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1. Bedaquiline and clofazimine resistance in Mycobacterium tuberculosis: an in-vitro and in-silico data analysis

Author

Sonnenkalb, L, Carter, JJ, Spitaleri, A, Iqbal, Z, Hunt, M, Malone, KM, Utpatel, C, Cirillo, DM, Rodrigues, C, Nilgiriwala, KS, Fowler, PW, Merker, M, Niemann, S, Barilar, I, Battaglia, S, Borroni, E, Brandao, AP, Brankin, A, Cabibbe, AM, Carter, J, Claxton, P, Clifton, DA, Cohen, T, Coronel, J, Crook, DW, Dreyer, V, Earle, SG, Escuyer, V, Ferrazoli, L, Fu Gao, G, Gardy, J, Gharbia, S, Ghisi, KT, Ghodousi, A, Gibertoni Cruz, AL, Grandjean, L, Grazian, C, Groenheit, R, Guthrie, JL, He, W, Hoffmann, H, Hoosdally, SJ, Ismail, NA, Jarrett, L, Joseph, L, Jou, R, Kambli, P, Khot, R, Knaggs, J, Koch, A, Kohlerschmidt, D, Kouchaki, S, Lachapelle, AS, Lalvani, A, Grandjean Lapierre, S, Laurenson, IF, Letcher, B, Lin, W-H, Liu, C, Liu, D, Mandal, A, Mansjö, M, Matias, D, Meintjes, G, De Freitas Mendes, F, Mihalic, M, Millard, J, Miotto, P, Mistry, N, Moore, D, Musser, KA, Ngcamu, D, Hoang, NN, Nimmo, C, Okozi, N, Oliveira, RS, Omar, SV, Paton, N, Peto, TEA, Watanabe Pinhata, JM, Plesnik, S, Puyen, ZM, Rabodoarivelo, MS, Rakotosamimanana, N, Rancoita, PMV, Rathod, P, Rodger, G, Rodwell, TC, Roohi, E, Santos-Lazaro, D, Shah, S, Kohl, TA, Smith, G, Solano, W, Supply, P, Surve, U, Tahseen, S, Thuong, NTT, Thwaites, G, Todt, K, Trovato, A, Van Rie, A, Vijay, S, Walker, TM, Walker, SA, Warren, R, Werngren, J, Wijkander, M, Wilkinson, RJ, Wilson, DJ, Wintringer, P, Yu, XX, Yang, Y, Zhao, Y, Yao, S-Y, Zhu, B, and Consortium, Comprehensive Resistance Prediction for Tuberculosis: an International

Subjects
Microbiology (medical), Infectious Diseases, Virology, Microbiology
Abstract

Background Bedaquiline is a core drug for the treatment of multidrug-resistant tuberculosis; however, the understanding of resistance mechanisms is poor, which is hampering rapid molecular diagnostics. Some bedaquiline-resistant mutants are also cross-resistant to clofazimine. To decipher bedaquiline and clofazimine resistance determinants, we combined experimental evolution, protein modelling, genome sequencing, and phenotypic data. Methods For this in-vitro and in-silico data analysis, we used a novel in-vitro evolutionary model using subinhibitory drug concentrations to select bedaquiline-resistant and clofazimine-resistant mutants. We determined bedaquiline and clofazimine minimum inhibitory concentrations and did Illumina and PacBio sequencing to characterise selected mutants and establish a mutation catalogue. This catalogue also includes phenotypic and genotypic data of a global collection of more than 14 000 clinical Mycobacterium tuberculosis complex isolates, and publicly available data. We investigated variants implicated in bedaquiline resistance by protein modelling and dynamic simulations. Findings We discerned 265 genomic variants implicated in bedaquiline resistance, with 250 (94%) variants affecting the transcriptional repressor (Rv0678) of the MmpS5–MmpL5 efflux system. We identified 40 new variants in vitro, and a new bedaquiline resistance mechanism caused by a large-scale genomic rearrangement. Additionally, we identified in vitro 15 (7%) of 208 mutations found in clinical bedaquiline-resistant isolates. From our in-vitro work, we detected 14 (16%) of 88 mutations so far identified as being associated with clofazimine resistance and also seen in clinically resistant strains, and catalogued 35 new mutations. Structural modelling of Rv0678 showed four major mechanisms of bedaquiline resistance: impaired DNA binding, reduction in protein stability, disruption of protein dimerisation, and alteration in affinity for its fatty acid ligand. Interpretation Our findings advance the understanding of drug resistance mechanisms in M tuberculosis complex strains. We have established an extended mutation catalogue, comprising variants implicated in resistance and susceptibility to bedaquiline and clofazimine. Our data emphasise that genotypic testing can delineate clinical isolates with borderline phenotypes, which is essential for the design of effective treatments. Funding Leibniz ScienceCampus Evolutionary Medicine of the Lung, Deutsche Forschungsgemeinschaft, Research Training Group 2501 TransEvo, Rhodes Trust, Stanford University Medical Scientist Training Program, National Institute for Health and Care Research Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Bill & Melinda Gates Foundation, Wellcome Trust, and Marie Skłodowska-Curie Actions.

