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.

Bedaquiline safety, efficacy, utilization and emergence of resistance following treatment of multidrug-resistant tuberculosis patients in South Africa: a retrospective cohort analysis.

BACKGROUND: This retrospective cohort study assessed benefits and risks of bedaquiline treatment in multidrug-resistant-tuberculosis (MDR-TB) combination therapy by evaluating safety, effectiveness, drug utilization and emergence of resistance to bedaquiline. METHODS: Data were extracted from a register of South African drug-resistant-tuberculosis (DR-TB) patients (Electronic DR-TB Register [EDRWeb]) for newly diagnosed patients with MDR-TB (including pre-extensively drug-resistant [XDR]-TB and XDR-TB and excluding rifampicin-mono-resistant [RR]-TB, as these patients are by definition not multidrug-resistant), receiving either a bedaquiline-containing or non-bedaquiline-containing regimen, at 14 sites in South Africa. Total duration of treatment and follow-up was up to 30 months, including 6 months' bedaquiline treatment. WHO treatment outcomes within 6 months after end-of-treatment were assessed in both patient groups. Longer term mortality (up to 30 months from treatment start) was evaluated through matching to the South African National Vital Statistics Register. Multivariable Cox proportional hazards analyses were used to predict association between receiving a bedaquiline-containing regimen and treatment outcome. RESULTS: Data were extracted from EDRWeb for 5981 MDR-TB patients (N = 3747 bedaquiline-treated; N = 2234 non-bedaquiline-treated) who initiated treatment between 2015 and 2017, of whom 40.7% versus 80.6% had MDR-TB. More bedaquiline-treated than non-bedaquiline-treated patients had pre-XDR-TB (27.7% versus 9.5%) and XDR-TB (31.5% versus 9.9%) per pre-2021 WHO definitions. Most patients with treatment duration data (94.3%) received bedaquiline for 6 months. Treatment success (per pre-2021 WHO definitions) was achieved in 66.9% of bedaquiline-treated and 49.4% of non-bedaquiline-treated patients. Death was reported in fewer bedaquiline-treated (15.4%) than non-bedaquiline-treated (25.6%) patients. Bedaquiline-treated patients had increased likelihood of treatment success and decreased risk of mortality versus non-bedaquiline-treated patients. In patients with evaluable drug susceptibility testing data, 3.5% of bedaquiline-susceptible isolates at baseline acquired phenotypic resistance. Few patients reported bedaquiline-related treatment-emergent adverse events (TEAEs) (1.8%), TEAE-related bedaquiline discontinuations (1.4%) and QTcF values > 500 ms (2.5%) during treatment. CONCLUSION: Data from this large cohort of South African patients with MDR-TB showed treatment with bedaquiline-containing regimens was associated with survival and effectiveness benefit compared with non-bedaquiline-containing regimens. No new safety signals were detected. These data are consistent with the positive risk-benefit profile of bedaquiline and warrant continued implementation in combination therapy for MDR-TB treatment.

A five-year review of prevalence and treatment outcomes of pre-extensively drug-resistant plus additional drug-resistant tuberculosis in the Henan Provincial Tuberculosis Clinical Medicine Research Centre.

