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1. Tuberculosis in Ukrainian War Refugees and Migrants in the Czech Republic and Slovakia: A Molecular Epidemiological Study.

Author

Dohál M, Dvořáková V, Šperková M, Pinková M, Ghodousi A, Omrani M, Porvazník I, Rasmussen EM, Škereňová M, Krivošová M, Wallenfels J, Konstantynovska O, Walker TM, Nikolayevskyy V, Cirillo DM, Solovič I, and Mokrý J

Subjects
Humans, Slovakia epidemiology, Ukraine epidemiology, Prospective Studies, Czech Republic epidemiology, Male, Female, Adult, Middle Aged, Young Adult, Adolescent, Incidence, Tuberculosis, Multidrug-Resistant epidemiology, Armed Conflicts, Refugees statistics & numerical data, Tuberculosis epidemiology, Tuberculosis transmission, Mycobacterium tuberculosis genetics, Mycobacterium tuberculosis isolation & purification, Transients and Migrants statistics & numerical data, Molecular Epidemiology
Abstract

Background: The war in Ukraine has led to significant migration to neighboring countries, raising public health concerns. Notable tuberculosis (TB) incidence rates in Ukraine emphasize the immediate requirement to prioritize approaches that interrupt the spread and prevent new infections., Methods: We conducted a prospective genomic surveillance study to assess migration's impact on TB epidemiology in the Czech Republic and Slovakia. Mycobacterium tuberculosis isolates from Ukrainian war refugees and migrants, collected from September 2021 to December 2022 were analyzed alongside 1574 isolates obtained from Ukraine, the Czech Republic, and Slovakia., Results: Our study revealed alarming results, with historically the highest number of Ukrainian tuberculosis patients detected in the host countries. The increasing number of cases of multidrug-resistant TB, significantly linked with Beijing lineage 2.2.1 (p < 0.0001), also presents substantial obstacles to control endeavors. The genomic analysis identified the three highly related genomic clusters, indicating the recent TB transmission among migrant populations. The largest clusters comprised war refugees diagnosed in the Czech Republic, TB patients from various regions of Ukraine, and incarcerated individuals diagnosed with pulmonary TB specialized facility in the Kharkiv region, Ukraine, pointing to a national transmission sequence that has persisted for over 14 years., Conclusions: The data showed that most infections were likely the result of reactivation of latent disease or exposure to TB before migration rather than recent transmission occurring within the host country. However, close monitoring, appropriate treatment, careful surveillance, and social support are crucial in mitigating future risks, though there is currently no evidence of local transmission in EU countries., (© 2023. The Author(s).)

Published
2024
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3. A smooth tubercle bacillus from Ethiopia phylogenetically close to the Mycobacterium tuberculosis complex.

Author

Yenew B, Ghodousi A, Diriba G, Tesfaye E, Cabibbe AM, Amare M, Moga S, Alemu A, Dagne B, Sinshaw W, Mollalign H, Meaza A, Tadesse M, Gamtesa DF, Abebaw Y, Seid G, Zerihun B, Getu M, Chiacchiaretta M, Gaudin C, Marceau M, Didelot X, Tolera G, Abdella S, Kebede A, Getahun M, Mehammed Z, Supply P, and Cirillo DM

Subjects
Animals, Humans, Phylogeny, Ethiopia, Africa, Eastern, Mycobacterium tuberculosis, Tuberculosis microbiology
Abstract

The Mycobacterium tuberculosis complex (MTBC) includes several human- and animal-adapted pathogens. It is thought to have originated in East Africa from a recombinogenic Mycobacterium canettii-like ancestral pool. Here, we describe the discovery of a clinical tuberculosis strain isolated in Ethiopia that shares archetypal phenotypic and genomic features of M. canettii strains, but represents a phylogenetic branch much closer to the MTBC clade than to the M. canettii strains. Analysis of genomic traces of horizontal gene transfer in this isolate and previously identified M. canettii strains indicates a persistent albeit decreased recombinogenic lifestyle near the emergence of the MTBC. Our findings support that the MTBC emergence from its putative free-living M. canettii-like progenitor is evolutionarily very recent, and suggest the existence of a continuum of further extant derivatives from ancestral stages, close to the root of the MTBC, along the Great Rift Valley., (© 2023. The Author(s).)

Published
2023
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4. 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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5. Countrywide implementation of whole genome sequencing: an opportunity to improve tuberculosis management, surveillance and contact tracing in low incidence countries.

Author

Cabibbe AM, Trovato A, De Filippo MR, Ghodousi A, Rindi L, Garzelli C, Baretti S, Allodi G, Mannino R, Rossolini GM, Bartoloni A, Tortoli E, and Cirillo DM

Subjects
Early Diagnosis, Humans, Incidence, Italy epidemiology, Mycobacterium tuberculosis isolation & purification, Tuberculosis diagnosis, Tuberculosis transmission, Contact Tracing, Mycobacterium tuberculosis genetics, Tuberculosis epidemiology, Whole Genome Sequencing
Abstract

Competing Interests: Conflict of interest: None declared.

