| 1. |
- Chesov, Elena, et al.
(författare)
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Emergence of bedaquiline resistance in a high tuberculosis burden country
- 2022
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Ingår i: European Respiratory Journal. - : European Respiratory Society. - 0903-1936 .- 1399-3003. ; 59:3
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: Bedaquiline has been classified as a group A drug for the treatment of multidrug-resistant tuberculosis (MDR-TB) by the World Health Organization; however, globally emerging resistance threatens the effectivity of novel MDR-TB treatment regimens.Objectives: We analysed pre-existing and emerging bedaquiline resistance in bedaquiline-based MDR-TB therapies, and risk factors associated with treatment failure and death.Methods: In a cross-sectional cohort study, we employed patient data, whole-genome sequencing (WGS) and phenotyping of Mycobacterium tuberculosis complex (MTBC) isolates. We could retrieve baseline isolates from 30.5% (62 out of 203) of all MDR-TB patients who received bedaquiline between 2016 and 2018 in the Republic of Moldova. This includes 26 patients for whom we could also retrieve a follow-up isolate.Measurements and main results: At baseline, all MTBC isolates were susceptible to bedaquiline. Among 26 patients with available baseline and follow-up isolates, four (15.3%) patients harboured strains which acquired bedaquiline resistance under therapy, while one (3.8%) patient was re-infected with a second bedaquiline-resistant strain. Treatment failure and death were associated with cavitary disease (p=0.011), and any additional drug prescribed in the bedaquiline-containing regimen with WGS-predicted resistance at baseline (OR 1.92 per unit increase, 95% CI 1.15–3.21; p=0.012).Conclusions: MDR-TB treatments based on bedaquiline require a functional background regimen to achieve high cure rates and to prevent the evolution of bedaquiline resistance. Novel MDR-TB therapies with bedaquiline require timely and comprehensive drug resistance monitoring.
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| 2. |
- Fekete, Sandor P., et al.
(författare)
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Computing Nonsimple Polygons of Minimum Perimeter
- 2016
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Ingår i: EXPERIMENTAL ALGORITHMS, SEA 2016. - Cham : SPRINGER INT PUBLISHING AG. - 9783319388502 - 9783319388519 ; , s. 134-149
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Konferensbidrag (refereegranskat)abstract
- We provide exact and approximation methods for solving a geometric relaxation of the Traveling Salesman Problem (TSP) that occurs in curve reconstruction: for a given set of vertices in the plane, the problem Minimum Perimeter Polygon (MPP) asks for a (not necessarily simply connected) polygon with shortest possible boundary length. Even though the closely related problem of finding a minimum cycle cover is polynomially solvable by matching techniques, we prove how the topological structure of a polygon leads to NP-hardness of the MPP. On the positive side, we show how to achieve a constant-factor approximation. When trying to solve MPP instances to provable optimality by means of integer programming, an additional difficulty compared to the TSP is the fact that only a subset of subtour constraints is valid, depending not on combinatorics, but on geometry. We overcome this difficulty by establishing and exploiting additional geometric properties. This allows us to reliably solve a wide range of benchmark instances with up to 600 vertices within reasonable time on a standard machine. We also show that using a natural geometry-based sparsification yields results that are on average within 0.5% of the optimum.
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| 3. |
- Fekete, Sándor P., et al.
(författare)
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Computing Nonsimple Polygons of Minimum Perimeter
- 2017
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Ingår i: Journal of Computational Geometry. - Ottawa, Canada : Carleton University * Department of Mathematics and Statistics. - 1920-180X. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- We consider the Minimum Perimeter Polygon Problem (MP3): for a given set V of points in the plane, find a polygon P with holes that has vertex set V , such that the total boundary length is smallest possible. The MP3 can be considered a natural geometric generalization of the Traveling Salesman Problem (TSP), which asks for a simple polygon with minimum perimeter. Just like the TSP, the MP3 occurs naturally in the context of curve reconstruction. Even though the closely related problem of finding a minimum cycle cover is polynomially solvable by matching techniques, we prove how the topological structure of a polygon leads to NP-hardness of the MP3. On the positive side, we provide constant-factor approximation algorithms. In addition to algorithms with theoretical worst-case guarantess, we provide practical methods for computing provably optimal solutions for relatively large instances, based on integer programming. An additional difficulty compared to the TSP is the fact that only a subset of subtour constraints is valid, depending not on combinatorics, but on geometry. We overcome this difficulty by establishing and exploiting geometric properties. This allows us to reliably solve a wide range of benchmark instances with up to 600 vertices within reasonable time on a standard machine. We also show that restricting the set of connections between points to edges of the Delaunay triangulation yields results that are on average within 0.5% of the optimum for large classes of benchmark instances.
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| 4. |
- Froberg, Gabrielle, et al.
(författare)
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Towards clinical breakpoints for non-tuberculous mycobacteria-Determination of epidemiological cut off values for the Mycobacterium avium complex and Mycobacterium abscessus using broth microdilution
- 2023
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Ingår i: Clinical Microbiology and Infection. - : ELSEVIER SCI LTD. - 1198-743X .- 1469-0691. ; 29:6, s. 758-764
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Tidskriftsartikel (refereegranskat)abstract
- Objective: For non-tuberculous mycobacteria (NTM), minimum inhibitory concentration (MIC) distri-butions of wild-type isolates have not been systematically evaluated despite their importance for establishing antimicrobial susceptibility testing (AST) breakpoints.Methods: We gathered MIC distributions for drugs used against the Mycobacterium avium complex (MAC) and Mycobacterium abscessus (MAB) obtained by commercial broth microdilution (SLOMYCOI and RAPMYCOI) from 12 laboratories. Epidemiological cut-off values (ECOFFs) and tentative ECOFFs (TEC-OFFs) were determined by EUCAST methodology including quality control (QC) strains.Results: The clarithromycin ECOFF was 16 mg/L for M. avium (n = 1271) whereas TECOFFs were 8 mg/L for M. intracellulare (n = 415) and 1 mg/L for MAB (n = 1014) confirmed by analysing MAB subspecies without inducible macrolide resistance (n = 235). For amikacin, the ECOFFs were 64 mg/L for MAC and MAB. For moxifloxacin, the WT spanned >8 mg/L for both MAC and MAB. For linezolid, the ECOFF and TECOFF were 64 mg/L for M. avium and M. intracellulare, respectively. Current CLSI breakpoints for amikacin (16 mg/L), moxifloxacin (1 mg/L) and linezolid (8 mg/L) divided the corresponding WT dis-tributions. For QC M. avium and M. peregrinum, >= 95% of MIC values were well within recommended QC ranges.Conclusion: As a first step towards clinical breakpoints for NTM, (T)ECOFFs were defined for several antimicrobials against MAC and MAB. Broad wild-type MIC distributions indicate a need for further method refinement which is now under development within the EUCAST subcommittee for anti-mycobacterial drug susceptibility testing. In addition, we showed that several CLSI NTM breakpoints are not consistent in relation to the (T)ECOFFs. Gabrielle Froeuroberg, Clin Microbiol Infect 2023;29:758 (c) 2023 The Author(s). Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4.0/).
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| 5. |
- 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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| 6. |
- 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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| 7. |
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