OBJECTIVES: This study investigated the prevalence and significant clinical outcomes of pre-extensively drug-resistant plus additional drug-resistant tuberculosis (pre-XDR-plus) in Henan Provincial Chest Hospital between 2017 and 2021. METHODS: We analysed and summarized the drug sensitivity test (DST) results of clinical Mycobacterium tuberculosis (MTB) strains in TB patients seeking care in the Tuberculosis Clinical Medical Research Centre of Henan Province between 2017 and 2021. Medical records of pre-extensively drug-resistant plus additional drug-resistant TB patients were statistically analysed, including demographic characteristics, regimens, and outcomes. RESULTS: Of the 3689 Mycobacterium tuberculosis strains, 639 (17.32%), 353 (9.56%), and 109 (2.95%), multidrug-resistant tuberculosis (MDR-TB), pre-extensively drug-resistant tuberculosis (pre-XDR), and pre-XDR-plus, respectively. The proportion of MDR decreased from 19.1% in 2017 to 17.5% in 2021 (χ2 = 0.686, P = 0.407), the proportion of pre-XDR from 11.4% in 2017 to 9.0% in 2021 (χ2 = 2.39, P = 0.122), and pre-XDR-plus from 4.7% in 2017 to 1.8% in 2020, with the declining trend was significant (χ2 = 9.348, P = 0.002). The most commonly used anti-TB drugs were pyrazinamide (PZA, 37/46, 80.43%) and cycloserine (CS, 32/46, 69.57%), followed by linezolid (LZD, 25/46, 54.35%), protionamide (TH, 25/46, 54.35%), and para-aminosalicylic acid (PAS, 23/46, 50.00%). Patients receiving the LZD regimen were 5 times more likely to have a favourable outcome than those not receiving LZD (OR = 6.421, 95% CI 2.101-19.625, P = 0.001). Patients receiving a regimen containing CS were 4 times more likely to have a favourable outcome compared to those not taking CS (OR = 5.444, 95% CI 1.650-17.926, P = 0.005). CONCLUSIONS: Our data suggest that the population of pre-XDR-plus had significantly decreased over the past five years in the Henan Provincial Chest Hospital. The COVID-19 and flood disaster affect TB patients' selection of medical services. In addition, the pre-XDR-plus patients whose regimens contain LZD or CS were more likely to have favourable outcomes.

Whole-genome analysis of drug-resistant Mycobacterium tuberculosis reveals novel mutations associated with fluoroquinolone resistance.

Multidrug-resistant and extensively drug-resistant tuberculosis (M/XDR-TB) remains a global public-health challenge. Known mutations in quinolone resistance-determination regions cannot fully explain phenotypic fluoroquinolone (FQ) resistance in Mycobacterium tuberculosis (Mtb). The aim of this study was to look for novel mutations in Mtb associated with resistance to FQ drugs using whole-genome sequencing analysis. Whole-genome sequences of 659 Mtb strains, including 214 with phenotypic FQ resistance and 445 pan-susceptible isolates, were explored for mutations associated with FQ resistance overall and with resistance to individual FQ drugs (ofloxacin, levofloxacin, moxifloxacin and gatifloxacin). Three novel genes (recC, Rv2005c and PPE59) associated with FQ resistance were identified (P < 0.00001 based on screening analysis and absence of relevant mutations in a pan-susceptible validation set of 360 strains). Nine novel single nucleotide polymorphisms (SNPs), including in gyrB (G5383A and G6773A), gyrA (G7892A), recC (G725900C and G726857T/C), Rv2005c (C2251373G, G2251420C and C2251725T) and PPE59 (C3847269T), were used for diagnostic performance analysis. Enhancing the known SNP set with five of these novel SNPs, including gyrA [G7892A (Leu247Leu)], recC [G725900C (Leu893Leu) and G726857T/C (Arg484Arg)], Rv2005c [G2251420C (Pro205Arg)] and PPE59 [C3847269T (Asn35Asn)] increased the sensitivity of detection of FQ-resistant Mtb from 83.2% (178/214) to 86.9% (186/214) while maintaining 100% specificity (360/360). No specific mutation associated with resistance to only a single drug (ofloxacin, levofloxacin, moxifloxacin or gatifloxacin) was found. In conclusion, this study reports possible additional mutations associated with FQ resistance in Mtb.

Evaluation of drug-resistant tuberculosis treatment outcome in Portugal, 2000-2016.

