[Study on the direct economic burden and relevant influencing factors of 233 multidrug/rifampicin-resistant pulmonary tuberculosis patients in Jiangsu Province].

Objective: To explore the direct economic burden and factors affecting out-of-pocket direct costs of multidrug-/rifampicin-resistant pulmonary tuberculosis (MDR/RR-PTB) patients in Jiangsu Province. Methods: MDR/RR-PTB patients diagnosed and treated at 13 municipal tuberculosis (TB)-designated hospitals in Jiangsu Province between January 1, 2021, and December 31, 2022, were included, and basic information and direct economic costs were obtained through questionnaires and hospital information systems. Stepwise multiple linear regression was used to analyze the factors influencing patients' out-of-pocket direct costs. Results: The age of the 233 MDR/RR-PTB patients was (44.04±15.64) years. The M(Q1, Q3) direct medical expense of the patients was 134 051.00 (98 934.01,163 205.73) Yuan, of which the M(Q1,Q3) reimbursement by health insurance or policy reduction was 100 462.10 (78 120.00,130 816.00) Yuan, and the M(Q1,Q3) out-of-pocket direct medical expense was 21 694.62 (14 734.83,37 813.00) Yuan. The M(Q1,Q3) direct non-medical expense was 4 971.00 (3 138.00,7 870.00) Yuan. Age, registered residence location, TB resulting in divorce or separation from spouse or partner, drug resistance test results, and treatment regimens were the influencing factors associated with out-of-pocket direct costs for MDR/RR-PTB patients. Conclusions: The direct economic burden caused by MDR/RR-PTB in Jiangsu Province is heavy. It is necessary to emphasize psychological guidance and care for MDR/RR-PTB patients, improve the diagnosis, treatment, and management of MDR/RR-PTB, and effectively reduce the economic burden of MDR/RR-PTB patients.

Evaluation of mycobacterial microscopy and culture results from clinical samples: A five-year analysis.

Introduction: Ehrlich-Ziehl-Neelsen (EZN) staining and culture methods are often used to diagnose tuberculosis. This study aimed to determine the acidfast bacteria (AFS) positivity rates in various clinical samples sent to our laboratory over five years and the growth and resistance rates in two different (solid and liquid) cultures and compare them with the data from Türkiye and the world. Materials and Methods: A total of 62.456 clinic samples were accepted in the microbiology laboratory between 2019 and 2024. The mycobacterial culture was performed by searching for acid-resistant bacilli microscopically and parallel inoculation media [solid Löwenstein-Jensen (L-J) and MGIT 960 liquid]. Those growing in the MGIT 960 system were identified using BD MGIT TBC Identification test kits that detect the MPT64 antigen. AFS and MPT64 antigenpositive samples were identified as Mycobacterium tuberculosis complex (MTBC) while AFS-positive samples and MPT64 antigen-negative results were classified as non-tuberculous mycobacteria (NTM). Drug susceptibility testing was performed with the BACTEC MGIT 960 SIRE kit. Susceptibility to NTM samples was not performed. Result: Out of a total of 120.829 samples, 95.101 were lung samples and 25.728 were extrapulmonary samples. AFS positivity was detected in 2961 (2.4%) samples. MTBC grew in 6854 (5.6%) samples, and NTM grew in 1506 (1.24%) samples. Contamination was detected in 7171 (5.9%) media. Two thousand one hundred and sixty-nine susceptibility tests were performed. Considering antibiotic resistance rates, isoniazid resistance was detected in 154 (7%), rifampicin resistance in 140 (6.4%), ethambutol resistance in 18 (0.8%), and streptomycin resistance in 120 (0.5%) samples. All four-drug resistance was observed in 91 (4.1%) samples. AFP positivity and resistance rates for rifampicin have decreased significantly, while there have been no significant changes in NTM rates over the years. Conclusions: When our data was determined, the sensitivity of microscopy was low. It is understood that mycobacterial culture and microscopy must be evaluated together to exclude tuberculosis infection. The high mycobacterial culture positivity rate, which is 5.6%, is due to the high number of follow-up patients and new referrals. It is seen that the change in sensitivity rates is due to the period of the COVID-19 epidemic, and it is similar to World Health Organization (WHO) data.

Nine months of bedaquiline, linezolid, levofloxacin, clofazimine, and cycloserine chemotherapy for rifampicin/multidrug-resistant tuberculosis: a multicenter, randomized, open-label non-inferiority trial in China.