Published
2023
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2. A crowd of BashTheBug volunteers reproducibly and accurately measure the minimum inhibitory concentrations of 13 antitubercular drugs from photographs of 96-well broth microdilution plates

Author

Fowler, P.W., Wright, C., Spiers, H., Zhu, T., Baeten, E.M.L., Hoosdally, S.W., Cruz, A.L.G., Roohi, A., Kouchaki, S., Walker, T.M., Peto, T.E.A., Miller, G., Lintott, C., Clifton, D., Crook, D.W., Walker, A.S., Barilar, I., Battaglia, S., Borroni, E., Brandao, A.P., Brankin, A., Cabibbe, A.M., Carter, J., Chetty, D., Cirillo, D.M., Claxton, P., Clifton, D.A., Cohen, T., Coronel, Jorge, Dreyer, V., Earle, S.G., Escuyer, V., Ferrazoli, L., Gao, G.F., Gardy, J., Gharbia, S., Ghisi, K.T., Ghodousi, A., Grandjean, Louis, Grazian, C., Groenheit, R., Guthrie, J.L., He, W., Hoffmann, H., Hoosdally, S.J., Martinhunt, M., Iqbal, Z., Ismail, N.A., Jarrett, L., Joseph, L., Jou, R., Kambli, P., Khot, R., Knaggs, J., Koch, A., Kohlerschmidt, D., Lachapelle, A.S., Lalvani, A., Lapierre, S.G., Laurenson, I.F., Letcher, B., Lin, W.-H., Liu, C., Liu, D., Malone, K.M., Mandal, A., Mansjõ, M., Matias, D., Meintjes, G., Mendes, F.D.F., Merker, M., Mihalic, M., Millard, J., Miotto, P., Mistry, N., Moore, David Alexander James, Musser, K.A., Ngcamu, D., Nhung, H.N., Niemann, S., Nilgiriwala, K.S., Nimmo, C., O’Donnell, M., Okozi, N., Oliveira, R.S., Omar, S.V., Paton, N., Pinhata, J.M.W., Plesnik, S., Puyen, Z.M., Rabodoarivelo, M.S., Rakotosamimanana, N., Rancoita, P.M.V., Rathod, P., Robinson, E., Rodger, G., Rodrigues, C., Rodwell, T.C., Santos-Lazaro, D., Shah, S., Kohl, T.A., Smith, G., Solano, Walter, Spitaleri, A., Supply, P., Steyn, A.J.C., Surve, U., Tahseen, S., Thuong, N.T.T., Thwaites, G., Todt, K., Trovato, A., Utpatel, C., Van Rie, A., Vijay, S., Warren, R., Werngren, J., Wijkander, M., Wilkinson, R.J., Wilson, D.J., Wintringer, P., Xiao, Y.-X., Yang, Y., Yanlin, Z., Yao, S.-Y., Zhu, B., The Zooniverse Volunteer Community, The CRyPTIC Consortium, Community, The Zooniverse Volunteer, Consortium, The CRyPTIC, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), and Wellcome Trust

Subjects
Volunteers, Model organisms, infectious disease, [SDV]Life Sciences [q-bio], Immunology, Antitubercular Agents, Infectious Disease, Microbial Sensitivity Tests, Zooniverse Volunteer Community, 0601 Biochemistry and Cell Biology, antibiotics, General Biochemistry, Genetics and Molecular Biology, Imaging, minimum inhibitory concentrations, antitubercular drugs, citizen science, M. tuberculosis, Humans, clinical microbiology, Human Biology & Physiology, General Immunology and Microbiology, CRyPTIC Consortium, Prevention, General Neuroscience, FOS: Clinical medicine, microbiology, BashTheBug, Mycobacterium tuberculosis, General Medicine, microdilution plates, Emerging Infectious Diseases, Infectious Diseases, Good Health and Well Being, tuberculosis, 5.1 Pharmaceuticals, photographs, Antimicrobial Resistance, Biochemistry and Cell Biology, Development of treatments and therapeutic interventions, Infection
Abstract

Tuberculosis is a respiratory disease that is treatable with antibiotics. An increasing prevalence of resistance means that to ensure a good treatment outcome it is desirable to test the susceptibility of each infection to different antibiotics. Conventionally, this is done by culturing a clinical sample and then exposing aliquots to a panel of antibiotics, each being present at a pre-determined concentration, thereby determining if the sample isresistant or susceptible to each sample. The minimum inhibitory concentration (MIC) of a drug is the lowestconcentration that inhibits growth and is a more useful quantity but requires each sample to be tested at a range ofconcentrations for each drug. Using 96-well broth micro dilution plates with each well containing a lyophilised pre-determined amount of an antibiotic is a convenient and cost-effective way to measure the MICs of several drugs at once for a clinical sample. Although accurate, this is still an expensive and slow process that requires highly-skilled and experienced laboratory scientists. Here we show that, through the BashTheBug project hosted on the Zooniverse citizen science platform, a crowd of volunteers can reproducibly and accurately determine the MICs for 13 drugs and that simply taking the median or mode of 11-17 independent classifications is sufficient. There is therefore a potential role for crowds to support (but not supplant) the role of experts in antibiotic susceptibility testing.Tuberculosis is a bacterial respiratory infection that kills about 1.4 million people worldwide each year. While antibiotics can cure the condition, the bacterium responsible for this disease