Published
2018
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6. 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, Philip W, Wright, Carla, Spiers, Helen, Zhu, Tingting, Baeten, Elisabeth ML, Hoosdally, Sarah W, Cruz, Ana L Gibertoni, Roohi, Aysha, Kouchaki, Samaneh, Walker, Timothy M, Peto, Timothy EA, Miller, Grant, Lintott, Chris, Clifton, David, Crook, Derrick W, Walker, A Sarah, Barilar, Ivan, Battaglia, Simone, Borroni, Emanuele, Brandao, Angela Pires, Brankin, Alice, Cabibbe, Andrea Maurizio, Carter, Joshua, Cirillo, Daniela Maria, Claxton, Pauline, Clifton, David A, Cohen, Ted, Coronel, Jorge, Earle, Sarah G, Escuyer, Vincent, Ferrazoli, Lucilaine, Gao, George F, Gardy, Jennifer, Gharbia, Saheer, Ghisi, Kelen Teixeira, Ghodousi, Arash, Cruz, Ana Luıza Gibertoni, Grazian, Clara, Guthrie, Jennifer L, He, Wencong, Hoffmann, Harald, Hoosdally, Sarah J, Hunt, Martin, Iqbal, Zamin, Ismail, Nazir Ahmed, Jarrett, Lisa, Joseph, Lavania, Jou, Ruwen, Kambli, Priti, Knaggs, Jeff, Koch, Anastasia, Kohlerschmidt, Donna, Lachapelle, Alexander S, Lalvani, Ajit, Lapierre, Simon Grandjean, Laurenson, Ian F, Letcher, Brice, Lin, Wan-Hsuan, Liu, Chunfa, Liu, Dongxin, Malone, Kerri M, Mandal, Ayan, Matias, Daniela, Meintjes, Graeme, Mendes, Flavia Freitas, Merker, Matthias, Mihalic, Marina, Millard, James, Miotto, Paolo, Mistry, Nerges, Moore, David, Dreyer, Viola, Chetty, Darren, Musser, Kimberlee A, Ngcamu, Dumisani, Nhung, Hoang Ngoc, Grandjean, Louis, Nilgiriwala, Kayzad Soli, Nimmo, Camus, Okozi, Nana, Oliveira, Rosangela Siqueira, Omar, Shaheed Vally, Paton, Nicholas, Pinhata, Juliana Maira Watanabe, Plesnik, Sara, Puyen, Zully M, Rabodoarivelo, Marie Sylvianne, Rakotosamimanana, Niaina, Rancoita, Paola MV, Rathod, Priti, Robinson, Esther, Rodger, Gillian, Rodrigues, Camilla, Rodwell, Timothy C, and Santos-Lazaro, David

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Clinical Sciences, Emerging Infectious Diseases, Infectious Diseases, Prevention, Antimicrobial Resistance, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Infection, Good Health and Well Being, Antitubercular Agents, Humans, Microbial Sensitivity Tests, Mycobacterium tuberculosis, Tuberculosis, Volunteers, Zooniverse Volunteer Community, CRyPTIC Consortium, M. tuberculosis, antibiotics, citizen science, clinical microbiology, infectious disease, microbiology, tuberculosis, Biochemistry and Cell Biology, Biological sciences, Biomedical and clinical sciences, Health sciences
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.

Published
2022

7. The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: a genotypic analysis

Author

Walker, Timothy M, Miotto, Paolo, Köser, Claudio U, Fowler, Philip W, Knaggs, Jeff, Iqbal, Zamin, Hunt, Martin, Chindelevitch, Leonid, Farhat, Maha R, Cirillo, Daniela Maria, Comas, Iñaki, Posey, James, Omar, Shaheed V, Peto, Timothy EA, Suresh, Anita, Uplekar, Swapna, Laurent, Sacha, Colman, Rebecca E, Nathanson, Carl-Michael, Zignol, Matteo, Walker, Ann Sarah, Crook, Derrick W, Ismail, Nazir, Rodwell, Timothy C, Consortium, the SeqTreat Consortium CRyPTIC, Walker, A Sarah, Steyn, Adrie JC, Lalvani, Ajit, Baulard, Alain, Christoffels, Alan, Mendoza-Ticona, Alberto, Trovato, Alberto, Skrahina, Alena, Lachapelle, Alexander S, Brankin, Alice, Piatek, Amy, Cruz, Ana Gibertoni, Koch, Anastasia, Cabibbe, Andrea Maurizio, Spitaleri, Andrea, Brandao, Angela P, Chaiprasert, Angkana, Barbova, Anna, Van Rie, Annelies, Ghodousi, Arash, Bainomugisa, Arnold, Mandal, Ayan, Roohi, Aysha, Javid, Babak, Zhu, Baoli, Letcher, Brice, Rodrigues, Camilla, Nimmo, Camus, NATHANSON, Carl-Michael, Duncan, Carla, Coulter, Christopher, Utpatel, Christian, Liu, Chunfa, Grazian, Clara, Kong, Clare, Wilson, Daniel J, Matias, Daniela, Jorgensen, Danielle, Zimenkov, Danila, Chetty, Darren, Moore, David AJ, Clifton, David A, van Soolingen, Dick, Liu, Dongxin, Kohlerschmidt, Donna, Barreira, Draurio, Ngcamu, Dumisani, Lazaro, Elias David Santos, Kelly, Ellis, Borroni, Emanuele, Roycroft, Emma, Andre, Emmanuel, Böttger, Erik C, Robinson, Esther, Menardo, Fabrizio, Mendes, Flavia F, Jamieson, Frances B, Coll, Francesc, Gao, George Fu, Kasule, George W, Rossolini, Gian Maria, Rodger, Gillian, Smith, E Grace, Meintjes, Graeme, Thwaites, Guy, Hoffmann, Harald, Albert, Heidi, Cox, Helen, Laurenson, Ian F, and Arandjelovic, Irena

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Microbiology, Clinical Sciences, Tuberculosis, Infectious Diseases, Rare Diseases, Antimicrobial Resistance, Orphan Drug, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Infection, Good Health and Well Being, Antitubercular Agents, Drug Resistance, Ethambutol, Microbial Sensitivity Tests, Mutation, Mycobacterium tuberculosis, World Health Organization, CRyPTIC Consortium, Seq&Treat Consortium, Immunology, Medical microbiology
Abstract

