Artificial intelligence-based radiographic extent analysis to predict tuberculosis treatment outcomes: a multicenter cohort study.

Predicting outcomes in pulmonary tuberculosis is challenging despite effective treatments. This study aimed to identify factors influencing treatment success and culture conversion, focusing on artificial intelligence (AI)-based chest X-ray analysis and Xpert MTB/RIF assay cycle threshold (Ct) values. In this retrospective study across six South Korean referral centers (January 1 to December 31, 2019), we included adults with rifampicin-susceptible pulmonary tuberculosis confirmed by Xpert assay from sputum samples. We analyzed patient characteristics, AI-based tuberculosis extent scores from chest X-rays, and Xpert Ct values. Of 230 patients, 206 (89.6%) achieved treatment success. The median age was 61 years, predominantly male (76.1%). AI-based radiographic tuberculosis extent scores (median 7.5) significantly correlated with treatment success (odds ratio [OR] 0.938, 95% confidence interval [CI] 0.895-0.983) and culture conversion at 8 weeks (liquid medium: OR 0.911, 95% CI 0.853-0.973; solid medium: OR 0.910, 95% CI 0.850-0.973). Sputum smear positivity was 49.6%, with a median Ct of 26.2. However, Ct values did not significantly correlate with major treatment outcomes. AI-based radiographic scoring at diagnosis is a significant predictor of treatment success and culture conversion in pulmonary tuberculosis, underscoring its potential in personalized patient management.

Antistreptococcal treatment of psoriasis: a systematic review.

Streptococcal infections may contribute to psoriasis development, and antistreptococcal treatments are considered potential therapies, but their effectiveness remains uncertain due to limited systematic evidence. Our objective was to analyze antistreptococcal therapies' effectiveness in improving psoriasis. We conducted a systematic review following PRISMA guidelines, evaluating antistreptococcal treatment efficacy in psoriasis patients from PubMed, Scopus, and Embase databases until August 14, 2022. Eligible studies included psoriasis patients undergoing antistreptococcal therapy, regardless of demographics or psoriasis type. 50 studies (1778 patients) were analyzed, with penicillins/aminopenicillins as the most studied antibiotics (21 studies), showing mixed outcomes, some reporting significant improvement in guttate psoriasis, while others showed no significant difference. Rifampin demonstrated positive results in most of ten studies, and macrolides showed varying effectiveness in two studies. Tonsillectomy in 14 studies (409 patients) mainly focusing on guttate and chronic plaque psoriasis showed positive outcomes, indicating improved symptoms and quality of life. Limitations include heterogeneous studies, sampling bias, and quality of evidence. This systematic review reveals limited and varied evidence for systemic antibiotic therapy efficacy in psoriasis treatment, while tonsillectomy emerges as a potentially beneficial antistreptococcal option, urging further well-designed, controlled studies with larger sample sizes and standardized protocols for better comparisons.

Late relapses in leprosy patients in Brazil: 10-year post-trial of uniform multidrug therapy (U-MDT/CT-BR).

BACKGROUND: Leprosy is a neglected dermato-neurologic, infectious disease caused by Mycobacterium leprae or M. lepromatosis. Leprosy is treatable and curable by multidrug therapy/MDT, consisting of 12 months rifampicin, dapsone and clofazimine for multibacillary/MB patients and for 6 months for paucibacillary/PB patients. The relapse rate is considered a crucial treatment outcome. A randomized Controlled Clinical Trial (U-MDT/CT-BR) conducted from 2007‒2012 compared clinical outcomes in MB patients after 12 months regular MDT/R-MDT and 6 months uniform MDT/U-MDT in two highly endemic Brazilian areas. OBJECTIVES: To estimate the 10 years relapse rate of MB patients treated with 6 months U-MDT. METHODS: The statistical analyses treated the data as a case-control study, sampled from the cohort generated for the randomized trial. Analyses estimated univariate odds ratio and applied logistic regression for multivariate analysis, controlling the confounding variables. RESULTS: The overall relapse rate was 4.08 %: 4.95 % (16 out of 323) in the U-MDT group and 3.10 % (9 out of 290) in the regular/R-MDT group. The difference in relapse proportion between U-MDT and R-MDT groups was 1.85 %, not statistically significant (Odds Ratio = 1.63, 95 % CI 0.71 to 3.74). However, misdiagnosis of relapses, may have introduced bias, underestimating the force of the association represented by the odds ratio. CONCLUSIONS: The relapse estimate of 10 years follow-up study of the first randomized, controlled study on U-MDT/CT-BR was similar to the R-MDT group, supporting strong evidence that 6 months U-MDT for MB patients is an acceptable option to be adopted by leprosy endemic countries worldwide. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00669643.