Published
2022
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3. Epidemiological cut-off values for a 96-well broth microdilution plate for high-throughput research antibiotic susceptibility testing of

Author

Fowler, P.W., Barilar, I., Battaglia, S., Borroni, E., Brandao, A.P., Brankin, A., Cabibbe, A.M., Carter, J., Cirillo, D.M., Claxton, P., Clifton, D.A., Cohen, T., Coronel, Jorge, Crook, D.W., Dreyer, V., Earle, S.G., Escuyer, V., Ferrazoli, L., Gao, G.F., Gardy, J., Gharbia, S., Ghisi, K.T., Ghodousi, A., Cruz, A.L.G., Grandjean, Louis, Grazian, C., Groenheit, R., Guthrie, J.L., He, W., Hoffmann, H., Hoosdally, S.J., Hunt, M., Iqbal, Z., Ismail, N.A., Jarrett, L., Joseph, L., Jou, R., Kambli, P., Khot, R., Knaggs, J., Koch, A., Kohlerschmidt, D., Kouchaki, S., Lachapelle, A.S., Lalvani, A., Lapierre, S.G., Laurenson, I.F., Letcher, B., Lin, W.-H., Liu, C., Liu, D., Malone, K.M., Mandal, A., Mansjö, M., Matias, D., Meintjes, G., de Freitas Mendes, F., Merker, M., Mihalic, M., Millard, J., Miotto, P., Mistry, N., Moore, David Alexander James, Musser, K.A., Ngcamu, D., Nhung, H.N., Niemann, S., Nilgiriwala, K.S., Nimmo, C., Okozi, N., Oliveira, R.S., Omar, S.V., Paton, N., Peto, T.E.A., Pinhata, J.M.W., Plesnik, S., Puyen, Z.M., Rabodoarivelo, M.S., Rakotosamimanana, N., Rancoita, P.M.V., Rathod, P., Robinson, E., Rodger, G., Rodrigues, C., Rodwell, T.C., Roohi, A., Santos-Lazaro, D., Shah, S., Kohl, T.A., Smith, G., Solano, Walter, Spitaleri, A., Supply, P., Surve, U., Tahseen, S., Thuong, N.T.T., Thwaites, G., Todt, K., Trovato, A., Utpatel, C., Van Rie, A., Vijay, S., Walker, T.M., Walker, A.S., Warren, R., Werngren, J., Wijkander, M., Wilkinson, R.J., Wilson, D.J., Wintringer, P., Xiao, Y.-X., Yang, Y., Yanlin, Z., Yao, S.-Y., Zhu, B., Consoritum, CRyPTIC, Walker, AS, and CRyPTIC Consortium

Subjects
microdilution, Pulmonary and Respiratory Medicine, tuberculosis, Respiratory, M. tuberculosis, Humans, Tuberculosis, Human medicine, infections, Microbial Sensitivity Tests, Mycobacterium tuberculosis, Anti-Bacterial Agents
Abstract

Drug susceptibility testing ofM. tuberculosisis rooted in a binary susceptible/resistant paradigm. While there are considerable advantages in measuring the minimum inhibitory concentrations (MICs) of a panel of drugs for an isolate, it is necessary to measure the epidemiological cut-off values (ECOFF/ECVs) to permit comparison with qualitative data. Here we present ECOFF/ECVs for 13 anti-tuberculosis compounds, including bedaquiline and delamanid, derived from 20 637 clinical isolates collected by 14 laboratories based in 11 countries on five continents. Each isolate was incubated for 14 days on a dry 96-well broth microdilution plate and then read. Resistance to most of the drugs due to prior exposure is expected and the MIC distributions for many of the compounds are complex, and therefore aphenotypicallywild-type population could not be defined. Since a majority of samples also underwent genetic sequencing, we defined agenotypicallywild-type population and measured the MIC of the 99th percentile by direct measurement andviafitting a Gaussian using interval regression. The proposed ECOFF/ECVs were then validated by comparing with the MIC distributions of high-confidence genetic variants that confer resistance and with qualitative drug susceptibility tests obtainedviathe Mycobacterial Growth Indicator Tube (MGIT) system or Microscopic-Observation Drug Susceptibility (MODS) assay. These ECOFF/ECVs will inform and encourage the more widespread adoption of broth microdilution: this is a cheap culture-based method that tests the susceptibility of 12–14 antibiotics on a single 96-well plate and so could help personalise the treatment of tuberculosis.

