Multidrug-resistant Tuberculosis Research Articles

Development of a proliposomal pretomanid dry powder inhaler as a novel alternative approach for combating pulmonary tuberculosis

Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) continue as public health concerns. Inhaled drug therapy for TB has substantial benefits in combating the causal agent of TB (Mycobacterium tuberculosis). Pretomanid is a promising candidate in an optional combined regimen for XDR-TB. Pretomanid has demonstrated high potency against M. tuberculosis in both the active and latent phases. Conventional spray drying was used to formulate pretomanid as dry powder inhalers (DPIs) for deep lung delivery using a proliposomal system with a trehalose coarse excipient to enhance the drug solubility. Co-spray drying with L-leucine protected hygroscopic trehalose in formulations and improved powder aerosolization. Higher amounts of L-leucine (40–50 % w/w) resulted in the formation of mesoporous particles with high percentages of drug content and entrapment efficiency. The aerosolized powders demonstrated both geometric and median aerodynamic diameters < 5 µm with > 90 % emitted dose and > 50 % fine particle fraction. Upon reconstitution in simulated physiological fluid, the proliposomes completely converted to liposomes, exhibiting suitable particle sizes (130–300 nm) with stable colloids and improving drug solubility, leading to higher drug dissolution compared to the drug alone. Inhalable pretomanid showed higher antimycobacterial activity than pretomanid alone. The formulations were safe for all broncho-epithelial cell lines and alveolar macrophages, thus indicating their potential suitability for DPIs targeting pulmonary TB.

Treatment outcomes of standardized injectable shorter regimen for multi-drugs resistant tuberculosis in Ethiopia: a retrospective cohort study

BackgroundThe injectable shorter multi-drug resistant tuberculosis (MDR-TB) regimen, has been reported to be less costly and more effective in the treatment of MDR-TB compared to the longer regimen. Ethiopia introduced the injectable shorter regimen (SR) in April 2018 following official recommendation by the World Health Organization (WHO) in 2016. While the WHO recommendation was based on evidence coming from extensive programmatic studies in some Asian and African countries, there is paucity of information on patient outcomes in the Ethiopian context. Thus, we aimed to assess the treatment outcomes and identify factors associated with the outcomes of MDR-TB patients on injectable SR.MethodsA multi-center facility-based retrospective cohort study was conducted in Ethiopia on 245 MDR-TB patients who were treated between April 2018 and March 2020. Data were collected from patients’ medical records and analyzed using SPSS version 25. Descriptive statistics was used to summarize the results while inferential analysis was employed to investigate predictors of treatment outcomes and survival status.ResultsA total of 245 patients were included in the study, with 129 (52.7%) of them being female. Median age of the patients was 27 (IQR: 21–33). The overall treatment success rate was 87.8%, with 156 (63.7%) cured and 59 (24.1%) patients who completed treatment. The unfavorable outcomes accounted for 12.2%, with 16 (6.5%) treatment failure, 8 (3.3%) death and 6 (2.4%) lost to follow up. Majority of the unfavorable outcomes occurred during the early phase of therapy, with median time to event of 1.8 months (95% CI: 0.99—2.69). The use of khat (a green leafy shrub abused for its stimulant like effect) and being diagnosed with MDR-TB than rifampicin resistant only, were identified as independent factors associated with unfavorable outcomes.ConclusionThe injectable SR for MDR-TB was found to have positive treatment outcomes in the context of programmatic management in Ethiopia.

Epidemiological features and temporal trends of the co-infection between HIV and tuberculosis, 1990–2021: findings from the Global Burden of Disease Study 2021

