versus Pseudomonas aeruginosa by targeting the AmgRS two-component system. In this study we examine the impact of rifampicin on the AG susceptibility of cystic fibrosis (CF) lung isolates of P. aeruginosa and the contribution of AmgRS to AG resistance in these isolates.MethodsamgR deletion derivatives of clinical isolates were constructed using standard gene replacement technology. Susceptibility to AGs ± rifampicin (at ½ MIC) was assessed using a serial 2-fold dilution assay.ResultsRifampicin showed a variable ability to potentiate AG activity versus the CF isolates, enhancing AG susceptibility between 2- and 128-fold. Most strains showed potentiation for at least two AGs, with only a few strains showing no AG potentiation by rifampicin. Notably, loss of amgR increased AG susceptibility although rifampicin potentiation of AG activity was still observed in the ΔamgR derivatives.ConclusionsAmgRS contributes to AG resistance in CF isolates of P. aeruginosa and rifampicin shows a variable ability to potentiate AG activity against these, highlighting the complexity of AG resistance in such isolates.
      PubDate: 2017-09-05
  • Influence of empirical double-active combination antimicrobial therapy
           compared with active monotherapy on mortality in patients with septic
           shock: a propensity score-adjusted and matched analysis
    • Authors: Ripa M; Rodríguez-Núñez O, Cardozo C, et al.
      Abstract: ObjectivesTo evaluate the influence on mortality of empirical double-active combination antimicrobial therapy (DACT) compared with active monotherapy (AM) in septic shock patients.MethodsA retrospective study was performed of monomicrobial septic shock patients admitted to a university centre during 2010–15. A propensity score (PS) was calculated using a logistic regression model taking the assigned therapy as the dependent variable, and used as a covariate in multivariate analysis predicting 7, 15 and 30 day mortality and for matching patients who received DACT or AM. Multivariate models comprising the assigned therapy group and the PS were built for specific patient subgroups.ResultsFive-hundred and seventy-six patients with monomicrobial septic shock who received active empirical antimicrobial therapy were included. Of these, 340 received AM and 236 DACT. No difference in 7, 15 and 30 day all-cause mortality was found between groups either in the PS-adjusted multivariate logistic regression analysis or in the PS-matched cohorts. However, in patients with neutropenia, DACT was independently associated with a better outcome at 15 (OR 0.29, 95% CI 0.09–0.92) and 30 (OR 0.25, 95% CI 0.08–0.79) days, while in patients with Pseudomonas aeruginosa infection DACT was associated with lower 7 (OR 0.12, 95% CI 0.02–0.7) and 30 day (OR 0.26, 95% CI 0.08–0.92) mortality.ConclusionsAll-cause mortality at 7, 15 and 30 days was similar in patients with monomicrobial septic shock receiving empirical double-active combination therapy and active monotherapy. However, a beneficial influence of empirical double-active combination on mortality in patients with neutropenia and those with P. aeruginosa infection is worthy of further study.
      PubDate: 2017-08-31
  • A framework for ensuring a balanced accounting of the impact of
           antimicrobial stewardship interventions
    • Authors: Toma M; Davey P, Marwick C, et al.
      Abstract: Drawing on a Cochrane systematic review, this paper examines the relatively limited range of outcomes measured in published evaluations of antimicrobial stewardship interventions (ASIs) in hospitals. We describe a structured framework for considering the range of consequences that ASIs can have, in terms of their desirability and the extent to which they were expected when planning an ASI: expected, desirable consequences (intervention goals); expected, undesirable consequences (intervention trade-offs); unexpected, undesirable consequences (unpleasant surprises); and unexpected, desirable consequences (pleasant surprises). Of 49 randomized controlled trials identified by the Cochrane review, 28 (57%) pre-specified increased length of stay and/or mortality as potential trade-offs of ASI, with measurement intended to provide reassurance about safety. In actuality, some studies found unexpected decreases in length of stay (a pleasant surprise). In contrast, only 11 (10%) of 110 interrupted time series studies included any information about unintended consequences, with 10 examining unexpected, undesirable outcomes (unpleasant surprises) using case–control, qualitative or cohort designs. Overall, a large proportion of the ASIs reported in the literature only assess impact on their targeted process goals—antimicrobial prescribing—with limited examination of other potential outcomes, including microbial and clinical outcomes. Achieving a balanced accounting of the impact of an ASI requires careful consideration of expected undesirable effects (potential trade-offs) from the outset, and more consideration of unexpected effects after implementation (both pleasant and unpleasant surprises, although the latter will often be more important). The proposed framework supports the systematic consideration of all types of consequences of improvement before and after implementation.
      PubDate: 2017-08-31
  • Novel multiresistance cfr plasmids in linezolid-resistant
           methicillin-resistant Staphylococcus epidermidis and vancomycin-resistant
           Enterococcus faecium (VRE) from a hospital outbreak: co-location of cfr
           and optrA in VRE
    • Authors: Lazaris A; Coleman D, Kearns A, et al.
