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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: 60, 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: 151, SJR: 0.652, h-index: 43)
American J. of Agricultural Economics     Hybrid Journal   (Followers: 38, SJR: 1.441, h-index: 77)
American J. of Epidemiology     Hybrid Journal   (Followers: 173, 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: 20)
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: 13, 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: 47, SJR: 4.362, h-index: 173)
Annals of the Entomological Society of America     Full-text available via subscription   (Followers: 8, SJR: 0.642, h-index: 53)
Annals of Work Exposures and Health     Hybrid Journal  
AoB Plants     Open Access   (Followers: 4, SJR: 0.78, h-index: 10)
Applied Economic Perspectives and Policy     Hybrid Journal   (Followers: 18, SJR: 0.884, h-index: 31)
Applied Linguistics     Hybrid Journal   (Followers: 53, SJR: 1.749, h-index: 63)
Applied Mathematics Research eXpress     Hybrid Journal   (Followers: 1, SJR: 0.779, h-index: 11)
Arbitration Intl.     Full-text available via subscription   (Followers: 21)
Arbitration Law Reports and Review     Hybrid Journal   (Followers: 14)
Archives of Clinical Neuropsychology     Hybrid Journal   (Followers: 31, SJR: 0.96, h-index: 71)
Aristotelian Society Supplementary Volume     Hybrid Journal   (Followers: 2, SJR: 0.102, h-index: 20)
Arthropod Management Tests     Hybrid Journal   (Followers: 2)
Astronomy & Geophysics     Hybrid Journal   (Followers: 46, SJR: 0.144, h-index: 15)
Behavioral Ecology     Hybrid Journal   (Followers: 51, SJR: 1.698, h-index: 92)
Bioinformatics     Hybrid Journal   (Followers: 285, 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: 16, SJR: 1.955, h-index: 55)
BJA : British J. of Anaesthesia     Hybrid Journal   (Followers: 165, SJR: 2.314, h-index: 133)
BJA Education     Hybrid Journal   (Followers: 65, SJR: 0.272, h-index: 20)
Brain     Hybrid Journal   (Followers: 66, SJR: 6.097, h-index: 264)
Briefings in Bioinformatics     Hybrid Journal   (Followers: 47, 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: 576, SJR: 1.373, h-index: 62)
British J. of Social Work     Hybrid Journal   (Followers: 87, 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: 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: 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: 45, 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: 4)
Chinese J. of Intl. Law     Hybrid Journal   (Followers: 22, 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: 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: 25, 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: 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: 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: 10, 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: 38, SJR: 2.052, h-index: 52)
ELT J.     Hybrid Journal   (Followers: 25, SJR: 1.26, h-index: 23)
English Historical Review     Hybrid Journal   (Followers: 55, 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: 28, 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: 52, 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: 179, 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: 29, 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: 13, 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: 15, 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: 14, SJR: 3.22, h-index: 39)
Geophysical J. Intl.     Hybrid Journal   (Followers: 35, SJR: 1.839, h-index: 119)
German History     Hybrid Journal   (Followers: 27, 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: 55, SJR: 0.505, h-index: 40)
Health Education Research     Hybrid Journal   (Followers: 14, SJR: 0.814, h-index: 80)
Health Policy and Planning     Hybrid Journal   (Followers: 23, 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: 30, SJR: 0.313, h-index: 20)
Holocaust and Genocide Studies     Hybrid Journal   (Followers: 27, SJR: 0.115, h-index: 13)
Human Molecular Genetics     Hybrid Journal   (Followers: 9, SJR: 4.288, h-index: 233)
Human Reproduction     Hybrid Journal   (Followers: 80, SJR: 2.271, h-index: 179)
Human Reproduction Update     Hybrid Journal   (Followers: 19, SJR: 4.678, h-index: 128)
Human Rights Law Review     Hybrid Journal   (Followers: 64, SJR: 0.7, h-index: 21)
ICES J. of Marine Science: J. du Conseil     Hybrid Journal   (Followers: 55, 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   (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: 9, SJR: 1.37, h-index: 81)
Industrial Law J.     Hybrid Journal   (Followers: 33, 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: 11, 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: 31)
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: 63, SJR: 0.613, h-index: 19)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 170, 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: 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: 35, 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: 34, 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: 48, SJR: 0.286, h-index: 34)
J. of Analytical Toxicology     Hybrid Journal   (Followers: 14, 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: 42, SJR: 1.341, h-index: 96)
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: 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: 10, SJR: 0.69, h-index: 36)
J. of Design History     Hybrid Journal   (Followers: 18, 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: 21)
J. of Experimental Botany     Hybrid Journal   (Followers: 14, SJR: 2.798, h-index: 163)
J. of Financial Econometrics     Hybrid Journal   (Followers: 23, 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: 8, 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: 41, 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]   [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  [370 journals]
  • Comparison of phenotypic and WGS-derived antimicrobial resistance profiles
           of Salmonella enterica serovars Typhi and Paratyphi
    • Authors: Day M; Doumith M, Do Nascimento V, et al.
      Abstract: ObjectivesSurveillance of antimicrobial resistance (AMR) in Salmonella enterica serovars Typhi and Paratyphi is essential to provide an evidence base for empirical treatment protocols and to monitor emerging AMR. We sought to compare phenotypic and WGS-based genotypic methods for the detection of AMR in Salmonella Typhi and Salmonella Paratyphi.MethodsWGS data from 603 isolates of Salmonella Typhi (n = 332) and Salmonella Paratyphi (n = 271) were mapped to genes or chromosomal mutations known to be associated with phenotypic AMR and compared with phenotypic susceptibility data interpreted using breakpoints recommended by EUCAST.ResultsThere were two (0.03%) discordant interpretations out of a possible 6030 isolate/antimicrobial class combinations. MDR (resistant to three or more classes of antimicrobial) was detected in 83/332 (25.0%) Salmonella Typhi isolates, but was not detected in Salmonella Paratyphi. Thirty-six (10.8%) isolates of Salmonella Typhi were resistant to ciprofloxacin (MIC >0.5 mg/L), with 33 (9.9%) of 332 exhibiting mutations in gyrA and parC, and 244 (73.5%) isolates had reduced susceptibility to ciprofloxacin (MIC 0.06–0.25 mg/L). In comparison, 209/227 (92.1%) isolates of Salmonella Paratyphi A exhibited resistance to ciprofloxacin (MIC >0.5 mg/L). No resistance to azithromycin or the third-generation cephalosporins was detected.ConclusionsWGS data provided a robust and informative approach for monitoring MDR and emerging resistance to ciprofloxacin in Salmonella Typhi and Salmonella Paratyphi. Phenotypic antimicrobial susceptibility testing continues to be performed to guide targeted individual patient treatment, but inferred AMR profiles from WGS data may be used for surveillance and to guide empirical therapy.
      PubDate: Tue, 05 Dec 2017 00:00:00 GMT
  • Darunavir/ritonavir monotherapy at a low dose (600/100 mg/day) in
           HIV-1-infected individuals with suppressed HIV viraemia
    • Authors: Seang S; Schneider L, Nguyen T, et al.
      Abstract: BackgroundDarunavir/ritonavir is a potent PI with a high genetic barrier and pharmacological robustness favourably investigated as monotherapy. Whether darunavir could be dose reduced in the context of monotherapy deserves investigation.MethodsPatients with HIV suppressed viraemia (plasma viral load <50 copies/mL for 12 months) under ART who had switched to darunavir/ritonavir monotherapy at 600/100 mg/day between 2013 and 2015 were included in this observational 48 week single-centre study. The primary outcome was the proportion of patients with virological success (defined as plasma viral load <50 copies/mL) at week 24. Secondary outcomes included treatment strategy success and resistance.ResultsThirty-one patients were included with the following baseline characteristics [median (IQR)]: age 52 years (47–57), CD4+ 649 cells/mm3 (463–813), ART duration 16.3 years (9.2–22.3), nadir CD4+ 195 cells/mm3 (144–261) and duration of HIV suppression 7.8 years (4.8–9.7). Prior to switch, ART consisted of PI monotherapy for 28 of 31 patients [darunavir/ritonavir 800/100 mg/day (n = 26), lopinavir/ritonavir (n = 1) and atazanavir/ritonavir (n = 1)] and a triple drug regimen for 3 of 31 patients. Within the 48 weeks of follow-up, no virological failure occurred and two patients discontinued 600/100 mg of darunavir/ritonavir due to side effects at week 16 and 40, leading to a virological suppression rate of 100% (95% CI = 89–100) at weeks 24 and 48. Strategy success rates were 96.8% (95% CI = 83.3–99.9) at week 24 and 93.5% (95% CI = 78.6–99.2) at week 48. Median (IQR) Ctrough values of 800/100 mg of darunavir/ritonavir and 600/100 mg of darunavir/ritonavir were 1537 ng/mL (1286–1724) and 1255 ng/mL (873–2161), respectively.ConclusionsA lower dose of darunavir/ritonavir used as monotherapy (600/100 mg/day) was highly effective in virologically suppressed HIV-infected patients. Further studies are needed to confirm these data.
      PubDate: Tue, 05 Dec 2017 00:00:00 GMT
  • Fungal-specific Cyp51 inhibitor VT-1598 demonstrates in vitro activity
           against Candida and Cryptococcus species, endemic fungi, including
           Coccidioides species, Aspergillus species and Rhizopus arrhizus
    • Authors: Wiederhold N; Patterson H, Tran B, et al.