BACKGROUND: We concurrently developed a prospective study to assess clinical outcomes among patients receiving 9-month bedaquiline (BDQ)-containing regimens, aiming to provide valuable data on the use of this short-course regimen in China. METHODS: This open-label, randomized, controlled, multicenter, non-inferiority trial was conducted at sixteen hospitals, and enrolled participants aged 18 years and older with pulmonary rifampicin/multidrug tuberculosis. Participants were randomly assigned, in a 1:1 ratio. Individuals within the standard-regimen group received 6 months of BDQ, linezolid, levofloxacin, clofazimine, and cycloserine plus 12 months of levofloxacin, and any three potentially effective drugs from clofazimine, cycloserine pyrazinamide, ethambutol and protionamide, whereas individuals within shorter-regimen group received 9 months of BDQ, linezolid, levofloxacin, clofazimine and cycloserine. The primary outcome was the percentage of participants with a composite unfavorable outcome (treatment failure, death, treatment discontinuation, or loss to follow-up) by the end of the treatment course after randomization in the modified intention-to-treat population. The noninferiority margin was 10%. This trial was registered with www.chictr.org.cn , ChiCTR2000029012. RESULTS: Between Jan 1, 2020, and Dec 31, 2023, 264 were screened and randomly assigned, 132 of 264 participants were assigned to the standard-regimen group and 132 were assigned to the shorter-regimen. Thirty-three (12.55%) of 264 participants were excluded from the modified intention-to-treat analysis. As a result, 231 participants were included in the modified intention-to-treat analysis (116 in the standard-regimen group and 115 in the shorter-regimen group).In the modified intention-to-treat population, unfavorable outcomes were reported in 19 (16.5%) of 115 participants for whom the outcome was assessable in the shorter-regimen group and 26 (22.4%) of 116 participants in the standard care group (risk difference 5.9 percentage points (97.5% CI - 5.8 to 17.5)). One death was reported in the standard-regimen group. The incidence of QTcF prolongation in the shorter-regimen group (22.6%, 26/115) was similar to the standard-regimen group (24.1%, 28/116). CONCLUSIONS: The 9-month, all-oral regimen is safe and efficacious for the treatment of pulmonary rifampicin/multidrug-resistant tuberculosis. The high incidence of QTc prolongation associated with the use of BDQ highlights the urgent need of routine electrocardiogram monitoring under treatment with BDQ-containing regimens in the Chinese population.

Macrophage targeted graphene oxide nanosystem synergize antibiotic killing and host immune defense for Tuberculosis Therapy.

Tuberculosis (TB), a deadly disease caused by Mycobacterium tuberculosis (Mtb) infection, remains one of the top killers among infectious diseases worldwide. How to increase targeting effects of current anti-TB chemotherapeutics and enhance anti-TB immunological responses remains a big challenge in TB and drug-resistant TB treatment. Here, mannose functionalized and polyetherimide protected graphene oxide system (GO-PEI-MAN) was designed for macrophage-targeted antibiotic (rifampicin) and autophagy inducer (carbamazepine) delivery to achieve more effective Mtb killings by combining targeted drug killing and host immunological clearance. GO-PEI-MAN system demonstrated selective uptake by in vitro macrophages and ex vivo macrophages from macaques. The endocytosed GO-PEI-MAN system would be transported into lysosomes, where the drug loaded Rif@Car@GO-PEI-MAN system would undergo accelerated drug release in acidic lysosomal conditions. Rif@Car@GO-PEI-MAN could significantly promote autophagy and apoptosis in Mtb infected macrophages, as well as induce anti-bacterial M1 polarization of Mtb infected macrophages to increase anti-bacterial IFN-γ and nitric oxide production. Collectively, Rif@Car@GO-PEI-MAN demonstrated effectively enhanced intracellular Mtb killing effects than rifampicin, carbamazepine or GO-PEI-MAN alone in Mtb infected macrophages, and could significantly reduce mycobacterial burdens in the lung of infected mice with alleviated pathology and inflammation without systemic toxicity. This macrophage targeted nanosystem synergizing increased drug killing efficiency and enhanced host immunological defense may be served as more effective therapeutics against TB and drug-resistant TB.

Massive cerebral tuberculomas, Pott's disease and hypercalcaemia secondary to Mycobacterium bovis in a patient with chronic kidney disease on peritoneal dialysis.

Tuberculosis (TB) is still a health problem in developing countries. Pulmonary involvement remains the most common clinical presentation. However, multiorgan involvement can be life-threatening. We present the case of a young woman on peritoneal dialysis who was admitted to hospitalisation for hypercalcaemia and low back pain. In his biochemical evaluation, suppressed intact parthyroid hormone (iPTH) and elevated 1,25-hydroxyvitamin D were detected. On a lumbar CT scan, a hypodense lesion in vertebral bodies compatible with Pott's disease was found. Positive cultures for Mycobacterium bovis were obtained in bronchoalveolar lavage and peritoneal fluid, for which specific treatment was initiated. Due to neurological deterioration, a CT scan was performed showing the presence of multiple tuberculomas. Retrospectively, the lack of an etiological diagnosis of chronic kidney disease, the initiation of dialysis 8 months before and the clear evidence of long-standing TB strongly suggest mycobacterium infection as the cause or trigger for the rapid decline in kidney function.