BackgroundThe co-infection of human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) and tuberculosis (TB) poses a significant clinical challenge and is a major global public health issue. This study aims to elucidate the disease burden of HIV-TB co-infection in global, regions and countries, providing critical information for policy decisions to curb the HIV-TB epidemic.MethodsThe ecological time-series study used data from the Global Burden of Disease (GBD) Study 2021. The data encompass the numbers of incidence, prevalence, mortality, and disability-adjusted life year (DALY), as well as age-standardized incidence rate (ASIR), prevalence rate (ASPR), mortality rate (ASMR), and DALY rate for HIV-infected drug-susceptible tuberculosis (HIV-DS-TB), HIV-infected multidrug-resistant tuberculosis (HIV-MDR-TB), and HIV-infected extensively drug-resistant tuberculosis (HIV-XDR-TB) from 1990 to 2021. from 1990 to 2021. The estimated annual percentage change (EAPC) of rates, with 95% confidence intervals (CIs), was calculated.ResultsIn 2021, the global ASIR for HIV-DS-TB was 11.59 per 100,000 population (95% UI: 0.37–13.05 per 100,000 population), 0.55 per 100,000 population (95% UI: 0.38–0.81 per 100,000 population), for HIV-MDR-TB, and 0.02 per 100,000 population (95% UI: 0.01–0.03 per 100,000 population) for HIV-XDR-TB. The EAPC for the ASIR of HIV-MDR-TB and HIV-XDR-TB from 1990 to 2021 were 4.71 (95% CI: 1.92–7.59) and 13.63 (95% CI: 9.44–18.01), respectively. The global ASMR for HIV-DS-TB was 2.22 per 100,000 population (95% UI: 1.73–2.74 per 100,000 population), 0.21 per 100,000 population (95% UI: 0.09–0.39 per 100,000 population) for HIV-MDR-TB, and 0.01 per 100,000 population (95% UI: 0.00–0.03 per 100,000 population) for HIV-XDR-TB in 2021. The EAPC for the ASMR of HIV-MDR-TB and HIV-XDR-TB from 1990 to 2021 were 4.78 (95% CI: 1.32–8.32) and 10.00 (95% CI: 6.09–14.05), respectively.ConclusionsThe findings indicate that enhancing diagnostic and treatment strategies, strengthening healthcare infrastructure, increasing access to quality medical care, and improving public health education are essential to combat HIV-TB co-infection.Graphical

Understanding the role of video direct observed therapy for patients on an oral short-course regimen for multi-drug resistant tuberculosis: findings from a qualitative study in Eswatini

BackgroundImproving treatment success rates among multi drug-resistant tuberculosis (MDR-TB) patients is critical to reducing its incidence and mortality, but adherence poses an important challenge. Video-based direct observed therapy (vDOT) may provide adherence benefits, while addressing the time and cost burden associated with community treatment supporter (CTS)-DOT. This study explored experiences of patients, family members and healthcare workers with different DOT modalities for adherence support in Eswatini.MethodsBetween April 2021 and May 2022, thirteen men and five women with MDR-TB, ten healthcare workers, and nine caregivers were purposively sampled to include a range of characteristics and experiences with DOT modalities. Data were generated through individual in-depth interviews and a smartphone messaging application (WhatsApp). Data coding was undertaken iteratively, and thematic analysis undertaken, supported by Nvivo.ResultsFour themes emerged that reflected participants’ experiences with different DOT modalities, including stigma, efficiency, perceived risks of TB acquisition, and patient autonomy. vDOT was appreciated by patients for providing them with privacy and shielding them from stigmatisation associated with being seen in TB clinics or with community treatment supporters. vDOT was also seen as more efficient than CTS-DOT. Health workers acknowledged that it saved time, allowing them to attend to more patients, while many patients found vDOT more convenient and less expensive by removing the need to travel for in-person consultations. Health workers also appreciated vDOT because it reduced risks of TB acquisition by minimising exposure through virtual patient monitoring. Although many patients appreciated greater autonomy in managing their illness through vDOT, others preferred human contact or struggled with making video recordings. Most family members appreciated vDOT, although some resented feeling removed from the process of supporting loved ones.ConclusionsvDOT was generally appreciated by MDR-TB patients, their family members and health workers as it addressed barriers to adherence which could contribute to improved treatment completion rates and reduced workplace exposure. However, patients should be offered an alternative to vDOT such as CTS-DOT if this modality does not suit their circumstances or preferences.

Burden of drug-resistant tuberculosis by the GeneXpert MTB/RIF assay and its clinico-epidemiological aspects at a tertiary care hospital in West Bengal

Multidrug -resistant tuberculosis (MDRTB) is a serious threat to mankind. India has the highest number of MDRTB cases, although majority remain undiagnosed due to inadequate diagnostic infrastructure, leading to increased community transmission and mortality. This one-year observational retrospective study highlighted the effectiveness of the National Tuberculosis Elimination Program (NTEP) for prompt detection of drug-resistant TB by GeneXpert MTB/RIF assay and revealed its associated clinico-epidemiological factors. The overall detection rates of MTB and RRTB were 20.70 % and 20.86 % respectively. The pediatric population had 7.69 % rifampicin resistance, and HIV was strongly associated with the development of TB and RRTB (P < 0.01).