Drug-resistant Mycobacterium tuberculosis among Nepalese patients at a tuberculosis referral center.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB), characterized by isoniazid and rifampicin resistance, is caused by chromosomal mutations that restrict treatment options and complicate tuberculosis management. This study sought to investigate the prevalence of pre-extensively drug-resistant (pre-XDR) and extensively drug-resistant (XDR) tuberculosis, as well as mutation pattern, in Nepalese patients with MDR/rifampicin-resistant (RR)-TB strains. METHODS: A cross-sectional study was conducted on MDR/RR-TB patients at the German Nepal Tuberculosis Project from June 2017 to June 2018. The MTBDRsl line probe assay identified pre-XDR-TB and XDR-TB. Pre-XDR-TB included MDR/RR-TB with resistance to any fluoroquinolone (FLQ), while XDR-TB included MDR/RR-TB with resistance to any FLQ and at least one additional group A drug. Mutation status was determined by comparing bands on reaction zones [gyrA and gyrB for FLQ resistance, rrs for SILD resistance, and eis for low-level kanamycin resistance, according to the GenoType MTBDRsl VER 2.0, Hain Lifescience GmbH, Nehren, Germany definition of pre-XDR and XDR] to the evaluation sheet. SPSS version 17.0 was used for data analysis. RESULTS: Out of a total of 171 patients with MDR/RR-TB, 160 had (93.57%) had MTBC, of whom 57 (35.63%) had pre-XDR-TB and 10 (6.25%) had XDR-TB. Among the pre-XDR-TB strains, 56 (98.25%) were FLQ resistant, while 1 (1.75%) was SLID resistant. The most frequent mutations were found at codons MUT3C (57.14%, 32/56) and MUT1 (23.21%, 13/56) of the gyrA gene. One patient had SLID resistant genotype at the MUT1 codon of the rrs gene (100%, 1/1). XDR-TB mutation bands were mostly detected on MUT1 (30%, 3/10) of the gyrA and rrs, MUT3C (30%, 3/10) of the gyrA, and MUT1 (30%, 3/10) of the rrs. CONCLUSIONS: Pre-XDR-TB had a significantly higher likelihood than XDR-TB, with different specific mutation bands present in gyrA and rrs genes.

Cat-scratch disease: a rare cause of osteomyelitis.

Cat-scratch disease is a zoonosis caused by Bartonella henselae, characterised by regional lymphadenopathy. Rarer presentations, such as osteomyelitis, can occur.We present an adolescent girl with severe right lumbar pain and fever, without animal contacts or recent travels. On examination, pain on flexion of torso, movement limitation and marked lordosis were noted, but there were no inflammatory signs, palpable masses or lymph nodes. Serological investigations revealed elevated inflammatory markers. Imaging revealed a paravertebral abscess with bone erosion. Several microbiological agents were ruled out. After a second CT-guided biopsy, PCR for Bartonella spp was positive. At this point, the family recalled having a young cat some time before. Cat-scratch disease was diagnosed, and complete recovery achieved after treatment with doxycycline and rifampicin.Cat-scratch disease is a challenging diagnosis in the absence of typical features. However, B. henselae must be investigated if common pathogens are ruled out and response to therapy is poor.

Determinants of multidrug-resistant tuberculosis among adults undergoing treatment for tuberculosis in Tigray Region, Ethiopia: a case-control study.