Response to treatment and low serum vitamin D levels in North Indian patients with treatment-naive category I and multi-drug resistant pulmonary tuberculosis.

BACKGROUND: Tuberculosis (TB) is a bacterial infection that usually affects the lungs, although it can also affect other parts of the body. Vitamin D deficiency and response to treatment have been demonstrated in patients with active TB in several studies, but not in MDR-TB patients, which is a new observation in the present study. OBJECTIVE: To study the time to initial sputum culture conversion and to associate baseline vitamin D levels and response to treatment in patients with PTB Cat I and MDR-TB. METHODS: A total of 897 North Indian participants were recruited and divided into three groups: treatment-naïve PTB Cat I, MDR-TB, and healthy controls. Serum biochemistry, including 25-hydroxyvitamin D and calcium, was measured in all participants with PTB, Cat I, and MDR-TB. RESULTS: PTB Cat I patients had high bacillary load grading at baseline compared to 2nd month followed by 6th month of treatment. More severe chest radiographic features, such as cavitation and the presence of bilateral disease at baseline. Mean sputum smear conversion times were 0.95 ± 0.7 months and culture conversion to negative occurred at a mean time of 0.8 ± 0.7 in PTB Cat I patients compared to MDR-TB patients on average sputum smear and time of 2.4 ± 3 months. Significantly lower mean serum 25-hyroxyvitamin D concentration was found in the 6th month than in the 2nd month and baseline in PTB Cat I. CONCLUSION: Low serum vitamin D deficiency was observed in both groups during treatment and is one of the important factors responsible for susceptibility to TB in both groups; however, its significance is uncertain. Patients with continuous positive sputum for multidrug-resistant tuberculosis (MDR-TB) had a worse prognosis than those with sputum bacteriology conversion. Two months into a treatment regimen, sputum smear conversions may be a useful indicator of an MDR-TB patient's prognosis.

Enhance the Antimycobacterial Activity of Streptomycin with Ebselen as an Antibiotic Adjuvant Through Disrupting Redox Homeostasis.

Purpose: Tuberculosis (TB) remains a major health threat worldwide, and the spread of drug-resistant (DR) TB impedes the reduction of the global disease burden. Ebselen (EbSe) targets bacterial thioredoxin reductase (bTrxR) and causes an imbalance in the redox status of bacteria. Previous work has shown that the synergistic action of bTrxR and sensitization to common antibiotics by EbSe is a promising strategy for the treatment of DR pathogens. Thus, we aimed to evaluate whether EbSe could enhance anti-TB drugs against Mycobacterium marinum (M. marinum) which is genetically related to Mycobacterium tuberculosis (Mtb) and resistant to many antituberculosis drugs. Methods: Minimum inhibitory concentrations (MIC) of isoniazid (INH), rifampicin (RFP), and streptomycin (SM) against M. marinum were determined by microdilution. The Bliss Independence Model was used to determine the adjuvant effects of EbSe over the anti-TB drugs. Thioredoxin reductase activity was measured using the DTNB assay, and its effects on bacterial redox homeostasis were verified by the elevation of intracellular ROS levels and intracellular GSH levels. The adjuvant efficacy of EbSe as an anti-TB drug was further evaluated in a mouse model of M. marinum infection. Cytotoxicity was observed in the macrophage cells Raw264.7 and mice model. Results: The results reveal that EbSe acts as an antibiotic adjuvant over SM on M. marinum. EbSe + SM disrupted the intracellular redox microenvironment of M. marinum by inhibiting bTrxR activity, which could rescue mice from the high bacterial load, and accelerated recovery from tail injury with low mammalian toxicity. Conclusion: The above studies suggest that EbSe significantly enhanced the anti-Mtb effect of SM, and its synergistic combination showed low mammalian toxicity in vitro and in vivo. Further efforts are required to study the underlying mechanisms of EbSe as an antibiotic adjuvant in combination with anti-TB drug MS.

Drug-resistant tuberculosis treatments, the case for a phase III platform trial.