      Abstract: BackgroundInvasive fungal infections, including those caused by yeasts, moulds and endemic organisms, can be significant causes of morbidity and mortality in immunocompromised hosts, those with multiple comorbidities and occasionally immunocompetent hosts. Current antifungal agents are often limited by drug toxicities, drug interactions or the development of resistance. VT-1598 is a novel tetrazole that has greater specificity for fungal Cyp51 than currently available triazoles and thus the potential for clinically significant drug interactions is reduced. We measured the in vitro activity of VT-1598 against clinical isolates of Candida and Cryptococcus species, endemic fungi, including Coccidioides, Blastomyces and Histoplasma, Aspergillus species and Rhizopus arrhizus.MethodsAntifungal susceptibility testing was performed by broth microdilution or macrodilution methods per CLSI standards. Clinical isolates of each species were used and clinically available antifungal agents were tested against each isolate.ResultsVT-1598 demonstrated in vitro activity against yeasts and moulds that was similar to or greater than that of clinically available antifungal agents, including amphotericin B, fluconazole, caspofungin, voriconazole and posaconazole. The in vitro activity of VT-1598 was also maintained against resistant isolates, including fluconazole-resistant Candida isolates. In vitro activity was also observed against endemic fungi, including Blastomyces, Histoplasma and both Coccidioides immitis and Coccidioides posadasii.ConclusionsVT-1598 demonstrated in vitro activity against yeasts, moulds and endemic fungi, which was maintained against isolates that had reduced susceptibility to other antifungals. Further studies are warranted to evaluate the in vivo efficacy of VT-1598 against various fungal pathogens.
      PubDate: Mon, 27 Nov 2017 00:00:00 GMT
  • Utilization of a clinical microbiology service at a Cambodian paediatric
           hospital and its impact on appropriate antimicrobial prescribing
    • Authors: Fox-Lewis S; Pol S, Miliya T, et al.
      Abstract: BackgroundAntimicrobial resistance threatens human health worldwide. Antimicrobial misuse is a major driver of resistance. Promoting appropriate antimicrobial use requires an understanding of how clinical microbiology services are utilized, particularly in resource-limited settings.ObjectivesTo assess the appropriateness of antimicrobial prescribing and the factors affecting utilization of the established clinical microbiology service (CMS). The CMS comprises the microbiology laboratory, clinical microbiologists (infection doctors) and antimicrobial treatment guidelines.MethodsThis mixed-methods study was conducted at a non-governmental Cambodian paediatric hospital. Empirical and post-culture antimicrobial prescriptions were reviewed from medical records. The random sample included 10 outpatients per week in 2016 (retrospective) and 20 inpatients per week for 4 weeks in the medical, neonatal and intensive care wards (prospective). Post-culture prescriptions were assessed in patients with positive blood and cerebrospinal fluid cultures from 1 January 2014 to 31 December 2016. Focus group discussions and semi-structured interviews with clinicians explored barriers and facilitators to use of the CMS.ResultsOnly 31% of outpatients were prescribed empirical antimicrobials. Post-culture prescriptions (394/443, 89%) were more likely to be appropriate than empirical prescriptions (447/535, 84%), based on treatment guidelines, microbiology advice and antimicrobial susceptibility test results (P = 0.015). Being comprehensive, accessible and trusted enabled CMS utilization. Clinical microbiologists provided a crucial human interface between the CMS and physicians. The main barriers were a strong clinical hierarchy and occasional communication difficulties.ConclusionsAntimicrobial prescribing in this hospital was largely appropriate. A culturally appropriate human interface linking the laboratory and physicians is essential in providing effective microbiology services and ensuring appropriate antimicrobial prescribing in resource-limited settings.
      PubDate: Fri, 24 Nov 2017 00:00:00 GMT
  • Rapid disc diffusion antibiotic susceptibility testing for Pseudomonas
           aeruginosa, Acinetobacter baumannii and Enterococcus spp.
    • Authors: Hombach M; Jetter M, Blöchliger N, et al.
      Abstract: BackgroundWe investigated the feasibility of rapid disc diffusion antibiotic susceptibility testing (rAST) with reading of inhibition zones after 6 and/or 8 h of incubation for Enterococcus faecalis, Enterococcus faecium, Pseudomonas aeruginosa and Acinetobacter baumannii. In addition, we evaluated discrimination of resistant populations from the WT populations at early timepoints and the requirement for clinical breakpoint adaptations for proper interpretation of rAST data.MethodsIn total, 815 clinical strains [E. faecalis (n = 135), E. faecium (n = 227), P. aeruginosa (n = 295) and A. baumannii (n = 158)] were included in this study. Disc diffusion plates were streaked, incubated and imaged using the WASPLabTM automation system. WT populations and non-WT populations were defined using epidemiological cut-offs.Results and conclusionsrAST at 6 and 8 h was possible for A. baumannii and enterococci with readability of inhibition zones >90%. Overall categorical agreement of rAST at 6 h with AST at 18 h was 97.2%, 97.4% and 95.3% for E. faecalis, E. faecium and A. baumannii, respectively. With few exceptions, major categorization error rates were <1% for A. baumannii, and vancomycin-resistant E. faecium were clearly separated from the WT at 6 h. For P. aeruginosa the average readability of inhibition zones was 68.9% at 8 h and we found an overall categorical agreement of 94.8%. Adaptations of clinical breakpoints and/or introduction of technical buffer zones, preferably based on aggregated population data from various epidemiological settings, are required for proper interpretation of rAST.
      PubDate: Thu, 23 Nov 2017 00:00:00 GMT
  • Bacterial zincophore [S,S]-ethylenediamine-N,N′-disuccinic acid is an
           effective inhibitor of MBLs
    • Authors: Proschak A; Kramer J, Proschak E, et al.
      Abstract: ObjectivesCarbapenemases such as MBLs are spreading among Gram-negative bacterial pathogens. Infections due to these MDR bacteria constitute a major global health challenge. Therapeutic strategies against carbapenemase-producing bacteria include β-lactamase inhibitor combinations. [S,S]-ethylenediamine-N,N′-disuccinic acid (EDDS) is a chelator and potential inhibitor of MBLs. We investigated the activity of EDDS in combination with imipenem against MBL-producing bacteria in vitro as well as in vivo.MethodsThe inhibitory activity of EDDS was analysed by means of a fluorescence-based assay using purified recombinant MBLs, i.e. NDM-1, VIM-1, SIM-1 and IMP-1. The in vitro activity of imipenem ± EDDS against mutants as well as clinical isolates expressing MBLs was evaluated by broth microdilution assay. The in vivo activity of imipenem ± EDDS was analysed in a Galleria mellonella infection model.ResultsEDDS revealed potent MBL inhibitory activity against purified NDM-1, weaker activity against VIM-1 and SIM-1, and marginal activity against IMP-1. EDDS did not exhibit any intrinsic antibacterial activity, but enabled a concentration-dependent potentiation of imipenem against mutants as well as clinical isolates expressing various MBLs. The in vivo model showed a significantly better survival rate for imipenem + EDDS-treated G. mellonella larvae infected with NDM-1-producing Klebsiella pneumoniae compared with monotherapy with imipenem.ConclusionsThe bacterial natural zincophore EDDS is a potent MBL inhibitor and in combination with imipenem overcomes MBL-mediated carbapenem resistance in vitro and in vivo.
      PubDate: Thu, 23 Nov 2017 00:00:00 GMT
  • In vitro and in vivo activity of single and dual antimicrobial agents
           against KPC-producing Klebsiella pneumoniae
    • Authors: Nath S; Moussavi F, Abraham D, et al.
      Abstract: ObjectivesOptions for treatment of infections due to KPC-producing Klebsiella pneumoniae are limited and combination therapy is often recommended. In this report, the in vitro and in vivo activity of potential therapeutic agents and combinations was assessed against four KPC-producing K. pneumoniae isolates.MethodsUsing clinically relevant concentrations, time–kill experiments and the Galleria mellonella model of infection were used to examine the activity of polymyxin B, ceftazidime/avibactam, meropenem, rifampicin and amikacin alone and in combination.ResultsTwo K. pneumoniae isolates were resistant to polymyxin B and had ceftazidime/avibactam MICs of 8/4 mg/L. When ceftazidime/avibactam was combined with either amikacin or meropenem, synergy was observed in vitro, and these combinations were associated with improved survival in the in vivo model. Improved survival was also observed using higher doses of ceftazidime/avibactam. The other two K. pneumoniae isolates were susceptible to polymyxin B and had lower (1/4 mg/L) MICs of ceftazidime/avibactam. For these two isolates, bactericidal activity was observed in vitro at ceftazidime/avibactam concentrations four times the MIC. At one-quarter of the MIC, synergy was observed when ceftazidime/avibactam was combined with meropenem. In the in vivo model with the two susceptible isolates, improved survival rates were observed following therapy with ceftazidime/avibactam monotherapy. For all four isolates, polymyxin B with or without rifampicin or meropenem performed poorly in the in vivo model.ConclusionsPending clinical studies, combining ceftazidime/avibactam with another agent (e.g. a carbapenem) should be considered when treating serious infections due to these pathogens, particularly for isolates with ceftazidime/avibactam MICs near the susceptibility breakpoint.