Treatment of drug-resistant tuberculosis (TB), which is usually less successful than that of drug-susceptible TB, represents a challenge for TB control and elimination. We aimed to evaluate treatment outcomes and to identify the factors associated with death among patients with MDR and XDR-TB in Portugal. We assessed MDR-TB cases reported for the period 2000-2016, using the national TB Surveillance System. Treatment outcomes were defined according to WHO recommendations. We identified the factors associated with death using logistic regression. We evaluated treatment outcomes of 294 MDR- and 142 XDR-TB patients. The treatment success rate was 73.8% among MDR- and 62.7% among XDR-TB patients (p = 0.023). The case-fatality rate was 18.4% among MDR- and 23.9% among XDR-TB patients. HIV infection (OR 4.55; 95% CI 2.31-8.99; p < 0.001) and resistance to one or more second-line injectable drugs (OR 2.73; 95% CI 1.26-5.92; p = 0.011) were independently associated with death among MDR-TB patients. HIV infection, injectable drug use, past imprisonment, comorbidities, and alcohol abuse are conditions that were associated with death early on and during treatment. Early diagnosis of MDR-TB and further monitoring of these patients are necessary to improve treatment outcome.

Tuberculosis: An Overview of the Immunogenic Response, Disease Progression, and Medicinal Chemistry Efforts in the Last Decade toward the Development of Potential Drugs for Extensively Drug-Resistant Tuberculosis Strains.

Tuberculosis (TB) is a slow growing, potentially debilitating disease that has plagued humanity for centuries and has claimed numerous lives across the globe. Concerted efforts by researchers have culminated in the development of various strategies to combat this malady. This review aims to raise awareness of the rapidly increasing incidences of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis, highlighting the significant modifications that were introduced in the TB treatment regimen over the past decade. A description of the role of pathogen-host immune mechanisms together with strategies for prevention of the disease is discussed. The struggle to develop novel drug therapies has continued in an effort to reduce the treatment duration, improve patient compliance and outcomes, and circumvent TB resistance mechanisms. Herein, we give an overview of the extensive medicinal chemistry efforts made during the past decade toward the discovery of new chemotypes, which are potentially active against TB-resistant strains.

Treatment outcomes of children and adolescents receiving drug-resistant TB treatment in a routine TB programme, Mumbai, India.

BACKGROUND: Childhood and adolescent drug-resistant TB (DR-TB) is one of the neglected infectious diseases. Limited evidence exists around programmatic outcomes of children and adolescents receiving DR-TB treatment. The study aimed to determine the final treatment outcomes, culture conversion rates and factors associated with unsuccessful treatment outcome in children and adolescents with DR-TB. METHODS: This is a descriptive study including children (0-9 years) and adolescents (10-19 years) with DR-TB were who were initiated on ambulatory based treatment between January 2017-June 2018 in Shatabdi hospital, Mumbai, India where National TB elimination programme(NTEP) Mumbai collaborates with chest physicians and Médecins Sans Frontières(MSF) in providing comprehensive care to DR-TB patients. The patients with available end-of-treatment outcomes were included. The data was censored on February 2020. RESULT: A total of 268 patients were included; 16 (6%) of them were children (0-9 years). The median(min-max) age was 17(4-19) years and 192 (72%) were females. Majority (199, 74%) had pulmonary TB. Most (58%) had MDR-TB while 42% had fluoroquinolone-resistant TB. The median(IQR) duration of treatment (n = 239) was 24(10-25) months. Median(IQR) time for culture-conversion (n = 128) was 3(3-4) months. Of 268 patients, 166(62%) had successful end-of-treatment outcomes (cured-112; completed treatment-54). Children below 10 years had higher proportion of successful treatment outcomes (94% versus 60%) compared to adolescents. Patients with undernutrition [adjusted odds-ratio, aOR (95% Confidence Interval, 95%CI): 2.5 (1.3-4.8) or those with XDR-TB [aOR (95% CI): 4.3 (1.3-13.8)] had higher likelihood of having unsuccessful DR-TB treatment outcome. CONCLUSION: High proportion of successful treatment outcome was reported, better than global reports. Further, the nutritional support and routine treatment follow up should be strengthened. All oral short and long regimens including systematic use of new TB drugs (Bedaquiline and Delamanid) should be rapidly scaled up in routine TB programme, especially for the paediatric and adolescent population.

