Isoniazid-resistant Tuberculosis Research Articles

The Hidden Epidemic of Isoniazid-Resistant Tuberculosis in South Africa

The Hidden Epidemic of Isoniazid-Resistant Tuberculosis in South Africa

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

IntroductionThis study aimed to analyze the risk factors associated with isoniazid-resistant and rifampicin-susceptible tuberculosis (Hr-TB) in adults.MethodThe 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.

Rapid resistance detection is reliable for prompt adaptation of isoniazid resistant tuberculosis management

ObjectivesAppropriate tuberculosis (TB) management requires anti-TB drugs resistance detection. We assessed the performance of rapid resistance detection assays and their impact on treatment adaptation, focusing on isoniazid resistant (Hr) TB. MethodsFrom 2016 to 2022, all TB cases enrolled in 3 hospitals were reviewed for phenotypic drug susceptibility testing (p-DST) and genotypic DST (g-DST) performed by rapid molecular testing, and next generation sequencing (NGS). Clinical characteristics, treatment and outcome were collected for Hr-TB patients. The concordance between g-DST and p-DST results, and delay between treatment initiation and results of g-DST and p-DST were respectively recorded to assess the contribution of DST results on Hr-TB management. ResultsAmong 654 TB cases enrolled, 29 were Hr-TB. Concordance between g-DST by rapid molecular methods and p-DST was 76.9 %, whilst concordance between NGS-based g-DST and p-DST was 98.7 %. Rapid resistance detection significantly fastened Hr-TB treatment adaptation (median delay between g-DST results and treatment modification was 6 days). It consisted in fluoroquinolone implementation for 17/23 patients; outcome was favourable except for 2 patients who died before DST reporting. ConclusionRapid resistance detection fastened treatment adaptation. Also, NGS-based g-DST showed almost perfect concordance with p-DST, thus providing rapid and safe culture-free DST alternative.

Incidence, Outcomes, and Risk Factors for Isoniazid-Resistant Tuberculosis from 2012 to 2022 in Eastern China.

Isoniazid-resistant, rifampicin-susceptible tuberculosis (Hr-TB) is the most frequent drug-resistant tuberculosis (DR-TB) in the world, and unfavorable outcomes of Hr-TB are more common compared to drug-susceptible TB. Considering there is no optimal regimen accepted worldwide, we undertook a retrospective cohort study in eastern China to estimate incidence trends and risk factors associated with unfavorable outcomes of Hr-TB. Between January 2012 and December 2022, all Hr-TB patients' information was extracted from the Tuberculosis Information Management System (TIMS), which is a national electronic information platform, to record TB patients' clinical information in this study. The incidence of Hr-TB was determined by the mid-year population according to census data published by the government. We categorized treatment regimens depending on fluoroquinolone (FQ) use, and potential risk factors were analyzed using multivariable logistic regression. A total of 3116 Hr-TB patients fulfilled the inclusion criteria and were enrolled in this study. The average annual rate of Hr-TB in the 11 years under investigation was 0.34 per 100,000 and increased to 0.53 per 100,000 until 2019. In total, six different treatment regimens were utilized in the study sites, and less than 1% of regimens adopted FQ. There was no difference in the unfavorable outcomes between the FQ-included and FQ-excluded groups (p = 0.22). The average treatment duration was 7.06 months, and the longest treatment was 26 months. Approximately 20% (637/3116) of Hr-TB patients had unfavorable outcomes, and 60.13% (383/637) of them proceeded to multidrug-resistant tuberculosis (MDR-TB). Treatment duration and a positive smear at the end of the 5th month were significantly associated with unfavorable outcomes (p < 0.001). The unfavorable treatment outcomes of Hr-TB are still high in eastern China, and the efficacy of FQ-containing regimens needs to be validated for Hr-TB treatment.

High-Dose Isoniazid Lacks EARLY Bactericidal Activity Against Isoniazid-resistant Tuberculosis Mediated by katG Mutations: A Randomized, Phase 2 Clinical Trial.