Most phase III trials in drug-resistant tuberculosis have either been underpowered to quantify differences in microbiological endpoints or have taken up to a decade to complete. Composite primary endpoints, dominated by differences in treatment discontinuation and regimen changes, may mask important differences in treatment failure and relapse. Although new regimens for drug-resistant tuberculosis appear very effective, resistance to new drugs is emerging rapidly. There is a need for shorter, safer and more tolerable regimens, including those active against bedaquiline-resistant tuberculosis. Transitioning from multiple regimen A versus regimen B trials to a single large phase III platform trial would accelerate the acquisition of robust estimates of relative efficacy and safety. Further efficiencies could be achieved by adopting modern adaptive platform designs. Collaboration among trialists, affected community representatives, funders and regulators is essential for developing such a phase III platform trial for drug-resistant tuberculosis treatment regimens.

La majorité des essais de phase III relatifs à la tuberculose pharmacorésistante soit n'étaient pas assez puissants pour quantifier les fluctuations au niveau des critères microbiologiques, soit étaient trop longs, se poursuivant parfois pendant dix ans. Les critères primaires composites, dominés par des différences dans l'interruption du traitement et les changements de schéma, pourraient dissimuler d'importantes variations en termes d'échec thérapeutique et de rechute. Bien que les nouveaux traitements contre la tuberculose pharmacorésistante semblent très efficaces, la résistance aux nouveaux médicaments évolue rapidement. Il est donc nécessaire d'opter pour des traitements plus courts, plus sûrs et mieux tolérés, y compris ceux actifs contre la tuberculose résistant à la bédaquiline. Délaisser la multitude d'essais opposant un schéma de traitement A à un schéma de traitement B pour se diriger vers un unique essai plateforme de phase III de grande envergure permettrait d'obtenir plus vite des estimations solides concernant l'innocuité et l'efficacité relative. En outre, adopter des modèles de plateforme modernes et adaptatifs contribuerait à de meilleures performances. Enfin, la collaboration entre investigateurs, représentants des communautés concernées, bailleurs de fonds et organismes de réglementation est essentielle à l'élaboration de ce type d'essai plateforme de phase III sur les traitements contre la tuberculose pharmacorésistante.

La mayoría de los ensayos en fase III sobre tuberculosis resistente a los fármacos no ha tenido la potencia suficiente para cuantificar diferencias en los criterios de valoración microbiológicos o ha tardado hasta una década en completarse. Los criterios de valoración principales compuestos, dominados por las diferencias en la interrupción del tratamiento y los cambios de régimen, pueden ocultar diferencias importantes en el fracaso del tratamiento y la recaída. Aunque los nuevos regímenes de tratamiento para la tuberculosis resistente a los fármacos parecen muy eficaces, la resistencia a los nuevos fármacos está apareciendo rápidamente. Se necesitan regímenes de tratamiento más cortos, seguros y tolerables, incluidos los activos contra la tuberculosis resistente a la bedaquilina. La transición de múltiples ensayos de régimen A frente a régimen B a un único gran ensayo de plataforma en fase III aceleraría la obtención de estimaciones sólidas de la eficacia y seguridad relativas. Podrían lograrse mayores eficiencias si se adoptaran diseños de plataforma adaptativos modernos. La colaboración entre los autores de los ensayos, los representantes de las comunidades afectadas, los financiadores y los reguladores es esencial para desarrollar un ensayo de plataforma en fase III de este tipo para los regímenes de tratamiento de la tuberculosis resistente a los fármacos.

Mycobacterial ß-carbonic anhydrases: Molecular biology, role in the pathogenesis of tuberculosis and inhibition studies.

Mycobacterium tuberculosis (Mtb), which causes tuberculosis (TB), is still a major global health problem. According to the World Health Organization (WHO), TB still causes more deaths worldwide than any other infectious agent. Drug-sensitive TB is treatable using first-line drugs; treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB requires second- and third-line drugs. However, due to the long duration of treatment, the noncompliance of patients with different levels of resistance of Mtb to these drugs has worsened the situation. Previously developed anti-TB drugs targeted the replication machinery, protein synthesis, and cell wall biosynthesis pathways of Mtb. Therefore, novel drugs targeting alternate pathways crucial for the survival and pathogenesis of Mtb in the human host are needed. The genome of Mtb encodes three ß-carbonic anhydrases (CAs) that are fundamental for pH homeostasis, hypoxia, survival, and pathogenesis. Recently, several studies have shown that the ß-CAs of Mtb could be inhibited both in vitro and in vivo using small chemical molecules, suggesting that these enzymes could be novel targets for developing anti-TB compounds that are devoid of resistance by Mtb. In addition, homologs of ß-CAs are absent in humans; therefore, drugs developed to target these enzymes might have minimal off-target effects. In this work, we describe the roles of ß-CAs in Mtb and discuss bioinformatics and cheminformatics tools used in development and discovery of novel inhibitors of these enzymes. In addition, we summarize the in vitro and in vivo studies demonstrating that the ß-CAs of Mtb are indeed druggable targets.