Published
2021

4. Antimicrobial susceptibility testing of Mycobacterium tuberculosis complex isolates – the EUCAST broth microdilution reference method for MIC determination

Author

Schön, T. (Thomas), Werngren, J. (Jim), Machado, D. (Diana), Borroni, E. (Emanuele), Wijkander, M. (Maria), Lina, G. (Gérard), Mouton, J.W. (Johan), Matuschek, E. (Erika), Kahlmeter, G., Giske, C.G. (Christian G.), Santin, M. (Miguel), Cirillo, D.M. (Daniela Maria), Viveiros, M. (Miguel), Cambau, E. (Emmanuelle), Schön, T. (Thomas), Werngren, J. (Jim), Machado, D. (Diana), Borroni, E. (Emanuele), Wijkander, M. (Maria), Lina, G. (Gérard), Mouton, J.W. (Johan), Matuschek, E. (Erika), Kahlmeter, G., Giske, C.G. (Christian G.), Santin, M. (Miguel), Cirillo, D.M. (Daniela Maria), Viveiros, M. (Miguel), and Cambau, E. (Emmanuelle)

Abstract

Scope: Several methods are used worldwide for antibiotic susceptibility testing (AST) for the Mycobacterium tuberculosis complex (MTBC). The variability in the results obtained with these methods hampers setting epidemiological cut-off (ECOFF) values and clinical breakpoints according to EUCAST guidelines. Methods for susceptibility testing and determination of the minimal inhibitory concentrations (MICs) need to be standardized for MTBC isolates for old and new agents. Our objective was to establish a standardized reference method for MIC determination for MTBC. Methods: The EUCAST antimycobacterial susceptibility testing subcommittee (AMST) compared protocols of MIC determination with regard to medium, inoculum preparation, antituberculous agent preparation, incubation, reading of the results and interpretation. Recommendations: The EUCAST reference method of MIC determination for MTBC is the broth microdilution method in Middlebrook 7H9-10% OADC medium. The final inoculum is a 105 CFU/mL suspension, obtained from a 10−2 dilution of a 0.5 McFarland suspension prepared after vortexing bacterial colonies with glass beads before suspending them in sterile water. The culture is maintained in a U-shaped 96-well polystyrene microtitre sterile plate with a lid incubated at 36° ± 1°C. Reading is done using an inverted mirror as soon as the 1:100 diluted control (i.e. 103 CFU/mL suspension) shows visual growth. The MIC, expressed in mg/L, is the lowest concentration that inhibits visual growth. Mycobacterium tuberculosis H37Rv ATCC 27294 is used as the reference strain and its targeted MIC values are within the range 0.03–0.12 for isoniazid, 0.12–0.5 for levofloxacin and 0.25–1 mg/L for amikacin. Conclusions: The EUCAST reference method for MTBC was endorsed by EUCAST after public consultation and will from now on be used to define EUCAST ECOFFs and clinical breakpoints. This reference method is not primarily intended to be used under routine conditions and the AST methods

Published
2020
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5. Antimicrobial susceptibility testing of Mycobacterium tuberculosis complex isolates – the EUCAST broth microdilution reference method for MIC determination

Author

Schön, T, Werngren, J, Machado, D, Borroni, E, Wijkander, M, Lina, G, Mouton, Johan, Matuschek, E, Kahlmeter, G, Giske, C, Santin, M, Cirillo, DM, Viveiros, M, Cambau, E, Schön, T, Werngren, J, Machado, D, Borroni, E, Wijkander, M, Lina, G, Mouton, Johan, Matuschek, E, Kahlmeter, G, Giske, C, Santin, M, Cirillo, DM, Viveiros, M, and Cambau, E

Published
2020

6. The role of familial factors and neuroticism in the association between exposure to offensive behaviors at work and long-term sickness absence due to common mental disorders - a prospective twin study.

Author

Wijkander M, Svedberg P, Narusyte J, Alaie I, Lindfors P, Xu T, and Magnusson Hanson LL

Subjects
Humans, Male, Female, Sweden epidemiology, Adult, Prospective Studies, Middle Aged, Workplace Violence statistics & numerical data, Workplace Violence psychology, Bullying psychology, Bullying statistics & numerical data, Neuroticism, Sick Leave statistics & numerical data, Mental Disorders epidemiology
Abstract