Trends of drug resistance in M. tuberculosis in a reference laboratory in Central India: Forging ahead towards TB elimination

PurposeThe National Tuberculosis Elimination Programme (NTEP) of the Government of India has strived to control tuberculosis (TB) in the country through various interventions. Understanding the trends of resistance patterns may provide insights into the effectiveness of TB control activities in the country. MethodsA total of 31,144 clinical samples were received from 2013 to 2022 from presumptive drug-resistant TB patients. All the specimens were decontaminated and subjected to the line probe assay for detection of resistance to rifampicin and isoniazid. Mycobacterium tuberculosis (MTB) was detected in 28,814 samples. Autoregressive integrated moving average model (ARIMA) was fitted to assess the trend over time. ResultsA decreasing trend in multi-drug resistant TB from 19 % in 2013 to 4 % in 2022 was seen. A decreasing trend in rifampicin monoresistance from 11.2 % in 2013 to 1.5 % in 2022 was seen, though there was an increase in resistance in 2017. No significant decreasing trends were seen in the proportion of isoniazid monoresistance from 8.3 % in 2013 to 7 % in 2022. ConclusionThe findings are encouraging, and to a considerable extent, affirm that India is well on track with regard to the goal of TB elimination.

Performance evaluation of the Xpert MTB/XDR test for the detection of drug resistance to Mycobacterium tuberculosis among people diagnosed with tuberculosis in South Africa.

Drug-resistant tuberculosis (TB) poses a significant public health concern in South Africa due to its complexity in diagnosis, treatment, and management. This study assessed the diagnostic performance of the Xpert MTB/XDR test for detecting drug resistance in patients with TB by using archived sputum sediments. This study analyzed 322 samples collected from patients diagnosed with TB between 2016 and 2019 across South Africa, previously characterized by phenotypic and genotypic methods. The Xpert MTB/XDR test was evaluated for its ability to detect resistance to isoniazid (INH), ethionamide (ETH), fluoroquinolones (FLQ), and second-line injectable drugs (SLIDs) compared with phenotypic drug susceptibility testing (pDST) and whole-genome sequencing (WGS). Culture, Xpert MTB/RIF Ultra, and Xpert MTB/RIF (G4) tests were performed to determine sensitivity and agreement with this test for TB detection. The sensitivities using a composite reference standard, pDST, and sequencing were >90% for INH, FLQ, amikacin (AMK), kanamycin (KAN), and capreomycin (CAP) resistance, meeting the WHO target product profile criteria for this class. A lower sensitivity of 65.9% (95% CI: 57.1-73.6) for ETH resistance was observed. The Xpert MTB/XDR showed a sensitivity of 98.3% (95% CI: 96.1-99.3) and specificity of 100% (95% CI: 86.7-100) compared with culture, a positive percent agreement (PPA) of 98.8% (95% CI: 93.7-99.8) and negative percent agreement (NPA) of 100.0% (95% CI: 78.5-100.0) compared with G4, and a PPA of 99.5% (95% CI: 97.3-99.9) and NPA of 100.0% (95% CI: 78.5-100.0) compared with Xpert MTB/RIF Ultra for detecting Mycobacterium tuberculosis. The test offers a promising solution for the rapid detection of drug-resistant TB and could significantly enhance control efforts in this setting.