      PubDate: Thu, 23 Nov 2017 00:00:00 GMT
  • Moxifloxacin target site concentrations in patients with pulmonary TB
           utilizing microdialysis: a clinical pharmacokinetic study
    • Authors: Heinrichs M; Vashakidze S, Nikolaishvili K, et al.
      Abstract: BackgroundMoxifloxacin is a second-line anti-TB drug that is useful in the treatment of drug-resistant TB. However, little is known about its target site pharmacokinetics. Lower drug concentrations at the infection site (i.e. in severe lung lesions including cavitary lesions) may lead to development and amplification of drug resistance. Improved knowledge regarding tissue penetration of anti-TB drugs will help guide drug development and optimize drug dosing.MethodsPatients with culture-confirmed drug-resistant pulmonary TB scheduled to undergo adjunctive surgical lung resection were enrolled in Tbilisi, Georgia. Five serum samples per patient were collected at different timepoints including at the time of surgical resection (approximately at Tmax). Microdialysis was performed in the ex vivo tissue immediately after resection. Non-compartmental analysis was performed and a tissue/serum concentration ratio was calculated.ResultsAmong the seven patients enrolled, the median moxifloxacin dose given was 7.7 mg/kg, the median age was 25.2 years, 57% were male and the median creatinine clearance was 95.4 mL/min. Most patients (71%) had suboptimal steady-state serum Cmax (total drug) concentrations. The median free moxifloxacin serum concentration at time of surgical resection was 1.23 μg/mL (range = 0.12–1.80) and the median free lung tissue concentration was 3.37 μg/mL (range = 0.81–5.76). The median free-tissue/free-serum concentration ratio was 3.20 (range = 0.66–28.08).ConclusionsMoxifloxacin showed excellent penetration into diseased lung tissue (including cavitary lesions) among patients with pulmonary TB. Moxifloxacin lung tissue concentrations were higher than those seen in serum. Our findings highlight the importance of moxifloxacin in the treatment of MDR-TB and potentially any patient with pulmonary TB and severe lung lesions.
      PubDate: Thu, 23 Nov 2017 00:00:00 GMT
  • Epidemic spread of Escherichia coli ST744 isolates carrying mcr-3 and
           blaCTX-M-55 in cattle in France
    • Authors: Haenni M; Beyrouthy R, Lupo A, et al.
      Abstract: Sir,
      PubDate: Wed, 22 Nov 2017 00:00:00 GMT
  • Genomic epidemiology and antimicrobial resistance of Neisseria gonorrhoeae
           in New Zealand
    • Authors: Lee R; Seemann T, Heffernan H, et al.
      Abstract: BackgroundAntimicrobial-resistant Neisseria gonorrhoeae is a major threat to public health. No studies to date have examined the genomic epidemiology of gonorrhoea in the Western Pacific Region, where the incidence of gonorrhoea is particularly high.MethodsA population-level study of N. gonorrhoeae in New Zealand (October 2014 to May 2015). Comprehensive susceptibility testing and WGS data were obtained for 398 isolates. Relatedness was inferred using phylogenetic trees, and pairwise core SNPs. Mutations and genes known to be associated with resistance were identified, and correlated with phenotype.ResultsEleven clusters were identified. In six of these clusters, >25% of isolates were from females, while in eight of them, >15% of isolates were from females. Drug resistance was common; 98%, 32% and 68% of isolates were non-susceptible to penicillin, ciprofloxacin and tetracycline, respectively. Elevated MICs to extended-spectrum cephalosporins (ESCs) were observed in 3.5% of isolates (cefixime MICs ≥ 0.12 mg/L, ceftriaxone MICs ≥ 0.06 mg/L). Only nine isolates had penA XXXIV genotypes, three of which had decreased susceptibility to ESCs (MIC = 0.12 mg/L). Azithromycin non-susceptibility was identified in 43 isolates (10.8%); two of these isolates had 23S mutations (C2611T, 4/4 alleles), while all had mutations in mtrR or its promoter.ConclusionsThe high proportion of females in clusters suggests transmission is not exclusively among MSM in New Zealand; re-assessment of risk factors for transmission may be warranted in this context. As elevated MICs of ESCs and/or azithromycin were found in closely related strains, targeted public health interventions to halt transmission are urgently needed.
      PubDate: Wed, 22 Nov 2017 00:00:00 GMT
  • Endoperoxide-based compounds: cross-resistance with artemisinins and
           selection of a Plasmodium falciparum lineage with a K13 non-synonymous
    • Authors: Paloque L; Witkowski B, Lelièvre J, et al.
      Abstract: BackgroundOwing to the emergence of multiresistant Plasmodium falciparum parasites in Southeast Asia, along with the impressive decrease in the efficacy of the endoperoxide compound artemisinin and of artemisinin-based combination therapies, the development of novel antimalarial drugs or combinations is required. Although several antiplasmodial molecules, such as endoperoxide-based compounds, are in advanced research or development, we do not know whether resistance to artemisinin derivatives might impact the efficacy of these new compounds.ObjectivesTo address this issue, the antiplasmodial efficacy of trioxaquines, hybrid endoperoxide-based molecules, was explored, along with their ability to select in vitro resistant parasites under discontinuous and dose-escalating drug pressure.MethodsThe in vitro susceptibilities of artemisinin- and trioxaquine-resistant laboratory strains and recent Cambodian field isolates were evaluated by different phenotypic and genotypic assays.ResultsTrioxaquines tested presented strong cross-resistance with artemisinin both in the artemisinin-resistant laboratory F32-ART5 line and in Cambodian field isolates. Trioxaquine drug pressure over 4 years led to the in vitro selection of the F32-DU line, which is resistant to trioxaquine and artemisinin, similar to the F32-ART lineage. F32-DU whole genome sequencing (WGS) revealed that resistance to trioxaquine was associated with the same non-synonymous mutation in the propeller domain of the K13 protein (M476I) that was found in the F32-ART lineage.ConclusionsThese worrisome results indicate the risk of cross-resistance between artemisinins and endoperoxide-based antiplasmodial drugs in the development of the K13 mutant parasites and question the usefulness of these molecules in the future therapeutic arsenal.
      PubDate: Tue, 21 Nov 2017 00:00:00 GMT
  • Oral glucan synthase inhibitor SCY-078 is effective in an experimental
           murine model of invasive candidiasis caused by WT and
           echinocandin-resistant Candida glabrata
    • Authors: Wiederhold N; Najvar L, Jaramillo R, et al.
      Abstract: BackgroundEchinocandins are recommended as first-line therapy against Candida glabrata infections, although increased resistance to this class has been reported worldwide and they are currently only available for parenteral administration. SCY-078 is an investigational glucan synthase inhibitor that is orally available.ObjectivesTo evaluate the in vivo efficacy of SCY-078 in an experimental model of invasive candidiasis due to WT and echinocandin-resistant C. glabrata isolates.MethodsNeutropenic ICR mice were inoculated intravenously with a WT isolate (SCY-078 and caspofungin MICs 0.25 and 0.125 mg/L, respectively) or an echinocandin-resistant isolate (SCY-078 and caspofungin MICs 1 and 0.5 mg/L, respectively). Treatment with placebo, SCY-078 (8, 30 or 40 mg/kg orally every 12 h) or caspofungin (1 mg/kg by intraperitoneal injection once daily) began 24 h later. Kidney fungal burden was measured on day 8 post-inoculation.ResultsSignificant reductions in kidney fungal burden were observed with 30 mg/kg SCY-078 against both isolates and with the 40 mg/kg dose against the echinocandin-resistant isolate. These results were supported by SCY-078 plasma concentration data at the higher doses, where levels above the MICs for both isolates were observed 12 h after the last oral dose. Reductions in fungal burden were also observed with caspofungin against the WT isolate, but not against the resistant isolate.ConclusionsSCY-078 demonstrated in vivo efficacy against infections caused by both WT and echinocandin-resistant C. glabrata isolates in this experimental model. This orally available glucan synthase inhibitor has potential as a therapy against echinocandin-resistant C. glabrata infections.
      PubDate: Tue, 21 Nov 2017 00:00:00 GMT
  • Impact of antimicrobial stewardship interventions on Clostridium difficile
           infection and clinical outcomes: segmented regression analyses
    • Authors: Patton A; Davey P, Harbarth S, et al.
      Abstract: BackgroundAntimicrobial exposure is associated with increased risk of Clostridium difficile infection (CDI), but the impact of prescribing interventions on CDI and other outcomes is less clear.ObjectivesTo evaluate the effect of an antimicrobial stewardship intervention targeting high-risk antimicrobials (HRA), implemented in October 2008, and to compare the findings with similar studies from a systematic review.MethodsAll patients admitted to Medicine and Surgery in Ninewells Hospital from October 2006 to September 2010 were included. Intervention effects on HRA use (dispensed DDD), CDI cases and mortality rates, per 1000 admissions per month, were analysed separately in Medicine and Surgery using segmented regression of interrupted time series (ITS) data. Data from comparable published studies were reanalysed using the same method.ResultsSix months post-intervention, there were relative reductions in HRA use of 33% (95% CI 11–56) in Medicine and 32% (95% CI 19–46) in Surgery. At 12 months, there was an estimated reduction in CDI of 7.0 cases/1000 admissions [relative change −24% (95% CI − 55 to 6)] in Medicine, but no change in Surgery {estimated 0.1 fewer cases/1000 admissions [−2% (95% CI − 116 to 112)]}. Mortality reduced throughout the study period, unaffected by the intervention. In all six comparable studies, HRA use reduced significantly, but reductions in CDI rates were only statistically significant in two and none measured mortality. Pre-intervention CDI rates and trends influenced the intervention effect.ConclusionsDespite large reductions in HRA prescribing and reductions in CDI, demonstrating real-world impact of stewardship interventions remains challenging.
