Valeriu Crudu

Scopus Publications

A new method for detecting mixed Mycobacterium tuberculosis infection and reconstructing constituent strains provides insights into transmission
Benjamin Sobkowiak, Patrick Cudahy, Melanie H. Chitwood, Taane G. Clark, Caroline Colijn, Louis Grandjean, Katharine S. Walter, Valeriu Crudu, and Ted Cohen
Springer Science and Business Media LLC
Abstract Background Mixed infection with multiple strains of the same pathogen in a single host can present clinical and analytical challenges. Whole genome sequence (WGS) data can identify signals of multiple strains in samples, though the precision of previous methods can be improved. Here, we present MixInfect2, a new tool to accurately detect mixed samples from Mycobacterium tuberculosis short-read WGS data. We then evaluate three approaches for reconstructing the underlying mixed constituent strain sequences. This allows these samples to be included in downstream analysis to gain insights into the epidemiology and transmission of mixed infections. Methods We employed a Gaussian mixture model to cluster allele frequencies at mixed sites (hSNPs) in each sample to identify signals of multiple strains. Building upon our previous tool, MixInfect, we increased the accuracy of classifying in vitro mixed samples through multiple improvements to the bioinformatic pipeline. Major and minor proportion constituent strains were reconstructed using three approaches and assessed by comparing the estimated sequence to the known constituent strain sequence. Lastly, mixed infections in a real-world Mycobacterium tuberculosis population from Moldova were detected with MixInfect2 and clusters of recent transmission that included major and minor constituent strains were built. Results All 36/36 in vitro mixed and 12/12 non-mixed samples were correctly classified with MixInfect2, and major strain proportions were estimated with high accuracy (within 3% of the true strain proportion), outperforming previous tools. Reconstructed major strain sequences closely matched the true constituent sequence by taking the allele at the highest frequency at hSNPs, while the best-performing approach to reconstruct the minor proportion strain sequence was identifying the closest non-mixed isolate in the same population, though no approach was effective when the minor strain proportion was at 5%. Finally, fewer mixed infections were identified in Moldova than previous estimates (6.6% vs 17.4%) and we found multiple instances where the constituent strains of mixed samples were present in transmission clusters. Conclusions MixInfect2 accurately detects samples with evidence of mixed infection from short-read WGS data and provides an excellent estimate of the mixture proportions. While there are limitations in reconstructing the constituent strain sequences of mixed samples, we present recommendations for the best approach to include these isolates in further analyses.

Diagnostic accuracy study of STANDARD TB-Feron FIA and STANDARD TB-Feron ELISA tests for tuberculosis infection diagnosis in Eastern European setting
Valeriu Crudu, Dumitru Chesov, Alexandru Codreanu, Nadejda Turcanu, Nelly Ciobanu, Liuba Nepoliuc, and Doina Rusu
Elsevier BV

Understanding tuberculosis transmission and progression: A prospective cohort study of index cases and close contacts in Moldova
Rehan R. Syed, Donald G. Catanzaro, Naomi Hillery, Valeriu Crudu, Elena Tudor, Nelly Ciobanu, Alexandru Codreanu, Maryam Kheirandish Borujeni, Antonino Catanzaro, and Timothy C. Rodwell
Public Library of Science (PLoS)
Objectives This study aims to determine the progression rate, risk factors and timeline for the progression from exposure to active tuberculosis (TB) in a high-risk population. Using a prospective cohort in the Republic of Moldova, we investigated pulmonary TB disease progression among close contacts of patients with TB in a low-burden country with high rates of drug-resistant TB. Methods Close contacts of patients with newly diagnosed TB were recruited and monitored to evaluate for progression rates to active TB. Data collected included demographic information, medical and exposure history, and clinical samples. Follow-up clinical evaluations of close contacts were conducted at regular intervals over at least 24 months to monitor for progression to TB disease. Results The overall incidence rate of TB disease among close contacts was 3.7%. Among the close contacts, 2.3% were identified as progressor cases, developing TB disease more than 30 days after index case treatment initiation. Thirteen (1.3%) were co-prevalent cases, diagnosed within 30 days of index case treatment initiation. Identified risk factors for progression included male sex, active tobacco use, prior TB infection, and frequent, prolonged exposure to index cases. Close contacts with daily exposure of more than eight hours had a significantly higher risk of disease progression (adjusted OR: 4.28, 95% CI: 1.79–10.23). Conclusion The incidence of TB disease among close contacts was consistent with global findings, highlighting the need for enhanced diagnostic tools and targeted interventions to manage TB transmission and progression. These results underscore the importance of contact tracing and progression monitoring in low-burden, high drug-resistant TB settings. Future research should focus on developing a better understanding of factors contributing to the risk for and timeline of TB disease progression, and more precise methods, including biomarkers, to identify individuals at the highest risk for progression from TB exposure to active disease.

