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| 2. |
- Heyckendorf, Jan, et al.
(författare)
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What Is Resistance? Impact of Phenotypic versus Molecular Drug Resistance Testing on Therapy for Multi-and Extensively Drug-Resistant Tuberculosis
- 2018
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Ingår i: Antimicrobial Agents and Chemotherapy. - : AMER SOC MICROBIOLOGY. - 0066-4804 .- 1098-6596. ; 62:2
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Tidskriftsartikel (refereegranskat)abstract
- Rapid and accurate drug susceptibility testing (DST) is essential for the treatment of multi-and extensively drug-resistant tuberculosis (M/XDR-TB). We compared the utility of genotypic DST assays with phenotypic DST (pDST) using Bactec 960 MGIT or Lowenstein-Jensen to construct M/XDR-TB treatment regimens for a cohort of 25 consecutive M/XDR-TB patients and 15 possible anti-TB drugs. Genotypic DST results from Cepheid GeneXpert MTB/RIF (Xpert) and line probe assays (LPAs; Hain GenoType MTBDRplus 2.0 and MTBDRsl 2.0) and whole-genome sequencing (WGS) were translated into individual algorithmderived treatment regimens for each patient. We further analyzed if discrepancies between the various methods were due to flaws in the genotypic or phenotypic test using MIC results. Compared with pDST, the average agreement in the number of drugs prescribed in genotypic regimens ranged from just 49% (95% confidence interval [ CI], 39 to 59%) for Xpert and 63% (95% CI, 56 to 70%) for LPAs to 93% (95% CI, 88 to 98%) for WGS. Only the WGS regimens did not contain any drugs to which pDST showed resistance. Importantly, MIC testing revealed that pDST likely underestimated the true rate of resistance for key drugs (rifampin, levofloxacin, moxifloxacin, and kanamycin) because critical concentrations (CCs) were too high. WGS can be used to rule in resistance even in M/XDR strains with complex resistance patterns, but pDST for some drugs is still needed to confirm susceptibility and construct the final regimens. Some CCs for pDST need to be reexamined to avoid systematic false-susceptible results in low-level resistant isolates.
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| 3. |
- Koehler, Niklas, et al.
(författare)
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Pretomanid-resistant tuberculosis
- 2023
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Ingår i: Journal of Infection. - : W B SAUNDERS CO LTD. - 0163-4453 .- 1532-2742. ; 86:5, s. 520-524
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 4. |
- Mardor, Israel, et al.
(författare)
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Determining spontaneous fission properties by direct mass measurements with the FRS Ion Catcher
- 2020
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Ingår i: ND 2019. - : EDP Sciences. - 9782759891061
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Konferensbidrag (refereegranskat)abstract
- We present a direct method to measure fission product yield distributions (FPY) and isomeric yield ratios (IYR) for spontaneous fission (SF) fragments. These physical properties are of utmost importance to the understanding of basic nuclear physics, the astrophysical rapid neutron capture process ('r process') of nucle-osynthesis, neutron star composition, and nuclear reactor safety. With this method, fission fragments are produced by spontaneous fission from a source that is mounted in a cryogenic stopping cell (CSC), thermalized and stopped within it, and then extracted and transported to a multiple-reflection time-of-flight mass-spectrometer (MR-TOF-MS). We will implement the method at the FRS Ion Catcher (FRS-IC) at GSI (Germany), whose MR-TOF-MS relative mass accuracy (similar to 10(-7)) and resolving power (similar to 600,000 FWHM) are sufficient to separate all isobars and numerous isomers in the fission fragment realm. The system's essential element independence and its fast simultaneous mass measurement provide a new direct way to measure isotopic FPY distributions, which is complementary to existing methods. It will enable nuclide FPY measurements in the high fission peak, which is hardly accessible by current techniques. The extraction time of the CSC, tens of milliseconds, enables a direct measurement of independent fission yields, and a first study of the temporal dependence of FPY distributions in this duration range. The ability to resolve isomers will further enable direct extraction of numerous IYRs while performing the FPY measurements. The method has been recently demonstrated at the FRS-ICr for SF with a 37 kBq Cf-252 fission source, where about 70 different fission fragments have been identified and counted. In the near future, it will be used for systematic studies of SF with a higher-activity Cf-252 source and a Cm-248 source. The method can be implemented also for neutron induced fission at appropriate facilities.
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| 5. |
- Merker, Matthias, et al.
(författare)
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Phylogenetically informative mutations in genes implicated in antibiotic resistance in Mycobacterium tuberculosis complex
- 2020
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Ingår i: Genome Medicine. - : BMC. - 1756-994X. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background A comprehensive understanding of the pre-existing genetic variation in genes associated with antibiotic resistance in the Mycobacterium tuberculosis complex (MTBC) is needed to accurately interpret whole-genome sequencing data for genotypic drug susceptibility testing (DST). Methods We investigated mutations in 92 genes implicated in resistance to 21 anti-tuberculosis drugs using the genomes of 405 phylogenetically diverse MTBC strains. The role of phylogenetically informative mutations was assessed by routine phenotypic DST data for the first-line drugs isoniazid, rifampicin, ethambutol, and pyrazinamide from a separate collection of over 7000 clinical strains. Selected mutations/strains were further investigated by minimum inhibitory concentration (MIC) testing. Results Out of 547 phylogenetically informative mutations identified, 138 were classified as not correlating with resistance to first-line drugs. MIC testing did not reveal a discernible impact of a Rv1979c deletion shared by M. africanum lineage 5 strains on resistance to clofazimine. Finally, we found molecular evidence that some MTBC subgroups may be hyper-susceptible to bedaquiline and clofazimine by different loss-of-function mutations affecting a drug efflux pump subunit (MmpL5). Conclusions Our findings underline that the genetic diversity in MTBC has to be studied more systematically to inform the design of clinical trials and to define sound epidemiologic cut-off values (ECOFFs) for new and repurposed anti-tuberculosis drugs. In that regard, our comprehensive variant catalogue provides a solid basis for the interpretation of mutations in genotypic as well as in phenotypic DST assays.
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