      PubDate: Tue, 21 Nov 2017 00:00:00 GMT
  • Ceftazidime/avibactam alone or in combination with aztreonam against
           colistin-resistant and carbapenemase-producing Klebsiella pneumoniae
    • Authors: Jayol A; Nordmann P, Poirel L, et al.
      Abstract: Sir,
      PubDate: Sat, 18 Nov 2017 00:00:00 GMT
  • Molecular relatedness of ESBL/AmpC-producing Escherichia coli from humans,
           animals, food and the environment: a pooled analysis
    • Authors: Dorado-García A; Smid J, van Pelt W, et al.
      Abstract: BackgroundIn recent years, ESBL/AmpC-producing Escherichia coli (ESBL/AmpC-EC) have been isolated with increasing frequency from animals, food, environmental sources and humans. With incomplete and scattered evidence, the contribution to the human carriage burden from these reservoirs remains unclear.ObjectivesTo quantify molecular similarities between different reservoirs as a first step towards risk attribution.MethodsPooled data on ESBL/AmpC-EC isolates were recovered from 35 studies in the Netherlands comprising >27 000 samples, mostly obtained between 2005 and 2015. Frequency distributions of ESBL/AmpC genes from 5808 isolates and replicons of ESBL/AmpC-carrying plasmids from 812 isolates were compared across 22 reservoirs through proportional similarity indices (PSIs) and principal component analyses (PCAs).ResultsPredominant ESBL/AmpC genes were identified in each reservoir. PCAs and PSIs revealed close human–animal ESBL/AmpC gene similarity between human farming communities and their animals (broilers and pigs) (PSIs from 0.8 to 0.9). Isolates from people in the general population had higher similarities to those from human clinical settings, surface and sewage water and wild birds (0.7–0.8), while similarities to livestock or food reservoirs were lower (0.3–0.6). Based on rarefaction curves, people in the general population had more diversity in ESBL/AmpC genes and plasmid replicon types than those in other reservoirs.ConclusionsOur ‘One Health’ approach provides an integrated evaluation of the molecular relatedness of ESBL/AmpC-EC from numerous sources. The analysis showed distinguishable ESBL/AmpC-EC transmission cycles in different hosts and failed to demonstrate a close epidemiological linkage of ESBL/AmpC genes and plasmid replicon types between livestock farms and people in the general population.
      PubDate: Sat, 18 Nov 2017 00:00:00 GMT
  • Miltefosine-resistant Leishmania infantum strains with an impaired MT/ROS3
           transporter complex retain amphotericin B susceptibility
    • Authors: Mondelaers A; Hendrickx S, Van Bockstal L, et al.
      Abstract: ObjectivesIncreasing numbers of miltefosine treatment failures in visceral leishmaniasis therapy and reports of miltefosine resistance in the Indian subcontinent resulted in the recommendation to use liposomal amphotericin B as first-line therapy. Cross-resistance between miltefosine and amphotericin B has recently been documented, suggesting a role of mutations in the miltefosine transporter, a complex encoded by the MT and ROS3 genes. This study aimed to further explore the putative role of MT/ROS3 defects in the molecular basis of amphotericin B cross-resistance.MethodsThe susceptibility profiles of different miltefosine-resistant Leishmania infantum strains with well-characterized mutations in the transporter complex and the corresponding episomally restored susceptible parasite lines were determined using both the routine extracellular promastigote assay and the intracellular amastigote assay.ResultsIn vitro amastigote and promastigote susceptibility testing of the two miltefosine-resistant and the episomally reconstituted L. infantum lines revealed full susceptibility to amphotericin B, despite the variable miltefosine susceptibility profile.ConclusionsMutations present in either the MT and/or ROS3 gene are not sufficient to elicit higher tolerance to amphotericin B. Additional synergistic adaptations may be responsible for the miltefosine/amphotericin B cross-resistance described earlier.
      PubDate: Sat, 18 Nov 2017 00:00:00 GMT
  • Evaluation of short exposure times of antimicrobial wound solutions
           against microbial biofilms: from in vitro to in vivo
    • Authors: Johani K; Malone M, Jensen S, et al.
      Abstract: ObjectivesTest the performance of topical antimicrobial wound solutions against microbial biofilms using in vitro, ex vivo and in vivo model systems at clinically relevant exposure times.MethodsTopical antimicrobial wound solutions were tested under three different conditions: (in vitro) 4% w/v Melaleuca oil, polyhexamethylene biguanide, chlorhexidine, povidone iodine and hypochlorous acid were tested at short duration exposure times for 15 min against 3 day mature biofilms of Staphylococcus aureus and Pseudomonas aeruginosa; (ex vivo) hypochlorous acid was tested in a porcine skin explant model with 12 cycles of 10 min exposure, over 24 h, against 3 day mature P. aeruginosa biofilms; and (in vivo) 4% w/v Melaleuca oil was applied for 15 min exposure, daily, for 7 days, in 10 patients with chronic non-healing diabetic foot ulcers complicated by biofilm.ResultsIn vitro assessment demonstrated variable efficacy in reducing biofilms ranging from 0.5 log10 reductions to full eradication. Repeated instillation of hypochlorous acid in a porcine model achieved <1 log10 reduction (0.77 log10, P = 0.1). Application of 4% w/v Melaleuca oil in vivo resulted in no change to the total microbial load of diabetic foot ulcers complicated by biofilm (median log10 microbial load pre-treatment = 4.9 log10 versus 4.8 log10, P = 0.43).ConclusionsShort durations of exposure to topical antimicrobial wound solutions commonly utilized by clinicians are ineffective against microbial biofilms, particularly when used in vivo. Wound solutions should not be used as a sole therapy and clinicians should consider multifaceted strategies that include sharp debridement as the gold standard.
      PubDate: Sat, 18 Nov 2017 00:00:00 GMT
  • A systematic review of interventions and performance measures for
           antifungal stewardship programmes
    • Authors: Bienvenu A; Argaud L, Aubrun F, et al.
      Abstract: ObjectivesAntifungal resistance is a significant and emerging threat. Stewardship programmes (SPs) have been proposed as an opportunity to optimize antifungal use. While examples of antifungal SP implementation have been recently described, there is yet to be an overview of interventions and their impacts on performance measures.MethodsWe systematically reviewed published articles using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses check-list 2009. MEDLINE was searched using the term ‘antifungal stewardship’ on 15 February 2017. Eligible studies were those that described an antifungal SP and included an intervention and an evaluation of performance measures.ResultsA total of 97 studies were identified and 14 were included. Only five studies reported an antifungal stewardship team composed of all the recommended members. The main intervention was the formulation of recommendations to change treatment (12 of 14). The main performance measure collected was antifungal consumption (10 of 14), followed by antifungal expenditure (7 of 14), adherence to therapeutic advice (4 of 14) and impact on mortality (4 of 14). Antifungal consumption was reduced by 11.8% to 71% and antifungal expenditure by as much as 50%. Adherence to therapeutic advice ranged from 40% to 88%, whereas antifungal SPs had no impact on mortality.ConclusionsAll antifungal SPs had an impact, in particular on antifungal consumption and antifungal expenditure. Active intervention including a review of prescriptions seems to have more impact than implementation of treatment guidelines only. According to available published studies, antifungal consumption appears to be the most achievable performance measure to evaluate the impact of an antifungal SP.
      PubDate: Thu, 16 Nov 2017 00:00:00 GMT
  • Association between prior antibiotic therapy and subsequent risk of
           community-acquired infections: a systematic review
    • Authors: Malik U; Armstrong D, Ashworth M, et al.
      Abstract: BackgroundAntibiotic use can have negative unintended consequences including disruption of the human microbiota, which is thought to protect against pathogen overgrowth. We conducted a systematic review to assess whether there is an association between exposure to antibiotics and subsequent risk of community-acquired infections.MethodsWe searched MEDLINE, EMBASE and Web of Science for studies published before 30 June 2017, examining the association between antibiotic use and subsequent community-acquired infection. Infections caused by Clostridium difficile and fungal organisms were excluded. Studies focusing exclusively on resistant organism infections were also excluded.ResultsEighteen of 22588 retrieved studies met the inclusion criteria. From these, 16 studies reported a statistically significant association between antibiotic exposure and subsequent risk of community-acquired infection. Infections associated with prior antibiotic use included Campylobacter jejuni infection (one study), recurrent furunculosis (one study), invasive Haemophilus influenzae type b infection (one study), infectious mastitis (one study), meningitis (one study), invasive pneumococcal disease (one study), Staphylococcus aureus skin infection (one study), typhoid fever (two studies), recurrent boils and abscesses (one study), upper respiratory tract infection and urinary tract infection (one study) and Salmonella infection (five studies), although in three studies on Salmonella infection the effect was of marginal statistical significance.ConclusionsWe found an association between prior antibiotic use and subsequent risk of a diverse range of community-acquired infections. Gastrointestinal and skin and soft tissue infections were most frequently found to be associated with prior antibiotic exposure. Our findings support the hypothesis that antibiotic use may predispose to future infection risk, including infections caused by both antibiotic-resistant and non-resistant organisms.
