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[This corrects the article DOI: 10.3389/fphar.2025.1667592.].

The standard treatment for tuberculosis is the isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) regimen. Despite its efficacy, this regimen has limitations, including prolonged treatment duration and poor clinical outcomes in drug-resistant cases. This back translational study assessed the efficacy of alternative drug combinations, focusing on high-dose rifamycins (rifampicin and rifapentine) and substituting moxifloxacin for ethambutol in the HRZE regimen. Using a preclinical high-burden aerosol model of tuberculosis in BALB/c mice, we tested seven treatment combinations, including high-dose rifampicin (HD-RIF), high-dose rifapentine (HD-RPT), and moxifloxacin. By day 12, the HD-RIF+HZM and HD-RPT+HZM regimens reduced lung bacterial burdens from 6.59 ± 0.08 log CFU in untreated controls to 3.70 ± 0.19 and 3.91 ± 0.43 log CFU, respectively. By day 54, bacterial loads were undetectable (<1 log CFU) in all groups except for HRZE (1.48 ± 0.32 log CFU). RS ratio analysis showed lower ratios for HD-RIF+HZM and HD-RPT+HZM compared to HRZE by day 26, indicating a superior ability of both regimens to interrupt rRNA synthesis. Histopathological analysis revealed similar granulomatous changes across all treatment groups. Mass spectrometry confirmed higher systemic exposure for HD-RIF and HD-RPT groups than RIF used in HRZE. The findings indicate that higher doses of rifamycins and the substitution of moxifloxacin offer improved bactericidal activity and could shorten TB treatment duration.

Background Establishing efficacy benchmarks in preclinical tuberculosis (TB) models is essential for optimizing and prioritizing therapeutic regimens. However, standardized classification methods for comparing high-performing regimens are currently lacking. This study defines a quantitative framework utilizing rifampicin-based regimens in a high-burden aerosol BALB/c mouse model, incorporating both male and female mice to assess potential sex-specific treatment responses. Methods Mice were infected with Mycobacterium tuberculosis Erdman strain and treated for 4 or 8 weeks with rifampicin (R), rifampicin plus pyrazinamide (RZ), or rifampicin, isoniazid, and pyrazinamide (RHZ). Treatments were administered orally five days a week. The bacterial burden in the lungs and spleens was quantified by CFU enumeration. Pharmacokinetic analysis confirmed drug exposures. To establish classification benchmarks, treatment efficacy was evaluated using quartile performance thresholds and Cohen’s d effect size analysis. Results All regimens reduced lung CFUs compared to controls. RHZ demonstrated a high benchmark, achieving mean reductions of 3 ± 0.5 Log 10 CFUs at 4 weeks and 4 ± 0.4 Log 10 CFUs at 8 weeks, with clearance below detection limits in most mice. The R and RZ regimens achieved intermediate reductions. No statistically significant sex differences in bacterial clearance were observed. Pharmacokinetic analysis confirmed equivalent drug exposures across sexes. Quartile ranking (> 75th percentile) and Cohen’s d calculations (Cohen’s d > 15) consistently classified RHZ as the benchmark high-performing regimen at both time points, showing exceptional efficacy. Conclusion This study establishes a quantitative framework for evaluating TB treatments in a preclinical high-burden BALB/c mouse model. The dual-metric classification framework provides sex-inclusive, quantitative performance criteria that enhance the translational relevance of preclinical efficacy studies. This approach sets relative benchmarks that support the comparative evaluation of novel regimens and helps to align preclinical performance with clinical expectations.

Pediatric tuberculosis is a major cause of mortality and morbidity in children due to high transmission, poor diagnostic tools, and various respiratory diseases mimicking TB. Identifying risk factors will provide evidence for clinicians to strongly relate their diagnosis to the associated pathology. Studies were retrieved from PubMed, Embase, and Google Scholar, systematically reviewed, and meta-analyzed for various risk factors and their association with pediatric TB. Meta-analysis depicted that four out of eleven risk factors were significant—contact with known TB cases (OR 6.42 [3.85,10.71]), exposure to smoke (OR 2.61 [1.24, 5.51]), overcrowding in the houses (OR 2.29 [1.04, 5.03]), and, poor household conditions (OR 2.65 [1.38, 5.09]). Although significant odds ratio estimates were obtained, we observed heterogeneity in the studies included.     Conclusion : The study findings demand the constant screening of risk factors such as contact with known TB cases, exposure to smoke, overcrowding, and, poor household conditions for the development of pediatric TB. What is Known: • Knowledge of the risk factors of a disease is of utmost importance in the planning and institution of its control measures. Well-established risk factors in the occurrence of TB in the pediatric group are HIV positivity, older age and close contact with a known case of TB . What is New: • In addition to what is already known; this review and meta-analysis has identified exposure to indoor smoking, overcrowding and poor household conditions as important risk factors for developing pediatric TB . • Implications of the study: The findings highlight that in addition to routine contact screening for the pediatric group, the children living in poor household conditions and getting exposed to passive indoor smoking demand more attention to prevent the development of pediatric TB.