Observational studies suggest that high-dose isoniazid may be efficacious in treating multidrug-resistant tuberculosis (MDR-TB). However, its activity against Mycobacterium tuberculosis (M.tb) with katG mutations (which typically confer high-level resistance) is not established. To characterize early bactericidal activity (EBA) of high-dose isoniazid in patients with tuberculosis caused by katG-mutated M.tb. A5312 was a Phase 2A randomized, open-label trial. Participants with tuberculosis caused by katG-mutated M.tb were randomized to receive 15 or 20 mg/kg isoniazid daily for 7 days. Daily sputum samples were collected for quantitative culture. Intensive PK sampling was performed on day 6. Data were pooled across all A5312 participants for analysis (drug-sensitive, inhA-mutated, and katG-mutated M.tb). EBA was determined using nonlinear mixed-effects modelling. Of 80 treated participants, 21 had katG-mutated M.tb. Isoniazid PK was best described by a two-compartment model with an effect of NAT2 acetylator phenotype on clearance. Model-derived Cmax and AUC in the 15 and 20 mg/kg groups were 15.0 and 22.1 mg/L and 57.6 and 76.8 mg∙h/L, respectively. Isoniazid bacterial kill was described using an effect compartment and a sigmoidal Emax relationship. Isoniazid potency against katG-mutated M.tb was approximately 10-fold lower than against inhA-mutated M.tb. The highest dose (20 mg/kg) did not demonstrate measurable EBA, except in a subset of slow NAT2 acetylators (who experienced the highest concentrations). There were no grade 3 or higher drug-related adverse events. This study found negligible bactericidal activity of high-dose isoniazid (15-20 mg/kg) in the majority of participants with tuberculosis caused by katG-mutated M.tb. Clinical trial registration available at www. gov, ID: NCT01936831.

Genetic mechanisms of co-emergence of INH-resistant Mycobacterium tuberculosis strains during the standard course of antituberculosis therapy.

The incidence of isoniazid (INH) resistant Mycobacterium tuberculosis is increasing globally. This study aimed to identify the molecular mechanisms behind the development of INH resistance in M. tuberculosis strains collected from the same patients during the standard course of treatment. Three M. tuberculosis strains were collected from a patient before and during antituberculosis (anti-TB) therapy. The strains were characterized using phenotypic drug susceptibility tests, Mycobacterial Interspersed Repeated Unit-Variable-Number Tandem Repeats (MIRU-VNTR), and whole-genome sequencing (WGS) to identify mutations associated with INH resistance. To validate the role of the novel mutations in INH resistance, the mutated katG genes were electroporated into a KatG-deleted M. tuberculosis strain (GA03). Three-dimensional structures of mutated KatG were modeled to predict their impact on INH binding. The pre-treatment strain was susceptible to INH. However, two INH-resistant strains were isolated from the patient after anti-TB therapy. MIRU-VNTR and WGS revealed that the three strains were clonally identical. A missense mutation (P232L) and a nonsense mutation (Q461Stop) were identified in the katG of the two post-treatment strains, respectively. Transformation experiments showed that katG of the pre-treatment strain restored INH susceptibility in GA03, whereas the mutated katG genes from the post-treatment strains rendered negative catalase activity and INH resistance. The protein model indicated that P232L reduced INH-KatG binding affinity while Q461Stop truncated gene transcription. Our results showed that the two katG mutations, P232L and Q461Stop, accounted for the co-emergence of INH-resistant clones during anti-TB therapy. The inclusion of these mutations in the design of molecular assays could increase the diagnostic performance.IMPORTANCEThe evolution of drug-resistant strains of Mycobacterium tuberculosis within the lung lesions of a patient has a detrimental impact on treatment outcomes. This is particularly concerning for isoniazid (INH), which is the most potent first-line antimycobacterial drug. However, the precise genetic factors responsible for drug resistance in patients have not been fully elucidated, with approximately 15% of INH-resistant strains harboring unknown genetic factors. This raises concerns about the emergence of drug-resistant clones within patients, further contributing to the global epidemic of resistance. In this study, we revealed the presence of two novel katG mutations, which emerged independently due to the stress exerted by antituberculosis (anti-TB) treatment on a parental strain. Importantly, we experimentally demonstrated the functional significance of both mutations in conferring resistance to INH. Overall, this research sheds light on the genetic mechanisms underlying the evolution of INH resistance within patients and provides valuable insights for improving diagnostic performance by targeting specific mutations.