      PubDate: Tue, 14 Nov 2017 00:00:00 GMT
  • Distribution of putative virulence markers in Enterococcus faecium:
           towards a safety profile review
    • Authors: Freitas A; Tedim A, Novais C, et al.
      Abstract: ObjectivesThe criteria for identification of Enterococcus faecium (Efm) with the ability to cause human infections are currently being debated by the European Food Safety Authority (EFSA). Strains that have an MIC of ampicillin of ≤ 2 mg/L and lack IS16/esp/hyl genes should be regarded as safe for use as feed additives in animal nutrition, despite the lack of knowledge about putative virulence marker (PVM) distribution in community Efm. We analysed the distribution of major PVM and ampicillin phenotypes in large Efm collections to investigate further the safety of strains from a public health perspective.MethodsThirty-three PVM were assessed by PCR/sequencing among clonally disparate Efm (n = 328; 1986–2015) from different origins. We analysed ampicillin susceptibility (Etest/broth microdilution) according to EUCAST guidelines, clonal relationship (MLST) and genomic location of PVM (S1-PFGE/hybridization).ResultsInfection-derived Efm were more enriched in PVM and the increase in ampicillin MIC was positively correlated with an enrichment in different PVM. PVM coding for surface (esp/sgrA/ecbA/complete acm) and pili proteins, or others enhancing colonization (hyl/ptsD/orf1481) or plasticity (IS16), were strongly associated with clinical Efm (mostly clade A1), but also observed in clades A2/B at different rates. ptsD was a good marker of ampicillin-resistant Efm. ptsD, IS16, orf1481, sgrA and hospital variants of complete pili gene clusters are proposed as markers to assess the safety of Efm strains.ConclusionsOur study expands on the distribution of PVM in diverse Efm lineages and demonstrates the enrichment in infection-derived strains of PVM not previously included in EFSA’s list of Efm safety criteria. The evidence of relevant Efm infection markers can impact the risk assessment of Efm strains in different public health contexts.
      PubDate: Tue, 14 Nov 2017 00:00:00 GMT
  • Polymyxin derivatives NAB739 and NAB815 are more effective than polymyxin
           B in murine Escherichia coli pyelonephritis
    • Authors: Vaara M; Vaara T, Vingsbo Lundberg C.
      Abstract: ObjectivesExtremely multiresistant strains of Enterobacteriaceae, such as those of Escherichia coli and Klebsiella pneumoniae, are emerging and spreading at a worrisome speed. Polymyxins (polymyxin B, colistin) are used as last-line therapy against such strains, in spite of their notable nephrotoxicity that may even require discontinuation of the therapy. We have previously developed polymyxin derivatives NAB739 and NAB815 that are better tolerated in cynomolgus monkeys than polymyxin B and are, in contrast to polymyxin B, excreted in the cynomolgus urine to a very significant degree. Here we have compared the efficacy of these NAB compounds and polymyxin B in the therapy of murine pyelonephritis caused by E. coli.MethodsThe challenge organism was a uropathogenic E. coli clinical isolate. Mice were inoculated via urethral catheterization with 5 × 108 cfu. All treatment groups consisted of 12 animals. On day 1 and day 2 post-infection, the mice were treated subcutaneously with NAB739, NAB815, polymyxin B or vehicle twice a day and on day 3 post-infection the animals were sacrificed. cfu in the kidney and bladder tissues and in the urine were determined.ResultsNAB739 reduced the bacterial burden in the kidney, urine and bladder at doses approximately 10-fold lower than those of polymyxin B. In the kidneys, the half-maximal effective dose (ED50) was 9-fold lower for NAB739 than for polymyxin B (0.24 mg/kg versus 2.1 mg/kg, respectively). NAB815 was as effective as NAB739.ConclusionsNAB739 and NAB815 were unequivocally more effective than polymyxin B in the murine pyelonephritis model.
      PubDate: Tue, 14 Nov 2017 00:00:00 GMT
  • Activity of colistin alone or in combination with rifampicin or meropenem
           in a carbapenem-resistant bioluminescent Pseudomonas aeruginosa
           intraperitoneal murine infection model
    • Authors: Cai Y; Yang D, Wang J, et al.
      Abstract: BackgroundCarbapenem-resistant Pseudomonas aeruginosa (CRPA) infections represent a major therapeutic problem and combination therapy may be the chemotherapeutic option.MethodsBioluminescent CRPA was developed through sequential subcultures in subinhibitory concentrations of meropenem from an engineered strain of bioluminescent PA Xen5. Then CRPA was injected intraperitoneally to establish an intraperitoneal murine infection model. Treatments of colistin alone or combined with rifampicin or meropenem were started 1 h after infection. In vivo bioluminescence imaging was applied dynamically at 0 h, and 2 and 5 h after treatment. Ex vivo bacterial counts from liver, kidney, spleen, lung and blood samples were also determined 5 h after treatment.ResultsIn vivo imaging showed that both low- and high-dose colistin combined with rifampicin resulted in a significant decrease in bioluminescence signals compared with monotherapy of colistin or rifampicin alone, whereas colistin and meropenem combination therapy did not show a greater bactericidal effect compared with monotherapy. Ex vivo bacterial count results also confirmed that combination of both low- and high-dose colistin with rifampicin resulted in significantly reduced colony counts from five kinds of tissue samples. However, only combination of high-dose colistin + meropenem resulted in reduced colony counts merely in lung and blood samples.ConclusionsCompared with single drugs, colistin and rifampicin combination therapy could exert synergistic effects, which might provide a better alternative when treating CRPA infections in clinical practice. Combination of colistin and meropenem should be considered with caution because it barely shows any synergism in the present in vivo model.
      PubDate: Tue, 14 Nov 2017 00:00:00 GMT
  • Pharmacokinetics/pharmacodynamics of systemically administered polymyxin B
           against Klebsiella pneumoniae in mouse thigh and lung infection models
    • Authors: Landersdorfer C; Wang J, Wirth V, et al.
      Abstract: BackgroundThe pharmacokinetic/pharmacodynamic (PK/PD) relationship for polymyxin B against Klebsiella pneumoniae infections is not known.MethodsDose-fractionation studies with subcutaneous polymyxin B were conducted in neutropenic mice in which infection with three strains of K. pneumoniae had been produced in thighs or lungs. Dosing (thigh infection 0.5–120 mg/kg/day; lung infection 5–120 mg/kg/day) commenced 2 h after inoculation, and bacterial burden was measured 24 h later. Plasma exposure measures for unbound polymyxin B were from population pharmacokinetic analysis of single doses and plasma protein binding by ultracentrifugation. The inhibitory sigmoid dose–effect model was employed to determine the relationship between exposure and efficacy. Antibacterial activities of polymyxin B and colistin against thigh infection were compared at equimolar doses generating exposures resulting in maximal antibacterial activity.ResultsThe pharmacokinetics of polymyxin B were well described by a model comprising parallel linear and saturable pathways for absorption and elimination. Plasma binding of polymyxin B was constant (P > 0.05) over the range ∼0.9–37 mg/L; average (±SD) percentage bound was 91.4 ± 1.65. In thigh infection, antibacterial effect was well correlated with fAUC/MIC (R2 = 0.89). Target values of fAUC/MIC for stasis and 1 log10 kill were 1.22–13.5 and 3.72–28.0, respectively; 2 log10 kill was not achieved for any strain, even at the highest tolerated dose. There was no difference (P > 0.05) in antibacterial activity between polymyxin B and colistin with equimolar doses. It was not possible to achieve stasis in lung infection, even at the highest dose tolerated by mice.ConclusionsThe results will assist in the design of optimized dosage regimens of polymyxin B.
      PubDate: Tue, 14 Nov 2017 00:00:00 GMT
  • Antibiotic susceptibility of clinical Legionella pneumophila serogroup 1
           strains isolated in Germany
    • Authors: Koshkolda T; Lück C.
      Abstract: Sir,
      PubDate: Thu, 09 Nov 2017 00:00:00 GMT
  • Emergence of multiple carbapenemase-producing organisms in single
           patients: an increasing threat to treatment of infection
    • Authors: An J; Lai K, Ma Y, et al.
      Abstract: Sir,
      PubDate: Thu, 09 Nov 2017 00:00:00 GMT
  • Mutations in MetG (methionyl-tRNA synthetase) and TrmD [tRNA
           (guanine-N1)-methyltransferase] conferring meropenem tolerance in
           Burkholderia thailandensis
    • Authors: Yi H; Lee H, Cho K, et al.