Tuberculosis: An Update on Pathophysiology, Molecular Mechanisms of Drug Resistance, Newer Anti-TB Drugs, Treatment Regimens and Host- Directed Therapies.

Human tuberculosis (TB) is primarily caused by Mycobacterium tuberculosis (Mtb) that inhabits inside and amidst immune cells of the host with adapted physiology to regulate interdependent cellular functions with intact pathogenic potential. The complexity of this disease is attributed to various factors such as the reactivation of latent TB form after prolonged persistence, disease progression specifically in immunocompromised patients, advent of multi- and extensivelydrug resistant (MDR and XDR) Mtb strains, adverse effects of tailor-made regimens, and drug-drug interactions among anti-TB drugs and anti-HIV therapies. Thus, there is a compelling demand for newer anti-TB drugs or regimens to overcome these obstacles. Considerable multifaceted transformations in the current TB methodologies and molecular interventions underpinning hostpathogen interactions and drug resistance mechanisms may assist to overcome the emerging drug resistance. Evidently, recent scientific and clinical advances have revolutionised the diagnosis, prevention, and treatment of all forms of the disease. This review sheds light on the current understanding of the pathogenesis of TB disease, molecular mechanisms of drug-resistance, progress on the development of novel or repurposed anti-TB drugs and regimens, host-directed therapies, with particular emphasis on underlying knowledge gaps and prospective for futuristic TB control programs.

In vivo bactericidal effect of colistin-linezolid combination in a murine model of MDR and XDR Acinetobacter baumannii pneumonia.

Recently, paradoxical combinations of colistin with anti-Gram-positive bacterial agents were introduced as a treatment alternative for multidrug-resistant Acinetobacter baumannii (MDRAB) infection. We assessed the therapeutic efficacy of the colistin-linezolid combination regimen in vitro and in a murine model of Acinetobacter baumannii pneumonia. A multidrug-resistant clinical strain (MDRAB31) and an extensively drug-resistant clinical strain (XDRAB78) were used in this study. The survival rates of mice and bacterial counts in lung tissue were used to assess the effects of colistin-linezolid combination. The survival rates of colistin-linezolid combination groups significantly increased compared with colistin groups for MDRAB31 (72% versus 32%, P = 0.03) and for XDRAB78 (92% versus 68%, P = 0.031). The colistin-linezolid combination groups significantly reduced the bacterial counts in lung tissue compared with colistin groups for MDRAB31 and for XDRAB78 (P < 0.05). The colistin-linezolid combination had a bactericidal and synergistic effect compared with colistin alone in time-kill assay and in murine model of pneumonia. Our data demonstrated the synergistic effect of colistin-linezolid combination regimen as a treatment alternative for the severe pulmonary infection caused by MDRAB and XDRAB.

From pulmonary susceptible tuberculosis to extensively drug resistant tuberculosis: An interesting case report of a young Indian girl.

Tuberculosis is one of the top ten causes of death and the leading cause from a single infectious agent. Drug-resistant Tuberculosis continues to be a public health crisis. Urgent action is required to improve the coverage and quality of diagnosis, treatment and care for people with drug-resistant Tuberculosis. Patients with pulmonary Tuberculosis can spread the disease by coughing, sneezing, or simply talking. For that reason, it is important to diagnosis Tuberculosis in order to start treatment as soon as possible. In the present manuscript we present the case of a 25-year-old Indian HIV-negative female, no comorbidity, with a history of drug susceptible tuberculosis diagnosed in 2015 which advanced in extensively drug-resistant tuberculosis after two years of treatment. This case report highlights the risk of mismanagement of patient affected by Tuberculosis and the consequences related which could harm the patient's health.

Second-line Drug Resistance Characterization in Mycobacterium tuberculosis by Genotype MTBDRsl Assay.

