The highest estimated prevalence of MDR-TB is in India and China. However, the largest number of patients who have been diagnosed with MDR-TB live in the European Region of the WHO. In Belarus, Kazakhstan, Kyrgyzstan, the Republic of Moldova, the Russian Federation and Ukraine, more than 25% of all new patients who have not received treatment for TB in the past, have MDR-TB. 1 Less than one third of notified TB patients worldwide are evaluated with drug susceptibility testing (DST) for RMP; only half of patients with RMP resistance or MDR-TB undergo DST for FQs and second-line injectable drugs. 1 Only 20% of MDR-TB cases have access to adequate treatment. 3,4 It is predicted that the number of patients with MDR-TB and XDR-TB in highburden countries will continue to rise in the coming decades. 5 Treatment for MDR-TB is challenging for patients, relatives, healthcare providers and health systems. 6 The level of drug resistance of the causative strain of M. tuberculosis can be highly variable. 7 Depending on the DST results, current WHO treatment recommendations range from 9 to 20 months of daily combination antibiotic treatment. 8 The treatment is characterised by a high frequency of adverse drug events, often leading to changes in the regimen. 9 Due to high costs, some of the second-line drugs are not available in countries where they are needed most. 10 Despite all of our efforts, according to the latest WHO report, only 55% of patients with MDR-TB and 34% of patients with XDR-TB achieve a successful treatment outcome. 1 Treatment outcomes in MDR-TB and XDR-TB are highly dependent upon available resources. It was recently shown that relapse-free cure-rates in patients with M/XDR-TB can be similar to patients with drug-susceptible TB (DS-TB) when sufficient resources are provided, 11 and treatment can be personalised. 12 The aim of the present article is to update previous TBNET (Tuberculosis Network European Trials) recommendations on the optimal management of patients with M/XDR-TB. 6

Tuberculosis is a bacterial infectious disease that is mainly transmitted from human to human via infectious aerosols. Currently, tuberculosis is the leading cause of death by an infectious disease worldwide. In the past decade, the number of patients affected by tuberculosis has increased by ∼20 percent and the emergence of drug-resistant strains of Mycobacterium tuberculosis challenges the goal of elimination of tuberculosis in the near future. For the last 50 years, management of patients with tuberculosis has followed a standardized management approach. This standardization neglects the variation in human susceptibility to infection, immune response, the pharmacokinetics of drugs, and the individual duration of treatment needed to achieve relapse-free cure. Here we propose a package of precision medicine-guided therapies that has the prospect to drive clinical management decisions, based on both host immunity and M. tuberculosis strains genetics. Recently, important scientific discoveries and technological advances have been achieved that provide a perspective for individualized rather than standardized management of patients with tuberculosis. For the individual selection of best medicines and host-directed therapies, personalized drug dosing, and treatment durations, physicians treating patients with tuberculosis will be able to rely on these advances in systems biology and to apply them at the bedside.

According to the World Health Organization (WHO), tuberculosis is the leading cause of death attributed to a single microbial pathogen worldwide. In addition to the large number of patients affected by tuberculosis, the emergence of Mycobacterium tuberculosis drug-resistance is complicating tuberculosis control in many high-burden countries. During the past 5 years, the global number of patients identified with multidrug-resistant tuberculosis (MDR-TB), defined as bacillary resistance at least against rifampicin and isoniazid, the two most active drugs in a treatment regimen, has increased by more than 20% annually. Today we experience a historical peak in the number of patients affected by MDR-TB. The management of MDR-TB is characterized by delayed diagnosis, uncertainty of the extent of bacillary drug-resistance, imprecise standardized drug regimens and dosages, very long duration of therapy and high frequency of adverse events which all translate into a poor prognosis for many of the affected patients. Major scientific and technological advances in recent years provide new perspectives through treatment regimens tailor-made to individual needs. Where available, such personalized treatment has major implications on the treatment outcomes of patients with MDR-TB. The challenge now is to bring these adances to those patients that need them most.

