Impact of the COVID-19 pandemic on the real-world diagnostic infrastructure for tuberculosis-An ESGMYC collaborative study.

We determined the impact of the COVID-19 pandemic on mycobacterial diagnostic services. 40 laboratories from 22 countries completed an online questionnaire covering the redeployment of the laboratory infrastructure and/or staff for SARS-CoV-2 testing, staff shortages and supply chain disruptions. 28 laboratories reported monthly numbers of samples processed for mycobacterial investigations and monthly numbers of M. tuberculosis complex (MTBC) PCRs performed between October 1st 2018 and October 31st 2020. More than half (23/40) of the participating TB laboratories reported having performed COVID-19 diagnostics in the early phase of the pandemic, in part with negative impact on the mycobacterial service activities. All participating laboratories reported shortages of consumables and laboratory equipment due to supply chain issues. Average monthly sample numbers decreased by 24% between January 2020 and October 2020 compared to pre-pandemic averages. At the end of the study period, most participating laboratories had not returned to pre-pandemic average MTBC PCR throughput.

Availability of drugs and resistance testing for bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaL(M)) regimen for rifampicin-resistant tuberculosis in Europe.

OBJECTIVES: Multidrug-resistant/rifampicin-resistant tuberculosis is a major obstacle to successful tuberculosis control. The recommendation by the WHO to use bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaL(M)) for 6 months, based on results of two trials with high efficacy and low toxicity, has revolutionized treatment options. METHODS: In this study, representatives of the Tuberculosis Network European Trials group in 44 of 54 countries of the WHO Europe region documented the availability of the medicines and drug susceptibility testing (DST) of the BPaL(M) regimen through a structured questionnaire between September and November 2023. RESULTS: In total, 24 of 44 (54.5%), 42 of 44 (95.5%), 43 of 44 (97.7%), and 43 of 44 (97.7%) countries had access to pretomanid, bedaquiline, linezolid, and moxifloxacin, respectively. Overall, 23 of 44 (52.3%) countries had access to all the drugs composing the BPaL(M) regimen. In total, 21 of 44 (47.7%), 37 of 44 (84.1%), 40 of 44 (90.9%), and 41 of 44 (93.2%) countries had access to DST for pretomanid, bedaquiline, linezolid, and moxifloxacin, respectively. Overall, DST was available for all medicines composing the BPaL(M) regimen in 21 of 44 (47.7%) countries, including countries where pretomanid DST was available at specialized laboratories. The availability of DST for the drugs the countries had access to, varied from 87.5% to 95.3% (pretomanid 21 of 24 (87.5%), bedaquiline 37 of 42 (88.1%), linezolid 40 of 43 (93.1%) and moxifloxacin 41 of 43 (95.3%)). DISCUSSION: In only about half of the countries participating in the survey, clinicians had access to all the BPaL(M) regimen drugs. A complete DST for the BPaL(M) medicines was possible in less than half of the countries, because of the low accessibility of DST for pretomanid. Equal access to new regimens is urgently needed in Europe and a rapid scale up of DST, especially for pretomanid, is important to prevent unnoticed spread of drug resistance.

[Advances in antibiotic therapy for tuberculosis]. / Avancées dans l'antibiothérapie de la tuberculose.

ADVANCES IN ANTIBIOTIC THERAPY FOR TUBERCULOSIS. Treatment of tuberculosis is experiencing significant advancements. For the first time, a therapeutic regimen based on rifapentine and moxifloxacin allows for a reduction of treatment duration of drug-susceptible tuberculosis from 6 to 4 months. Regarding multidrug-resistant tuberculosis, combinations of new antituberculosis drugs (bedaquiline, linezolid, delamanid/pretomanid, moxifloxacin) have the potential to reduce the treatment duration from 20 to 6 months. Additionally, considering the extent of anatomical involvement and bacterial burden allows for strategies that involve variable treatment durations based on the severity of the disease. The new tuberculosis treatments thus appear to be shorter and more personalized.

AVANCÉES DANS L'ANTIBIOTHÉRAPIE DE LA TUBERCULOSE. Le traitement de la tuberculose connaît de grandes avancées. Pour la première fois, un protocole thérapeutique à base de rifapentine et moxifloxacine permet de réduire de six à quatre mois la durée du traitement des tuberculoses à bacilles sensibles. S'agissant des tuberculoses à bacilles multirésistants, des combinaisons de nouveaux antituberculeux (bédaquiline, linézolide, délamanide-prétomanide, moxifloxacine) permettent de réduire de vingt à six mois la durée du traitement. Enfin, la prise en compte de l'importance de l'atteinte anatomique et de la charge bacillaire permet d'envisager des stratégies incluant des durées de traitement variables selon l'importance de l'atteinte. Les nouveaux traitements de la tuberculose apparaissent donc plus courts et plus personnalisés.