Spatial pattern of isoniazid-resistant tuberculosis and its associated factors among a population with migrants in China: a retrospective population-based study.

Isoniazid-resistant, rifampicin-susceptible tuberculosis (Hr-TB) globally exhibits a high prevalence and serves as a potential precursor to multidrug-resistant tuberculosis (MDR-TB). Recognizing the spatial distribution of Hr-TB and identifying associated factors can provide strategic entry points for interventions aimed at early detection of Hr-TB and prevention of its progression to MDR-TB. This study aims to analyze spatial patterns and identify socioeconomic, demographic, and healthcare factors associated with Hr-TB in Shanghai at the county level. We conducted a retrospective study utilizing data from TB patients with available Drug Susceptible Test (DST) results in Shanghai from 2010 to 2016. Spatial autocorrelation was explored using Global Moran's I and Getis-Ord statistics. A Bayesian hierarchical model with spatial effects was developed using the INLA package in R software to identify potential factors associated with Hr-TB at the county level. A total of 8,865 TB patients with DST were included in this analysis. Among 758 Hr-TB patients, 622 (82.06%) were new cases without any previous treatment history. The drug-resistant rate of Hr-TB among new TB cases in Shanghai stood at 7.20% (622/8014), while for previously treated cases, the rate was 15.98% (136/851). Hotspot areas of Hr-TB were predominantly situated in southwestern Shanghai. Factors positively associated with Hr-TB included the percentage of older adult individuals (RR = 3.93, 95% Crl:1.93-8.03), the percentage of internal migrants (RR = 1.35, 95% Crl:1.15-1.35), and the number of healthcare institutions per 100 population (RR = 1.17, 95% Crl:1.02-1.34). We observed a spatial heterogeneity of Hr-TB in Shanghai, with hotspots in the Songjiang and Minhang districts. Based on the results of the models, the internal migrant population and older adult individuals in Shanghai may be contributing factors to the emergence of areas with high Hr-TB notification rates. Given these insights, we advocate for targeted interventions, especially in identified high-risk hotspots and high-risk areas.

Management of newborns and healthcare workers exposed to isoniazid-resistant congenital tuberculosis in the neonatal intensive care unit

Management of newborns and healthcare workers (HCWs) exposed to congenital tuberculosis (TB) in the neonatal intensive care unit (NICU) has been reported rarely. To outline a contact investigation process for individuals exposed to congenital TB in the NICU and investigate nosocomial transmission. Additionally, to assess the efficacy and safety of window prophylaxis in exposed newborns. A baby, born at a gestational age of 28+ 1 weeks, was diagnosed with isoniazid-resistant congenital TB on the 39th day of admission to the level IV NICU. Newborns and HCWs exposed cumulatively for ≥8h underwent contact investigation and follow-up for a year. Eighty-two newborns underwent contact investigation. All newborns displayed normal chest X-rays, and 42 hospitalized newborns tested negative for acid-fast bacilli stain and Xpert® MTB/RIF assay in their endotracheal sputum or gastric juices. Eighty received window prophylaxis: six of 75 on rifampin experienced mild adverse events, and none of the five on levofloxacin. After 12 weeks, five (6.1%) had a positive tuberculin skin test, all of whom had already received the Bacillus Calmette-Guérin vaccine and tested negative on TB interferon-gamma releasing assay. Of 119 exposed HCWs, three (2.5%) were diagnosed with latent TB infection and completed a four-month rifampin therapy. There was no active TB disease among exposed newborns and HCWs during a one-year follow-up. Timely diagnosis of congenital TB is crucial for minimizing transmission among exposed neonates and HCWs in the NICU setting. In cases of isoniazid-resistant index patients, even premature newborns may consider the use of rifampin or levofloxacin for window prophylaxis.