Objectives: The aim of this study was to investigate associations between exposure to work-related violence/threats and harassment, and future sickness absence (SA) due to common mental disorders (CMDs), taking familial factors (shared genetics and early-life environment) and neuroticism into account., Methods: The study sample included 8795 twin individuals from the Swedish Twin Project of Disability Pension and Sickness Absence (STODS), including survey data from the Study of Twin Adults: Genes and Environment (STAGE). Self-reported work-related violence and/or threats as well as work-related harassment (including bullying) and national register data on SA due to CMDs were analyzed using standard logistic regression, and conditional logistic regression among complete twin pairs discordant on exposures. Individuals were followed for a maximum of 13 years. Interactions between neuroticism and exposures were assessed using both multiplicative and additive interaction analyses., Results: Exposure to work-related violence/threats was associated with higher odds of SA due to CMDs when adjusting for age, sex, marital status, children, education, type of living area, work characteristics, and symptoms of depression and burnout (OR 2.11, 95% CI 1.52-2.95). Higher odds of SA due to CMDs were also found for exposure to harassment (OR 1.52, 95% CI 1.10-2.11) and a combined indicator of exposure to violence/threats and/or harassment (OR 1.98, 95% CI 1.52-2.59), compared with the unexposed. Analyses of twins discordant on exposure, using the unexposed co-twin as reference, showed reduced ORs. These ORs were still elevated but no longer statistically significant, potentially due to a lack of statistical power. No multiplicative interaction was found between neuroticism and exposure to work-related violence/threats, or harassment. However, a statistically significant additive interaction was found between neuroticism and exposure to violence/threats, indicating higher odds of SA due to CMDs in the group scoring lower on neuroticism., Conclusions: Exposure to work-related offensive behaviors was associated with SA due to CMDs. However, the results indicated that these associations may be partly confounded by familial factors. In addition, an interaction between exposure and neuroticism was suggested. Thus, when possible, future studies investigating associations and causality between offensive behaviors at work and mental health-related outcomes, should consider familial factors and neuroticism., (© 2024. The Author(s).)

Published
2024
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7. In vitro activity of new combinations of β-lactam and β-lactamase inhibitors against the Mycobacterium tuberculosis complex.

Author

Economou Lundeberg E, Andersson V, Wijkander M, Groenheit R, Mansjö M, Werngren J, Cortes T, Barilar I, Niemann S, Merker M, Köser CU, and Davies Forsman L

Abstract

As meropenem-clavulanic acid is recommended for the treatment of drug-resistant tuberculosis, the repurposing of new carbapenem combinations may provide new treatment options, including oral alternatives. Therefore, we studied the in vitro activities of meropenem-vaborbactam, meropenem-clavulanic acid, and tebipenem-clavulanic acid. One hundred nine Mycobacterium tuberculosis complex (MTBC) clinical isolates were tested, of which 69 were pan-susceptible and the remaining pyrazinamide- or multidrug-resistant. Broth microdilution MICs were determined using the EUCAST reference method. Meropenem and tebipenem were tested individually and in combination with vaborbactam 8 mg/L and clavulanic-acid 2 and 4 mg/L, respectively. Whole-genome sequencing was performed to explore resistance mechanisms. Clavulanic acid lowered the modal tebipenem MIC approximately 16-fold (from 16 to 1 mg/L). The modal meropenem MIC was reduced twofold by vaborbactam compared with an approximately eightfold decrease by clavulanic acid. The only previously described high-confidence carbapenem resistance mutation, crfA T62A, was shared by a subgroup of lineage 4.3.4.1 isolates and did not correlate with elevated MICs. The presence of a β-lactamase inhibitor reduced the MTBC MICs of tebipenem and meropenem. The resulting MIC distribution was lowest for the orally available drugs tebipenem-clavulanic acid. Whether this in vitro activity translates to similar or greater clinical efficacy of tebipenem-clavulanic acid compared with the currently WHO-endorsed meropenem-clavulanic acid requires clinical studies. IMPORTANCE Repurposing of already approved antibiotics, such as β-lactams in combination with β-lactamase inhibitors, may provide new treatment alternatives for drug-resistant tuberculosis. Meropenem-clavulanic acid was more active in vitro compared to meropenem-vaborbactam. Notably, tebipenem-clavulanic acid showed even better activity, raising the potential of an all-oral treatment option. Clinical data are needed to investigate whether the better in vitro activity of tebipenem-clavulanic acid correlates with greater clinical efficacy compared with the currently WHO-endorsed meropenem-clavulanic acid.

Published
2023
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8. Exposure to work-related violence and/or threats of violence as a predictor of certified sickness absence due to mental disorders: a prospective cohort study of 16,339 Swedish men and women in paid work.

Author

Wijkander M, Farrants K, and Magnusson Hanson LL

Subjects
Male, Child, Humans, Female, Sweden epidemiology, Prospective Studies, Violence, Sick Leave, Exposure to Violence, Mental Disorders epidemiology
Abstract

Objectives: The aim of this prospective cohort study was to investigate if exposure to work-related violence and/or threats of violence predict certified sickness absence due to mental disorders., Methods: Information on work-related exposure to violence and/or threats of violence were derived from the biannual Swedish Longitudinal Occupational Survey of Health (SLOSH) study 2012-2016, including individuals in paid work across Sweden and from different occupations/sectors (n = 16,339). Certified sickness absence due to mental disorders were ascertained from register data from the Swedish Social Insurance Agency. Odds ratios of certified sickness absence due to mental disorders according to exposure to work-related violence were estimated using multiple logistic regression. Several potential confounding variables, such as demographic and socio-economic factors, age, sex, cohabitation, children living at home, socio-economic status, educational level, as well as other types of psychosocial work environmental factors, were adjusted for in the analyses., Results: In the total study sample, 9% reported exposure to violence and/or threats of violence and the prevalence of sickness absence due to mental disorders was 5%. Exposure to work-related violence and/or threats of violence was associated prospectively with certified sickness absence due to mental disorders (odds ratio 1.46, 95% confidence interval 1.17-1.82, p < 0.01). Analysis of possible interaction showed no difference in association when comparing women to men and different age groups., Conclusions: Exposure to work-related violence and/or threats of violence appear to increase the odds of certified sickness absence due to mental disorders. Preventive measures aiming to lower the risk of exposure is thus of great importance., (© 2022. The Author(s).)