BACKGROUND: Multidrug-resistant tuberculosis is a type of tuberculosis that is resistant to at least the first-line antituberculosis drugs namely, rifampicin and isoniazid. However, most of these studies were limited only to a single hospital. Therefore, this study aimed to identify the determinants of multidrug-resistant tuberculosis among adults undergoing treatment for tuberculosis in the Tigray region of Ethiopia. METHODS: Hospital-based unmatched case-control study was conducted from 1 April 2019 to 30 June 2019. A simple random sampling method was used to select the required sample size. Variables at a p value less than 0.25 in bivariate analysis were entered into a multivariable analysis to identify the determinant factors of multidrug-resistant tuberculosis. Finally, the level of significance was declared at p<0.05. RESULTS: Rural residence (adjusted OR (AOR) 2.54; 95% CI 1.34 to 4.83), HIV (AOR 4.5; 95% CI 1.4 to 14.2), relapse (AOR 3.86; 95% CI 1.98 to 7.5), return after lost follow-up (AOR 6.29; 95% CI 1.64 to 24.2), treatment failure (AOR 5.87; 95% CI 1.39 to 24.8) were among the determinants of multidrug-resistant tuberculosis. CONCLUSION: Rural residence, HIV, relapses, return after lost follow-up and treatment failure were the identified determinant factors of multidrug-resistance tuberculosis.

Effectiveness, cost, and safety of four regimens recommended by WHO for RR/MDR-TB treatment: a cohort study in Eastern China.

BACKGROUND: To compare the effectiveness, cost, and safety of four regimens recommended by the World Health Organization (WHO) for rifampicin resistance/multidrug-resistance tuberculosis (RR/MDR-TB) Treatment in Eastern China. METHODS: We performed a cohort study among patients with RR/MDR between 2020 and 2022 in Jiangsu Province. The treatment success rate, cost, and drug adverse reaction rate were compared. RESULTS: Between 2020 and 2022, 253 RR/MDR-TB patients were enrolled in the study. 37 (14.62%), 76 (30.04%), 74 (29.25%), and 66 (26.09%) patients had the short-term regimens, the new long-term oral regimens, the new long-term injectable regimens, and the traditional long-term regimens, respectively. The treatment success rate was the highest among patients treated with the short-term regimen (75.68%) and was the lowest among patients treated with the traditional long-term regimens (60.61%). The estimated mean cost per favorable outcome was 142.61 thousand Chinese Yuan (CNY), and the short-term regimens showed the lowest cost in the four regimes (88.51 thousand CNY vs. 174.24 thousand CNY, 144.00 thousand CNY, and 134.98 thousand CNY). Incremental cost-effectiveness ratios of the short-term regimens, the new long-term oral regimen, and the new long-term injectable regimens were -3083.04, 6040.09, and 819.68 CNY compared to the traditional long-term regimens. CONCLUSIONS: For RR/MDR-TB patients in China who meet the criteria for short-term regimens, the short-term regimens were proven to be the most cost-effective of the four regimens recommended by WHO. For RR/MDR-TB patients in China who don't meet the criteria for short-term regimens, the new long-term injectable regimens are more cost-effective than the remaining two regimens.

This is the first study to evaluate the effectiveness, cost, and safety of four regimens recommended by the WHO for RR/MDR-TB treatment in China.For RR/MDR-TB patients in China who meet the criteria for the short-term regimens, the short-term regimens were proven to be the most cost-effective of the four regimens recommended by WHO.

Risk factors of adult isoniazid-resistant and rifampicin-susceptible tuberculosis in Nanjing, 2019-2021.