Association of indicators of extensive disease and rifampin-resistant tuberculosis treatment outcomes: an individual participant data meta-analysis.

BACKGROUND: Indicators of extensive disease-acid fast bacilli (AFB) smear positivity and lung cavitation-have been inconsistently associated with clinical rifampin-resistant/multidrug-resistant tuberculosis (RR/MDR-TB) outcomes. We evaluated the association of these indicators with end-of-treatment outcomes. METHODS: We did an individual participant data meta-analysis of people treated for RR/MDR-TB with longer regimens with documented AFB smear and chest radiography findings. We compared people AFB smear-negative without cavities to people: (1) smear-negative with lung cavities; (2) smear-positive without lung cavities and (3) AFB smear-positive with lung cavities. Using multivariable logistic regression accounting for demographic, treatment and clinical factors, we calculated adjusted ORs (aOR) for any unfavourable outcome (death, lost to follow-up, failure/recurrence), and mortality and treatment failure/recurrence alone. RESULTS: We included 5596 participants; included participants significantly differed from excluded participants. Overall, 774 (13.8%) were AFB smear-negative without cavities, 647 (11.6%) only had cavities, 1424 (25.4%) were AFB smear-positive alone and 2751 (49.2%) were AFB smear-positive with cavities. The median age was 37 years (IQR: 28-47), 3580 (64%) were male and 686 (12.5%) had HIV. Compared with participants AFB smear-negative without cavities, aOR (95% CI) for any unfavourable outcome was 1.0 (0.8 to 1.4) for participants smear-negative with lung cavities, 1.2 (0.9 to 1.5) if smear-positive without cavities and 1.6 (1.3 to 2.0) if AFB smear-positive with lung cavities. Odds were only significantly increased for mortality (1.5, 95% CI 1.1 to 2.1) and failure/recurrence (2.2, 95% CI 1.5 to 3.3) among participants AFB smear-positive with lung cavities. CONCLUSION: Only the combination of AFB smear-positivity and lung cavitation was associated with unfavourable outcomes, suggesting they may benefit from stronger regimens.

Recent advances in the treatment of tuberculosis.

BACKGROUND: Tuberculosis (TB) is a global health challenge and one of the leading causes of death worldwide. In the last decade, the TB treatment landscape has dramatically changed. After long years of stagnation, new compounds entered the market (bedaquiline, delamanid, and pretomanid) and phase III clinical trials have shown promising results towards shortening duration of treatment for both drug-susceptible (Study 31/A5349, TRUNCATE-TB, and SHINE) and drug-resistant TB (STREAM, NiX-TB, ZeNix, and TB-PRACTECAL). Dose optimization of rifamycins and repurposed drugs has also brought hopes of further development of safe and effective regimens. Consequently, international and WHO clinical guidelines have been updated multiple times in the last years to keep pace with these advances. OBJECTIVES: This narrative review aims to summarize the state-of-the-art on treatment of drug-susceptible and drug-resistant TB, as well as recent trial results and an overview of ongoing clinical trials. SOURCES: A non-systematic literature review was conducted in PubMed and MEDLINE, focusing on the treatment of TB. Ongoing clinical trials were listed according to the authors' knowledge and completed consulting clinicaltrials.gov and other publicly available websites (www.resisttb.org/clinical-trials-progress-report, www.newtbdrugs.org/pipeline/trials). CONTENT: This review summarizes the recent, major changes in the landscape for drug-susceptible and drug-resistant treatment, with a specific focus on their potential impact on patient outcomes and programmatic TB management. Moreover, insights in host-directed therapies, and advances in pharmacokinetics and pharmacogenomics are discussed. A thorough outline of ongoing therapeutic clinical trials is presented, highlighting different approaches and goals in current TB clinical research. IMPLICATIONS: Future research should be directed to individualize regimens and protect these recent breakthroughs by preventing and identifying the selection of drug resistance and providing widespread, affordable, patient-centred access to new treatment options for all people affected by TB.

Clinical implications of molecular drug resistance testing for Mycobacterium tuberculosis: a 2023 TBnet/RESIST-TB consensus statement.