Published
2023
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9. Ancient and recent differences in the intrinsic susceptibility of Mycobacterium tuberculosis complex to pretomanid.

Author

Bateson A, Ortiz Canseco J, McHugh TD, Witney AA, Feuerriegel S, Merker M, Kohl TA, Utpatel C, Niemann S, Andres S, Kranzer K, Maurer FP, Ghodousi A, Borroni E, Cirillo DM, Wijkander M, Toro JC, Groenheit R, Werngren J, Machado D, Viveiros M, Warren RM, Sirgel F, Dippenaar A, Köser CU, Sun E, and Timm J

Subjects
Antitubercular Agents pharmacology, Humans, Microbial Sensitivity Tests, Mycobacterium tuberculosis genetics, Nitroimidazoles, Tuberculosis microbiology
Abstract

Objectives: To develop a robust phenotypic antimicrobial susceptibility testing (AST) method with a correctly set breakpoint for pretomanid (Pa), the most recently approved anti-tuberculosis drug., Methods: The Becton Dickinson Mycobacterial Growth Indicator Tube™ (MGIT) system was used at six laboratories to determine the MICs of a phylogenetically diverse collection of 356 Mycobacterium tuberculosis complex (MTBC) strains to establish the epidemiological cut-off value for pretomanid. MICs were correlated with WGS data to study the genetic basis of differences in the susceptibility to pretomanid., Results: We observed ancient differences in the susceptibility to pretomanid among various members of MTBC. Most notably, lineage 1 of M. tuberculosis, which is estimated to account for 28% of tuberculosis cases globally, was less susceptible than lineages 2, 3, 4 and 7 of M. tuberculosis, resulting in a 99th percentile of 2 mg/L for lineage 1 compared with 0.5 mg/L for the remaining M. tuberculosis lineages. Moreover, we observed that higher MICs (≥8 mg/L), which probably confer resistance, had recently evolved independently in six different M. tuberculosis strains. Unlike the aforementioned ancient differences in susceptibility, these recent differences were likely caused by mutations in the known pretomanid resistance genes., Conclusions: In light of these findings, the provisional critical concentration of 1 mg/L for MGIT set by EMA must be re-evaluated. More broadly, these findings underline the importance of considering the global diversity of MTBC during clinical development of drugs and when defining breakpoints for AST., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Published
2022
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10. Genotypic Resistance of Pyrazinamide but Not Minimum Inhibitory Concentration Is Associated With Longer Time to Sputum Culture Conversion in Patients With Multidrug-resistant Tuberculosis.

Author

Kuhlin J, Davies Forsman L, Mansjö M, Jonsson Nordvall M, Wijkander M, Wagrell C, Jonsson J, Groenheit R, Werngren J, Schön T, and Bruchfeld J

Subjects
Amidohydrolases genetics, Antitubercular Agents pharmacology, Antitubercular Agents therapeutic use, Cohort Studies, Humans, Microbial Sensitivity Tests, Mutation, Pyrazinamide pharmacology, Pyrazinamide therapeutic use, Sputum, Mycobacterium tuberculosis genetics, Tuberculosis, Multidrug-Resistant drug therapy
Abstract

Background: Pyrazinamide (PZA) resistance in multidrug-resistant tuberculosis (MDR-TB) is common; yet, it is not clear how it affects interim and treatment outcomes. Although rarely performed, phenotypic drug susceptibility testing (pDST) is used to define PZA resistance, but genotypic DST (gDST) and minimum inhibitory concentration (MIC) could be beneficial. We aimed to assess the impact of PZA gDST and MIC on time to sputum culture conversion (SCC) and treatment outcome in patients with MDR-TB., Methods: Clinical, microbiological, and treatment data were collected in this cohort study for all patients diagnosed with MDR-TB in Sweden from 1992-2014. MIC, pDST, and whole-genome sequencing of the pncA, rpsA, and panD genes were used to define PZA resistance. A Cox regression model was used for statistical analyses., Results: Of 157 patients with MDR-TB, 56.1% (n = 88) had PZA-resistant strains and 49.7% (n = 78) were treated with PZA. In crude and adjusted analysis (hazard ratio [HR], 0.49; 95% conficence interval [CI], .29-.82; P = .007), PZA gDST resistance was associated with a 29-day longer time to SCC. A 2-fold decrease in dilutions of PZA MIC for PZA-susceptible strains showed no association with SCC in crude or adjusted analyses (HR, 0.98; 95% CI, .73-1.31; P = .89). MIC and gDST for PZA were not associated with treatment outcome., Conclusions: In patients with MDR-TB, gDST PZA resistance was associated with a longer time to SCC. Rapid PZA gDST is important to identify patients who may benefit from PZA treatment., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Published
2021
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11. Multicentre testing of the EUCAST broth microdilution reference method for MIC determination on Mycobacterium tuberculosis.