Dynamic PET reveals compartmentalized brain and lung tissue antibiotic exposures of tuberculosis drugs

Tuberculosis (TB) remains a leading cause of death, but antibiotic treatments for tuberculous meningitis, the deadliest form of TB, are based on those developed for pulmonary TB and not optimized for brain penetration. Here, we perform first-in-human dynamic 18F-pretomanid positron emission tomography (PET) in eight human subjects to visualize 18F-pretomanid biodistribution as concentration-time exposures in multiple compartments (NCT05609552), demonstrating preferential brain versus lung tissue partitioning. Preferential, antibiotic-specific partitioning into brain or lung tissues of several antibiotics, active against multidrug resistant (MDR) Mycobacterium tuberculosis strains, are confirmed in experimentally-infected mice and rabbits, using dynamic PET with chemically identical antibiotic radioanalogs, and postmortem mass spectrometry measurements. PET-facilitated pharmacokinetic modeling predicts human dosing necessary to attain therapeutic brain exposures. These data are used to design optimized, pretomanid-based regimens which are evaluated at human equipotent dosing in a mouse model of TB meningitis, demonstrating excellent bactericidal activity without an increase in intracerebral inflammation or brain injury. Importantly, several antibiotic regimens demonstrate discordant activities in brain and lung tissues in the same animal, correlating with tissue antibiotic exposures. These data provide a mechanistic basis for the compartmentalized activities of antibiotic regimens, with important implications for developing treatments for meningitis and other infections in compartments with unique antibiotic penetration.

Increased risk of adverse drug reactions by higher linezolid dose per weight in multidrug-resistant tuberculosis

ObjectivesLinezolid treatment has a high risk of toxicity and adverse drug reactions (ADR) are frequent. Few studies have investigated risk factors of major ADRs separately, therefore, we aimed to evaluate major ADRs including peripheral neuropathy in relation to risk factors and drug concentration levels of linezolid in a high-resource setting for multidrug-resistant tuberculosis (MDR-TB). MethodsWe conducted a retrospective cohort study including participants treated with a linezolid-containing MDR-TB regimen in Sweden 1992–2018. Data was collected from medical records. ADRs were classified according to Common Terminology Criteria for Adverse Events (version 5.0). ResultsOf all participants (n = 132), 43.2% were female and the median age 28 y. The median linezolid treatment was 6.5 months (IQR 3.0–12.7) with a median daily dose of 9.6 mg/kg/d. Any ADR was seen in 58.3% (n = 77) of participants, with 35.6% having peripheral neuropathy (n = 47), 27.3% anaemia (n = 36), 22.0% leukopenia (n = 36) while 6.1% (n = 8) had optic neuritis. The median time for peripheral neuropathy was 3.6 months (IQR 2.1–5.9) and 8.3 months (6.2–10.7) for optic neuritis. A >2.0 mg/L trough concentration (n = 40) was associated with anaemia (P = 0.0038) and thrombocytopenia (P = 0.009) but not with peripheral neuropathy. In multivariable analysis, a dose ≥12 mg/kg/d was associated with time to peripheral neuropathy (HR 2.89, 95% CI 1.08–7.74, P = 0.035), anaemia (HR 6.62, 95% CI 2.22–19.8, P = 0.001) and leukopenia (HR 5.23, 95% CI 1.48–18.5, P = 0.010). ConclusionsLinezolid ADRs were frequent in a high-resource setting. Structured, regular follow-up for ADRs and adjusting dosing according to body weight followed-up by monitoring of drug concentrations early may reduce toxicity.

Clinical Profile and Treatment Outcome of H-mono/Polydrug-resistant Tuberculosis: A Single-center Retrospective Study

ABSTRACT Background: Isoniazid-monoresistant tuberculosis (Hr-TB) is the most prevalent drug-resistant TB. It often precedes multidrug-resistant TB (MDR-TB) and poses a major threat in the fight against TB control. The treatment outcome in Hr-TB and polydrug-resistant TB (PDR-TB) other than MDR still remains unclear. Aim: The aim of the study is to determine the clinical characteristics and treatment outcome in H-mono/PDR-TB under programmatic conditions. Materials and Methods: The study design was retrospective observational. It was conducted at the respiratory medicine department of a tertiary care institute in Mumbai. The medical records for bacteriologically confirmed TB patients diagnosed between July 2021 and December 2022 were reviewed. A total of 827 patients were enrolled and among them 46 patients with H-mono/PDR-TB were analyzed. The demographic data, clinical characteristics, and treatment outcomes were recorded. Results: Among 46 patients of isoniazid mono-resistant/PDR-TB analyzed from 827 bacteriologically confirmed TB, 24 were women with a mean age of 30.5 years. Twenty-five (54.34%) were resistant to isoniazid and the remaining 21 (45.66%) were PDR-TB. Primary Hr-TB was detected in 43 (93%) patients. The KatG mutation in 30 (65.2%) patients was the most common form of isoniazid (INH) mono resistance followed by inhA mutation 16 (34.8%). The fluoroquinolone (FQ)-based treatment regime as per national program guidelines had favorable outcomes in 42 (91.3%). However, unfavorable outcome with progression to MDR was observed in 3 (6.52%) and death in 1 (2.18%) patients. Conclusion: H-mono/PDR-TB is the most prevalent DRTB and most of them have primary resistance to isoniazid. Availability of first and SL LPA and limited DST with FQ-based regime under the national program has improved treatment outcomes in Hr-TB/PDR-TB.