Correction to: The recent rapid expansion of multidrug resistant Ural lineage Mycobacterium tuberculosis in Moldova (Nature Communications, (2024), 15, 1, (2962), 10.1038/s41467-024-47282-9)
Melanie H. Chitwood, Caroline Colijn, Chongguang Yang, Valeriu Crudu, Nelly Ciobanu, Alexandru Codreanu, Jaehee Kim, Isabel Rancu, Kyu Rhee, Ted Cohen,et al.
Springer Science and Business Media LLC

The recent rapid expansion of multidrug resistant Ural lineage Mycobacterium tuberculosis in Moldova
Melanie H. Chitwood, Caroline Colijn, Chongguang Yang, Valeriu Crudu, Nelly Ciobanu, Alexandru Codreanu, Jaehee Kim, Isabel Rancu, Kyu Rhee, Ted Cohen,et al.
Springer Science and Business Media LLC
AbstractThe projected trajectory of multidrug resistant tuberculosis (MDR-TB) epidemics depends on the reproductive fitness of circulating strains of MDR M. tuberculosis (Mtb). Previous efforts to characterize the fitness of MDR Mtb have found that Mtb strains of the Beijing sublineage (Lineage 2.2.1) may be more prone to develop resistance and retain fitness in the presence of resistance-conferring mutations than other lineages. Using Mtb genome sequences from all culture-positive cases collected over two years in Moldova, we estimate the fitness of Ural (Lineage 4.2) and Beijing strains, the two lineages in which MDR is concentrated in the country. We estimate that the fitness of MDR Ural strains substantially exceeds that of other susceptible and MDR strains, and we identify several mutations specific to these MDR Ural strains. Our findings suggest that MDR Ural Mtb has been transmitting efficiently in Moldova and poses a substantial risk of spreading further in the region.

Identification of differentially recognized T cell epitopes in the spectrum of tuberculosis infection
Sudhasini Panda, Jeffrey Morgan, Catherine Cheng, Mayuko Saito, Robert H. Gilman, Nelly Ciobanu, Valeriu Crudu, Donald G. Catanzaro, Antonino Catanzaro, Timothy Rodwell,et al.
Springer Science and Business Media LLC
AbstractThere is still incomplete knowledge of which Mycobacterium tuberculosis (Mtb) antigens can trigger distinct T cell responses at different stages of infection. Here, a proteome-wide screen of 20,610 Mtb-derived peptides in 21 patients mid-treatment for active tuberculosis (ATB) reveals IFNγ-specific T cell responses against 137 unique epitopes. Of these, 16% are recognized by two or more participants and predominantly derived from cell wall and cell processes antigens. There is differential recognition of antigens, including TB vaccine candidate antigens, between ATB participants and interferon-gamma release assay (IGRA + /−) individuals. We developed an ATB-specific peptide pool (ATB116) consisting of epitopes exclusively recognized by ATB participants. This pool can distinguish patients with pulmonary ATB from IGRA + /− individuals from various geographical locations, with a sensitivity of over 60% and a specificity exceeding 80%. This proteome-wide screen of T cell reactivity identified infection stage-specific epitopes and antigens for potential use in diagnostics and measuring Mtb-specific immune responses.