Disseminated MDR-TB missed in a patient treated with TNF inhibitor.

A previously healthy man developed pulmonary symptoms 2 weeks after starting treatment with a tumour necrosis factor (TNF) inhibitor. A negative interferon-gamma release assay (IGRA) test was obtained prior to TNF inhibitor exposure, without consideration of the fact that the patient was already immunosuppressed and had a previous positive IGRA test 17 months earlier. The patient was treated for pneumonia twice but did not achieve remission. His physical health progressively deteriorated over the following months. Malignancy was suspected but not found. Eight months after the onset of symptoms, Mycobacterium tuberculosis was found in samples from mediastinal lymph nodes, and the patient was diagnosed with multidrug-resistant tuberculosis (MDR-TB).This case illustrates the diagnostic challenge of TB, the need to raise awareness of the increased risk of TB in patients treated with TNF inhibitors and the need to increase knowledge regarding the effect of immunosuppressive agents on IGRA tests.

The Mycobacterium tuberculosis Cell Wall: An Alluring Drug Target for Developing Newer Anti-TB Drugs-A Perspective.

The Mycobacterium cell wall is a capsule-like structure comprising of various layers of biomolecules such as mycolic acid, peptidoglycans, and arabinogalactans, which provide the Mycobacteria a sort of cellular shield. Drugs like isoniazid, ethambutol, cycloserine, delamanid, and pretomanid inhibit cell wall synthesis by inhibiting one or the other enzymes involved in cell wall synthesis. Many enzymes present across these layers serve as potential targets for the design and development of newer anti-TB drugs. Some of these targets are currently being exploited as the most druggable targets like DprE1, InhA, and MmpL3. Many of the anti-TB agents present in clinical trials inhibit cell wall synthesis. The present article covers a systematic perspective of developing cell wall inhibitors targeting various enzymes involved in cell wall biosynthesis as potential drug candidates for treating Mtb infection.

Coexistence of pulmonary thromboembolism and pulmonary tuberculosis: a diagnostic dilemma.

A man in his early 50s with previously treated pulmonary tuberculosis (TB) presented with a 3-month history of cough, expectoration and progressive breathlessness, accompanied by significant weight loss. Examination revealed tachycardia, tachypnoea, hypoxaemia and unilateral diminished breath sounds. Investigations showed anaemia, leucocytosis and a homogeneous opacity on the left side of the CXR. ECG and echocardiography suggested pulmonary thromboembolism (PTE). A CT pulmonary angiogram confirmed a chronic embolus and a severely fibrosed left lung. A comprehensive thrombophilia workup yielded normal results and the PTE was attributed to his history of TB. Sputum analysis confirmed reactivated TB, leading to the initiation of antitubercular therapy. The patient improved clinically with plans for a repeat CT pulmonary angiography to assess the need for pulmonary thromboendarterectomy after completing TB treatment. This case highlights the possible association of TB and PTE, its management and why it should be considered as a differential diagnosis in patients with a history of TB presenting with exacerbated breathlessness.

A machine-learning based model for automated recommendation of individualized treatment of rifampicin-resistant tuberculosis.

BACKGROUND: Rifampicin resistant tuberculosis remains a global health problem with almost half a million new cases annually. In high-income countries patients empirically start a standardized treatment regimen, followed by an individualized regimen guided by drug susceptibility test (DST) results. In most settings, DST information is not available or is limited to isoniazid and fluoroquinolones. Whole genome sequencing could more accurately guide individualized treatment as the full drug resistance profile is obtained with a single test. Whole genome sequencing has not reached its full potential for patient care, in part due to the complexity of translating a resistance profile into the most effective individualized regimen. METHODS: We developed a treatment recommender clinical decision support system (CDSS) and an accompanying web application for user-friendly recommendation of the optimal individualized treatment regimen to a clinician. RESULTS: Following expert stakeholder meetings and literature review, nine drug features and 14 treatment regimen features were identified and quantified. Using machine learning, a model was developed to predict the optimal treatment regimen based on a training set of 3895 treatment regimen-expert feedback pairs. The acceptability of the treatment recommender CDSS was assessed as part of a clinical trial and in a routine care setting. Within the clinical trial setting, all patients received the CDSS recommended treatment. In 8 of 20 cases, the initial recommendation was recomputed because of stock out, clinical contra-indication or toxicity. In routine care setting, physicians rejected the treatment recommendation in 7 out of 15 cases because it deviated from the national TB treatment guidelines. A survey indicated that the treatment recommender CDSS is easy to use and useful in clinical practice but requires digital infrastructure support and training. CONCLUSIONS: Our findings suggest that global implementation of the novel treatment recommender CDSS holds the potential to improve treatment outcomes of patients with RR-TB, especially those with 'difficult-to-treat' forms of RR-TB.