The Liebeskind-Srogl Cross-Coupling Reaction as a Crucial Step in the Synthesis of New Squaramide-Based Antituberculosis Agents.

The synthesis of an extensive series of new squaramides with high potential in treating drug-resistant tuberculosis employing the Liebeskind-Srogl cross-coupling reaction is presented. Using the protocol given and various substrates, we assessed the scope and limitations of our methodology and prepared an extensive range of desired compounds. Moreover, 1H NMR spectra in solution show the presence of two rotational conformers (rotamers) in special cases. The results of antimycobacterial activity demonstrate the highly selective substrate specificity of the tested squaramides, requiring an efficient and widely applicable synthetic approach needed for the discovery of lead compounds. Our synthetic strategy confirms the versatility of squaramides that can be easily transformed into diverse functionalized molecules.

Malnutrition and unsuccessful tuberculosis treatment among people with multi-drug resistant tuberculosis in Uganda: A retrospective analysis

RationaleMulti-drug-resistant tuberculosis (MDR-TB) poses a significant public health challenge to the control and successful eradication of TB globally. Suboptimal treatment outcomes are common among persons with MDR-TB necessitating a need to understand the contextual factors. ObjectiveWe determined the factors associated with unsuccessful TB treatment among persons with MDR-TB at a large TB Unit in Central Uganda. MethodsWe retrospectively reviewed medical records for all persons with MDR-TB at Mubende Regional Referral Hospital MDR-TB Clinic in Central Uganda. The patients were treated with either second-line, modified second-line, or individualized anti-TB regimens and completed treatment between January 2012 and October 2023. The primary outcome was unsuccessful TB treatment defined as death, treatment failure, or loss to follow-up and measured as a binary outcome. We used a multivariable binary logistic regression analysis to determine the factors independently associated with unsuccessful TB treatment at a 5 % statistical significance level. We reported the adjusted odds ratio (aOR) and the 95 % confidence interval (CI). Measurements and resultsWe analyzed data from 98 persons with MDR-TB who were aged 15–78 years (mean 36.4 ± 15.4 years). Of these, 40 (40.8 %) were cured, 25 (25.5 %) completed TB treatment, 1 (1.0 %) had treatment failure, 13 (13.3 %) died, and 19 (19.4 %) were lost to follow-up. Overall, 33 (33.7 %) participants had unsuccessful TB treatment which was associated with older age for a 1-year increase in age (aOR 1.05, 95 % CI 1.01–1.09), malnutrition—mid-upper arm circumference of <12.5 cm (aOR 2.99, 95 % CI 1.16–7.98), and previous TB treatment (aOR 0.28, 95 % CI 0.10–0.77). ConclusionUnsuccessful TB treatment is high among persons with MDR-TB at this TB Unit. It is more likely as age advances and when persons with MDR-TB have malnutrition, but less likely when they have been previously treated for TB. Therefore, interventions to improve treatment outcomes may be beneficial for persons with MDR-TB who are older, malnourished, and those newly diagnosed with the disease. For example, routine nutritional assessment and counseling, including nutritional support for malnourished persons with MDR-TB may be needed to optimize their TB treatment success.