Accuracy of cobas MTB and MTB-RIF/INH for Detection of Mycobacterium tuberculosis and Drug Resistance
Margaretha de Vos, Anura David, Karthickeyan Duraisamy, Darshaalini Nadarajan, Ecaterina Noroc, Adam Penn-Nicholson, Valeriu Crudu, Sidhartha Giri, Florian P. Maurer, Sanghamitra Pati,et al.
Elsevier BV

Corrigendum to—“Identifying local foci of tuberculosis transmission in Moldova using a spatial multinomial logistic regression model” [eBioMedicine 102(2024) 105085] (eBioMedicine (2024) 102, (S2352396424001208), (10.1016/j.ebiom.2024.105085))
Yu Lan, Valeriu Crudu, Nelly Ciobanu, Alexandru Codreanu, Melanie H. Chitwood, Benjamin Sobkowiak, Joshua L. Warren, and Ted Cohen
Elsevier BV

Impact and cost-effectiveness of the 6-month BPaLM regimen for rifampicin-resistant tuberculosis in Moldova: A mathematical modeling analysis
Lyndon P. James, Fayette Klaassen, Sedona Sweeney, Jennifer Furin, Molly F. Franke, Reza Yaesoubi, Dumitru Chesov, Nelly Ciobanu, Alexandru Codreanu, Valeriu Crudu,et al.
Public Library of Science (PLoS)
Background Emerging evidence suggests that shortened, simplified treatment regimens for rifampicin-resistant tuberculosis (RR-TB) can achieve comparable end-of-treatment (EOT) outcomes to longer regimens. We compared a 6-month regimen containing bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) to a standard of care strategy using a 9- or 18-month regimen depending on whether fluoroquinolone resistance (FQ-R) was detected on drug susceptibility testing (DST). Methods and findings The primary objective was to determine whether 6 months of BPaLM is a cost-effective treatment strategy for RR-TB. We used genomic and demographic data to parameterize a mathematical model estimating long-term health outcomes measured in quality-adjusted life years (QALYs) and lifetime costs in 2022 USD ($) for each treatment strategy for patients 15 years and older diagnosed with pulmonary RR-TB in Moldova, a country with a high burden of TB drug resistance. For each individual, we simulated the natural history of TB and associated treatment outcomes, as well as the process of acquiring resistance to each of 12 anti-TB drugs. Compared to the standard of care, 6 months of BPaLM was cost-effective. This strategy was estimated to reduce lifetime costs by $3,366 (95% UI: [1,465, 5,742] p < 0.001) per individual, with a nonsignificant change in QALYs (−0.06; 95% UI: [−0.49, 0.03] p = 0.790). For those stopping moxifloxacin under the BPaLM regimen, continuing with BPaL plus clofazimine (BPaLC) provided more QALYs at lower cost than continuing with BPaL alone. Strategies based on 6 months of BPaLM had at least a 93% chance of being cost-effective, so long as BPaLC was continued in the event of stopping moxifloxacin. BPaLM for 6 months also reduced the average time spent with TB resistant to amikacin, bedaquiline, clofazimine, cycloserine, moxifloxacin, and pyrazinamide, while it increased the average time spent with TB resistant to delamanid and pretomanid. Sensitivity analyses showed 6 months of BPaLM to be cost-effective across a broad range of values for the relative effectiveness of BPaLM, and the proportion of the cohort with FQ-R. Compared to the standard of care, 6 months of BPaLM would be expected to save Moldova’s national TB program budget $7.1 million (95% UI: [1.3 million, 15.4 million] p = 0.002) over the 5-year period from implementation. Our analysis did not account for all possible interactions between specific drugs with regard to treatment outcomes, resistance acquisition, or the consequences of specific types of severe adverse events, nor did we model how the intervention may affect TB transmission dynamics. Conclusions Compared to standard of care, longer regimens, the implementation of the 6-month BPaLM regimen could improve the cost-effectiveness of care for individuals diagnosed with RR-TB, particularly in settings with a high burden of drug-resistant TB. Further research may be warranted to explore the impact and cost-effectiveness of shorter RR-TB regimens across settings with varied drug-resistant TB burdens and national income levels.

Drug-Resistant Tuberculosis, Georgia, Kazakhstan, Kyrgyzstan, Moldova, and Ukraine, 2017-2022
Victor Naestholt Dahl, Tetiana Butova, Alex Rosenthal, Alina Grinev, Andrei Gabrielian, Sergo Vashakidze, Natalia Shubladze, Bekzat Toxanbayeva, Lyailya Chingissova, Valeriu Crudu,et al.
Centers for Disease Control and Prevention (CDC)
In 2021, the World Health Organization recommended new extensively drug-resistant (XDR) and pre-XDR tuberculosis (TB) definitions. In a recent cohort of TB patients in Eastern Europe, we show that XDR TB as currently defined is associated with exceptionally poor treatment outcomes, considerably worse than for the former definition (31% vs. 54% treatment success).