Background Thirty countries with the highest tuberculosis (TB) burden bear 87% of the world’s TB cases. Delayed diagnosis and treatment are detrimental to TB prognosis and sustain TB transmission in the community, making TB elimination a great challenge, especially in these countries. Our objective was to elucidate the duration and determinants of delayed diagnosis and treatment of pulmonary TB in high TB-burden countries. Methods We conducted a systematic review and meta-analysis of quantitative and qualitative studies by searching four databases for literature published between 2008 and 2018 following PRISMA guidelines. We performed a narrative synthesis of the covariates significantly associated with patient, health system, treatment, and total delays. The pooled median duration of delay and effect sizes of covariates were estimated using random-effects meta-analyses. We identified key qualitative themes using thematic analysis. Results This review included 124 articles from 14 low- and lower-middle-income countries (LIC and LMIC) and five upper-middle-income countries (UMIC). The pooled median duration of delays (in days) were—patient delay (LIC/LMIC: 28 (95% CI 20–30); UMIC: 10 (95% CI 10–20), health system delay (LIC/LMIC: 14 (95% CI 2–28); UMIC: 4 (95% CI 2–4), and treatment delay (LIC/LMIC: 14 (95% CI 3–84); UMIC: 0 (95% CI 0–1). There was consistent evidence that being female and rural residence was associated with longer patient delay. Patient delay was also associated with other individual, interpersonal, and community risk factors such as poor TB knowledge, long chains of care-seeking through private/multiple providers, perceived stigma, financial insecurities, and poor access to healthcare. Organizational and policy factors mediated health system and treatment delays. These factors included the lack of resources and complex administrative procedures and systems at the health facilities. We identified data gaps in 11 high-burden countries. Conclusions This review presented the duration of delays and detailed the determinants of delayed TB diagnosis and treatment in high-burden countries. The gaps identified could be addressed through tailored approaches, education, and at a higher level, through health system strengthening and provision of universal health coverage to reduce delays and improve access to TB diagnosis and care. PROSPERO registration : CRD42018107237.

Backgrounds Most significant findings from the Global Tuberculosis (TB) Report 2023 indicate that India, Indonesia, China, the Philippines, Pakistan, Nigeria, Bangladesh, and the Democratic Republic of the Congo (DRC) collectively contribute to approximately two-thirds of global TB cases. This study aims to provide crucial data-driven insights and references to improve TB control measures through a comprehensive analysis of these eight high-burden countries. Methods The eight high-burden TB countries analyzed in this study include India, Indonesia, China, the Philippines, Pakistan, Nigeria, Bangladesh, and the DRC. Age-standardized incidence rates (ASIR) of TB were derived from the Global Burden of Diseases Study 2021 data. Temporal trends were analyzed using Joinpoint regression. An age-period-cohort model was applied to examine the risk ratios (RR) of TB across diverse age groups, periods, and birth cohorts. A Bayesian age-period-cohort framework was employed to predict the ASIR of TB by 2030. Results The study found that the Philippines (average annual percentage change = 3.1%, P  < 0.001) exhibited an upward trend from 1990 to 2021. In India, the Philippines, Pakistan, and Bangladesh, the RR of TB incidence exceeded 1 after individuals reached 25 years old. Notably, the RR has shown a consistent upward trend since 2001, peaking during the period of 2017–2021 with an estimated RR of 1.5 ( P  < 0.001) in the Philippines. Similarly, the highest RR was observed during the period of 2017–2021 reaching 1.1 ( P  < 0.001) in the DRC. In the Philippines, the markedly increasing RR values for TB have been observed among individuals born after 1997–2001. Projections suggest that the ASIR of TB is expected to follow a continued upward trajectory, with an estimated rate of 392.9 per 100,000 by 2030 in the Philippines; India and Indonesia are projected to achieve less than 20.0% of the target set by the World Health Organization (WHO). Conclusions Among the eight high-burden countries, the Philippines, India and Indonesia are diverging from the goals set by the WHO, and the risk of TB in the Philippines and the DRC shows a trend toward affecting younger populations, which suggests that the management strategies for TB patients need to be further strengthened. Graphical Abstract