INTRODUCTION: This study aimed to analyze the risk factors associated with isoniazid-resistant and rifampicin-susceptible tuberculosis (Hr-TB) in adults. METHOD: The clinical data of 1,844 adult inpatients diagnosed with culture-positive pulmonary tuberculosis (PTB) in Nanjing Second Hospital from January 2019 and December 2021 were collected. All culture positive strain from the patient specimens underwent drug susceptibility testing (DST). Among them, 166 patients with Hr-TB were categorized as the Hr-TB group, while the remaining 1,678 patients were classified as having drug-susceptible tuberculosis (DS-TB). Hierarchical logistic regression was employed for multivariate analysis to identify variables associated with Hr-TB. RESULTS: Multivariate logistic regression analysis revealed that individuals with diabetes mellitus (DM) (OR 1.472, 95% CI 1.037-2.088, p = 0.030) and a history of previous tuberculosis treatment (OR 2.913, 95% CI 1.971-4.306, p = 0.000) were at higher risk of developing adult Hr-TB, with this risk being more pronounced in male patients. Within the cohort, 1,640 patients were newly treated, and among them, DM (OR 1.662, 95% CI 1.123-2.461, p = 0.011) was identified as risk factors for Hr-TB. CONCLUSIONS: Diabetes mellitus is a risk factor for Hr-TB in adults, and the contribution of diabetes as a risk factor was more pronounced in the newly treatment or male subgroup. And previous TB treatment history is also a risk factor for Hr-TB in adults.

Concomitantly Diagnosed Disseminated M kansasii Infection and Hairy Cell Leukemia With Review of Pathophysiology.

The association between Hairy Cell Leukemia (HCL) and non-tuberculous mycobacterial infections (NTMs) is well described, most notably Mycobacterium kansasii. The exact pathophysiology is not known. We report a case of a 31-year-old male with concomitantly diagnosed HCL and disseminated M kansasii infection who presented with rash, pancytopenia, and bulky axillary lymphadenopathy. The M kansasii was initially diagnosed through use of cell-free DNA detection and confirmed by bone marrow and lymph node cultures. Hairy Cell Leukemia was diagnosed with peripheral flow cytometry and confirmed via the same bone marrow sample. His HCL was put into remission with a single course of cladribine and rituximab chemotherapy; however, his M kansasii infection persisted for 6 months despite aggressive antimicrobial and surgical therapy. It was finally controlled using high-dose rifampin in combination with azithromycin and ethambutol. This case highlights the known link between HCL and M kansasii. Furthermore, it hints at potential causes beyond chemotherapy-induced immunocompromise. Notable possibilities include HCL cells acting as sanctuary sites for M kansasii to evade the immune system, and subclinical M kansasii infections causing NLRP3 inflammasome overactivation to trigger the oncogenic transformation to HCL. More research into the pathophysiologic link between HCL and M kansasii infections would allow for more effective prevention, diagnosis, and treatment of these severe atypical infections which are the major cause of morbidity in the cladribine era of HCL treatment.

Post-exposure prophylaxis in leprosy (PEOPLE): a cluster randomised trial.

BACKGROUND: Post-exposure prophylaxis (PEP) using single-dose rifampicin reduces progression from infection with Mycobacterium leprae to leprosy disease. We compared effectiveness of different administration modalities, using a higher (20 mg/kg) dose of rifampicin-single double-dose rifampicin (SDDR)-PEP. METHODS: We did a cluster randomised study in 16 villages in Madagascar and 48 villages in Comoros. Villages were randomly assigned to four study arms and inhabitants were screened once a year for leprosy, for 4 consecutive years. All permanent residents (no age restriction) were eligible to participate and all identified patients with leprosy were treated with multidrug therapy (SDDR-PEP was provided to asymptomatic contacts aged ≥2 years). Arm 1 was the comparator arm, in which no PEP was provided. In arm 2, SDDR-PEP was provided to household contacts of patients with leprosy, whereas arm 3 extended SDDR-PEP to anyone living within 100 m. In arm 4, SDDR-PEP was offered to household contacts and to anyone living within 100 m and testing positive to anti-phenolic glycolipid-I. The main outcome was the incidence rate ratio (IRR) of leprosy between the comparator arm and each of the intervention arms. We also assessed the individual protective effect of SDDR-PEP and explored spatial associations. This trial is registered with ClinicalTrials.gov, NCT03662022, and is completed. FINDINGS: Between Jan 11, 2019, and Jan 16, 2023, we enrolled 109 436 individuals, of whom 95 762 had evaluable follow-up data. Our primary analysis showed a non-significant reduction in leprosy incidence in arm 2 (IRR 0·95), arm 3 (IRR 0·80), and arm 4 (IRR 0·58). After controlling for baseline prevalence, the reduction in arm 3 became stronger and significant (IRR 0·56, p=0·0030). At an individual level SDDR-PEP was also protective with an IRR of 0·55 (p=0·0050). Risk of leprosy was two to four times higher for those living within 75 m of an index patient at baseline. INTERPRETATION: SDDR-PEP appears to protect against leprosy but less than anticipated. Strong spatial associations were observed within 75 m of index patients. Targeted door-to-door screening around index patients complemented by a blanket SDDR-PEP approach will probably have a substantial effect on transmission. FUNDING: European and Developing Countries Clinical Trials Partnership. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Genotypic and phenotypic drug resistance patterns of Mycobacterium tuberculosis isolated from presumptive pulmonary tuberculosis patients in Ethiopia: A multicenter study.