Author

Schön T, Werngren J, Machado D, Borroni E, Wijkander M, Lina G, Mouton J, Matuschek E, Kahlmeter G, Giske C, Santin M, Cirillo DM, Viveiros M, and Cambau E

Subjects
Amikacin pharmacology, Bacteriological Techniques, Humans, Isoniazid pharmacology, Levofloxacin pharmacology, Microbial Sensitivity Tests methods, Reproducibility of Results, Antitubercular Agents pharmacology, Microbial Sensitivity Tests standards, Mycobacterium tuberculosis drug effects
Abstract

Objectives: The first objective of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) subcommittee for antimycobacterial susceptibility testing (AMST), launched in 2016, was to set a reference method for determining the MICs of antituberculous agents, since many protocols are used worldwide and a consensus one is needed for the determination of microbiological breakpoints., Methods: During 2017 and 2018, MIC determination protocols were evaluated prospectively in a multicentre study within the four AMST laboratories. MIC results were obtained for isoniazid, levofloxacin and amikacin on the reference strain Mycobacterium tuberculosis H37Rv ATCC 27294. Broth microdilution (BMD) in Middlebrook 7H9 and solid medium dilution (SMD) in Middlebrook 7H10 were performed using two inoculum concentrations. MICs were interpreted with regard to visual and 99% inhibition after 7, 14 or 21 days of incubation for BMD and 21 days for SMD., Results: Following the EUCAST reference protocol, intra- and inter-assay agreements were within ±1 MIC dilution for >95% of the observations for the three drugs in both methods. MIC values, presented as MIC mode (range) for BMD and SMD respectively, were: 0.03 (0.015-0.06) mg/L and 0.12 (0.06-0.25) mg/L for isoniazid, 0.25 mg/L (0.25-0.5) and 0.5 mg/L (0.12-0.5) for levofloxacin, and 0.5 mg/L (0.5-1.0) and 0.5 mg/L (0.5-1.0) for amikacin., Conclusions: Both SMD and BMD were reproducible and eligible as a reference method for MIC determination of the Mycobacterium tuberculosis complex (MTBC). BMD was finally selected as the EUCAST reference method. From now on it will be used to set epidemiological cut-off values and clinical breakpoints of new and old antituberculous agents., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2021
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12. Antimicrobial susceptibility testing of Mycobacterium tuberculosis complex isolates - the EUCAST broth microdilution reference method for MIC determination.

Author

Schön T, Werngren J, Machado D, Borroni E, Wijkander M, Lina G, Mouton J, Matuschek E, Kahlmeter G, Giske C, Santin M, Cirillo DM, Viveiros M, and Cambau E

Subjects
Humans, Microbial Viability drug effects, Mycobacterium tuberculosis drug effects, Practice Guidelines as Topic, Reference Standards, Anti-Bacterial Agents pharmacology, Microbial Sensitivity Tests standards, Mycobacterium tuberculosis growth & development
Abstract

Scope: Several methods are used worldwide for antibiotic susceptibility testing (AST) for the Mycobacterium tuberculosis complex (MTBC). The variability in the results obtained with these methods hampers setting epidemiological cut-off (ECOFF) values and clinical breakpoints according to EUCAST guidelines. Methods for susceptibility testing and determination of the minimal inhibitory concentrations (MICs) need to be standardized for MTBC isolates for old and new agents. Our objective was to establish a standardized reference method for MIC determination for MTBC., Methods: The EUCAST antimycobacterial susceptibility testing subcommittee (AMST) compared protocols of MIC determination with regard to medium, inoculum preparation, antituberculous agent preparation, incubation, reading of the results and interpretation., Recommendations: The EUCAST reference method of MIC determination for MTBC is the broth microdilution method in Middlebrook 7H9-10% OADC medium. The final inoculum is a 10 5  CFU/mL suspension, obtained from a 10 -2 dilution of a 0.5 McFarland suspension prepared after vortexing bacterial colonies with glass beads before suspending them in sterile water. The culture is maintained in a U-shaped 96-well polystyrene microtitre sterile plate with a lid incubated at 36° ± 1°C. Reading is done using an inverted mirror as soon as the 1:100 diluted control (i.e. 10 3  CFU/mL suspension) shows visual growth. The MIC, expressed in mg/L, is the lowest concentration that inhibits visual growth. Mycobacterium tuberculosis H37Rv ATCC 27294 is used as the reference strain and its targeted MIC values are within the range 0.03-0.12 for isoniazid, 0.12-0.5 for levofloxacin and 0.25-1 mg/L for amikacin., Conclusions: The EUCAST reference method for MTBC was endorsed by EUCAST after public consultation and will from now on be used to define EUCAST ECOFFs and clinical breakpoints. This reference method is not primarily intended to be used under routine conditions and the AST methods will need to be calibrated against this reference method to be used with EUCAST breakpoints., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2020
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13. Minimum Inhibitory Concentrations of Fluoroquinolones and Pyrazinamide Susceptibility Correlate to Clinical Improvement in Multidrug-resistant Tuberculosis Patients: A Nationwide Swedish Cohort Study Over 2 Decades.