      Abstract: ObjectivesAlthough meropenem is widely used to treat Burkholderia infections, the response of Burkholderia pathogens to this antibiotic is largely unexplored.MethodsBurkholderia thailandensis, a model for Burkholderia spp., particularly Burkholderia mallei and Burkholderia pseudomallei, was challenged with a lethal level of meropenem and survivors were isolated. The genomes of two of the isolates were analysed to identify mutated genes and these genes were then specifically examined in more isolates to profile mutation diversity. Mutants were characterized to investigate the biological basis underlying survival against meropenem.ResultsOne of two genes associated with tRNA metabolism [metG or trmD, encoding methionyl-tRNA synthetase or tRNA (guanine-N1)-methyltransferase, respectively] was found to be mutated in the two survivors. A single nucleotide substitution and a frameshift mutation were found in metG and trmD, respectively. Five different substitution mutations affecting methionine- or tRNA-binding sites were found in metG during further screening. The mutants exhibited slowed growth and increased tolerance not only to meropenem but also various other antibiotics. This tolerance required intact RelA, a key stringent response.ConclusionsSpecific mutations affecting the tRNA pool, particularly those in metG, play a pivotal role in the B. thailandensis response to meropenem challenge. This mechanism of antibiotic tolerance is important because it can reduce the effectiveness of meropenem and thereby facilitate chronic infection by Burkholderia pathogens. In addition, specific mutations found in MetG will prove useful in the effort to develop new drugs to completely inhibit this essential enzyme, while preventing stringent-response-mediated antibiotic tolerance in pathogens.
      PubDate: Thu, 09 Nov 2017 00:00:00 GMT
  • Increase in antimicrobial resistance and emergence of major international
           high-risk clonal lineages in dogs and cats with urinary tract infection:
           16 year retrospective study
    • Authors: Marques C; Belas A, Franco A, et al.
      Abstract: ObjectivesTo evaluate temporal trends in antimicrobial resistance, over 16 years, in bacteria isolated from dogs and cats with urinary tract infection (UTI) and the clonal lineages of bacteria harbouring critical antimicrobial resistance mechanisms.MethodsAntimicrobial susceptibility testing was conducted for 948 bacteria isolated from dogs and cats with UTI (1999–2014). Resistance mechanisms were detected by PCR, namely ESBL/AmpC in third-generation cephalosporin (3GC)-resistant Escherichia coli and Proteus mirabilis, mecA in methicillin-resistant staphylococci, and aac(6′)-Ieaph(2″)-Ia and aph(2″)-1d in high-level gentamicin-resistant (HLGR) enterococci. Resistant bacteria were typed by MLST, and temporal trends in E. coli and Enterobacteriaceae antimicrobial resistance were determined by logistic regression.ResultsEnterobacteriaceae had a significant temporal increase in resistance to amoxicillin/clavulanate, 3GCs, trimethoprim/sulfamethoxazole, fluoroquinolones, gentamicin and tetracycline (P < 0.001). An increase in MDR was also detected (P < 0.0001). 3GC resistance was mainly caused by the presence of blaCTX-M-15 and blaCMY-2 in E. coli and the presence of blaCMY-2 in P. mirabilis. Two major 3GC-resistant E. coli clonal lineages were detected: O25b:H4-B2-ST131 and ST648. The mecA gene was detected in 9.2% (n = 11/119) of Staphylococcus spp., including MRSA clonal complex (CC) 5 (n = 2) and methicillin-resistant Staphylococcus epidermidis CC5 (n = 4). A temporal increase in MDR methicillin-resistant Staphylococcus pseudintermedius was detected (P = 0.0069). Some ampicillin-resistant and/or HLGR Enterococcus spp. were found to belong to hospital-adapted CCs, namely Enterococcus faecalis ST6-CC6 (n = 1) and Enterococcus faecium CC17 (n = 8).ConclusionsThe temporal increase in antimicrobial resistance and in MDR bacteria causing UTI in dogs and cats creates important therapeutic limitations in veterinary medicine. Furthermore, the detection of MDR high-risk clonal lineages raises public health concerns since companion animals with UTI may contribute to the spread of such bacteria.
      PubDate: Thu, 09 Nov 2017 00:00:00 GMT
  • A model-informed preclinical approach for prediction of clinical
           pharmacodynamic interactions of anti-TB drug combinations
    • Authors: Clewe O; Wicha S, de Vogel C, et al.
      Abstract: BackgroundIdentification of pharmacodynamic interactions is not reasonable to carry out in a clinical setting for many reasons. The aim of this work was to develop a model-informed preclinical approach for prediction of clinical pharmacodynamic drug interactions in order to inform early anti-TB drug development.MethodsIn vitro time–kill experiments were performed with Mycobacterium tuberculosis using rifampicin, isoniazid or ethambutol alone as well as in different combinations at clinically relevant concentrations. The multistate TB pharmacometric (MTP) model was used to characterize the natural growth and exposure–response relationships of each drug after mono exposure. Pharmacodynamic interactions during combination exposure were characterized by linking the MTP model to the general pharmacodynamic interaction (GPDI) model with successful separation of the potential effect on each drug’s potency (EC50) by the combining drug(s).ResultsAll combinations showed pharmacodynamic interactions at cfu level, where all combinations, except isoniazid plus ethambutol, showed more effect (synergy) than any of the drugs alone. Using preclinical information, the MTP-GPDI modelling approach was shown to correctly predict clinically observed pharmacodynamic interactions, as deviations from expected additivity.ConclusionsWith the ability to predict clinical pharmacodynamic interactions, using preclinical information, the MTP-GPDI model approach outlined in this study constitutes groundwork for model-informed input to the development of new and enhancement of existing anti-TB combination regimens.
      PubDate: Thu, 09 Nov 2017 00:00:00 GMT
  • Highly variable absorption of clavulanic acid during the day: a population
           pharmacokinetic analysis
    • Authors: De Velde F; De Winter B, Koch B, et al.
      Abstract: ObjectivesTo calculate the clavulanic acid exposure of oral amoxicillin/clavulanic acid dosing regimens, to investigate variability using a population pharmacokinetic model and to explore target attainment using Monte Carlo simulations.MethodsTwo groups of healthy male volunteers received amoxicillin/clavulanic acid tablets at the start of a standard meal on two separate days 1 week apart. One group (n = 14) received 875/125 mg q12h and 500/125 mg q8h and the other group (n = 15) received 500/125 mg q12h and 250/125 mg q8h. In total, 1479 blood samples were collected until 8–12 h after administration. Concentrations were analysed using non-compartmental (WinNonLin) and population pharmacokinetic (NONMEM) methods.ResultsMedian Cmax and AUC0–8 were 2.21 mg/L (0.21–4.35) and 4.99 mg·h/L (0.44–8.31), respectively. In 40/58 daily concentration–time profiles, Cmax and AUC0–8 of the morning dose were higher than with later doses. The final population model included a lag time (0.447 h), first-order absorption (3.99 h−1 at 8:00 h, between-subject variability 52.8%, between-occasion variability 48.5%), one distribution compartment (33.0 L, between-subject variability 23.9%) and first-order elimination (24.6 L/h, between-subject variability 26.7%). Bioavailability (fixed at 1 at 8:00 h, between-occasion variability 28.2%) and absorption rate decreased over the day. For 97.5% of the simulated population after 125 mg q12h or q8h, %fT > Ct at 0.5 mg/L was 8.33% (q12h) and 15.2% (q8h), %fT > Ct at 1 mg/L was 0% (q12h + q8h), and fAUC0–24 was 3.61 (q12h) and 5.56 (q8h)  mg·h/L.ConclusionsClavulanic acid absorption in healthy volunteers is highly variable. Bioavailability and absorption rate decrease over the day. The model developed here may serve to suggest clavulanic acid dosing regimens to optimize efficacy and prevent underdosing.
      PubDate: Thu, 09 Nov 2017 00:00:00 GMT
  • Identification and genomic characterization of a KPC-2-, NDM-1- and
           NDM-5-producing Klebsiella michiganensis isolate
    • Authors: Zheng B; Xu H, Yu X, et al.
      Abstract: Sir,
      PubDate: Wed, 08 Nov 2017 00:00:00 GMT
  • Evaluation of the KPC K-SeT® immunochromatographic assay for the rapid
           detection of KPC carbapenemase producers from positive blood cultures
    • Authors: Riccobono E; Antonelli A, Pecile P, et al.
      Abstract: Sir,
      PubDate: Wed, 08 Nov 2017 00:00:00 GMT
  • Active antimicrobial efflux in Staphylococcus epidermidis: building up of
           resistance to fluoroquinolones and biocides in a major opportunistic
    • Authors: Costa S; Viveiros M, Pomba C, et al.
      Abstract: ObjectivesTo analyse the efflux-mediated response of Staphylococcus epidermidis to ethidium bromide (EtBr), a substrate of multidrug efflux pumps (EPs).MethodsThe susceptible reference strain S. epidermidis ATCC 12228 was exposed to a step-wise adaptation to EtBr. The resulting EtBr-adapted strains were characterized regarding their antibiotic and biocide susceptibility by MIC determination and evaluation of efflux activity by re-determination of MICs in the presence of known efflux inhibitors and real-time fluorometry. Mutations in the QRDR of grlA and gyrA were screened by sequencing. The expression levels of S. epidermidis homologues of the main Staphylococcus aureus EP genes were quantified by RT–qPCR.ResultsExposure to EtBr led to a gradual increase in resistance to antimicrobials, with the final EtBr-adapted strain, ATCC 12228_EtBr, displaying phenotypic resistance to fluoroquinolones and reduced susceptibility to several antiseptics and disinfectants, although no mutations were detected in the QRDR of the grlA/gyrA genes. A reduction in the MICs of fluoroquinolones and selected biocides promoted by efflux inhibitors suggested an efflux-mediated response to EtBr exposure. Detailed analysis of the EtBr-adapted strains detected a gradual increase in efflux activity. Gene expression assays revealed a temporal activation of S. epidermidis EPs, with an early response involving norA, SE2010 and SE1103 followed by a late response mediated by norA, which coincided with the occurrence of the mutation −1A→T in the norA promoter region.ConclusionsThis study demonstrated that S. epidermidis has the potential to develop a multiple resistance phenotype mediated by efflux when exposed to a non-antibiotic substrate of multidrug EPs.