BackgroundMolecular diagnostics are considered the most promising route to achieving rapid, universal drug susceptibility testing for Mycobacterium tuberculosiscomplex (MTBC). We aimed to generate a WHO endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction.MethodsA candidate gene approach was used to identify mutations as associated with resistance, or consistent with susceptibility, for 13 WHO endorsed anti-tuberculosis drugs. 38,215 MTBC isolates with paired whole-genome sequencing and phenotypic drug susceptibility testing data were amassed from 45 countries. For each mutation, a contingency table of binary phenotypes and presence or absence of the mutation computed positive predictive value, and Fisher's exact tests generated odds ratios and Benjamini-Hochberg corrected p-values. Mutations were graded as Associated with Resistance if present in at least 5 isolates, if the odds ratio was >1 with a statistically significant corrected p-value, and if the lower bound of the 95% confidence interval on the positive predictive value for phenotypic resistance was >25%. A series of expert rules were applied for final confidence grading of each mutation.Findings15,667 associations were computed for 13,211 unique mutations linked to one or more drugs. 1,149/15,667 (7·3%) mutations were classified as associated with phenotypic resistance and 107/15,667 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was >80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were classified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs.InterpretationThis first WHO endorsed catalogue of molecular targets for MTBC drug susceptibility testing provides a global standard for resistance interpretation. Its existence should encourage the implementation of molecular diagnostics by National Tuberculosis Programmes.FundingUNITAID, Wellcome, MRC, BMGF.

Published
2022

9. 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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10. Evaluating the efficacy of whole genome sequencing in predicting susceptibility profiles for first-line antituberculosis drugs.

Author

Ghodousi, Arash, Omrani, Maryam, Torri, Stefania, Teymouri, Hedyeh, Russo, Giulia, Vismara, Chiara, Matteelli, Alberto, Codecasa, Luigi Ruffo, and Cirillo, Daniela Maria

Subjects
*WHOLE genome sequencing, *ANTITUBERCULAR agents, *MYCOBACTERIUM tuberculosis, *DRUG resistance, *ISONIAZID, *RIFAMPIN
Abstract

This study aimed to examine the efficacy of whole genome sequencing (WGS) in accurately predicting susceptibility profiles, potentially eliminating the need for conventional phenotypic drug susceptibility testing (pDST) for first-line antituberculosis drugs in routine tuberculosis diagnosis. Over the period of 2017 to 2020, 1114 Mycobacterium tuberculosis complex isolates were collected with drug susceptibility testing conducted using the MGIT960 system and WGS performed for predicting drug resistance profiles. In addition, we implemented a new algorithm with an updated WGS workflow, omitting pan-susceptible strains from pDST. Results showed that out of 1075 analysed isolates, WGS-based genotypic sensitivity predictions for isoniazid, rifampicin, ethambutol, and pyrazinamide were 100% (95% CI, 99.6–100%), 100% (95% CI, 99.62–100%), 99.8% (95% CI, 99.26–99.94%), and 100% (95% CI, 99.63–100%), respectively. In contrast, the WGS-based genotypic resistance prediction, was 98.85% (95% CI, 93.77–99.79%) for isoniazid, 94.74% (95% CI, 82.71–98.54%) for rifampicin, 86.96% (95% CI, 67.87–95.46%) for ethambutol, and 75.7% (95% CI, 59.9–86.63%) for pyrazinamide. Moreover, WGS enabled the implementation of a new testing algorithm that made it unnecessary to perform pDST in 954 of all 1075 samples (88.7%) and in 890 of 901 pan-susceptible samples (98.8%). Integrating WGS into tuberculosis management offers significant potential to replace phenotypic drug susceptibility testing, especially for problematic drugs like pyrazinamide and ethambutol, potentially improving treatment outcomes. [ABSTRACT FROM AUTHOR]

Published
2025
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11. 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

12. Ancient and recent differences in the intrinsic susceptibility of Mycobacterium tuberculosis complex to pretomanid

Author

Anna Bateson, Julio Ortiz Canseco, Timothy D. McHugh, Adam A. Witney, Silke Feuerriegel, Matthias Merker, Thomas A. Kohl, Christian Utpatel, Stefan Niemann, Sönke Andres, Katharina Kranzer, Florian P Maurer, Arash Ghodousi, Emanuele Borroni, Daniela Maria Cirillo, Maria Wijkander, Juan C. Toro, Ramona Groenheit, Jim Werngren, Diana Machado, Miguel Viveiros, Robin M. Warren, Frederick Sirgel, Anzaan Dippenaar, Claudio U. Köser, Eugene Sun, Juliano Timm, Instituto de Higiene e Medicina Tropical (IHMT), Global Health and Tropical Medicine (GHTM), and TB, HIV and opportunistic diseases and pathogens (THOP)

Subjects
Pharmacology, Microbiology (medical), Pharmacology. Therapy, Antitubercular Agents, Microbial Sensitivity Tests, Mycobacterium tuberculosis, Infectious Diseases, SDG 3 - Good Health and Well-being, Nitroimidazoles, Humans, Tuberculosis, Pharmacology (medical), Human medicine, Biology
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.