Treatment for multidrug-resistant tuberculosis: A comparative analysis of programmatic outcome indicators between Buenaventura and other municipalities of Valle del Cauca, Colombia / Tratamiento para tuberculosis resistente a rifampicina o multirresistente: análisis comparativo de indicadores programáticos entre Buenaventura y otros municipios del Valle del Cauca, Colombia

Introduction. Proper management of multidrug-resistant tuberculosis is a prioritized strategy for tuberculosis control worldwide. Objective. To evaluate differences concerning demographic and clinical characteristics and programmatic indicators of Buenaventura patient cohort with confirmed diagnosis of multidrug-resistant tuberculosis, compared to those of the other municipalities from Valle del Cauca, Colombia, 2013-2016. Materials and methods. We conducted an analytical cohort study to compare records of patients older than 15 years with multidrug-resistant tuberculosis included in the Programa de Tuberculosis de Buenaventura (with para-aminosalicylic acid) versus the other municipalities of Valle del Cauca (without para-aminosalicylic). Results. Ninety-nine cases were recorded with a median age of 40 years (IQR = 26 - 53); in Buenaventura, 56% of the patients were women, while in the other municipalities, men predominated with 67%; 95% had health insurance. The most common comorbidity was diabetes (14%). Adverse reactions to antituberculosis medications in Buenaventura were 1.3 times more frequent than in the other municipalities (OR = 2.3; 95% CI = 0.993 - 5.568; p = 0.04). In Buenaventura, the mortality rate was 5% compared to the 15% reported in the other municipalities. Treatment failures were not reported in Buenaventura, but 35% did not continue with the follow-up. Treatment success was higher in Buenaventura (56 %). Conclusion. A strengthened program in Buenaventura presented better programmatic results than those from the other municipalities of Valle del Cauca. Access to molecular tests, availability of shortened treatments, and continuous monitoring to identify adverse reactions to antituberculosis medications are routes for all other control programs.

Introducción. El manejo adecuado de la tuberculosis multirresistente es una estrategia priorizada para el control de la tuberculosis en el mundo. Objetivo. Evaluar las diferencias entre las características demográficas y clínicas, y los indicadores programáticos de los pacientes con diagnóstico confirmado de tuberculosis pulmonar resistente a rifampicina o multirresistente en Buenaventura, frente a la cohorte de los demás municipios del Valle del Cauca entre 2013 y 2016. Materiales y métodos. Se desarrolló un estudio analítico de cohortes para comparar los registros de pacientes mayores de 15 años con tuberculosis multirresistente, del Programa de Tuberculosis de Buenaventura (con ácido paraaminosalicílico), frente a los demás municipios del Valle del Cauca (sin ácido paraaminosalicílico). Resultados. Se registraron 99 casos con una mediana de edad de 40 años (RIC = 26- 53); en Buenaventura, el 56 % eran mujeres; en los demás municipios, predominaron los hombres (67 %); el 95 % de los evaluados tenía aseguramiento en salud. La comorbilidad más frecuente fue diabetes (14 %). Las reacciones adversas a medicamentos antituberculosos en Buenaventura fueron 1,3 veces más frecuentes que en los demás municipios (OR = 2,3; IC95 %: 0,993 - 5,568; p = 0,04). En Buenaventura falleció el 5 % de los casos frente al 15 % reportado en los demás municipios. No hubo fracasos con el tratamiento en Buenaventura, pero se reportó un 35 % de pérdida del seguimiento. El éxito del tratamiento fue mayor en Buenaventura en el 56 %. Conclusión. El programa fortalecido de Buenaventura presentó mejores resultados programáticos que los demás municipios del Valle del Cauca. El acceso a pruebas moleculares, la disponibilidad de tratamientos acortados y el seguimiento continuo para identificar reacciones adversas a medicamentos antituberculosos son un derrotero para todos los programas de control.

Rifampicin tolerance and growth fitness among isoniazid-resistant clinical Mycobacterium tuberculosis isolates from a longitudinal study.