Author

Forsman LD, Jonsson J, Wagrell C, Werngren J, Mansjö M, Wijkander M, Groenheit R, Hammar U, Giske CG, Schön T, and Bruchfeld J

Subjects
Adolescent, Adult, Cohort Studies, Drug Resistance, Multiple, Bacterial, Female, Humans, Kaplan-Meier Estimate, Male, Microbial Sensitivity Tests, Middle Aged, Retrospective Studies, Sweden epidemiology, Treatment Outcome, Tuberculosis, Multidrug-Resistant microbiology, Young Adult, Antitubercular Agents pharmacology, Fluoroquinolones pharmacology, Mycobacterium tuberculosis drug effects, Pyrazinamide pharmacology, Tuberculosis, Multidrug-Resistant drug therapy
Abstract

Background: Minimum inhibitory concentration (MIC) testing, unlike routine drug susceptibility testing (DST) at a single critical concentration, quantifies drug resistance. The association of MICs and treatment outcome in multidrug-resistant (MDR)-tuberculosis patients is unclear. Therefore, we correlated MICs of first- and second-line tuberculosis drugs with time to sputum culture conversion (tSCC) and treatment outcome in MDR-tuberculosis patients., Methods: Clinical and demographic data of MDR-tuberculosis patients in Sweden, including DST results, were retrieved from medical records from 1992 to 2014. MIC determinations were performed retrospectively for the stored individual Mycobacterium tuberculosis (Mtb) isolates using broth microdilution in Middlebrook 7H9. We fitted Cox proportional hazard models correlating MICs, DST results, and clinical variables to tSCC and treatment outcome., Results: Successful treatment outcome was observed in 83.5% (132/158) of MDR-tuberculosis patients. Increasing MICs of fluoroquinolones, diabetes, and age >40 years were significantly associated with unsuccessful treatment outcome. Patients treated with pyrazinamide (PZA) had a significantly shorter tSCC compared to patients who were not (median difference, 27 days)., Conclusions: Increasing MICs of fluoroquinolones were correlated with unsuccessful treatment outcome in MDR-tuberculosis patients. Further studies, including MIC testing and clinical outcome data to define clinical Mtb breakpoints, are warranted. PZA treatment was associated with shorter tSCC, highlighting the importance of PZA DST., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Published
2019
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14. Detection of Mycobacterium tuberculosis pncA Mutations by the Nipro Genoscholar PZA-TB II Assay Compared to Conventional Sequencing.

Author

Willby MJ, Wijkander M, Havumaki J, Johnson K, Werngren J, Hoffner S, Denkinger CM, and Posey JE

Subjects
Antitubercular Agents pharmacology, Drug Resistance, Bacterial genetics, Humans, Microbial Sensitivity Tests methods, Mycobacterium tuberculosis drug effects, Promoter Regions, Genetic genetics, Pyrazinamide pharmacology, Tuberculosis, Multidrug-Resistant, Bacterial Proteins genetics, Biological Assay methods, Mutation genetics, Mycobacterium tuberculosis genetics
Abstract

Pyrazinamide (PZA) is a standard component of first-line treatment regimens for Mycobacterium tuberculosis and is included in treatment regimens for drug-resistant M. tuberculosis whenever possible. Therefore, it is imperative that susceptibility to PZA be assessed reliably prior to the initiation of therapy. Currently available growth-based PZA susceptibility tests are time-consuming, and results can be inconsistent. Molecular tests have been developed for most first-line antituberculosis drugs; however, a commercial molecular test is not yet available for rapid detection of PZA resistance. Recently, a line probe assay, the Nipro Genoscholar PZA-TB II assay, was developed for the detection of mutations within the pncA gene, including the promoter region, that are likely to lead to PZA resistance. The sensitivity and specificity of this assay were evaluated by two independent laboratories, using a combined total of 249 strains with mutations in pncA or its promoter and 21 strains with wild-type pncA Overall, the assay showed good sensitivity (93.2% [95% confidence interval, 89.3 to 95.8%]) and moderate specificity (91.2% [95% confidence interval, 77.0 to 97.0%]) for the identification of M. tuberculosis strains predicted to be resistant to PZA on the basis of the presence of mutations (excluding known PZA-susceptible mutations) in the pncA coding region or promoter. The assay shows promise for the molecular prediction of PZA resistance., (Copyright © 2017 American Society for Microbiology.)

Published
2017
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