Drug-resistant tuberculosis is a substantial health-care concern worldwide. Despite culture-based methods being considered the gold standard for drug susceptibility testing, molecular methods provide rapid information about the Mycobacterium tuberculosis mutations associated with resistance to anti-tuberculosis drugs. This consensus document was developed on the basis of a comprehensive literature search, by the TBnet and RESIST-TB networks, about reporting standards for the clinical use of molecular drug susceptibility testing. Review and the search for evidence included hand-searching journals and searching electronic databases. The panel identified studies that linked mutations in genomic regions of M tuberculosis with treatment outcome data. Implementation of molecular testing for the prediction of drug resistance in M tuberculosis is key. Detection of mutations in clinical isolates has implications for the clinical management of patients with multidrug-resistant or rifampicin-resistant tuberculosis, especially in situations when phenotypic drug susceptibility testing is not available. A multidisciplinary team including clinicians, microbiologists, and laboratory scientists reached a consensus on key questions relevant to molecular prediction of drug susceptibility or resistance to M tuberculosis, and their implications for clinical practice. This consensus document should help clinicians in the management of patients with tuberculosis, providing guidance for the design of treatment regimens and optimising outcomes.

Availability and costs of medicines for the treatment of tuberculosis in Europe.

OBJECTIVES: To evaluate the access to comprehensive diagnostics and novel antituberculosis medicines in European countries. METHODS: We investigated the access to genotypic and phenotypic Mycobacterium tuberculosis drug susceptibility testing and the availability of antituberculosis drugs and calculated the cost of drugs and treatment regimens at major tuberculosis treatment centres in countries of the WHO European region where rates of drug-resistant tuberculosis are the highest among all WHO regions. Results were stratified by middle-income and high-income countries. RESULTS: Overall, 43 treatment centres from 43 countries participated in the study. For WHO group A drugs, the frequency of countries with the availability of phenotypic drug susceptibility testing was as follows: (a) 75% (30/40) for levofloxacin, (b) 82% (33/40) for moxifloxacin, (c) 48% (19/40) for bedaquiline, and (d) 72% (29/40) for linezolid. Overall, of the 43 countries, 36 (84%) and 24 (56%) countries had access to bedaquiline and delamanid, respectively, whereas only 6 (14%) countries had access to rifapentine. The treatment of patients with extensively drug-resistant tuberculosis with a regimen including a carbapenem was available only in 17 (40%) of the 43 countries. The median cost of regimens for drug-susceptible tuberculosis, multidrug-resistant/rifampicin-resistant tuberculosis (shorter regimen, including bedaquiline for 6 months), and extensively drug-resistant tuberculosis (including bedaquiline, delamanid, and a carbapenem) were €44 (minimum-maximum, €15-152), €764 (minimum-maximum, €542-15152), and €8709 (minimum-maximum, €7965-11759) in middle-income countries (n = 12) and €280 (minimum-maximum, €78-1084), €29765 (minimum-maximum, €11116-40584), and €217591 (minimum-maximum, €82827-320146) in high-income countries (n = 29), respectively. DISCUSSION: In countries of the WHO European region, there is a widespread lack of drug susceptibility testing capacity to new and repurposed antituberculosis drugs, lack of access to essential medications in several countries, and a high cost for the treatment of drug-resistant tuberculosis.

Occurrence of extrapulmonary tuberculosis is associated with geographical origin: spatial characteristics of the Frankfurt TB cohort 2013-2018.

INTRODUCTION: Tuberculosis (TB) is caused by M. tuberculosis complex (MTB) and pulmonary tuberculosis (PTB) is its classical manifestation. However, in some regions of the world, extrapulmonary TB (EPTB) seems to be more frequent. METHODS: We performed a retrospective cohort study of all TB patients treated at University Hospital Frankfurt, Germany, for the time period 2013-2018. Patient charts were reviewed and demographic, clinical, and microbiological data recorded. Patients were subdivided according to their geographic origins. RESULTS: Of the 378 included patients, 309 were born outside Germany (81.7%). Three WHO regions were significantly associated with the occurrence of isolated EPTB: the South-East Asian Region (OR 3.37, CI 1.74-6.66, p < 0.001), the African Region (2.20, CI 1.25-3.90, p = 0.006), and the Eastern Mediterranean Region (OR 3.18, CI 1.78-5.76, p < 0.001). On a country level, seven countries of origin could be demonstrated to be significantly associated with the occurrence of isolated EPTB: India (OR 5.58, CI 2.30-14.20, p < 0.001), Nepal (OR 12.75, CI 1.73-259.28, p = 0.027), Afghanistan (OR 3.64, CI 1.14-11.98, p = 0.029), Pakistan (OR 3.64, CI 1.14-11.98, p = 0.029), Eritrea (OR 3.32, CI 1.52-7.47, p = 0.003), Somalia (OR 7.08, CI 2.77-19.43, p < 0.001), and Turkey (OR 9.56, CI 2.52-47.19, p = 0.002). CONCLUSION: Geographical origin is a predictor for the occurrence of extrapulmonary TB. This might be linked to a delay in diagnosis in these patients, as well as specific responsible impairments of the host's immune system, possible virulence factors of MTB, and relevant comorbidities.