Manipulation of solid dosage forms for oral administration to paediatric patients for drug-resistant tuberculosis in South Africa: an observation study

BackgroundChildren represent a particularly vulnerable demographic in the context of drug-resistant (DR) tuberculosis (TB) due to their increased likelihood of close contact with adults diagnosed with the disease. Approximately 25 000–30 000 children develop DR-TB annually. While treatment success rates for DR-TB in children surpass those in adults, children and adolescents encounter distinct challenges throughout the diagnosis and treatment of DR-TB (including MDR-TB, Pre-XDR TB, and XDR-TB).AimTo identify current practices in drug administration to children diagnosed with DR-TB where appropriate dosage forms are not available in South Africa.MethodAn observational study was carried out at the study site to determine how medication prescribed was manipulated and administered by nursing staff to paediatric patients in the wards.ResultsThe observational study identified 8 drugs used in DR-TB at the study site, where some manipulation to the formulation was necessary to enable administration to paediatric patients. Linezolid and para-aminosalicylic acid are the only drugs available and registered in the South Africa in a formulation that is suitable for administration to paediatric patients. Activities carried out by nursing staff to enable the administration of DR-TB medication included cutting capsules and tablets and dissolving the tablet or capsule contents in distilled water to obtain the required suitable dose.DiscussionLack of availability of suitable dosage forms for paediatrics patients results in several challenges, such as additional time required for drug preparation, increased time duration of medication administration, and unpalatability of drugs. These challenges may subsequently affect compliance and therapeutic outcomes of the treatment of paediatric patients, especially as outpatients.ConclusionResearch needs to focus on the development of appropriate dosage forms for the paediatric population and focus on identifying cases of DR-TB in children. This will assist in building evidence to advocate for registration of child-friendly dosage forms thereby ensuring a sustainable supply of medication.

Predictors of mortality among multidrug-resistant tuberculosis patients after decentralization of services in Tanzania from 2017 to 2019: retrospective cohort study

BackgroundMultidrug-resistant tuberculosis (MDR-TB) presents persistent global health challenges, characterized by low treatment success rates among patients enrolled for treatment. The World Health Organization recommends decentralization to improve outcomes. This study aims to assess predictors of mortality among MDR-TB patients after decentralization of services in Tanzania. This was a retrospective cohort study involving all MDR-TB patients enrolled in treatment in all 31 regions in Tanzania from 2017 to 2019. The overall mortality rate among MDR-TB patients was calculated using the incidence rate. Additionally, independent factors of MDR-TB mortality were determined using multivariable cox proportional hazards models.ResultsThe study followed 985 patients for a total of 12,929 months. During this time, it found that approximately 12 out of every 1000 patients died each month. Specifically, the death rates were about 18 out of 1000 patients at 6 months, 8 out of 1000 at 12 months, and 7 out of 1000 at 24 months. Patients who had both MDR-TB and HIV, as well as those who were malnourished, had a lower chance of surviving at 6, 12, and 24 months. Malnourished patients had almost three times the risk of dying [adjusted hazard ratio (aHR) 2.96, with a 95% confidence interval (CI) of 2.10–4.19], while those with HIV had nearly double the risk [aHR 1.91, with a 95% CI of 1.37–2.65].ConclusionIn summary, our study on MDR-TB patient outcomes in Tanzania between 2017 and 2019 reveals a pattern of high mortality rates within the first 6 months of treatment. Furthermore, malnutrition and HIV co-infection were found to be significant predictors of mortality. To decrease mortality, it is crucial to closely monitor patients during the initial 6 months of treatment, especially those who are malnourished or co-infected with HIV, and ensure they receive appropriate and timely care. Additionally, further investigation is needed to find out what may be contributing to possible rise in mortality rate.

From crisis to cure: harnessing the potential of mycobacteriophages in the battle against tuberculosis.

Tuberculosis (TB) is a serious and fatal disease caused by Mycobacterium tuberculosis (Mtb). The World Health Organization reported an estimated 1.30 million TB-related deaths in 2022. The escalating prevalence of Mtb strains classified as being multi-, extensively, extremely, or totally drug resistant, coupled with the decreasing efficacies of conventional therapies, necessitates the development of novel treatments. As viruses that infect Mycobacterium spp., mycobacteriophages may represent a strategy to combat and eradicate drug-resistant TB. More exploration is needed to provide a comprehensive understanding of mycobacteriophages and their genome structure, which could pave the way toward a definitive treatment for TB. This review focuses on the properties of mycobacteriophages, their potential in diagnosing and treating TB, the benefits and drawbacks of their application, and their use in human health. Specifically, we summarize recent research on mycobacteriophages targeted against Mtb infection and newly developed mycobacteriophage-based tools to diagnose and treat diseases caused by Mycobacterium spp. We underscore the urgent need for innovative approaches and highlight the potential of mycobacteriophages as a promising avenue for developing effective diagnosis and treatment to combat drug-resistant Mycobacterium strains.