Published
2021

13. The Anti-Mycobacterial Activity Of Ag, ZnO, And Ag- ZnO Nanoparticles Against MDR- And XDR-Mycobacterium tuberculosis

Author

Seyed Mohammad Amini, Mostafa Ghalami Nobar, Davood Darban-Sarokhalil, Arash Ghodousi, Mohsen Heidary, Alireza Jafari, Morteza Kamalzadeh, and Saeed Zaker Bostanabad

Subjects
0301 basic medicine, Pharmacology, food.ingredient, Tuberculosis, biology, Serial dilution, Chemistry, 030106 microbiology, Broth microdilution, technology, industry, and agriculture, Nanoparticle, biology.organism_classification, medicine.disease, Mycobacterium tuberculosis, 03 medical and health sciences, 0302 clinical medicine, Infectious Diseases, food, Anti mycobacterial, medicine, Agar, Pharmacology (medical), 030212 general & internal medicine, Cell culture assays, Nuclear chemistry
Abstract

Background Nowadays, tuberculosis (TB) is one of the top ten leading causes of mortality worldwide. The emergence of multidrug-resistant (MDR) - and extensively drug-resistant (XDR) - Mycobacterium tuberculosis (M. tuberculosis) is identified as one of the most challenging threats to TB control. Thus, new and safe nano-drugs are urgently required for the elimination of TB. The aim of this study was to investigate the anti-bacterial effects of Ag, ZnO, and Ag-ZnO nanoparticles (NPs) on MDR- and XDR-M. tuberculosis. Materials and methods In this study, Ag, ZnO, and Ag-ZnO NPs were synthesized by the chemical reduction and chemical deposition methods. NPs were characterized using ultraviolet-visible spectroscopy, dynamic light scattering, and transmission electron microscopy. Then, various dilutions of NPs were prepared and their minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) were determined against M. tuberculosis strains using the broth microdilution and agar microdilution methods. Finally, MTT test and cell culture assay were performed. Results The effects of concentrations of 1-128 µg/mL Ag NPs, ZnO NPs, 2Ag: 8ZnO, 8Ag:2ZnO, 3Ag: 7ZnO, 7Ag:3ZnO, and 5Ag:5ZnO on M. tuberculosis strains were investigated. MIC results showed the inhibitory effect of 1 µg/mL of all NPs against XDR-M. tuberculosis. In addition, the concentrations of 4 µg/mL Ag, 8 µg/mL 5Ag:5ZnO, 8 µg/mL 7Ag:3ZnO, 32 µg/mL 3Ag:7ZnO, 16 µg/mL 8Ag:2ZnO, and 64 µg/mL 2Ag:8ZnO inhibited MDR-M. tuberculosis growth. However, MBC results indicated the inability of Ag, ZnO and Ag-ZnO NPs, either in combination or alone, to kill MDR- or XDR-M. tuberculosis. Conclusion To the best of our knowledge, this is the first study to evaluate the effects of Ag and ZnO NPs against MDR and XDR strains of M. tuberculosis. According to the results, Ag and ZnO NPs showed bacteriostatic effects against drug-resistant strains of M. tuberculosis. Therefore, these NPs may be considered as promising anti-mycobacterial nano-drugs. However, further studies are required to affirm the bactericidal effects of these NPs against TB.

Published
2019
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14. Outbreak of pre- and extensively drug-resistant tuberculosis in northern Italy: urgency of cross-border, multidimensional, surveillance systems

Author

Elisa Tagliani, Luigi Codecasa, Daniela Maria Cirillo, Marino Faccini, Sabrina Senatore, Paola Castellotti, Arash Ghodousi, Anna Lamberti, Simone Villa, Maurizio Ferrarese, and Emanuele Borroni

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, Tuberculosis, business.industry, Download, Public health, Extensively Drug-Resistant Tuberculosis, Conflict of interest, Antitubercular Agents, Outbreak, Extensively drug-resistant tuberculosis, Mycobacterium tuberculosis, Public relations, medicine.disease, Northern italy, Disease Outbreaks, Italy, Nothing, Tuberculosis, Multidrug-Resistant, medicine, Humans, business
Abstract

Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) is one major public health threat because of reduced treatment options available and the poor patients’ outcome. New antimicrobials and regimens have been developed in recent years, but their effectiveness has been hampered by the rise and spread of drug-resistant strains. Whole genome sequencing (WGS) has emerged as a tool able to revolutionize TB surveillance and clinical management of TB. This approach is now widely used by public health agencies in detecting outbreaks and transmission chains, thus supporting the formulation of evidence-based health policies. Moreover, WGS can predict the drug-susceptibility profile of Mycobacterium tuberculosis complex (MTBC) strains, often in combination with phenotypic antimicrobial susceptibility testing (AST) and minimum inhibitory concentration (MIC) determination for the optimal clinical management of drug-resistant TB [1]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Villa has nothing to disclose. Conflict of interest: Dr. Tagliani has nothing to disclose. Conflict of interest: Dr. Borroni has nothing to disclose. Conflict of interest: Dr. Castellotti has nothing to disclose. Conflict of interest: Dr. Ferrarese has nothing to disclose. Conflict of interest: Dr. Ghodousi has nothing to disclose. Conflict of interest: Dr. Lamberti has nothing to disclose. Conflict of interest: Dr. Senatore has nothing to disclose. Conflict of interest: Dr. Faccini has nothing to disclose. Conflict of interest: Dr. Cirillo has nothing to disclose. Conflict of interest: Dr. Codecasa has nothing to disclose.

Published
2021

15. Mycobacterium tuberculosis: The Organism’s Genomics and Evolution

Author

Arash Ghodousi, Enrico Tortoli, and Daniela Maria Cirillo

Subjects
Comparative genomics, education.field_of_study, Tuberculosis, biology, Population, Genomics, Computational biology, biology.organism_classification, medicine.disease, Mycobacterium tuberculosis, Slowly growing Mycobacteria, Mycobacterium tuberculosis complex, Infectious disease (medical specialty), medicine, education
Abstract

Tuberculosis is still the leading cause of human death due to an infectious disease. The causative agents of tuberculosis are a group of closely related slow growing mycobacteria known as the Mycobacterium tuberculosis complex (MTBC). Thanks to recent advances in whole-genome sequencing technologies coupled with analyses of large collections of MTBC isolates from all over the world, several new insights have been achieved, including an improved understanding of the origin of the MTBC as an obligate pathogen, its molecular evolution and population genetic characteristics both between and within hosts, as well as many aspects related to antibiotic resistance. The purpose of this chapter is to summarize these recent discoveries and discuss their relevance for better understanding of this organism, genomics, and evolution.