Identifying local foci of tuberculosis transmission in Moldova using a spatial multinomial logistic regression model
Yu Lan, Valeriu Crudu, Nelly Ciobanu, Alexandru Codreanu, Melanie H. Chitwood, Benjamin Sobkowiak, Joshua L. Warren, and Ted Cohen
Elsevier BV

Impact of Mycobacterium tuberculosis strain type on multidrug-resistant tuberculosis severity, Republic of Moldova
Elena Chesov, Dumitru Chesov, Maja Reimann, Viola Dreyer, Christian Utpatel, Matthias I. Gröschel, Nelly Ciobanu, Valeriu Crudu, Christoph Lange, Jan Heyckendorf,et al.
Elsevier BV

Predicting stringent QuantiFERON-TB Gold Plus conversions in contacts of tuberculosis patients
Sheng-Wei Pan, Donald G. Catanzaro, Marva Seifert, Rehan R. Syed, Naomi Hillery, Mei-Lin Ho, Valeriu Crudu, Elena Tudor, Nelly Ciobanu, Alexandru Codreanu,et al.
Elsevier BV

Limited Nosocomial Transmission of Drug-Resistant Tuberculosis, Moldova
Ecaterina Noroc, Dumitru Chesov, Matthias Merker, Matthias I. Gröschel, Ivan Barilar, Viola Dreyer, Nelly Ciobanu, Maja Reimann, Valeriu Crudu, and Christoph Lange
Centers for Disease Control and Prevention (CDC)
Applying whole-genome-sequencing, we aimed to detect transmission events of multidrug-resistant/rifampin-resistant strains of Mycobacterium tuberculosis complex at a tuberculosis hospital in Chisinau, Moldova. We recorded ward, room, and bed information for each patient and monitored in-hospital transfers over 1 year. Detailed molecular and patient surveillance revealed only 2 nosocomial transmission events.

Clinical Evaluation of the XDR-LFC Assay for the Molecular Detection of Isoniazid, Rifampin, Fluoroquinolone, Kanamycin, Capreomycin, and Amikacin Drug Resistance in a Prospective Cohort
Rehan R. Syed, Donald G. Catanzaro, Rebecca E. Colman, Christopher G. Cooney, Yvonne Linger, Alexander V. Kukhtin, Rebecca C. Holmberg, Ryan Norville, Valeriu Crudu, Nelly Ciobanu,et al.
American Society for Microbiology
While the goal of universal drug susceptibility testing has been a key component of the WHO End TB Strategy, in practice, this remains inaccessible to many. Rapid molecular tests for tuberculosis (TB) and antituberculosis drug resistance could significantly improve access to testing.

Economic evaluation of shortened, bedaquiline-containing treatment regimens for rifampicin-resistant tuberculosis (STREAM stage 2): a within-trial analysis of a randomised controlled trial
Laura Rosu, Jason J Madan, Ewan M Tomeny, Malaisamy Muniyandi, Jasper Nidoi, Mamo Girma, Valentina Vilc, Priyanka Bindroo, Rajdeep Dhandhukiya, Adamu K Bayissa,et al.
Elsevier BV

Transcontinental spread and evolution of Mycobacterium tuberculosis W148 European/Russian clade toward extensively drug resistant tuberculosis
Matthias Merker, Jean-Philippe Rasigade, Maxime Barbier, Helen Cox, Silke Feuerriegel, Thomas A. Kohl, Egor Shitikov, Kadri Klaos, Cyril Gaudin, Rudy Antoine,et al.
Springer Science and Business Media LLC
AbstractTransmission-driven multi-/extensively drug resistant (M/XDR) tuberculosis (TB) is the largest single contributor to human mortality due to antimicrobial resistance. A few major clades of the Mycobacterium tuberculosis complex belonging to lineage 2, responsible for high prevalence of MDR-TB in Eurasia, show outstanding transnational distributions. Here, we determined factors underlying the emergence and epidemic spread of the W148 clade by genome sequencing and Bayesian demogenetic analyses of 720 isolates from 23 countries. We dated a common ancestor around 1963 and identified two successive epidemic expansions in the late 1980s and late 1990s, coinciding with major socio-economic changes in the post-Soviet Era. These population expansions favored accumulation of resistance mutations to up to 11 anti-TB drugs, with MDR evolving toward additional resistances to fluoroquinolones and second-line injectable drugs within 20 years on average. Timescaled haplotypic density analysis revealed that widespread acquisition of compensatory mutations was associated with transmission success of XDR strains. Virtually all W148 strains harbored a hypervirulence-associated ppe38 gene locus, and incipient recurrent emergence of prpR mutation-mediated drug tolerance was detected. The outstanding genetic arsenal of this geographically widespread M/XDR strain clade represents a “perfect storm” that jeopardizes the successful introduction of new anti-M/XDR-TB antibiotic regimens.