BACKGROUND: The emergence of drug-resistant tuberculosis (DR-TB) has been a major obstacle to global tuberculosis control programs, especially in developing countries, including Ethiopia. This study investigated drug resistance patterns and associated mutations of Mycobacterium tuberculosis Complex (MTBC) isolates from the Amhara, Gambella, and Benishangul-Gumuz regions of Ethiopia. METHODS: A cross-sectional study was conducted using 128 MTBC isolates obtained from patients with presumptive tuberculosis (TB). Phenotypic (BACTEC MGIT 960) and genotypic (MTBDRplus and MTBDRsl assays) methods were used for drug susceptibility testing. Data were entered into Epi-info and analyzed using SPSS version 25. Frequencies and proportions were determined to describe drug resistance levels and associated mutations. RESULTS: Of the 127 isolates recovered, 100 (78.7%) were susceptible to four first-line anti-TB drugs. Any drug resistance, polydrug resistance, and multi-drug resistance (MDR) were detected in 21.3% (27), 15.7% (20), and 15% (19) of the isolates, respectively, by phenotypic and/or genotypic methods. Mono-resistance was observed for Isoniazid (INH) (2, 1.6%) and Streptomycin (STR) (2, 1.6%). There were two genotypically discordant RIF-resistant cases and one INH-resistant case. One case of pre-extensively drug-resistant TB (pre-XDR-TB) and one case of extensively drug-resistant TB (XDR-TB) were identified. The most frequent gene mutations associated with INH and rifampicin (RIF) resistance were observed in the katG MUT1 (S315T1) (20, 76.9%) and rpoB (S531L) (10, 52.6%) genes, respectively. Two MDR-TB isolates were resistant to second-line drugs; one had a mutation in the gyrA MUT1 gene, and the other had missing gyrA WT1, gyrA WT3, and rrs WT1 genes without any mutation. CONCLUSIONS: The detection of a significant proportion of DR-TB cases in this study suggests that DR-TB is a major public health problem in Ethiopia. Thus, we recommend the early detection and treatment of DR-TB and universal full first-line drug-susceptibility testing in routine system.

Comparative evaluation of intensified short course regimen and standard regimen for adults TB meningitis: a protocol for an open label, multi-center, parallel arms, randomized controlled superiority trial (INSHORT trial).