Published
2021
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16. Assessment of the GenoType MTBDRsl VER 2.0 compared to the phenotypic drug susceptibility testing and whole genome sequencing for the rapid detection of resistance to fluoroquinolone and second-line injectable drugs among rifampicin-resistant Mycobacterium tuberculosis isolates

Author

Jalil Kardan-Yamchi, Mohammad Mehdi Feizabadi, Daniela Maria Cirillo, Abbas Rahimi Foroushani, Gholamreza Hamzelou, Sirus Amini, and Arash Ghodousi

Subjects
Tuberculosis, Capreomycin, Genotype, Antitubercular Agents, Microbial Sensitivity Tests, Biology, Biochemistry, Microbiology, Mycobacterium tuberculosis, Drug Resistance, Multiple, Bacterial, Tuberculosis, Multidrug-Resistant, Genetics, medicine, Humans, Molecular Biology, Gene, Whole genome sequencing, Whole Genome Sequencing, Broth microdilution, Kanamycin, General Medicine, medicine.disease, biology.organism_classification, Virology, Rifampin, medicine.drug, Fluoroquinolones
Abstract

Molecular techniques have considerable advantages for rapid detection, a reduction of infectiousness, prevention of further resistance development and surveillance of drug-resistant TB. MTBDRsl VER 2.0 was used to detect resistance to second-line anti-tuberculosis drugs on 35 rifampicin-resistant M. tuberculosis (RR-MTB) isolates compared to the minimum inhibitory concentrations (MICs) and whole genome sequencing (WGS). The MTBDRsl VER 2.0 (Hain Life Science, Nehren, Germany) and WGS (San Diego, CA, USA) were performed for tracing mutations in resistant-related genes involved in resistance to fluoroquinolone (FLQ) and second-line injectable drugs. The broth microdilution method using 7H9 Middlebrook media supplemented with OADC was used to determine the MICs. The MTBDRsl VER 2.0 correctly detected 5/6 (83.3%) of FLQ-resistant strains. The MUT1 A1401G (seven strains) and MUT2 G1484T (one strain) mutations in rrs gene were detected in eight AMK/KAN/CAP-resistant strains. Four low-level KAN-resistant strains with the G-10A/C-12T (three strains) and eis C-14T (one strain) mutations in eis gene was diagnosed using MTBDRsl VER 2.0. Five errors were found in detecting resistance to kanamycin and capreomycin compared to the phenotypic drug susceptibility testing and WGS. Failling wild-type bands without improved mutant bands did not indicate a reliable resistance. WGS could efficiently resolve the discrepancies of the results. MTBDRsl showed better performance in detecting XDR strains than pre-XDR.

Published
2020

17. In vivo microevolution of Mycobacterium tuberculosis and transient emergence of atpE_Ala63Pro mutation during treatment in a pre-XDR TB patient

Author

Sabira Tahseen, Arash Ghodousi, Alamdar Hussain Rizvi, Nasim Akhtar, Abdul Ghafoor, Faisal Masood Khanzada, Daniela Maria Cirillo, and Alberto Trovato

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, Tuberculosis, business.industry, Conflict of interest, Drug resistance, medicine.disease, chemistry.chemical_compound, Regimen, chemistry, Nothing, Pretomanid, Linezolid, medicine, Bedaquiline, Intensive care medicine, business
Abstract

Bedaquiline a novel anti TB drug for the treatment of multidrug-resistant tuberculosis (MDR-TB) recommended by the World Health Organization (WHO) [1] and recently upgraded to Group A drugs as one of the three key drugs along with linezolid and fluoroquinolones to be included in all MDR-TB regimens. Based on this grouping of second line drugs, the extensively drug resistant (XDR) TB is redefined as MDR/RR-TB that is resistant to a fluoroquinolone and to either bedaquiline or linezolid or both. Moreover bedaquiline in combination with pretomanid and linezolid is a part of BPaL regimen recommended for treating adult pulmonary TB patients having pre-XDR TB or MDR-TB which is either non-responsive or -intolerant to recommended standard treatment [2]. However globally emerging resistance to bedaquiline threatens the effectiveness of novel treatment regimens for drug resistant TB. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Arash Ghodousi has nothing to disclose. Conflict of interest: Alamdar Hussain Rizvi has nothing to disclose. Conflict of interest: Faisal Masood Khanzada has nothing to disclose. Conflict of interest: Nasim Akhtar has nothing to disclose. Conflict of interest: Abdul Ghafoor has nothing to disclose. Conflict of interest: Alberto Trovato has nothing to disclose. Conflict of interest: Daniela Maria Cirillo has nothing to disclose. Conflict of interest: Sabira Tahseen has nothing to disclose.

Published
2021
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18. Isoniazid Resistance in Mycobacterium tuberculosis Is a Heterogeneous Phenotype Composed of Overlapping MIC Distributions with Different Underlying Resistance Mechanisms

Author

Claudio U. Köser, Eranga Karunaratne, Arash Ghodousi, Stefan Niemann, Daniela Maria Cirillo, Elisa Tagliani, and Jennifer Perera

Subjects
Pharmacology, Whole genome sequencing, Genetics, 0303 health sciences, Tuberculosis, 030306 microbiology, INHA, Isoniazid, Drug resistance, Biology, bacterial infections and mycoses, medicine.disease, biology.organism_classification, Phenotype, Mycobacterium tuberculosis, 03 medical and health sciences, Infectious Diseases, medicine, Pharmacology (medical), Mycobacteria growth indicator tube, 030304 developmental biology, medicine.drug
Abstract

MIC testing using the Bactec mycobacteria growth indicator tube system 960 of 70 phylogenetically diverse, isoniazid-resistant clinical strains of Mycobacterium tuberculosis revealed a complex pattern of overlapping MIC distributions. Whole-genome sequencing explained most of the levels of resistance observed. The MIC distribution of strains with only inhA promoter mutations was split by the current concentration endorsed by the Clinical and Laboratory Standards Institute to detect low-level resistance to isoniazid and is, consequently, likely not optimally set.