      PubDate: Wed, 08 Nov 2017 00:00:00 GMT
  • CNS penetration of ART in HIV-infected children
    • Authors: Van den Hof M; Blokhuis C, Cohen S, et al.
      Abstract: BackgroundPaediatric data on CNS penetration of antiretroviral drugs are scarce.ObjectivesTo evaluate CNS penetration of antiretroviral drugs in HIV-infected children and explore associations with neurocognitive function.Patients and methodsAntiretroviral drug levels were measured in paired CSF and blood samples of clinically stable HIV-infected children between 8 and 18 years old on long-term combined ART. Plasma drug concentrations were corrected for protein binding. We evaluated CNS penetration using CSF/plasma ratios and compared CSF concentrations with the IC50 as a surrogate marker for effectiveness. Blood–brain barrier permeability was assessed for possible confounding. Associations with neurocognitive function were explored using linear regression analysis.ResultsMedian CSF/plasma ratios (IQR) were: lopinavir 0.059 (0.024–0.157, n = 7), efavirenz 0.681 (0.555–0.819, n = 12), tenofovir 0.021 (0.020–0.024, n = 4), lamivudine 0.464 (0.331–0.607, n = 17), emtricitabine 0.365 (0.343–0.435, n = 3), nevirapine 1.203 (n = 1), zidovudine 0.718 (0.711–1.227, n = 5) and abacavir 1.344 (0.670–2.450, n = 10). CSF concentrations were below the IC50 for tenofovir (100%), emtricitabine (100%), abacavir (50%) and zidovudine (17%). Lamivudine, lopinavir, efavirenz and nevirapine concentrations were all above the IC50. All participants were virologically suppressed in blood and CSF. CSF drug concentrations were not associated with blood–brain barrier permeability or neurocognitive function.ConclusionsWe showed adequate CSF concentrations of lamivudine, lopinavir, efavirenz and nevirapine, and potential suboptimal CSF concentrations of tenofovir, abacavir and emtricitabine in long-term treated HIV-infected children. None the less, the use of combined antiretroviral drugs led to adequate viral suppression.
      PubDate: Wed, 08 Nov 2017 00:00:00 GMT
  • A CPAnet consensus statement on research priorities for chronic pulmonary
           aspergillosis: a neglected fungal infection that requires attention
    • Authors: Godet C; Alastruey-Izquierdo A, Flick H, et al.
      Abstract: Chronic pulmonary aspergillosis (CPA) is a severe fungal infection with a high morbidity and mortality, and is usually seen in immunocompetent patients with respiratory disorders. Clinical presentation is nonspecific and often overlaps with the symptoms and the radiological pattern caused by the underlying disease. Clinical management of CPA is further hampered by limited information about the epidemiology, disease dynamics, sensitivity and specificity of different mycological tests, mechanisms of antifungal resistance, efficient treatment and management strategies. In order to contribute to a better understanding and to improve CPA patient management and outcome, we established the Chronic Pulmonary Aspergillosis Network (CPAnet), a self-organized multinational research collaboration. Key research priorities, defined by using a modified Delphi process, include the establishment of a multinational web-based registry, the validation of different diagnostic tests, the establishment of a culture collection from samples of patients with proven CPA and the establishment of a consensus on a treatment outcome definition.
      PubDate: Mon, 06 Nov 2017 00:00:00 GMT
  • Increased expression of Qnr is sufficient to confer clinical resistance to
           ciprofloxacin in Escherichia coli
    • Authors: Garoff L; Yadav K, Hughes D.
      Abstract: BackgroundCiprofloxacin, a fluoroquinolone, targets two essential bacterial enzymes, DNA gyrase and topoisomerase IV. Plasmid-borne qnr genes, encoding proteins that protect DNA gyrase and topoisomerase IV from inhibition by fluoroquinolones, contribute to resistance development. However, the presence of a plasmid-borne qnr gene alone is insufficient to confer clinical resistance.ObjectivesWe asked whether the level of expression of qnr was a limiting factor in its ability to confer clinical resistance and whether expression could be increased without reducing fitness or viability.MethodsqnrB and qnrS were recombineered onto the chromosome of Escherichia coli under the control of constitutive promoters of various strengths. Expression was measured by qPCR, MIC and relative fitness as a function of expression level were determined.ResultsFor both qnr genes there was a positive relationship between the level of qnr mRNA and the MIC of ciprofloxacin. The highest MICs achieved with qnrB or qnrS as the sole resistance determinant were 0.375 and 1 mg/L, respectively, and were reached at expression levels that did not affect growth rate or viability. The qnrS-mediated MIC is above the EUCAST clinical breakpoint for resistance to ciprofloxacin. In the absence of Lon protease activity, overexpression of qnr genes was associated with high fitness cost, possibly explaining observations of toxicity in other genetic backgrounds.ConclusionsThe ability to generate a high MIC without incurring a fitness cost shows that, in an appropriate genetic context, qnrS has the potential to generate clinical resistance to ciprofloxacin in one step.
      PubDate: Thu, 02 Nov 2017 00:00:00 GMT
  • Origin of the plasmid-mediated fosfomycin resistance gene fosA3
    • Authors: Ito R; Pacey M, Mettus R, et al.
      Abstract: BackgroundfosA3 is the most commonly reported plasmid-mediated fosfomycin resistance gene among Enterobacteriaceae.ObjectivesTo identify the origin of fosA3.MethodsThe chromosome of Kluyvera georgiana clinical strain YDC799 was fully sequenced with single-molecule real-time sequencing. Comparative genetic analysis was performed for K. georgiana YDC799, K. georgiana type strain ATCC 51603 and representative fosA3-carrying plasmids. fosA genes were cloned in Escherichia coli to confirm function.ResultsK. georgiana YDC799 harboured fosA (designated fosAKG) and blaCTX-M-8 on the chromosome. The genetic environments surrounding fosA3 and bounded by IS26 were nearly identical with the corresponding regions of K. georgiana YDC799 and ATCC 51603. The amino acid sequence of FosAKG from YDC799 and K. georgiana ATCC 51603 shared 99% and 94% identity with FosA3, respectively. Cloned FosAKG conferred fosfomycin resistance with an MIC of >1024 mg/L for E. coli.ConclusionsThe plasmid-mediated fosA3 gene was likely mobilized from the chromosome of K. georgiana by an IS26-mediated event.
      PubDate: Thu, 02 Nov 2017 00:00:00 GMT
  • Cytomegaloviraemia clearance with foscarnet during renal replacement
    • Authors: Wieruszewski P; Vijayvargiya P, Wilhelm M, et al.
      Abstract: Sir,
      PubDate: Tue, 31 Oct 2017 00:00:00 GMT
  • Complete nucleotide sequences of two KPC-2-encoding plasmids from the same
           Citrobacter freundii isolate
    • Authors: Zheng B; Huang C, Xu H, et al.
      Abstract: Sir,
      PubDate: Mon, 30 Oct 2017 00:00:00 GMT
  • Comment on: Role of cephalosporins in the era of Clostridium difficile
    • Authors: Nagar A.
      Abstract: Sir,
      PubDate: Mon, 30 Oct 2017 00:00:00 GMT
  • Emerging resistant clones of Mycobacterium tuberculosis in a
           spatiotemporal context
    • Authors: Vyazovaya A; Levina K, Zhuravlev V, et al.
      Abstract: ObjectivesWe assessed the genetic structure of the Mycobacterium tuberculosis population in Estonia with a special focus on major epidemic/endemic clones and drug resistance determinants. We investigated the hypothesis of the decisive impact of massive human influx on the locally circulating genotypes. Estonia received a mass immigration from Russia during 1945–90 followed by enhanced interaction with the EU since 1991.MethodsThe study sample included M. tuberculosis isolates from patients newly diagnosed with TB in 2014 in North Estonia (including the capital Tallinn). The isolates were subjected to first- and second-line drug susceptibility testing, detection of mutations in rpoB, katG, inhA, rrs, embB and gyrA and lineage/clone-specific genotyping.ResultsOf the M. tuberculosis isolates, 39.8% were assigned to the Beijing genotype; 56.8% of them were MDR. In contrast, all three major non-Beijing genotypes (LAM, Haarlem and Ural) were mainly drug susceptible. MDR was more prevalent among Beijing B0/W148-cluster isolates (81.8%) compared with other Beijing isolates (20.0%; P = 0.0007). The pre-XDR phenotype was found in eight isolates, of which six belonged to Beijing B0/W148. All rifampicin-resistant and ofloxacin-resistant and 97% of isoniazid-resistant isolates harboured resistance mutations in rpoB, gyrA and katG. The rpoB S531L, katG S315T and embB M306V mutations were the most prevalent.ConclusionsThe major pool of the Beijing isolates was brought to Estonia before 1990. However, an active circulation of the most hazardous MDR-associated Beijing B0/W148-cluster started only in the last 20 years and its significantly increased circulation presents the major threat to TB control in Estonia. The overwhelming prevalence of the rpoB531 and katG315 mutations in the MDR-associated Beijing isolates requires attention.