Antibiotic tolerance in Mycobacterium tuberculosis reduces bacterial killing, worsens treatment outcomes, and contributes to resistance. We studied rifampicin tolerance in isolates with or without isoniazid resistance (IR). Using a minimum duration of killing assay, we measured rifampicin survival in isoniazid-susceptible (IS, n=119) and resistant (IR, n=84) isolates, correlating tolerance with bacterial growth, rifampicin minimum inhibitory concentrations (MICs), and isoniazid-resistant mutations. Longitudinal IR isolates were analyzed for changes in rifampicin tolerance and genetic variant emergence. The median time for rifampicin to reduce the bacterial population by 90% (MDK90) increased from 1.23 days (IS) and 1.31 days (IR) to 2.55 days (IS) and 1.98 days (IR) over 15-60 days of incubation, indicating fast and slow-growing tolerant sub-populations. A 6 log10-fold survival fraction classified tolerance as low, medium, or high, showing that IR is linked to increased tolerance and faster growth (OR = 2.68 for low vs. medium, OR = 4.42 for low vs. high, p-trend = 0.0003). High tolerance in IR isolates was associated with rifampicin treatment in patients and genetic microvariants. These findings suggest that IR tuberculosis should be assessed for high rifampicin tolerance to optimize treatment and prevent the development of multi-drug-resistant tuberculosis.

The performance of Xpert MTB/RIF and MTBDRplus within a Programmatic setting at TB Laboratory in Rio de Janeiro, Brazil.

BACKGROUND: Few studies in routine settings have confirmed the high accuracy of the Xpert MTB/RIF assay for detecting rifampicin resistance (RR) and the first-line probe assay (FL-LPA) for detecting both RR and isoniazid resistance (INHR). METHODS: The performance of Xpert MTB/RIF and MTBDRplus VER 2.0 LPA was evaluated in 180 Mycobacterium tuberculosis samples collected from January 2018 to December 2019 in Rio de Janeiro, Brazil. The results were compared with those from BACTEC MGIT 960 culture and drug susceptibility testing (DST). Whole-genome sequencing was performed on the samples with discordant results. RESULTS: The Xpert MTB/RIF assay showed a sensitivity (Se) of 93.3% and a specificity (Sp) of 97.6%, detecting RR. The performance of FL-LPA to identify RIF and INH resistance was, respectively, (Se) 100% and 83.3% and (Sp) 98.8% and 100%. Among 18 clinical isolates with INHR detected by FL-LPA, mutations in the katG gene were observed in 100% of samples, of which only two (11.1%) had mutations in both katG and inhA genes. Overall, the discordant results were identified in 9 (5%) samples. Among the four Xpert RIF-resistant and DST-sensitive, two harbored mutations in rpoB Leu430Pro. Among the four FL-LPA-sensitive and DST-resistant, one had a mutation in inhA 17G>T. FL-LPA showed high accuracy in detecting RR and INHR. CONCLUSIONS: The MTBDRplus test demonstrated excellent performance in detecting RR, and INHR in clinical isolates under routine conditions at a reference laboratory in Rio de Janeiro, Brazil. Incorporating both tests can improve drug-resistant tuberculosis treatment outcomes and monitor the INHR incidence.

Two Cases of Testicular Tuberculosis and Review of the Recent Literature.

In this review, two cases of testicular tuberculosis (TB) are presented, and another 58 cases published in PubMed between January 1, 2012, and July 31, 2023, are reviewed. Testicular TB remains a disease mainly of the developing world, with one notable exception - the infections caused as a result of Bacillus Calmette-Guérin infusion immunotherapy for bladder cancer. Its clinical course is subacute; however, it might get disseminated and become life-threatening; therefore, prompt diagnosis is very important. The diagnosis can be quite challenging, and testicular tissue is the sample with the highest diagnostic yield, either for microbiological or histopathological diagnosis. On the other hand, its treatment follows the standard guidelines for TB treatment; however, the avoidance of an unnecessary orchiectomy is important.

Affecting Factors Unfavorable Treatment Outcomes of Rifampicin-resistant/Multidrug-resistant Tuberculosis Patients Treated with Long-term Regimen.

BACKGROUND: Drug-resistant tuberculosis (DR-TB) poses a significant threat to global TB control and remains a major public health issue. This study aims to evaluate treatment outcomes and identify risk factors for unfavorable outcomes in patients with multi-DR-TB (MDR-TB) treated at a major reference hospital in Istanbul. METHODS: We conducted a retrospective analysis of 413 patients with rifampicin-resistant and MDR-TB who received treatment between January 1, 2013, and December 31, 2023, at the University of Health Sciences Süreyyapasa Chest Diseases Training and Research Hospital. Patients were treated following the World Health Organization and national guidelines, with regimens tailored to individual drug resistance profiles and side effect management. Demographic data, comorbidities, microbiological follow-up, drug resistance patterns, treatment regimens, and radiological findings were analyzed. RESULTS: Treatment success was achieved in 350 patients (84.74%). Thirty-two patients (7.74%) were lost to follow-up, and 32 patients (7.74%) died. Logistic regression analysis identified several factors associated with unfavorable treatment outcomes: comorbidities (odds ratio [OR]: 7.555, P = 0.001), quinolone resistance (OR: 3.695, P = 0.030), and bronchiectasis (OR: 4.126, P = 0.013). Additional significant factors included male gender (P = 0.007), foreign-born status (P = 0.013), age over 35 years (P = 0.002), previous treatment history (P = 0.058), and drug side effects (P = 0.012). CONCLUSION: The long-term regimen for MDR-TB was found to be highly successful, with an 84.74% treatment success rate. Effective treatment regimens, close patient follow-up, early recognition of side effects, and comprehensive management are crucial for achieving successful outcomes. Identifying and addressing risk factors such as comorbidities, drug resistance, and specific patient demographics can further improve treatment success rates. This study underscores the importance of tailored treatment strategies and robust patient management in combating MDR-TB.