Published
2019
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19. Acquisition of Cross-Resistance to Bedaquiline and Clofazimine following Treatment for Tuberculosis in Pakistan

Author

Arash Ghodousi, Alamdar Hussain Rizvi, Sabira Tahseen, Emanuele Borroni, Alberto Trovato, Mehmood Qadir, Faisal Masood Khanzada, Abdul Ghafoor, Daniela Maria Cirillo, and Aurangzaib Quadir Baloch

Subjects
Microbiology (medical), medicine.medical_specialty, antibiotic resistance, Tuberculosis, Antitubercular Agents, Microbial Sensitivity Tests, Reference laboratory, Clofazimine, 03 medical and health sciences, Minimum inhibitory concentration, chemistry.chemical_compound, Acquired resistance, Antibiotic resistance, Mechanisms of Resistance, multidrug resistance, Drug Resistance, Multiple, Bacterial, Internal medicine, medicine, XDR, Humans, Pakistan, Pharmacology (medical), bedaquiline, Diarylquinolines, Cross-resistance, Retrospective Studies, 030304 developmental biology, Pharmacology, Whole genome sequencing, 0303 health sciences, Whole Genome Sequencing, 030306 microbiology, business.industry, Drug Resistance, Microbial, Mycobacterium tuberculosis, medicine.disease, Virology, Multiple drug resistance, Regimen, Infectious Diseases, tuberculosis, chemistry, whole-genome sequencing, Dry powder, Mutation, Bedaquiline, business, medicine.drug
Abstract

We report on the first six cases of acquired resistance to bedaquiline in Pakistan. Seventy sequential isolates from 30 drug-resistant-tuberculosis patients on bedaquiline-containing regimens were retrospectively tested for bedaquiline resistance by MIC testing and by the detection of mutations in relevant genes. We documented cases failing therapy that developed specific mutations in Rv0678 and had increased MICs associated with cross-resistance to clofazimine during treatment., We report on the first six cases of acquired resistance to bedaquiline in Pakistan. Seventy sequential isolates from 30 drug-resistant-tuberculosis patients on bedaquiline-containing regimens were retrospectively tested for bedaquiline resistance by MIC testing and by the detection of mutations in relevant genes. We documented cases failing therapy that developed specific mutations in Rv0678 and had increased MICs associated with cross-resistance to clofazimine during treatment. This study underlines the relevance of surveillance programs following the introduction of new drugs.

Published
2021
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20. Phenotypic and genotypic resistance of drug-resistant Mycobacterium tuberculosis isolates to first and second-line anti-TB drugs in Iran

Author

Arash Ghodousi, Sirus Amini, Jalil Kardan-Yamchi, Daniela Maria Cirillo, Hamidreza Abtahi, Masoumeh Douraghi, Hossein Kazemian, Mohammad Mehdi Feizabadi, and Gholamreza Hamzelou

Subjects
Microbiology (medical), Whole genome sequencing, Drug, Tuberculosis, medicine.drug_class, media_common.quotation_subject, Antibiotics, Drug resistance, Biology, medicine.disease, biology.organism_classification, Virology, Mycobacterium tuberculosis, Infectious Diseases, Genotype, medicine, Gene, media_common
Abstract

Aims and objectives: Treatment of patients with drug-resistant tuberculosis is time-consuming and requires expensive drugs with more toxicity. Proper and timely identification of drug-resistant genotypes and determining the minimum inhibitory concentrations (MICs) alongside with the molecular basis of resistance can minimize the risk of further resistance development. Methods: Multidrug-resistant Mycobacterium tuberculosis (MDR-MTB) strains from different provinces were identified at Tehran Regional Reference Laboratory for Tuberculosis. Drug susceptibility testing for the first and second-line anti-TB drugs were performed and compared to the whole genome sequencing (WGS) results. Results: Simultaneous resistance to antibiotics included in each of the fluoroquinolones and second-line injectable drug families was observed in most of the MDR isolates. Sequencing was able to detect resistance to anti-TB drugs with a proper sensitivity. The most prevalent lineage among the Iranian MDR strains was Beijing. Conclusions: Mutations in drug resistance-related genes were mostly in accordance with the phenotypic drug susceptibility testing results. Drug-resistant tuberculosis can be identified quickly using molecular techniques. However, genetic background of resistance for some antibiotics were remained for more investigation.