Budget impact of next-generation sequencing for diagnosis of TB drug resistance in Moldova
L. Cates, A. Codreanu, N. Ciobanu, H. Fosburgh, C. J. Allender, H. Centner, D. M. Engelthaler, V. Crudu, T. Cohen, and N. A. Menzies
International Union Against Tuberculosis and Lung Disease
BACKGROUND Diagnosing drug resistance is critical for choosing effective TB treatment regimens. Next-generation sequencing (NGS) represents an alternative approach to conventional phenotypic drug susceptibility testing (pDST) for diagnosing TB drug resistance.METHODS We undertook a budget impact analysis estimating the costs of introduction and routine use of NGS in the Moldovan National TB Programme. We conducted an empirical costing study and collated price and operating characteristics for NGS platforms. We examined multiple NGS scenarios in comparison to the current approach (pDST) for pre-treatment drug resistance testing over 2021–2025.RESULTS Annual testing volume ranged from 912 to 1,926 patients. For the pDST scenario, we estimated total costs of US$362,000 (2021 USD) over the 5-year study period. Total costs for NGS scenarios ranged from US$475,000 to US$1,486,000. Lowest cost NGS options involved targeted sequencing as a replacement for pDST, and excluded individuals diagnosed as RIF-susceptible on Xpert® MTB/RIF. For all NGS scenarios, the majority (55–80%) of costs were devoted to reagent kits. Start-up costs of NGS were small relative to routine costs borne each year.CONCLUSION NGS adoption will require expanded resources compared to conventional pDST. Further work is required to better understand the feasibility of NGS in settings such as Moldova.

Investigating resistance in clinical Mycobacterium tuberculosis complex isolates with genomic and phenotypic antimicrobial susceptibility testing: a multicentre observational study
Iris Finci, Audrey Albertini, Matthias Merker, Sönke Andres, Nino Bablishvili, Ivan Barilar, Tatiana Cáceres, Valeriu Crudu, Eduardo Gotuzzo, Nchimunya Hapeela,et al.
Elsevier BV

Predicting resistance to fluoroquinolones among patients with rifampicin-resistant tuberculosis using machine learning methods
Shiying You, Melanie H. Chitwood, Kenneth S. Gunasekera, Valeriu Crudu, Alexandru Codreanu, Nelly Ciobanu, Jennifer Furin, Ted Cohen, Joshua L. Warren, and Reza Yaesoubi
Public Library of Science (PLoS)
Background Limited access to drug-susceptibility tests (DSTs) and delays in receiving DST results are challenges for timely and appropriate treatment of multi-drug resistant tuberculosis (TB) in many low-resource settings. We investigated whether data collected as part of routine, national TB surveillance could be used to develop predictive models to identify additional resistance to fluoroquinolones (FLQs), a critical second-line class of anti-TB agents, at the time of diagnosis with rifampin-resistant TB. Methods and findings We assessed three machine learning-based models (logistic regression, neural network, and random forest) using information from 540 patients with rifampicin-resistant TB, diagnosed using Xpert MTB/RIF and notified in the Republic of Moldova between January 2018 and December 2019. The models were trained to predict the resistance to FLQs based on demographic and TB clinical information of patients and the estimated district-level prevalence of resistance to FLQs. We compared these models based on the optimism-corrected area under the receiver operating characteristic curve (OC-AUC-ROC). The OC-AUC-ROC of all models were statistically greater than 0.5. The neural network model, which utilizes twelve features, performed best and had an estimated OC-AUC-ROC of 0.87 (0.83,0.91), which suggests reasonable discriminatory power. A limitation of our study is that our models are based only on data from the Republic of Moldova and since not externally validated, the generalizability of these models to other populations remains unknown. Conclusions Models trained on data from phenotypic surveillance of drug-resistant TB can predict resistance to FLQs based on patient characteristics at the time of diagnosis with rifampin-resistant TB using Xpert MTB/RIF, and information about the local prevalence of resistance to FLQs. These models may be useful for informing the selection of antibiotics while awaiting results of DSTs.