      PubDate: Mon, 30 Oct 2017 00:00:00 GMT
  • Expanding the potential of NAI-107 for treating serious ESKAPE pathogens:
           synergistic combinations against Gram-negatives and bactericidal activity
           against non-dividing cells
    • Authors: Brunati C; Thomsen T, Gaspari E, et al.
      Abstract: ObjectivesTo characterize NAI-107 and related lantibiotics for their in vitro activity against Gram-negative pathogens, alone or in combination with polymyxin, and against non-dividing cells or biofilms of Staphylococcus aureus. NAI-107 was also evaluated for its propensity to select or induce self-resistance in Gram-positive bacteria.MethodsWe used MIC determinations and chequerboard experiments to establish the antibacterial activity of the examined compounds against target microorganisms. Time–kill assays were used to evaluate killing of exponential and stationary-phase cells. The effects on biofilms (growth inhibition and biofilm eradication) were evaluated using biofilm-coated pegs. The frequency of spontaneous resistant mutants was evaluated by either direct plating or by continuous sub-culturing at 0.5 × MIC levels, followed by population analysis profiles.ResultsThe results showed that NAI-107 and its brominated variant are highly active against Neisseria gonorrhoeae and some other fastidious Gram-negative pathogens. Furthermore, all compounds strongly synergized with polymyxin against Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa, and showed bactericidal activity. Surprisingly, NAI-107 alone was bactericidal against non-dividing A. baumannii cells. Against S. aureus, NAI-107 and related lantibiotics showed strong bactericidal activity against dividing and non-dividing cells. Activity was also observed against S. aureus biofilms. As expected for a lipid II binder, no significant resistance to NAI-107 was observed by direct plating or serial passages.ConclusionsOverall, the results of the current work, along with previously published results on the efficacy of NAI-107 in experimental models of infection, indicate that this lantibiotic represents a promising option in addressing the serious threat of antibiotic resistance.
      PubDate: Mon, 30 Oct 2017 00:00:00 GMT
  • Undetectable antimicrobial plasma concentrations in an HIV-positive
           patient with protein-losing enteropathy and chylothorax during
           Mycobacterium genavense and Leishmania abdominal infections
    • Authors: Motta I; Trunfio M, Calcagno A, et al.
      Abstract: Sir,
      PubDate: Wed, 25 Oct 2017 00:00:00 GMT
  • Chlamydia trachomatis antimicrobial susceptibility in colorectal and
           endocervical cells
    • Authors: Foschi C; Salvo M, Cevenini R, et al.
      Abstract: BackgroundRectal Chlamydia trachomatis infections represent one of the most common sexually transmitted infections in the MSM population. Although current treatment guidelines suggest the use of either azithromycin or doxycycline, several clinical studies reported on azithromycin treatment failures in the case of rectal C. trachomatis localizations. In this context, the biological reasons behind the lack of azithromycin efficacy for C. trachomatis infections at the rectal level are still poorly understood.ObjectivesTo evaluate the in vitro antimicrobial susceptibility of several C. trachomatis strains in two different cell lines, mimicking the urogenital localization and the rectal site of infection.MethodsThe susceptibility to macrolides (i.e. azithromycin and erythromycin), doxycycline and levofloxacin was assessed for 20 C. trachomatis strains, belonging to the most frequently reported genovars (D, E, F and G), both in human endocervical cells (HeLa cells) and in colorectal cells (Caco-2 cells). Moreover, a correlation between MIC values and C. trachomatis bacterial load was investigated in both cell lines.ResultsFor all the C. trachomatis strains, regardless of the genovar, macrolides showed higher MIC and MBC values (2-fold dilutions) in Caco-2 cells compared with HeLa cells, whereas for doxycycline and levofloxacin, no significant differences were found between the two cell lines. Moreover, azithromycin MICs were significantly higher with increasing levels of C. trachomatis elementary bodies on Caco-2 cells.ConclusionsThe higher azithromycin MICs observed in colorectal cells, together with the positive correlation between MICs and C. trachomatis loads found, could explain azithromycin treatment failure for C. trachomatis infections at the rectal site.
      PubDate: Wed, 25 Oct 2017 00:00:00 GMT
  • Impact of requiring re-authorization of restricted antibiotics on day 3 of
    • Authors: Eljaaly K; Elarabi S, Alshehri S, et al.
      Abstract: BackgroundPre-authorization of restricted antibiotics is a core component of an antibiotic stewardship programme (ASP). On day 3, information about culture results and clinical status is typically available. Our objective was to compare an ASP that requires initial authorization alone with one requiring initial authorization and re-authorization on day 3 of therapy.MethodsA single-centre, retrospective, before and after study was conducted. Randomly selected adults were eligible if receiving a restricted antibiotic for ≥3 days during April to June in 2012 (pre-intervention) and during the same months in 2013 (post-intervention). The target sample size was 166 patients. The intervention required re-authorization of restricted antibiotics that were continuing on day 3. The days of therapy of restricted antibiotic(s), length of hospital stay (LOS) and hospital mortality were compared between pre- and post-intervention periods.ResultsThe ASP intervention was associated with a decrease in median days of therapy from 5 (4–9) to 4 (3–5) days (P < 0.001) for all restricted agents, from 5 (3–6) to 3 (3–5) days for broad-spectrum Gram-negative agents (P < 0.001) and from 6.5 (6–7) to 3 (3–4.5) days for oral vancomycin. The proportion of subjects receiving restricted agents for >4 days decreased from 57.8% to 30.1% (P < 0.001). LOS decreased from 8 (5–17) to 6 (5–9) days (P = 0.005) without a significant change in hospital mortality.ConclusionsRequiring re-authorization of restricted antibiotics on day 3 of therapy in addition to initial authorization was associated with reduction in overall consumption of restricted antibiotics and LOS without adversely affecting hospital mortality.
      PubDate: Wed, 25 Oct 2017 00:00:00 GMT
  • Metronidazole: an update on metabolism, structure–cytotoxicity and
           resistance mechanisms
    • Authors: Dingsdag S; Hunter N.
      Abstract: Metronidazole, a nitroimidazole, remains a front-line choice for treatment of infections related to inflammatory disorders of the gastrointestinal tract including colitis linked to Clostridium difficile. Despite >60 years of research, the metabolism of metronidazole and associated cytotoxicity is not definitively characterized. Nitroimidazoles are prodrugs that are reductively activated (the nitro group is reduced) under low oxygen tension, leading to imidazole fragmentation and cytotoxicity. It remains unclear if nitroimidazole reduction (activation) contributes to the cytotoxicity profile, or whether subsequent fragmentation of the imidazole ring and formed metabolites alone mediate cytotoxicity. A molecular mechanism underpinning high level (>256 mg/L) bacterial resistance to metronidazole also remains elusive. Considering the widespread use of metronidazole and other nitroimidazoles, this review was undertaken to emphasize the structure–cytotoxicity profile of the numerous metabolites of metronidazole in human and murine models and to examine conflicting reports regarding metabolite–DNA interactions. An alternative hypothesis, that DNA synthesis and repair of existing DNA is indirectly inhibited by metronidazole is proposed. Prokaryotic metabolism of metronidazole is detailed to discuss new resistance mechanisms. Additionally, the review contextualizes the history and current use of metronidazole, rates of metronidazole resistance including metronidazole MDR as well as the biosynthesis of azomycin, the natural precursor of metronidazole. Changes in the gastrointestinal microbiome and the host after metronidazole administration are also reviewed. Finally, novel nitroimidazoles and new antibiotic strategies are discussed.
      PubDate: Wed, 25 Oct 2017 00:00:00 GMT
  • Interim outcomes of delamanid for the treatment of MDR- and XDR-TB in
           South Korea
    • Authors: Mok J; Kang H, Hwang S, et al.
      Abstract: ObjectivesDelamanid is a new anti-TB drug, but few data exist on its use outside clinical trials. The purpose of this study was to evaluate the efficacy as well as the safety and tolerability of a delamanid-containing regimen for 24 weeks in the treatment of MDR- and XDR-TB.MethodsWe performed a retrospective cohort study among patients with MDR/XDR-TB who were treated with a delamanid-containing regimen in seven hospitals in South Korea.ResultsA total of 32 patients with MDR-TB, of which 6 (18.8%) were XDR-TB, were included and all completed 24 weeks of delamanid treatment. Of 19 patients (59.4%) who had positive culture sputum at the initiation of delamanid treatment, the proportion of culture conversion at 8 weeks was 72.2% (13 of 18) in solid medium and 50.0% (7 of 14) in liquid medium. The proportion of culture conversion at 24 weeks was 94.4% (17 of 18) in solid medium and 92.9% (13 of 14) in liquid medium. The median time to culture conversion was 33 days (range = 5–81) using solid medium and 57 days (range = 8–96) using liquid medium. Of the 32 patients, there was no serious adverse event or death. Three patients developed a transient QTcF of > 500 ms.ConclusionsThe use of delamanid combined with optimized background regimens has the potential to achieve high culture conversion rates at 24 weeks with an acceptable safety and tolerability profile in patients with MDR/XDR-TB.
      PubDate: Mon, 23 Oct 2017 00:00:00 GMT
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