Efficacy and Tolerability of Concomitant Use of Bedaquiline and Delamanid for Multidrug- and Extensively Drug-Resistant Tuberculosis: A Systematic Review and Meta-Analysis.

The introduction of two novel drugs, bedaquiline and delamanid, has given hope for better and shorter treatments of drug-resistant tuberculosis. A systematic review was conducted to evaluate the efficacy and safety of concomitant bedaquiline and delamanid administration. Pooled estimates of World Health Organization-defined favorable treatment outcome and significant QTc-interval prolongation (QTc ≥500 ms or ≥60 ms increase from baseline) were calculated using a random-effects model. Thirteen studies including a total of 1031 individuals with multidrug-resistant/rifampicin-resistant tuberculosis who received bedaquiline and delamanid were included. The pooled estimate of favorable treatment outcome was 73.1% (95% confidence interval [CI]: 64.3-81.8%). Sputum culture conversion at 6 months ranged from 61% to 95%. Overall, the pooled proportion of QTc-prolongation was 7.8% (95% CI: 4.1-11.6%) and few cardiac events were reported (0.8%; n = 6/798). Rates of sputum culture conversion and favorable treatment outcome were high in patients treated concomitantly with bedaquiline and delamanid, and the treatment seemed tolerable with low rates of clinically significant cardiac toxicity.

Association Between Increased Linezolid Plasma Concentrations and the Development of Severe Toxicity in Multidrug-Resistant Tuberculosis Treatment.

BACKGROUND: Treatment of multidrug-resistant (MDR) tuberculosis with linezolid is characterized by high rates of adverse events. Evidence on therapeutic drug monitoring to predict drug toxicity is scarce. This study aimed to evaluate the association of linezolid trough concentrations with severe toxicity. METHODS: We retrospectively assessed consecutive patients started on linezolid for MDR tuberculosis between 2011 and 2017. The primary outcome was severe mitochondrial toxicity (SMT) due to linezolid, defined as neurotoxicity or myelotoxicity leading to drug discontinuation. The impact of plasma linezolid trough concentrations >2 mg/L was assessed in multivariate Cox proportional hazards models including time-varying covariates. RESULTS: SMT occurred in 57 of 146 included patients (39%) at an incidence rate of 0.38 per person-year (95% confidence interval, .30-.49). A maximum linezolid trough concentration >2 mg/L was detected in 52 patients (35.6%), while the mean trough concentration was >2 mg/L in 22 (15%). The adjusted hazard ratio for SMT was 2.35 (95% confidence interval, 1.26-4.38; P = .01) in patients with a mean trough concentration >2 mg/L and 2.63 (1.55-4.47; P < .01) for SMT after the first detection of a trough concentration >2 mg/L. In an exploratory analysis, higher maximum trough concentrations were dose-dependently associated with toxicity, while lowering elevated trough concentrations did not restore baseline risk. CONCLUSIONS: Linezolid trough concentrations >2 mg/L are strongly associated with the development of severe treatment-emergent toxicity in patients treated for MDR tuberculosis. Pending further prospective evidence, an individual risk-benefit assessment on the continuation of linezolid treatment is warranted in any patient with trough concentrations >2 mg/L.

Preventive Therapy for Contacts of Drug-Resistant Tuberculosis.

Preventing the progression of a drug-resistant tuberculosis (DR-TB) infection to disease is an important pillar of the DR-TB elimination strategy. International guidelines have recently proposed fluoroquinolones for tuberculosis preventive therapy (TPT) in DR-TB contacts, although the available evidence is low quality. The pooled data from small observational studies suggest that a fluoroquinolone-based TPT is safe, effective and cost-effective as a preventive treatment in DR-TB contacts. Three clinical trials are currently ongoing to generate higher quality evidence on the efficacy of levofloxacin and delamanid as a DR-TB preventive therapy. Additional evidence is also needed, regarding TPT treatment in fluoroquinolone-resistant-TB contacts, patient and health care worker perceptions on DR-TB preventive therapy for contacts, and the service delivery models to increase DR-TPT access. This state-of-the-art review presents the current literature on TPT for contacts of DR-TB cases, focusing on the available evidence and international guidelines.

Revised Definitions of Tuberculosis Resistance and Treatment Outcomes, France, 2006-2019.