Tuberculosis (TB) remains a main hurdle for national programs due to increase in drug resistance to antitubercular drugs. World Health Organization (WHO)-endorsed Line Probe Assay, Genotype MTBDRsl Ver 2.0, gives opportunity for rapid diagnosis and molecular characterization of different mutations in drug targets of fluoroquinolone (FQ) and second-line injectable drugs (SLID). We, retrospectively, analyzed the data of Genotype MTBDRsl Ver 2.0 from January 2018 to June 2018. A total of 863 isolates of Mycobacterium tuberculosis, 687 rifampicin resistant and 176 isoniazid resistant only, were screened for drug resistance in FQ and SLID. All the isolates were tested for Genotype MTBDRsl Ver 2.0 according to the manufacturer's instructions. The FQ and SLID resistance were detected in 295 (34.2%) and 70 (8.1%) isolates, respectively. Among newly diagnosed and follow-up rifampicin-resistant TB (RR TB) patients, the FQ resistance was 25.8% and 44.5%, respectively. The most common mutation (42.7%) in FQ-resistant isolates was MUT3C in gyrA gene. Both SLID and FQ resistance were detected in 59 (6.8%) RR TB isolates. The mono SLID resistance was detected in 12 (1.7%) isolates of RR TB. Genotype MTBDRsl Ver 2.0 assay is a rapid and important tool for the diagnosis and molecular characterization of second-line drug resistance under programmatic conditions.

Tetany in an Extensively Drug Resistant Tuberculosis (XDR-TB) Patient Treated with Capreomycin.

Gross electrolytes disturbances including hypokalemia, hypomagnesaemia, and hypocalcaemia have been reported in tuberculosis patients who have been treated with capreomycin.1-3 Capreomycin is recommended in the treatment of M. tuberculosis isolates resistant to kanamycin at baseline in multi drug resistant tuberculosis patients (MDR - TB) and treatment of extensively drug resistant tuberculosis (XDR-TB) under programmatic management of drug resistant tuberculosis (PMDT) in India.4 We report a case of tetany in a extensively drug resistant tuberculosis (XDR-TB) patient treated with capreomycin. She developed hypokalemia after 7 weeks of administration of injection capreomycin intramuscularly daily in dose of 750 mg. Hypokalemia was refractory to intravenous potassium replacement therapy. At 12 weeks during the treatment she developed tetany and hypocalcaemia. Hypomagnesaemia was also associated with hypocalcaemia and hypokalemia. Normal level of serum potassium and calcium were achieved with correction of hypomagnesaemia.

Revisiting the ß-Lactams for Tuberculosis Therapy with a Compound-Compound Synthetic Lethality Approach.

The suboptimal effectiveness of ß-lactam antibiotics against Mycobacterium tuberculosis has hindered the utility of this compound class for tuberculosis treatment. However, the results of treatment with a second-line regimen containing meropenem plus a ß-lactamase inhibitor were found to be encouraging in a case study of extensively drug-resistant tuberculosis (M. C. Payen, S. De Wit, C. Martin, R. Sergysels, et al., Int J Tuberc Lung Dis 16:558-560, 2012, https://doi.org/10.5588/ijtld.11.0414). We hypothesized that the innate resistance of M. tuberculosis to ß-lactams is mediated in part by noncanonical accessory proteins that are not considered the classic targets of ß-lactams and that small-molecule inhibitors of those accessory targets might sensitize M. tuberculosis to ß-lactams. In this study, we screened an NIH small-molecule library for the ability to sensitize M. tuberculosis to meropenem. We identified six hit compounds, belonging to either the N-arylindole or benzothiophene chemotype. Verification studies confirmed the synthetic lethality phenotype for three of the N-arylindoles and one benzothiophene derivative. The latter was demonstrated to be partially bioavailable via oral administration in mice. Structure-activity relationship studies of both structural classes identified analogs with potent antitubercular activity, alone or in combination with meropenem. Transcriptional profiling revealed that oxidoreductases, MmpL family proteins, and a 27-kDa benzoquinone methyltransferase could be the targets of the N-arylindole potentiator. In conclusion, our compound-compound synthetic lethality screening revealed novel small molecules that were capable of potentiating the action of meropenem, presumably via inhibition of the innate resistance conferred by ß-lactam accessory proteins. ß-Lactam compound-compound synthetic lethality may be an alternative approach for drug-resistant tuberculosis.