Integrating landmark modeling framework and machine learning algorithms for dynamic prediction of tuberculosis treatment outcomes
Maryam Kheirandish, Donald Catanzaro, Valeriu Crudu, and Shengfan Zhang
Oxford University Press (OUP)
Abstract Objective This study aims to establish an informative dynamic prediction model of treatment outcomes using follow-up records of tuberculosis (TB) patients, which can timely detect cases when the current treatment plan may not be effective. Materials and Methods We used 122 267 follow-up records from 17 958 new cases of pulmonary TB in the Republic of Moldova. A dynamic prediction framework integrating landmark modeling and machine learning algorithms was designed to predict patient outcomes during the course of treatment. Sensitivity and positive predictive value (PPV) were calculated to evaluate performance of the model at critical time points. New measures were defined to determine when follow-up laboratory tests should be conducted to obtain most informative results. Results The random-forest algorithm performed better than support vector machine and penalized multinomial logistic regression models for predicting TB treatment outcomes. For all 3 outcome classes (ie, cured, not cured, and died after 24 months following treatment initiation), sensitivity and PPV of prediction models improved as more follow-up information was collected. Specifically, sensitivity and PPV increased from 0.55 to 0.84 and from 0.32 to 0.88, respectively, for the not cured class. Conclusion The dynamic prediction framework utilizes longitudinal laboratory test results to predict patient outcomes at various landmarks. Sputum culture and smear results are among the important variables for prediction; however, the most recent sputum result is not always the most informative one. This framework can potentially facilitate a more effective treatment monitoring program and provide insights for policymakers toward improved guidelines on follow-up tests.

Benchmarking the empirical accuracy of short-read sequencing across the M. tuberculosis genome
Maximillian Marin, Roger Vargas, Michael Harris, Brendan Jeffrey, L Elaine Epperson, David Durbin, Michael Strong, Max Salfinger, Zamin Iqbal, Irada Akhundova,et al.
Oxford University Press (OUP)
Abstract Motivation Short-read whole-genome sequencing (WGS) is a vital tool for clinical applications and basic research. Genetic divergence from the reference genome, repetitive sequences and sequencing bias reduces the performance of variant calling using short-read alignment, but the loss in recall and specificity has not been adequately characterized. To benchmark short-read variant calling, we used 36 diverse clinical Mycobacterium tuberculosis (Mtb) isolates dually sequenced with Illumina short-reads and PacBio long-reads. We systematically studied the short-read variant calling accuracy and the influence of sequence uniqueness, reference bias and GC content. Results Reference-based Illumina variant calling demonstrated a maximum recall of 89.0% and minimum precision of 98.5% across parameters evaluated. The approach that maximized variant recall while still maintaining high precision (&lt;99%) was tuning the mapping quality filtering threshold, i.e. confidence of the read mapping (recall = 85.8%, precision = 99.1%, MQ ≥ 40). Additional masking of repetitive sequence content is an alternative conservative approach to variant calling that increases precision at cost to recall (recall = 70.2%, precision = 99.6%, MQ ≥ 40). Of the genomic positions typically excluded for Mtb, 68% are accurately called using Illumina WGS including 52/168 PE/PPE genes (34.5%). From these results, we present a refined list of low confidence regions across the Mtb genome, which we found to frequently overlap with regions with structural variation, low sequence uniqueness and low sequencing coverage. Our benchmarking results have broad implications for the use of WGS in the study of Mtb biology, inference of transmission in public health surveillance systems and more generally for WGS applications in other organisms. Availability and implementation All relevant code is available at https://github.com/farhat-lab/mtb-illumina-wgs-evaluation. Supplementary information Supplementary data are available at Bioinformatics online.