Definitions of resistance in multidrug-resistant tuberculosis (MDR TB) and extensively drug-resistant tuberculosis (XDR TB) have been updated. Pre-XDR TB, defined as MDR TB with additional resistance to fluoroquinolones, and XDR TB, with additional resistance to bedaquiline or linezolid, are frequently associated with treatment failure and toxicity. We retrospectively determined the effects of pre-XDR/XDR TB resistance on outcomes and safety of MDR TB treatment in France. The study included 298 patients treated for MDR TB at 3 reference centers during 2006-2019. Of those, 205 (68.8%) cases were fluoroquinolone-susceptible MDR TB and 93 (31.2%) were pre-XDR/XDR TB. Compared with fluoroquinolone-susceptible MDR TB, pre-XDR/XDR TB was associated with more cavitary lung lesions and bilateral disease and required longer treatment. Overall, 202 patients (67.8%) had favorable treatment outcomes, with no significant difference between pre-XDR/XDR TB (67.7%) and fluoroquinolone-susceptible MDR TB (67.8%; p = 0.99). Pre-XDR/XDR TB was not associated with higher risk for serious adverse events.

Clinical Features and Outcome of Multidrug-Resistant Osteoarticular Tuberculosis: A 12-Year Case Series from France.

The optimal treatment for osteoarticular infection due to multidrug-resistant tuberculosis strains (MDR-OATB) remains unclear. This study aims to evaluate the diagnosis, management and outcome of MDR-OATB in France. We present a case series of MDR-OATB patients reviewed at the French National Reference Center for Mycobacteria between 2007 and 2018. Medical history and clinical, microbiological, treatment and outcome data were collected. Twenty-three MDR-OATB cases were reported, representing 3% of all concurrent MDR-TB cases in France. Overall, 17 were male, and the median age was 32 years. Six patients were previously treated for TB, including four with first-line drugs. The most frequently affected site was the spine (n = 16). Bone and joint surgery were required in 12 patients. Twenty-one patients (91%) successfully completed the treatment with a regimen containing a mean of four drugs (range, 2-6) for a mean duration of 20 months (range, 13-27). Overall, high rates of treatment success were achieved following WHO MDR-TB treatment guidelines and individualized patient management recommendations by the French National TB Consilium. However, the optimal combination of drugs, duration of treatment and role of surgery in the management of MDR-OATB remains to be determined.

Molecular detection of isoniazid monoresistance improves tuberculosis treatment: A retrospective cohort in France.

OBJECTIVES: Isoniazid-monoresistant tuberculosis (HR-TB) requires early diagnosis and adapted treatment to achieve optimal outcomes. The primary aim of the study was to assess the impact of the implementation of rapid diagnostic tests on HR-TB treatment in France. METHODS: We designed a retrospective multicentre study including consecutive HR-TB patients diagnosed in 2016 and 2017. Implementation of a molecular assay detecting isoniazid resistance directly on a clinical sample was recorded. The association between early implementation of such assays and adequate treatment was assessed by a multivariable Cox proportional hazards model. RESULTS: Overall, 99 HR-TB patients were included from 20 University Hospitals. Among all smear-positive HR-TB patients, only 26% beneficiated from early molecular HR detection. This detection was independently associated with shorter time to adequate treatment (HR = 2.0 [1.1-3.8], p = 0.03). CONCLUSION: In our study, molecular detection of HR on an initial sample was independently associated with earlier treatment adaptation.

Consensus management recommendations for less common non-tuberculous mycobacterial pulmonary diseases.

The 2020 clinical practice guideline for the treatment of non-tuberculous mycobacterial pulmonary disease (NTM-PD) by the American Thoracic Society, European Respiratory Society, European Society of Clinical Microbiology and Infectious Diseases, and Infectious Diseases Society of America; and the 2017 management guideline by the British Thoracic Society covered pulmonary diseases in adults caused by Mycobacterium avium complex, Mycobacterium kansasii, Mycobacterium xenopi, and Mycobacterium abscessus. In order to provide evidence-based recommendations for the treatment of less common non-tuberculous mycobacterial (NTM) species in adult patients without cystic fibrosis or HIV infection, our expert panel group performed systematic literature searches to provide management guidance for pulmonary diseases caused by seven additional organisms: Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium genavense, Mycobacterium gordonae, Mycobacterium malmoense, Mycobacterium simiae, and Mycobacterium szulgai. Treatment recommendations were developed by a structured consensus process. The evidence from the scientific literature published in English for treatment recommendations for pulmonary diseases caused by other NTM species was of very low quality, with the exception of M malmoense, and based on the evaluation of case reports and case series. For M malmoense, results from two randomised controlled trials and three retrospective cohort studies provided a better evidence base for treatment recommendations, although the evidence was still of low quality.