BACKGROUND: Despite several incremental improvements in the management of tuberculous meningitis (TBM), the mortality rates remain high. In spite of national and international guidelines, variation in the choice, dose, and duration of drugs exist between countries and clinicians. We propose to evaluate a shorter and more effective regimen containing agents with augmented intracerebral drug exposure and anti-inflammatory approaches to improve disability-free survival among patients with TBM. Our strategy incorporates the various developments in the field of TBM over the last two decades and only few trials have evaluated a composite of these strategies in the overall outcomes of TBM. METHODS: An open label, parallel arms, randomized controlled superiority trial will be conducted among 372 participants across 6 sites in India. Eligible participants will be randomly allocated in 1:1:1 ratio into one of the three arms. The intervention arm consists of 2 months of high-dose rifampicin (25 mg/kg), moxifloxacin (400 mg), pyrazinamide, isoniazid, aspirin (150 mg), and steroids followed by rifampicin, isoniazid, and pyrazinamide for 4 months. The second intervention arm includes all the drugs as per the first arm except aspirin and the patients in the control arm will receive treatment according to the National TB Elimination Program guidelines. All participants will be followed up for 1 year after the treatment.  DISCUSSION: Current WHO regimens have agents with poor central nervous system drug exposure and is too long. It does not reflect the accumulating evidence in the field. We propose a comprehensive clinical trial incorporating the emerging evidence accrued over the last two decades to shorten the duration and improve the treatment outcomes. This multi-centric trial may generate crucial evidence with policy and practice implications in the treatment of TBM. TRIAL REGISTRATION: Clinical Trial Registry India CTRI/2023/05/053314. Registered on 31 May 2023 ( https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=ODYzMzg=&Enc=&userName=CTRI/2023/05/053314 ). CLINICALTRIALS: gov NCT05917340. Registered on 6 August 2023 ( https://classic. CLINICALTRIALS: gov/ct2/show/NCT05917340 ). PROTOCOL VERSION: Version 1.3 dated 12 July 2023.

Testing novel strategies for patients hospitalised with HIV-associated disseminated tuberculosis (NewStrat-TB): protocol for a randomised controlled trial.

BACKGROUND: HIV-associated tuberculosis (TB) contributes disproportionately to global tuberculosis mortality. Patients hospitalised at the time of the diagnosis of HIV-associated disseminated TB are typically severely ill and have a high mortality risk despite initiation of tuberculosis treatment. The objective of the study is to assess the safety and efficacy of both intensified TB treatment (high dose rifampicin plus levofloxacin) and immunomodulation with corticosteroids as interventions to reduce early mortality in hospitalised patients with HIV-associated disseminated TB. METHODS: This is a phase III randomised controlled superiority trial, evaluating two interventions in a 2 × 2 factorial design: (1) high dose rifampicin (35 mg/kg/day) plus levofloxacin added to standard TB treatment for the first 14 days versus standard tuberculosis treatment and (2) adjunctive corticosteroids (prednisone 1.5 mg/kg/day) versus identical placebo for the first 14 days of TB treatment. The study population is HIV-positive patients diagnosed with disseminated TB (defined as being positive by at least one of the following assays: urine Alere LAM, urine Xpert MTB/RIF Ultra or blood Xpert MTB/RIF Ultra) during a hospital admission. The primary endpoint is all-cause mortality at 12 weeks comparing, first, patients receiving intensified TB treatment to standard of care and, second, patients receiving corticosteroids to those receiving placebo. Analysis of the primary endpoint will be by intention to treat. Secondary endpoints include all-cause mortality at 2 and 24 weeks. Safety and tolerability endpoints include hepatoxicity evaluations and corticosteroid-related adverse events. DISCUSSION: Disseminated TB is characterised by a high mycobacterial load and patients are often critically ill at presentation, with features of sepsis, which carries a high mortality risk. Interventions that reduce this high mycobacterial load or modulate associated immune activation could potentially reduce mortality. If found to be safe and effective, the interventions being evaluated in this trial could be easily implemented in clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT04951986. Registered on 7 July 2021 https://clinicaltrials.gov/study/NCT04951986.

Economic implications of novel regimens for tuberculosis treatment in three high-burden countries: a modelling analysis.