Identification of antimycobacterial 8-hydroxyquinoline derivatives as in vitro enzymatic inhibitors of Mycobacterium tuberculosis enoyl-acyl carrier protein reductase

The increasing prevalence of drug-resistant Mycobacterium tuberculosis strains stimulates the discovery of new drug candidates. Among them are 8-hydroxyquinoline (8HQ) derivatives that exhibited antimicrobial properties. Unfortunately, there is a lack of data assessing possible targets for this class mainly against Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (MtInhA), a validated target in this field. Thus, the main purpose of this study was to identify 8HQ derivatives that are active against M. tuberculosis and MtInhA. Initially, the screening against the microorganism of a small antimicrobial library and its new derivatives that possess some structural similarity with MtInhA inhibitors identified four 7-substituted-8HQ (series 5 – 5a, 5c, 5d and 5i) and four 5-substituted-8HQ active derivatives (series 7 – 7a, 7c, 7d and 7j). In general, the 7-substituted 8-HQs were more potent and, in the enzymatic assay, were able to inhibit MtInhA at low micromolar range. However, the 5-substituted-8-HQs that presented antimycobacterial activity were not able to inhibit MtInhA. These findings indicate the non-promiscuous nature of 8-HQ derivatives and emphasize the significance of selecting appropriate substituents to achieve in vitro enzyme inhibition. Finally, 7-substituted-8HQ series are promising new derivatives for structure-based drug design and further development.

An Overview of the Management of Drug-Resistant Tuberculosis in Six French-Speaking African Countries from 2018 to 2022.

Drug-resistant tuberculosis (DR-TB) poses a significant public health challenge, particularly in resource-limited settings. The prevalence and management of DR-TB in African countries require comprehensive strategies to improve patient outcomes and control the spread of the disease. Aggregated routine data (from 2018 to 2022) on multidrug-resistant TB (MDR-TB) were collected from the National TB Programs (NTPs) from all six countries. The diagnostic capacity for MDR-TB was globally insufficient. The system for collecting and transporting samples was sometimes inoperative. A total of 2353 cases of MDR-TB were reported, with 86.4% receiving treatment. The gap between the expected number of MDR-TB cases and the number reported per country varied from 51.5% to 88.0%, depending on the year. Fifty-two extensively drug-resistant (XDR) TB cases received treatment regimens over five years, with variations across countries. All patients received free follow-up examinations, nutritional and financial support for travel expenses to the outpatient care and treatment centers. The MDR-TB treatment success rates for all regimens between 2018 and 2021 ranged from 44.4 to 90.9%, varying by country and year. The information system relied on primary tools, reporting tools, and digital solutions. Progress has been made in MDR-TB management; however, challenges persist, necessitating resources to enhance access to rapid molecular screening tests.

Drug resistance in drug-resistant tuberculosis patients with and without diabetes mellitus: a comparative analysis

BackgroundThis dual burden of tuberculosis (TB) and diabetes mellitus (DM) has become a global public health concern. This study aims to compare drug resistance in drug-resistant tuberculosis (DR-TB) patients with and without DM and analyse the risk factors of multidrug-resistant tuberculosis (MDR-TB).MethodsA total of 893 DR-TB patients were admitted to Wenzhou Central Hospital between January 2018 and December 2022. After excluding 178 cases with incomplete clinical and laboratory data, 715 patients were included in the study. These patients were then categorized into two groups based on the presence of type 2 DM: the DM group (160 cases) and the non-DM group (555 cases). Demographic information, baseline clinical characteristics, laboratory and imaging test results, clinical diagnoses, and other relevant data were collected for analysis. Statistical analysis was conducted on demographic information, clinical parameters, drug resistance spectrum, and risk factors for multidrug resistance.ResultsIn both the DM and non-DM groups, the order of resistance to first-line anti-tuberculosis drugs is isoniazid, streptomycin, rifampicin, and ethambutol. There is no significant difference in the proportion of mono-resistant tuberculosis, polydrug-resistant tuberculosis, and multidrug-resistant tuberculosis between the two groups (P > 0.05). The prevalence of MDR-TB in both groups shows a downward trend between 2018 and 2022, but the trend is not statistically significant (P > 0.05). Among patients without DM, residence in rural areas, retreatment of tuberculosis, pulmonary cavity, and uric acid ≥ 346 µmol/L are identified as independent risk factors for MDR-TB. Among patients with DM, residence in rural areas, retreatment of tuberculosis, pulmonary cavity, and HbA1c ≥ 9.8% were identified as independent risk factors for MDR-TB.ConclusionIsoniazid is the most resistant drug among DR-TB patients with and without DM. There is no statistically significant difference in drug resistance patterns between the two groups. Some progress has been made in the prevention and control of DR-TB in this area, but the effect is not very significant. There are differences in the risk factors of MDR-TB between patients with and without DM.