Background The burden of neglected tropical diseases (NTDs), HIV/AIDS, tuberculosis, and malaria pose significant public health challenges in Ethiopia. This study aimed to the explore service availability and readiness for NTD care among Ethiopian health facilities treating tuberculosis (TB), HIV/AIDS, and/or malaria. Methods This study utilized secondary data from the Ethiopian Service Provision Assessment 2021–22 survey. The availability of services was calculated as the percentage of HIV/AIDS, tuberculosis, or malaria facilities providing NTD services. Facilities were considered highly prepared to manage any type of NTD if they scored at least half (> 50%) of the tracer items listed in each of the three domains (staff training and guidelines, equipment, and essential medicines). Descriptive statistics and logistic regression models were employed to present the study findings and analyze factors influencing facility readiness, respectively. Results Out of 403 health facilities providing NTD care nationally, 179, 183, and 197 also offer TB, HIV/AIDS, and malaria services, respectively. The majority of TB (90.1%), HIV/AIDS (89.6%), and malaria (90.9%) facilities offer soil-transmitted helminth services, followed by trachoma (range 87–90%). The percentages of the aforementioned facilities with at least one trained staff member for any type of NTD were 87.2%, 88.4%, and 82.1%, respectively. The percentage of facilities with guidelines for any type of NTD was relatively low (range 3.7–4.1%). Mebendazole was the most widely available essential medicine, ranging from 69 to 70%. The overall readiness analysis indicated that none of the included facilities (TB = 11.9%; HIV/AIDS = 11.6%; and malaria = 10.6%) were ready to offer NTD care. Specifically, a higher level of readiness was observed only in the domain of medicines across these facilities. Hospitals had better readiness to offer NTD care than did health centers and clinics. Furthermore, a significant associations were observed between facility readiness and factors such as facility type, region, presence of routine management meetings, types of NTD services provided, and fixed costs for services. Conclusions Ethiopian health facilities treating TB, HIV/AIDS, and malaria had an unsatisfactory overall service availability and a lack of readiness to provide NTD care. Given the existing epidemiological risks and high burden of TB, HIV/AIDS, malaria, and NTDs in Ethiopia, there is an urgent need to consider preparing and implementing a collaborative infectious disease care plan to integrate NTD services in these facilities.

Background Timely detection of drug-resistant tuberculosis (DR-TB) is essential for effective treatment and preventing poor outcomes. Rapid molecular diagnostics are promising alternatives to conventional phenotypic drug susceptibility testing (pDST), offering faster and more accessible detection of resistance. This study evaluated the cost-effectiveness of rapid molecular assays, alone or combined with pDST, for detecting resistance to isoniazid, rifampicin, and fluoroquinolones from a South African healthcare provider perspective. Methods A decision-analytic model was developed to simulate TB-related outcomes for a hypothetical cohort of microbiologically confirmed TB patients. Nine diagnostic strategies were evaluated: pDST alone; four rapid molecular tests (line probe assays [LPAs], Xpert MTB/RIF [Xpert] followed by Xpert MTB/XDR [Xpert XDR], Xpert MTB/RIF Ultra [Xpert Ultra] followed by Xpert XDR, and targeted next-generation sequencing [tNGS]); and combinations pairing each molecular test with pDST. Outcomes included early treatment rates, mortality, direct medical costs, disability-adjusted life-years (DALYs), and incremental cost-effectiveness ratios (ICERs). Base-case, sensitivity, and scenario analyses were performed. Results In the base-case analysis, ‘Xpert followed by Xpert XDR + pDST’ was the preferred cost-effective strategy, with an ICER of USD 6,554/DALY averted—below South Africa's GDP per capita threshold. While ‘tNGS + pDST’ yielded the greatest health benefits—lowest DALYs (1.9877), highest early treatment rate (995.54/1,000 tested), and lowest mortality (90.22/1000 tested)—its ICER (USD 25,918/DALY averted) exceeded three times the GDP per capita, rendering it not cost-effective. Sensitivity analyses highlighted the impact of diagnostic accuracy and treatment timing on cost-effectiveness outcomes. Probabilistic sensitivity analysis showed ‘tNGS + pDST’ had the highest probability of being cost-effective when the willingness-to-pay threshold exceeded USD 10,500/DALY averted. Diagnostic replacement scenario analysis revealed that tNGS alone could be a cost-effective alternative (ICER = USD 1712 per DALY averted) when pDST was unavailable. An extended two-year time horizon analysis confirmed base-case robustness. Conclusions Combining rapid molecular diagnostics with pDST offers a cost-effective and clinically beneficial approach for DR-TB detection in high-burden settings. The Xpert-based strategy provides an optimal balance of diagnostic yield, early treatment, and economic efficiency in South Africa. tNGS represents a feasible alternative in settings where pDST is inaccessible, warranting further evaluation for broader implementation.