      Abstract: BackgroundLinezolid is often the drug of last resort to treat infections caused by Gram-positive cocci. Linezolid resistance can be mutational (23S rRNA or L-protein) or, less commonly, acquired [predominantly cfr, conferring resistance to phenicols, lincosamides, oxazolidinones, pleuromutilins and streptogramin A compounds (PhLOPSA) or optrA, encoding oxazolidinone and phenicol resistance].ObjectivesTo investigate the clonality and genetic basis of linezolid resistance in 13 linezolid-resistant (LZDR) methicillin-resistant Staphylococcus epidermidis (MRSE) isolates recovered during a 2013/14 outbreak in an ICU in an Irish hospital and an LZDR vancomycin-resistant Enterococcus faecium (VRE) isolate from an LZDR-MRSE-positive patient.MethodsAll isolates underwent PhLOPSA susceptibility testing, 23S rRNA sequencing, DNA microarray profiling and WGS.ResultsAll isolates exhibited the PhLOPSA phenotype. The VRE harboured cfr and optrA on a novel 73 kb plasmid (pEF12-0805) also encoding erm(A), erm(B), lnu(B), lnu(E), aphA3 and aadE. One MRSE (M13/0451, from the same patient as the VRE) harboured cfr on a novel 8.5 kb plasmid (pSEM13-0451). The remaining 12 MRSE lacked cfr but exhibited linezolid resistance-associated mutations and were closely related to (1–52 SNPs) but distinct from M13/0451 (202–223 SNPs).ConclusionsUsing WGS, novel and distinct cfr and cfr/optrA plasmids were identified in an MRSE and VRE isolate, respectively, as well as a cfr-negative LZDR-MRSE ICU outbreak and a distinct cfr-positive LZDR-MRSE from the same ICU. To our knowledge, this is the first report of cfr and optrA on a single VRE plasmid. Ongoing surveillance of linezolid resistance is essential to maintain its therapeutic efficacy.
      PubDate: 2017-08-28
  • Characterization of two novel variants of staphylococcal cassette
    • Authors: Chang S; Lee M, Yeh C, et al.
      Abstract: ObjectivesStaphylococcus lugdunensis, a species of CoNS, has become an important hospital pathogen because of increasing resistance to β-lactam antibiotics such as methicillin and oxacillin. Methicillin resistance is mainly due to the acquisition of the staphylococcal cassette chromosome (SCC) mec (SCCmec). Little is known about the structure of SCCmec in methicillin- or oxacillin-resistant CoNS.MethodsWGS was performed to determine the structure of SCCmec elements of two clinical S. lugdunensis isolates: CMUH-22 and CMUH-25.ResultsThese elements were found to be flanked by DRs and IRs with unique mosaic structures and a common integration site in the 3′ end of the rlmH gene. The sequences of the regions located between rlmH and the ISSau4-like transposase genes of both elements were similar to those of SCCmec Vt of Staphylococcus aureus PM1. The SCCmec (type V, 5C2&4) of CMUH-25 harboured a novel ccrC complex and a C2-like mec complex in opposite orientations, similar to the type V SCCmec of S. aureus WIS. The sequences of the ccrA4B4 genes and J1 and J2 regions of CMUH-25 were similar to those of the SCC element of Staphylococcus haemolyticus NCTC 11042. In contrast, portions of the sequence of the J1 region of type Vt (5C2) SCCmec in strain CMUH-22 were highly similar to portions of those of Staphylococcus epidermidis RP62A and the composite SCCmec type V of S. aureus WAMRSA40.ConclusionsThese observations suggest that the SCCmec elements of CMUH-25 and CMUH-22 evolved separately and assembled through different recombination events.
      PubDate: 2017-08-23
  • Expression of acquired macrolide resistance genes in Haemophilus
    • Authors: Atkinson C; Kunde D, Tristram S.
      Abstract: ObjectivesTo investigate the phenotypic effect of expression of selected acquired macrolide resistance genes (AMRGs) in non-typeable Haemophilus influenzae (NTHi).MethodsThe AMRGs erm(A), erm(B) and erm(C) were cloned into Escherichia coli JM109 using the shuttle vector pLS88; constructed plasmids extracted from suitable clones were used to transform H. influenzae Rd by electroporation. Erythromycin and azithromycin MICs for suitable transformants were determined by broth microdilution. AMRG expression was determined using quantitative PCR on transformant cDNA with locked nucleic acid dual-labelled hydrolysis probes.ResultsExpression of all AMRGs was observed in the transformants. Some variation in expression between the AMRGs was apparent, but expression of all genes was associated with a notable increase in erythromycin and azithromycin MICs compared with untransformed H. influenzae Rd.ConclusionsWhile the establishment of erm genes within WT populations of NTHi remains contentious, H. influenzae is capable of expression of erm. Expression may be associated with a subsequent decreased susceptibility to macrolides in isolates and future monitoring of these genes in NTHi isolates is warranted.