Published
2021
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21. Clofazimine: A useful antibiotic for drug-resistant tuberculosis

Author

Lanfranco Fattorini, Saeed Khoshnood, Arash Ghodousi, Reza Mirnejad, Habibollah Mirzaei, Mohsen Heidary, Arezoo Asadi, and Davood Darban-Sarokhalil

Subjects
0301 basic medicine, Drug, Tuberculosis, medicine.drug_class, media_common.quotation_subject, 030106 microbiology, Antibiotics, Respiratory chain, Antitubercular Agents, Drug resistance, Pharmacology, Clofazimine, Mycobacterium tuberculosis, 03 medical and health sciences, Tuberculosis, Multidrug-Resistant, medicine, Animals, Humans, media_common, biology, business.industry, Drug resistant tuberculosis, General Medicine, biology.organism_classification, medicine.disease, Anti-Bacterial Agents, business, medicine.drug
Abstract

Drug resistance is still the major threat to global tuberculosis (TB) control, and drug-resistant (DR) Mycobacterium tuberculosis (M. tuberculosis) strains have become the main challenge worldwide. Currently used antibiotics for treatment of DR-TB are often poorly tolerated and not sufficiently effective. Since the therapeutic options are still limited, the main strategy for treatment of DR-TB is to repurpose existing anti-mycobacterial agents. Clofazimine (CFZ) is one such drug that has recently attracted interest against DR-TB. CFZ is a hydrophobic riminophenazine that was initially synthesized as an anti-TB antibiotic. Although the mechanisms of action of CFZ are not yet entirely understood, it has been suggested that outer membrane is its primary action site, and the respiratory chain and ion transporters are the putative targets. In this review, we will discuss the anti-mycobacterial properties of CFZ, and provide new insights into the clinical use of this drug.

Published
2018

22. Countrywide implementation of whole genome sequencing: an opportunity to improve tuberculosis management, surveillance and contact tracing in low incidence countries

Author

Alberto Trovato, Gian Maria Rossolini, Maria Rosaria De Filippo, Laura Rindi, Guendalina Allodi, Carlo Garzelli, Arash Ghodousi, Daniela Maria Cirillo, Alessandro Bartoloni, Simonetta Baretti, Roberta Mannino, Enrico Tortoli, and Andrea M. Cabibbe

Subjects
0301 basic medicine, Pulmonary and Respiratory Medicine, medicine.medical_specialty, medicine.medical_treatment, MEDLINE, 03 medical and health sciences, 0302 clinical medicine, Tuberculosis diagnosis, Epidemiology, medicine, Humans, Tuberculosis, National level, Intensive care medicine, Whole genome sequencing, Whole Genome Sequencing, business.industry, Incidence (epidemiology), Incidence, Mycobacterium tuberculosis, 030104 developmental biology, Early Diagnosis, 030228 respiratory system, Italy, Tuberculosis management, Contact Tracing, business, Contact tracing
Abstract

Whole genome sequencing can be adopted at national level as routine assay for diagnosis, universal drug susceptibility testing and epidemiological investigation of TB cases in low incidence countrieshttp://ow.ly/KA7I30jr0Wo

Published
2018

23. Whole genome sequencing in Mycobacterium tuberculosis

Author

Arash Ghodousi, Daniela Maria Cirillo, Andrea Spitaleri, and Paolo Miotto

Subjects
0301 basic medicine, Drug, Whole genome sequencing, Tuberculosis, biology, business.industry, media_common.quotation_subject, 030106 microbiology, General Medicine, Computational biology, medicine.disease, biology.organism_classification, Mycobacterium tuberculosis, 03 medical and health sciences, 030104 developmental biology, Medicine, business, media_common
Abstract

Fighting the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) requires a proper and personalized use of new antitubercular drugs. To achieve this goal, the sensitivity profile to antitubercular drug should be available in a short-time and results should be highly reliable be used for patient-care.

Published
2019
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24. The Anti-Mycobacterial Activity Of Ag, ZnO, And Ag- ZnO Nanoparticles Against MDR- And XDR-Mycobacterium tuberculosis.

Author

Heidary, Mohsen, Bostanabad, Saeed Zaker, Amini, Seyed Mohammad, Jafari, Alireza, Nobar, Mostafa Ghalami, Ghodousi, Arash, Kamalzadeh, Morteza, and Darban-Sarokhalil, Davood

Subjects
SILVER sulfide, TUBERCULOSIS, MYCOBACTERIUM tuberculosis, CHEMICAL reduction, TRANSMISSION electron microscopy, ULTRAVIOLET-visible spectroscopy, LINEZOLID, PYRAZINAMIDE
Abstract

Background: Nowadays, tuberculosis (TB) is one of the top ten leading causes of mortality worldwide. The emergence of multidrug-resistant (MDR) – and extensively drug-resistant (XDR) – Mycobacterium tuberculosis (M. tuberculosis) is identified as one of the most challenging threats to TB control. Thus, new and safe nano-drugs are urgently required for the elimination of TB. The aim of this study was to investigate the anti-bacterial effects of Ag, ZnO, and Ag-ZnO nanoparticles (NPs) on MDR- and XDR-M. tuberculosis. Materials and methods: In this study, Ag, ZnO, and Ag-ZnO NPs were synthesized by the chemical reduction and chemical deposition methods. NPs were characterized using ultraviolet–visible spectroscopy, dynamic light scattering, and transmission electron microscopy. Then, various dilutions of NPs were prepared and their minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) were determined against M. tuberculosis strains using the broth microdilution and agar microdilution methods. Finally, MTT test and cell culture assay were performed. Results: The effects of concentrations of 1–128 μg/mL Ag NPs, ZnO NPs, 2Ag: 8ZnO, 8Ag:2ZnO, 3Ag: 7ZnO, 7Ag:3ZnO, and 5Ag:5ZnO on M. tuberculosis strains were investigated. MIC results showed the inhibitory effect of 1 μg/mL of all NPs against XDR-M. tuberculosis. In addition, the concentrations of 4 μg/mL Ag, 8 μg/mL 5Ag:5ZnO, 8 μg/mL 7Ag:3ZnO, 32 μg/mL 3Ag:7ZnO, 16 μg/mL 8Ag:2ZnO, and 64 μg/mL 2Ag:8ZnO inhibited MDR-M. tuberculosis growth. However, MBC results indicated the inability of Ag, ZnO and Ag-ZnO NPs, either in combination or alone, to kill MDR- or XDR-M. tuberculosis. Conclusion: To the best of our knowledge, this is the first study to evaluate the effects of Ag and ZnO NPs against MDR and XDR strains of M. tuberculosis. According to the results, Ag and ZnO NPs showed bacteriostatic effects against drug-resistant strains of M. tuberculosis. Therefore, these NPs may be considered as promising anti-mycobacterial nano-drugs. However, further studies are required to affirm the bactericidal effects of these NPs against TB. [ABSTRACT FROM AUTHOR]

Published
2019
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25. Development of a new DNA extraction protocol for PFGE typing of Mycobacterium tuberculosis complex.