BACKGROUND: With numerous trials investigating novel drug combinations to treat tuberculosis, we aimed to evaluate the extent to which future improvements in tuberculosis treatment regimens could offset potential increases in drug costs. METHODS: In this modelling analysis, we used an ingredients-based approach to estimate prices at which novel regimens for rifampin-susceptible and rifampin-resistant tuberculosis treatment would be cost-neutral or cost-effective compared with standards of care in India, the Philippines, and South Africa. We modelled regimens meeting targets set in the WHO's 2023 Target Regimen Profiles (TRPs). Our decision-analytical model tracked cohorts of adults initiating rifampin-susceptible or rifampin-resistant tuberculosis treatment, simulating their health outcomes and costs accumulated during and following treatment under standard-of-care and novel regimen scenarios. Price thresholds included short-term cost-neutrality (considering only savings accrued during treatment), medium-term cost-neutrality (additionally considering savings from averted retreatments and secondary cases), and cost-effectiveness (incorporating willingness-to-pay for improved health outcomes). FINDINGS: Total medium-term costs per person treated using standard-of-care regimens were estimated at US$450 (95% uncertainty interval 310-630) in India, $560 (350-860) in the Philippines, and $730 (530-1090) in South Africa for rifampin-susceptible tuberculosis (current drug costs $46) and $2100 (1590-2810) in India, $2610 (2090-3280) in the Philippines, and $3790 (3090-4630) in South Africa for rifampin-resistant tuberculosis (current drug costs $432). A rifampin-susceptible tuberculosis regimen meeting the optimal targets defined in the TRPs could be cost-neutral in the short term at drug costs of $140 (90-210) per full course in India, $230 (130-380) in the Philippines, and $280 (180-460) in South Africa. For rifampin-resistant tuberculosis, short-term cost-neutral thresholds were higher with $930 (720-1230) in India, $1180 (980-1430) in the Philippines, and $1480 (1230-1780) in South Africa. Medium-term cost-neutral prices were approximately $50-100 higher than short-term cost-neutral prices for rifampin-susceptible tuberculosis and $250-550 higher for rifampin-resistant tuberculosis. Health system cost-neutral prices that excluded patient-borne costs were 45-70% lower (rifampin-susceptible regimens) and 15-50% lower (rifampin-resistant regimens) than the cost-neutral prices that included patient costs. Cost-effective prices were substantially higher. Shorter duration was the most important driver of medium-term savings with novel regimens, followed by ease of adherence. INTERPRETATION: Improved tuberculosis regimens, particularly shorter regimens or those that facilitate better adherence, could reduce overall costs, potentially offsetting higher prices. FUNDING: WHO.

Impact and cost-effectiveness of the 6-month BPaLM regimen for rifampicin-resistant tuberculosis in Moldova: A mathematical modeling analysis.

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

Development of a multiplex droplet digital PCR method for detection and monitoring of Mycobacterium tuberculosis and drug-resistant tuberculosis.

BACKGROUND: The prevalence of multidrug-resistant tuberculosis (MDR-TB) among Korean tuberculosis patients is about 4.1%, which is higher than the OECD average of 2.6%. Inadequate drug use and poor patient compliance increase MDR-TB prevalence through selective pressure. Therefore, prompt detection of drug resistance in tuberculosis patients at the time of diagnosis and quantitative monitoring of these resistant strains during treatment are crucial. METHODS: A multiplex droplet digital PCR (ddPCR) assay was developed and assessed using DNA material of nine Mycobacterium tuberculosis strains with known mutation status that were purchased from the Korean National Tuberculosis Association. We collected a total of 18 MDR-TB residual samples referred for PCR analysis. Total DNA was extracted from the samples and subjected to the quadruplex ddPCR assay. Their results were compared to those of known resistance phenotypes. RESULTS: The analytical sensitivity and specificity of the multiplex ddPCR assay for detecting INH, RIF, EMB, FQ, and SM resistance-causing mutations ranged from 71.43 to 100% and 94.12-100%, respectively. Follow-up sample results showed that the quadruplex ddPCR assay was sensitive enough to detect IS6110 and other mutations even after onset of treatment. CONCLUSIONS: We developed a sensitive and accurate multiplex ddPCR assay that can detect the presence of tuberculosis quantitatively and resistance-conveying mutations concurrently. This tool could aid clinicians in the diagnosis and treatment monitoring of tuberculosis.

Amoxicillin/clavulanate in combination with rifampicin/clarithromycin is bactericidal against Mycobacterium ulcerans.