Diagnostics Evaluation of Smart Sure™ Mycobacterium tuberculosis Screening Kit and Smart Sure™ Multidrug-resistant Tuberculosis Detection Kit on Nonsputum Specimens at a Tertiary Care Center of North India.

BACKGROUND: Tuberculosis (TB) is caused due to the infection of Mycobacterium tuberculosis (MTB) and it can infect the various parts of the human body. The disease is highly prevalent and is the second most common cause of death worldwide after COVID-19. Apart from sputum specimen, it is exceedingly difficult to diagnose due to its paucibacillary nature. The current study was intended to evaluate the accuracy of Smart Sure™ MTB and multidrug-resistant-TB (MDR-TB) kits (Genetix Biotech Asia Pvt. Ltd., India) with Xpert ultra and Mycobacterium growth indicator tube (MGIT) culture on nonsputum specimens from TB suspects. METHODS: A total of 205 nonsputum specimens were received between October 2023 and May 2024 at Intermediate Reference Laboratory, Department of Medicine, All India Institute of Medical Sciences, New Delhi, India. Xpert ultra and Smart Sure™ MTB and MDR-TB tests were done directly on samples. However, processed specimens were used for MGIT culture and drug-susceptibility testing (DST). Invalid and MGIT contaminated specimens were excluded from the final calculation. RESULTS: Overall, sensitivity and specificity of Smart Sure™ MTB screening kit was 71.59% and 98.28%, respectively, with Xpert ultra and 68.35% and 90.83%, respectively, with MGIT culture. While comparing with both Xpert ultra and MGIT-DST to detect rifampicin (RIF) resistant, Smart Sure™ MDR-TB kits showed sensitivity of 75.0% and 100% of specificity. However, for isoniazid (INH) resistance, Smart Sure™ MDR-TB kits showed 100% of sensitivity and specificity with MGIT-DST. CONCLUSION: For the detection of MTB and its drug-resistance patterns (RIF and INH) in the specimens other than sputum, Smart Sure™ MTB and MDR-TB kits could play a vital role in TB endemic countries. While comparing the set-ups and skilled staffs, it required almost same as compared with previously approved WHO diagnostics used in resource-limited countries.

Pyrazinamide-induced Hyperuricemia in Pulmonary Tuberculosis Patients.

BACKGROUND: Pyrazinamide is one of the antitubercular drugs used for 2 months in the intensive phase. One of the adverse effects of pyrazinamide is hyperuricemia, with a symptom of arthralgia. This study aims to analyze the incidence of hyperuricemia and arthralgia and their causality in pulmonary tuberculosis (TB) patients undergoing treatment in the intensive phase. METHODS: It was an analytic observational study with a prospective cohort design. Three ml of blood from each pulmonary TB patient was withdrawn to examine uric acid levels before and after 2 months of treatment with pyrazinamide. The Wilcoxon test was used to analyze changes in uric acid levels and the Chi-square test to analyze the association between uric acid levels and arthralgia. Naranjo algorithm is used to analyze the causality of hyperuricemia. RESULTS: Twenty pulmonary TB patients met the inclusion criteria in this study. Eight out of 12 (60%) TB patients showed uric acid levels ≥7 mg/dl and 8 of them (66.6%) showed symptoms of arthralgia. The median uric acid level increased significantly before (5.14 mg/dl) and after 2 months of treatment (7.74 mg/dl), P-value = 0.001. Uric acid levels ≥7 mg/dl were significantly associated with arthralgia (P-value = 0.017; odds ratio 14.00; 95% confidence interval 1.25-156.61). Based on the Naranjo algorithm, those with hyperuricemia, eight and four patients had a total score of 7 and 8, respectively, which are classified as probable. CONCLUSION: Uric acid levels significantly increased during the intensive phase. Pulmonary TB patients with hyperuricemia are a risk factor for arthralgia.