Isoniazid mono-resistant tuberculosis: Time to take it seriously.

BACKGROUND/AIMS: In drug resistant tuberculosis (DRTB) suspects, rifampicin resistance has always been prioritized, hence Cartridge Based Nucleic Acid Amplification Test (CBNAAT) is recommended under Revised National Tuberculosis Control Programme (RNTCP), India. However, since it doesn't detect isoniazid resistance, rifampicin sensitive patients with unknown isoniazid status may be erroneously treated as drug sensitive TB, leading to poor treatment outcomes and emergence of multidrug resistant (MDR) TB. Hence isoniazid mono-resistance should be specifically looked for and treated as per recommendations. The objective of the present study, almost the first of its kind in India, was to evaluate the burden of isoniazid mono-resistance amongst patients diagnosed with DRTB and to study the association of different patient and disease related factors with treatment outcomes under the treatment regimen specific for isoniazid mono-resistance, started from January 1, 2017 in our state, under RNTCP. METHODS: It was a retrospective study which scrutinized medical records of 52 isoniazid mono-resistant TB patients started on treatment under RNTCP between January 1 to December 31, 2017. Necessary information on possible patient and disease related predicting factors like gender, age, type of mutation (katG/inhA), weight band (26-45 kg/46-70 kg), total serum protein/albumin levels, previous history of anti-tubercular treatment (ATT), history of smoking, HIV status, presence of diabetes mellitus (DM), presence of anemia, occurrence of adverse drug reactions (ADR) during treatment and duration of intensive phase (IP), was retrieved. These factors were analyzed for their possible association with treatment outcomes. RESULTS: Out of 103 DRTB patients enrolled, 50.5% (52/103) patients were diagnosed with isoniazid mono-resistance. 50/103 were MDR-TB and 1/103 were extensively-drug resistant TB (XDR-TB). Further analysis of these 52 isoniazid mono-resistant patients revealed:35 (67.3%) were males and 17 (32.7%) females. 27 (51.9%) patients were <30 years, 25 (48.1%) being ≥30 years of age. All patients were negative for HIV. 34/52 (65.4%) patients were declared cured, 15/52 were lost to follow up (LTFU) and 3/52 died (1 male, 2 females). Excluding these 3 patients who died, cure rates were significantly better in females (14/15 = 93.3%), with only 1/15 LTFU, than males (20/34 = 58.8% cure, 14/34 = 41.2% LTFU), (p = 0.019). Patients who were <30 years of age had significantly better cure rates (21/25 = 84%) with lesser LTFU's (4/25 = 16%), than those ≥30years of age (13/24 = 54.2% cure, 11/24 = 45.8% LTFU), (p = 0.032). Review of previous history of ATT revealed that 33 patients had primary isoniazid mono-resistance, 4 patients had previous history of being LTFU, 9 had recurrent TB and 3 were labeled as failure. Cure rates were significantly better in primary isoniazid mono-resistant patients (26/33 = 78.8%), than those with previous history of being LTFU(0/4), (p = 0.04). Type of mutation, weight band, total serum protein/albumin, history of smoking, presence of DM, presence of anemia, occurrence of ADR and duration of IP did not affect treatment outcomes. CONCLUSION: Isoniazid mono-resistance formed a major chunk of DRTB, with majority of the patients detected with primary mono-resistance. Strategically framed treatment regimens for isoniazid mono-resistance under RNTCP in India are effective in a wide range of population. Still, there are high chances of LTFU/default, which needs to be addressed on priority. Male gender, age ≥30 years and being LTFU in the past are associated with poorer cure rates, hence should be paid special attention.

A significant therapeutic effect of silymarin administered alone, or in combination with chemotherapy, in experimental pulmonary tuberculosis caused by drug-sensitive or drug-resistant strains: In vitro and in vivo studies.