      PubDate: 2017-08-23
  • Within-host spatiotemporal dynamics of systemic Salmonella infection
           during and after antimicrobial treatment
    • Authors: Rossi O; Dybowski R, Maskell D, et al.
      Abstract: ObjectivesWe determined the interactions between efficacy of antibiotic treatment, pathogen growth rates and between-organ spread during systemic Salmonella infections.MethodsWe infected mice with isogenic molecularly tagged subpopulations of either a fast-growing WT or a slow-growing ΔaroC Salmonella strain. We monitored viable bacterial numbers and fluctuations in the proportions of each bacterial subpopulation in spleen, liver, blood and mesenteric lymph nodes (MLNs) before, during and after the cessation of treatment with ampicillin and ciprofloxacin.ResultsBoth antimicrobials induced a reduction in viable bacterial numbers in the spleen, liver and blood. This reduction was biphasic in infections with fast-growing bacteria, with a rapid initial reduction followed by a phase of lower effect. Conversely, a slow and gradual reduction of the bacterial load was seen in infections with the slow-growing strain, indicating a positive correlation between bacterial net growth rates and the efficacy of ampicillin and ciprofloxacin. The viable numbers of either bacterial strain remained constant in MLNs throughout the treatment with a relapse of the infection with WT bacteria occurring after cessation of the treatment. The frequency of each tagged bacterial subpopulation was similar in the spleen and liver, but different from that of the MLNs before, during and after treatment.ConclusionsIn Salmonella infections, bacterial growth rates correlate with treatment efficacy. MLNs are a site with a bacterial population structure different to those of the spleen and liver and where the total viable bacterial load remains largely unaffected by antimicrobials, but can resume growth after cessation of treatment.
      PubDate: 2017-08-23
  • Disease-based antimicrobial stewardship: a review of active and passive
           approaches to patient management
    • Authors: Foolad F; Nagel J, Eschenauer G, et al.
      Abstract: Although new antimicrobial stewardship programmes (ASPs) often begin by targeting the reduction of antimicrobial use, an increasing focus of ASPs is to improve the management of specific infectious diseases. Disease-based antimicrobial stewardship emphasizes improving patient outcomes by optimizing antimicrobial use and increasing compliance with performance measures. Directing efforts towards the comprehensive management of specific infections allows ASPs to promote the shift in healthcare towards improving quality, safety and patient outcome metrics for specific diseases. This review evaluates published active and passive disease-based antimicrobial stewardship interventions and their impact on antimicrobial use and associated patient outcomes for patients with pneumonia, acute bacterial skin and skin structure infections, bloodstream infections, urinary tract infections, asymptomatic bacteriuria, Clostridium difficile infection and intra-abdominal infections. Current literature suggests that disease-based antimicrobial stewardship effects on medical management and patient outcomes vary based on infectious disease syndrome, resource availability and intervention type.
      PubDate: 2017-08-17
  • A large plasmid, pD46-4, carrying a complex resistance region in an
           extensively antibiotic-resistant ST25 Acinetobacter baumannii
    • Authors: Nigro S; Hall R.
      Abstract: Sir,
      PubDate: 2017-08-14
  • Pharmacokinetics and safety results from the Phase 3 randomized,
           open-label, study of intravenous posaconazole in patients at risk of
           invasive fungal disease
    • Authors: Cornely O; Robertson M, Haider S, et al.
      Abstract: ObjectivesA two-part (Phase 1B/3), sequential, open-label, multicentre study evaluated the pharmacokinetics (PK) and safety of intravenous (iv) posaconazole given as antifungal prophylaxis to neutropenic patients with AML or myelodysplastic syndrome (MDS) or to recipients at risk of invasive fungal disease (IFD) after allogeneic HSCT.MethodsPatients (N = 237) received 300 mg of posaconazole iv twice daily on day 1, followed by 300 mg of posaconazole iv once daily for 4–28 days. After at least 5 days, patients were randomly assigned to receive posaconazole oral suspension, 400 mg twice daily or 200 mg three times daily, to complete a 28 day treatment course. Primary PK parameters were steady-state average concentration over the dosing interval (Cavg) and posaconazole trough levels (Cmin).ResultsMean posaconazole Cmin was 1320 ng/mL (day 6) and 1297 ng/mL (day 8); steady-state Cmin was 1090 ng/mL (day 10). Mean steady-state posaconazole Cavg was 1500 ng/mL (day 10 or 14) and was similar in HSCT recipients (1560 ng/mL) and AML/MDS patients (1470 ng/mL). The most commonly reported treatment-related adverse events were diarrhoea (8%), nausea (5%) and rash (5%). IFD was reported in 3/237 patients (1%; 2 proven, 1 probable).ConclusionsIntravenous posaconazole at 300 mg was well tolerated, resulted in adequate steady-state systemic exposure and was associated with a low incidence of IFD in this population at high risk.Trial registry and, NCT01075984
      PubDate: 2017-08-09
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