Emergence of bedaquiline resistance in a high tuberculosis burden country
Elena Chesov, Dumitru Chesov, Florian P. Maurer, Sönke Andres, Christian Utpatel, Ivan Barilar, Ana Donica, Maja Reimann, Stefan Niemann, Christoph Lange,et al.
European Respiratory Society (ERS)
RationaleBedaquiline has been classified as a group A drug for the treatment of multidrug-resistant tuberculosis (MDR-TB) by the World Health Organization; however, globally emerging resistance threatens the effectivity of novel MDR-TB treatment regimens.ObjectivesWe analysed pre-existing and emerging bedaquiline resistance in bedaquiline-based MDR-TB therapies, and risk factors associated with treatment failure and death.MethodsIn a cross-sectional cohort study, we employed patient data, whole-genome sequencing (WGS) and phenotyping of Mycobacterium tuberculosis complex (MTBC) isolates. We could retrieve baseline isolates from 30.5% (62 out of 203) of all MDR-TB patients who received bedaquiline between 2016 and 2018 in the Republic of Moldova. This includes 26 patients for whom we could also retrieve a follow-up isolate.Measurements and main resultsAt baseline, all MTBC isolates were susceptible to bedaquiline. Among 26 patients with available baseline and follow-up isolates, four (15.3%) patients harboured strains which acquired bedaquiline resistance under therapy, while one (3.8%) patient was re-infected with a second bedaquiline-resistant strain. Treatment failure and death were associated with cavitary disease (p=0.011), and any additional drug prescribed in the bedaquiline-containing regimen with WGS-predicted resistance at baseline (OR 1.92 per unit increase, 95% CI 1.15–3.21; p=0.012).ConclusionsMDR-TB treatments based on bedaquiline require a functional background regimen to achieve high cure rates and to prevent the evolution of bedaquiline resistance. Novel MDR-TB therapies with bedaquiline require timely and comprehensive drug resistance monitoring.

RESEARCH ARTICLE Phylogeography and transmission of M. tuberculosis in Moldova: A prospective genomic analysis
Chongguang Yang, Benjamin Sobkowiak, Vijay Naidu, Alexandru Codreanu, Nelly Ciobanu, Kenneth S. Gunasekera, Melanie H. Chitwood, Sofia Alexandru, Stela Bivol, Marcus Russi,et al.
Public Library of Science (PLoS)
Background The incidence of multidrug-resistant tuberculosis (MDR-TB) remains critically high in countries of the former Soviet Union, where >20% of new cases and >50% of previously treated cases have resistance to rifampin and isoniazid. Transmission of resistant strains, as opposed to resistance selected through inadequate treatment of drug-susceptible tuberculosis (TB), is the main driver of incident MDR-TB in these countries. Methods and findings We conducted a prospective, genomic analysis of all culture-positive TB cases diagnosed in 2018 and 2019 in the Republic of Moldova. We used phylogenetic methods to identify putative transmission clusters; spatial and demographic data were analyzed to further describe local transmission of Mycobacterium tuberculosis. Of 2,236 participants, 779 (36%) had MDR-TB, of whom 386 (50%) had never been treated previously for TB. Moreover, 92% of multidrug-resistant M. tuberculosis strains belonged to putative transmission clusters. Phylogenetic reconstruction identified 3 large clades that were comprised nearly uniformly of MDR-TB: 2 of these clades were of Beijing lineage, and 1 of Ural lineage, and each had additional distinct clade-specific second-line drug resistance mutations and geographic distributions. Spatial and temporal proximity between pairs of cases within a cluster was associated with greater genomic similarity. Our study lasted for only 2 years, a relatively short duration compared with the natural history of TB, and, thus, the ability to infer the full extent of transmission is limited. Conclusions The MDR-TB epidemic in Moldova is associated with the local transmission of multiple M. tuberculosis strains, including distinct clades of highly drug-resistant M. tuberculosis with varying geographic distributions and drug resistance profiles. This study demonstrates the role of comprehensive genomic surveillance for understanding the transmission of M. tuberculosis and highlights the urgency of interventions to interrupt transmission of highly drug-resistant M. tuberculosis.

Detection of isoniazid, fluoroquinolone, ethionamide, amikacin, kanamycin, and capreomycin resistance by the Xpert MTB/XDR assay: a cross-sectional multicentre diagnostic accuracy study
Adam Penn-Nicholson, Sophia B Georghiou, Nelly Ciobanu, Mubin Kazi, Manpreet Bhalla, Anura David, Francesca Conradie, Morten Ruhwald, Valeriu Crudu, Camilla Rodrigues,et al.
Elsevier BV

Valeriu Crudu

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Scopus Publications