For many years, tuberculosis (TB) has been a major public health problem worldwide. Advances for treatment and eradication have been very limited. Silymarin (Sm) is a natural product with antioxidant and hepatoprotective activities that has been proposed as a complementary medicine to reduce the liver injury produced by the conventional anti-TB chemotherapy. Sm also has immunoregulatory and microbicide properties. In this study, we determined the effect of Sm on the growth control of mycobacteria. In vitro studies showed that Sm and Silibinin (the principal active compound of Sm) have microbicidal activity against drug-sensitive and multidrug-resistant (MDR) mycobacteria, induce the production of protective cytokines from infected macrophages, and improve the growth control of mycobacteria (p ≤ 0.0001). Studies in vivo using a model of progressive pulmonary TB in BALB/c mice infected with drug-sensitive or MDR mycobacteria have shown that Sm induces significant expression of Th-1 cytokines such as IFN-γ and IL-12 as well as TNFα, which produce significant therapeutic activity when administered alone and apparently have a synergistic effect with chemotherapy. These results suggest that Sm has a bactericidal effect and can contribute to the control and establishment of a TH1 protective immune response against mycobacterial infection. Thus, it seems that this flavonoid has a promising potential as adjuvant therapy in the treatment of TB.

Emergence of Low-level Delamanid and Bedaquiline Resistance During Extremely Drug-resistant Tuberculosis Treatment.

Two new drugs, delamanid and bedaquiline, have recently been approved for treatment of multidrug-resistant and extensively drug-resistant (XDR) tuberculosis. Here, we report a case of clofazimine, bedaquiline, and low-level delamanid resistances acquired during treatment of a patient with XDR tuberculosis.

A new oligonucleotide array for the detection of multidrug and extensively drug-resistance tuberculosis.

Drug-resistant tuberculosis (TB) is a global crisis and a threat to health security. Since conventional drug susceptibility testing (DST) takes several weeks, we herein described a molecular assay to rapidly identify multidrug-resistant (MDR) and extensively drug-resistant (XDR) and reveal transmission associated-mutations of Mycobacterium tuberculosis complex (MTBC) isolates in 6 to 7 hours. An array was designed with 12 pairs of primers and 60 single nucleotide polymorphisms of 9 genes: rpoB, katG, inhA, ahpC, embB, rpsL, gyrA, rrs and eis. We assessed the performance of the array using 176 clinical MTBC isolates. The results of culture-based DST were used as the gold standard, the GenoType MTBDRplus and MTBDRsl tests were used for parallel comparison, and gene sequencing was performed to resolve the discordance. The sensitivities and specificities of the array are comparable to those of the MTBDRplus test for resistance to isoniazid (INH) (100.0%, 96.7%) and rifampicin (RIF) (99.4%, 96.7%) and of the MTBDRsl test for resistance to fluoroquinolones (FQs) (100%, 100%) and second-line injectable drugs (SLIDs) (98.3%, 100%). The sensitivities of the array for detecting resistance to ethambutol and streptomycin were 79.3% and 64.9%, respectively. The array has potential as a powerful tool for clinical diagnosis and epidemiological investigations.

New drugs to treat difficult tuberculous and nontuberculous mycobacterial pulmonary disease.

PURPOSE OF REVIEW: Treatment of drug-sensitive tuberculosis (TB) is effective, whereas that of multidrug-resistant and extensively drug-resistant TB as well as nontuberculous mycobacterial (NTM) disease are less so. Therapy in general requires good adherence to potentially toxic drug regimens over prolonged periods. Poor adherence is associated with resistance development and poor outcome. This review will present promising new treatments, both new drugs and regimens, for difficult mycobacterial pulmonary infections. RECENT FINDINGS: A number of new and repurposed drugs including bedaquiline, delamanid, pretomanid, linezolid and clofazimine, and drug regimens, such as the The Evaluation of a Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB (STREAM) trial regimens, are currently progressing from basic research through clinical trials.