BACKGROUND: Buruli ulcer (BU) is a skin neglected tropical disease (NTD) caused by Mycobacterium ulcerans. WHO-recommended treatment requires 8-weeks of daily rifampicin (RIF) and clarithromycin (CLA) with wound care. Treatment compliance may be challenging due to socioeconomic determinants. Previous minimum Inhibitory Concentration and checkerboard assays showed that amoxicillin/clavulanate (AMX/CLV) combined with RIF+CLA were synergistic against M. ulcerans. However, in vitro time kill assays (TKA) are a better approach to understand the antimicrobial activity of a drug over time. Colony forming units (CFU) enumeration is the in vitro reference method to measure bacterial load, although this is a time-consuming method due to the slow growth of M. ulcerans. The aim of this study was to assess the in vitro activity of RIF, CLA and AMX/CLV combinations against M. ulcerans clinical isolates by TKA, while comparing four methodologies: CFU enumeration, luminescence by relative light unit (RLU) and optical density (at 600 nm) measurements, and 16S rRNA/IS2404 genes quantification. METHODOLOGY/PRINCIPAL FINDINGS: TKA of RIF, CLA and AMX/CLV alone and in combination were performed against different M. ulcerans clinical isolates. Bacterial loads were quantified with different methodologies after 1, 3, 7, 10, 14, 21 and 28 days of treatment. RIF+AMX/CLV and the triple RIF+CLA+AMX/CLV combinations were bactericidal and more effective in vitro than the currently used RIF+CLA combination to treat BU. All methodologies except IS2404 quantitative PCR provided similar results with a good correlation with CFU enumeration. Measuring luminescence (RLU) was the most cost-effective methodology to quantify M. ulcerans bacterial loads in in vitro TKA. CONCLUSIONS/SIGNIFICANCE: Our study suggests that alternative and faster TKA methodologies can be used in BU research instead of the cumbersome CFU quantification method. These results provide an in vitro microbiological support to of the BLMs4BU clinical trial (NCT05169554, PACTR202209521256638) to shorten BU treatment.

Prevalence and risk factors of anxiety and depression in patients with multi-drug/rifampicin-resistant tuberculosis.

Background: Mental health disorders in patients with multi-drug or rifampicin-resistant tuberculosis (MDR/RR-TB) receive consistent attention. Anxiety and depression can manifest and may impact disease progression in patients with MDR/RR-TB. Given the heightened stressors resulting from the COVID-19 pandemic, this scenario is even more concerning. Objective: To evaluate the prevalence of and risk factors associated with anxiety and depression among patients with MDR/RR-TB in southern China. Methods: A facility-based cross-sectional study was undertaken at Guangzhou Chest Hospital in southern China, encompassing a cohort of 219 patients undergoing outpatient and inpatient treatment for MDR/RR-TB. Anxiety and depressive symptoms were assessed using the 7-Item Generalized Anxiety Disorder (GAD-7) scale and Patient Health Questionnaire-9 (PHQ-9). The ramifications of anxiety and depression were examined using univariate and multivariate logistic regression analyses, with odds ratios (ORs) and age- and sex-adjusted ORs (AORs) employed to quantify their influence. All data underwent statistical analysis using SPSS 25.0, with statistical significance established at P < 0.05. Results: Two hundred and nineteen individuals with MDR/RR-TB were included in the study. The prevalence of anxiety and depression was 57.53% (n = 126) and 65.75% (n = 144), respectively, with 33.3% (n = 73) of the participants experiencing both conditions simultaneously. Multivariate logistic regression analysis revealed that an age of 20-40 years [anxiety AOR = 3.021, 95% confidence interval (CI): 1.240-7.360; depression AOR = 3.538, 95% CI: 1.219-10.268], disease stigma (anxiety AOR = 10.613, 95% CI: 2.966-37.975; depression AOR = 4.514, 95% CI: 2.051-10.108) and poor physical health (anxiety AOR = 7.636, 95% CI: 2.938-19.844; depression AOR = 6.190, 95% CI: 2.468-15.529) were significant risk factors for moderate levels of anxiety and depression. Conclusions: We found that individuals with MDR/RR-TB had an elevated risk of anxiety and depression. To decrease the likelihood of unfavorable treatment outcomes, it is imperative to carefully monitor the psychological wellbeing of patients with MDR/RR-TB and promptly address any detrimental psychiatric conditions.