Background Accurate estimates of malaria burden are crucial for allocating resources and designing effective control strategies. However, global reports often underestimate the burden in low- and middle-income countries, especially beyond the African region. This study addresses this gap by providing a longitudinal time-series analysis of malaria burden and spatio-temporal distribution in Sindh province, Pakistan. Methods Monthly suspected malaria cases reported from 1088 primary healthcare facilities managed by the PPHI-Sindh across 23 districts of Sindh Province (excluding seven districts of Karachi), Pakistan, were analysed over a 13-year period (2012–2024). Malaria incidence was determined by dividing total malaria cases by each health facility's catchment area population. Population-weighted estimates of malaria cases were calculated to account for variations in population size across districts. Yearly time-trend (with 95% CI), seasonal variation by month (with 95% CI), and a treemap illustrating the distribution of malaria burden across districts in Sindh. Results An incidence of 92 per 1000 people per annum of suspected malaria cases was reported at primary public healthcare facilities. Pooled estimates of 16.7 million cases occurred during a 13-year period, about 1.28 million cases annually. Marked heterogeneity observed in malaria burden across districts. Malaria positivity rate was 12.3%. Six districts (Khairpur, Sanghar, Naushero Feroze, Badin, Mirpurkhas, and Larkana) carried over 53% burden of malaria in Sindh. A distinct seasonal pattern with peak coinciding with the wet season and post-monsoon period was observed. Since the 2022 floods in Sindh, the malaria incidence has doubled, and it is persisting in the province. Conclusions The study highlights the substantial malaria burden with wet seasons and post-monsoon peaks in Sindh and identified few high-burden districts. The impact of 2022 flood seems to have persisted to 2024 and onwards, which needs immediate attention. Identification of high-burden districts could help tailor malaria control strategies. Also, the underestimation by global reports emphasizes the need for country-level and subnational analyses for informed decision-making. By addressing these gaps and refining burden estimates, Pakistan can develop more targeted strategies towards malaria control.

Mobile health (mHealth) implementation strategies in tuberculosis (TB) contact investigations are intended to increase community health workers' (CHWs) engagement in TB contact investigations and case detection. This scoping review aimed to map and synthesize existing evidence on the design and development of acceptable and feasible mHealth implementation strategies for CHW-led TB contact investigations. We conducted a scoping review following the Arksey and O'Malley framework and PRISMA-ScR guidelines. We searched PubMed, Scopus, Cochrane Library, Web of Science, and Google Scholar for English-language studies published through October 2024 on mHealth interventions for TB contact investigation by CHWs. Eligible studies included empirical studies conducted in high-burden countries (HBCs) for TB, HIV-associated TB, and MDR/RR-TB. Studies were screened, and data were extracted using Rayyan AI-assisted software. We mapped implementation strategies, barriers, facilitators, acceptability, and feasibility of mHealth interventions. Quantitative findings were described, and qualitative data were synthesized thematically. Nine studies were included. Most interventions used hybrid mHealth technologies for communication, case registration, health records, and decision support. Implementation strategies specified actors, actions, targets, temporality, dose, and justifications. Barriers were related to CHWs, digital systems, service implementation, and TB-affected persons. Facilitators included stakeholder support, CHW training, mHealth design, community engagement, and patient-centered approaches. Overall, CHWs perceived mHealth interventions as acceptable and feasible. Successful implementation in HBCs requires strengthened CHW capacity, reliable technology, optimizing interaction between CHWs and digital tools, and continuous monitoring and evaluation throughout implementation.