Author

Ghodousi, A., Vatani, S., Darban-Sarokhalil, D., Omrani, M., Fooladi, A. A., Khosaravi, A. D., and Feizabadi, M. M.

Subjects
*MYCOBACTERIUM tuberculosis, *PULSED-field gel electrophoresis, *GEL electrophoresis, *DNA, *MYCOBACTERIUM, *TUBERCULIN, *TUBERCULOSIS
Abstract

A modified pulsed-field gel electrophoresis (PFGE) protocol was developed and applied to clinical isolates of Mycobacterium tuberculosis complex to reduce the cost of using lyticase. This protocol reduces the expense of PFGE typing of Mycobacterium tuberculosis complex as it removes the use of lyticase during the spheroplast formation from these bacteria. [ABSTRACT FROM AUTHOR]

Published
2012

26. Acquisition of Cross-Resistance to Bedaquiline and Clofazimine following Treatment for Tuberculosis in Pakistan.

Author

Ghodousi, Arash, Rizvi, Alamdar, Baloch, Aurangzaib, Ghafoor, Abdul, Khanzada, Faisal, Qadir, Mehmood, Borroni, Emanuele, Trovato, Alberto, Tahseen, Sabira, and Cirillo, Daniela

Abstract

Aims and objectives: In the present study, we report on the first seven cases of acquired bedaquiline and clofazimine resistance identified in Pakistan. The study was conducted within the framework of a retrospective surveillance project to monitor the acquisition of resistance to bedaquiline implemented by the National TB Reference Laboratory in Pakistan and TB Supranational Reference Laboratory. Methods: Seventy three sequential isolates from 31 drug-resistant-tuberculosis patients on bedaquiline-containing regimens were retrospectively tested for bedaquiline resistance by MIC testing in 7H11 medium, and for all isolates showing an increased MIC compared to the baseline isolate, further MIC testing for bedaquiline and clofazimine was conducted using the Bactec MGIT960 (BD, Franklin Lakes, NJ, USA). The H37Rv (ATCC 27294) strain was used as a susceptible control in MIC testing. Bedaquiline dry powder was supplied by Janssen-Pharmaceutica (Beerse, Belgium). WGS was carried out with the Illumina Nextera-XT DNA sample preparation kit to prepare paired-end libraries of 150-bp read length to sequence on an Illumina NextSeq platform. Data analysis and single nucleotide polymorphism (SNP) calling were performed using the MTBseq-Pipeline on low-frequency detection mode. Genes associated with resistance to bedaquiline and/or clofazimine (atpE, Rv0678, pepQ, and Rv1979c) were screened for mutations. Results: We studied 73 isolates from patients (n=31; 8 MDR, 16 pre-XDR, and 7 XDR) enrolled in bedaquiline-containing regimens. The sequential isolates tested included two strains from 22 patients, three from 7 patients, and four from 2 patients. All baseline strains included in the study were sensitive to bedaquiline. Seven patients developed an increase in bedaquiline MICs in 7H11 medium (range, 0.125 to >0.5mg·liter−1) during therapy, and six of them became resistant to bedaquiline according to the current critical concentration proposed for the drug. In all seven patients we detected genetic variants in Rv0678 that were not present at baseline isolates. Moreover in five out of seven patients the treatment was ultimately failed. Conclusions: We documented cases failing therapy that developed specific mutations in Rv0678 and had increased MICs associated with cross-resistance to clofazimine during treatment. This study underlines the relevance of surveillance programs following the introduction of new drugs. [ABSTRACT FROM AUTHOR]

Published
2021
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27. Clofazimine: A useful antibiotic for drug-resistant tuberculosis.

Author

Mirnejad, Reza, Asadi, Arezoo, Khoshnood, Saeed, Mirzaei, Habibollah, Heidary, Mohsen, Fattorini, Lanfranco, Ghodousi, Arash, and Darban-Sarokhalil, Davood

Subjects
*TUBERCULOSIS treatment, *CLOFAZIMINE, *DRUG resistance in bacteria, *BIOCHEMICAL mechanism of action, *ANTIBACTERIAL agents, *DRUG efficacy, *THERAPEUTICS
Abstract

Drug resistance is still the major threat to global tuberculosis (TB) control, and drug-resistant (DR) Mycobacterium tuberculosis ( M. tuberculosis ) strains have become the main challenge worldwide. Currently used antibiotics for treatment of DR-TB are often poorly tolerated and not sufficiently effective. Since the therapeutic options are still limited, the main strategy for treatment of DR-TB is to repurpose existing anti-mycobacterial agents. Clofazimine (CFZ) is one such drug that has recently attracted interest against DR-TB. CFZ is a hydrophobic riminophenazine that was initially synthesized as an anti-TB antibiotic. Although the mechanisms of action of CFZ are not yet entirely understood, it has been suggested that outer membrane is its primary action site, and the respiratory chain and ion transporters are the putative targets. In this review, we will discuss the anti-mycobacterial properties of CFZ, and provide new insights into the clinical use of this drug. [ABSTRACT FROM AUTHOR]

Published
2018
Full Text
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