BackgroundIn vitro, animal model, and clinical evidence suggests that tuberculosis is not a monomorphic disease, and that host response to tuberculosis is protean with multiple distinct molecular pathways and pathologies (endotypes). We applied unbiased clustering to identify separate tuberculosis endotypes with classifiable gene expression patterns and clinical outcomes.MethodsA cohort comprised of microarray gene expression data from microbiologically confirmed tuberculosis patients were used to identify putative endotypes. One microarray cohort with longitudinal clinical outcomes was reserved for validation, as was two RNA-seq cohorts. Finally, a separate cohort of tuberculosis patients with functional immune responses was evaluated to clarify stimulated from unstimulated immune responses.ResultsA discovery cohort, including 435 tuberculosis patients and 533 asymptomatic controls, identified two tuberculosis endotypes. Endotype A is characterised by increased expression of genes related to inflammation and immunity and decreased metabolism and proliferation; in contrast, endotype B has increased activity of metabolism and proliferation pathways. An independent RNA-seq validation cohort, including 118 tuberculosis patients and 179 controls, validated the discovery results. Gene expression signatures for treatment failure were elevated in endotype A in the discovery cohort, and a separate validation cohort confirmed that endotype A patients had slower time to culture conversion, and a reduced cure rate. These observations suggest that endotypes reflect functional immunity, supported by the observation that tuberculosis patients with a hyperinflammatory endotype have less responsive cytokine production upon stimulation.ConclusionThese findings provide evidence that metabolic and immune profiling could inform optimisation of endotype-specific host-directed therapies for tuberculosis.

Background: Diagnosis of chronic pulmonary aspergillosis (CPA) is challenging. Symptoms are unspecific or missing, radiological findings are variable and proof of mycological evidence is limited by the accuracy of diagnostic tests. The goal of this study was to investigate diagnostic performance of galactomannan (GM), the newly formatted Aspergillus-specific lateral-flow-device test (LFD), and a number of cytokines in bronchoalveolar lavage fluid (BALF) samples obtained from patients with CPA, patients with respiratory disorders without CPA and healthy individuals.Methods: Patients with CPA (n = 27) and controls (n = 27 with underlying respiratory diseases but without CPA, and n = 27 healthy volunteers) were recruited at the Medical University of Graz, Austria and the Research Center Borstel, Germany between 2010 and 2018. GM, LFD and cytokine testing was performed retrospectively at the Research Center Borstel.Results: Sensitivity and specificity of GM testing from BALF with a cut off level of ≥0.5 optical density index (ODI) was 41 and 100% and 30 and 100% with a cut off level of ≥1.0 ODI. ROC curve analysis showed an AUC 0.718 (95% CI 0.581–0.855) for GM for differentiating CPA patients to patients with other respiratory diseases without CPA. The LFD resulted positive in only three patients with CPA (7%) and was highly specific. CPA patients did not differ significantly in the BALF cytokine profile compared to patients with respiratory disorders without CPA, but showed significant higher values for IFN-γ, IL-1b, IL-6, IL-8, and TNF-α compared to healthy individuals.Conclusion: Both GM and LFD showed insufficient performance for diagnosing CPA, with sensitivities of BALF GM below 50%, and sensitivity of the LFD below 10%. The high specificities may, however, result in a high positive predictive value and thereby help to identify semi-invasive or invasive disease.

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% (62/203) 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, 4/26 (15.3%) patients harbored strains which acquired bedaquiline resistance under therapy, while 1/26 (3.8%) patients 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 (p=0.012, OR 1.92 per unit increase, 95%CI 1.15–3.21).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.

Background Comprehensive and reliable drug susceptibility testing (DST) is urgently needed to provide adequate treatment regimens for patients with multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB). We determined whether next-generation sequencing (NGS) analysis of Mycobacterium tuberculosis complex isolates and genes implicated in drug resistance can guide the design of effective MDR/RR-TB treatment regimens. Methods NGS-based genomic DST predictions of M. tuberculosis complex isolates from MDR/RR-TB patients admitted to a TB reference center in Germany between 1 January 2015 and 30 April 2019 were compared with phenotypic DST results of mycobacteria growth indicator tubes (MGIT). Standardized treatment algorithms were applied to design individualized therapies based on either genomic or phenotypic DST results, and discrepancies were further evaluated by determination of minimal inhibitory drug concentrations (MICs) using Sensititre MYCOTBI and UKMYC microtiter plates. Results In 70 patients with MDR/RR-TB, agreement among 1048 pairwise comparisons of genomic and phenotypic DST was 86.3%; 76 (7.2%) results were discordant, and 68 (6.5%) could not be evaluated due to the presence of polymorphisms with yet unknown implications for drug resistance. Importantly, 549 of 561 (97.9%) predictions of drug susceptibility were phenotypically confirmed in MGIT, and 27 of 64 (42.2%) false-positive results were linked to previously described mutations mediating a low or moderate MIC increase. Virtually all drugs (99.0%) used in combination therapies that were inferred from genomic DST were confirmed to be susceptible by phenotypic DST. Conclusions NGS-based genomic DST can reliably guide the design of effective MDR/RR-TB treatment regimens.

Despite the advent of new diagnostics, drugs and regimens, tuberculosis (TB) remains a global public health threat. A significant challenge for TB control efforts has been the monitoring of TB therapy and determination of TB treatment success.