A study on factors influencing delayed sputum conversion in newly diagnosed pulmonary tuberculosis based on bacteriology and genomics

Conversion of sputum from positive to negative is one of the indicators to evaluate the efficacy of anti-tuberculosis treatment (ATT). We investigate the factors associated with delayed sputum conversion after 2 or 5 months of ATT from the perspectives of bacteriology and genomics. A retrospective study of sputum conversion in sputum positive 1782 pulmonary tuberculosis (PTB) was conducted from 2021 to 2022 in Beijing, China. We also designed a case-matched study including 24 pairs of delayed-sputum-conversion patients (DSCPs) and timely-sputum-conversion patients (TSCPs), and collect clinical isolates from DSCPs before and after ATT and initial isolates of TSCPs who successfully achieved sputum conversion to negative after 2 months of ATT. A total of 75 strains were conducted drug sensitivity testing (DST) of 13 anti-TB drugs and whole-genome sequencing (WGS) to analyze the risk factors of delayed conversion and the dynamics changes of drug resistance and genomics of Mycobacterium tuberculosis (MTB) during ATT. We found TSCPs have better treatment outcomes and whose initial isolates show lower levels of drug resistance. Clinical isolates of DSCPs showed dynamically changing of resistance phenotypes and intra-host heterogeneity. Single nucleotide polymorphism (SNP) profiles showed large differences between groups. The study provided insight into the bacteriological and genomic variation of delayed sputum conversion. It would be helpful for early indication of sputum conversion and guidance on ATT.

HIV Sero-Prevalence among Tuberculosis Patients in Bangladesh: a nationwide cross-sectional study

Introduction Bangladesh is committed to achieving the SDG target of ending the tuberculosis epidemic and achieving UHC by 2030. To inform policy and program decision-making, this nationwide sero-survey of HIV among tuberculosis patients was conducted. Methods The cross-sectional survey utilized a two-stage probability proportional to size (PPS) systematic random sampling technique for selected TB reporting centers (TRCs) from June 2020 to December 2021. The estimated 12,065 diagnosed tuberculosis patients, according to the NTP diagnostic algorithm, irrespective of age and sex, were included. The required information was collected through face-to-face interviews and record reviews using a pre-tested electronic TAB-based semi-structured questionnaire. With all aseptic precautions for all respondents who gave consent, 5 ml. venous blood was collected for the standard confirmatory test by 4th generation ELISA method for detection of antibody of HIV1/2/P24 antigen. Results Out of 12,065 TB patients surveyed, most of them were from the Dhaka division (25%), urban (76%), 55 years and above (28%), male (56%), married (82%), illiterate (36%) and living in a nuclear family (70%). A total of 12 (0.1%) HIV-positive cases were found among TB patients across the country, and the majority (33%) of them belonged to the age group of 35 to 44 years, male (58%), lower educational group (67%), urban resident (67%), and from nuclear family (77%). The HIV-positive patients found more among pulmonary TB patients (83%) who were detected bacteriologically positive (58%) but smear and gene expert negative (75%). Among them, none was found to have progressed to drug-resistant TB. Conclusion HIV affects the immune system, and TB is one of the leading causes of death in HIV-infected people. Although the rate is low, there is a need for continued efforts to prevent and treat TB in Bangladesh, particularly among older age groups, urban residents, and those with co-morbidities such as diabetes.