Pyrazinamide resistance due to pncA gene mutation and its association with treatment outcome among tuberculosis patients of South India- A longitudinal observational study

IntroductionMycobacterium tuberculosis has been extensively studied for mutations leading to drug resistance. Pyrazinamide is a drug acting on the semi-dormant bacteria that is responsible for relapse of tuberculosis. This drug helped reduce the treatment duration of tuberculosis from nine to six months. However, this drug is not being screened for resistance along with Rifampicin and Isoniazid. Aims and objectivesThis study aimed to estimate the proportion of pncA gene mutation among tuberculosis patients and its association between treatment outcomes, clinical characteristics, and phenotypic drug resistance. Methodology: A total of 154 samples included 73 drug-resistant and 81 drug-susceptible isolates. The isolates were subjected to DNA extraction and amplification using conventional PCR. The PCR product was sequenced by the Sanger sequencing method, and phenotypic drug susceptibility testing was done using the broth dilution method. The association of this gene with the treatment outcome was done by following up with the patients till the end of the regimen. ResultsNone of the drug susceptible tuberculosis patients showed significant non-synonymous mutations. Among the drug-resistant TB patients, seven unique significant mutations out of 73 isolates (9.6%) were distributed among Isoniazid-resistant tuberculosis and Multi-Drug Resistant Tuberculosis isolates. No association was found between the mutations and the clinical characteristics of the subjects harboring these isolates. ConclusionThis study estimated seven unique mutations in drug-resistant tuberculosis and none in drug-sensitive tuberculosis. Isolates harboring was not significantly associated with the participant's treatment outcome and other clinical characteristics. The pyrazinamide resistance testing by the phenotypic and genotypic methods was found to be in concordance.

Trends of Drug-Resistant Tuberculosis in an Urban and a Rural Area in China: A 10-Year Population-Based Molecular Epidemiological Study.

Drug resistance is the critical determinant for appropriate tuberculosis (TB) treatment regimens and an important indicator of the local TB burden. We aimed to investigate and compare trends in TB drug resistance in the urban Songjiang District of Shanghai from 2011 to 2020, and the rural Wusheng County of Sichuan Province from 2009 to 2020, to assess the effectiveness of local TB control and treatment programs. Whole-genome sequencing data of Mycobacterium tuberculosis were used to predict drug-resistance profiles and identify genomic clusters. Clustered, retreated cases of drug-resistant TB with identical resistance mutations, as well as all new resistant cases, were defined as transmitted resistance. The Cochran-Armitage trend test was used to identify trends in the proportions. Differences between groups were tested using the Wilcoxon rank sum or chi-square tests. The annual proportions of rifampicin-resistant (RR), isoniazid-resistant (INH-R) and multidrug-resistant (MDR) TB cases did not change significantly in Songjiang. In Wusheng, however, the percentage of total TB cases that were RR decreased from 13.2% in 2009 to 3.7% in 2020, the INH-R cases decreased from 16.5% to 7.3%, and the MDR cases decreased from 10.7% to 3.7%. In retreated cases, the percentage of drug resistance decreased in both Songjiang and Wusheng, suggesting improved treatment programs. Transmitted resistance accounted for more than two thirds of drug-resistant cases over the entire study periods, and in recent years this proportion has increased significantly in Songjiang. In both urban Songjiang and rural Wusheng, drug-resistant TB is mostly the result of transmission of drug resistant strains and the percentage of transmitted resistance will likely increase with on-going improvements in the TB treatment programs. Reducing the prevalence of drug resistance depends principally upon decreasing transmission through the prompt diagnosis and effective treatment of drug-resistant TB cases.

Co-resistance to isoniazid and second-line anti-tuberculosis drugs in isoniazid-resistant tuberculosis at a tertiary care hospital in Thailand.

The prevalence of isoniazid-resistant tuberculosis (Hr-TB) is the highest among other types of drug-resistant tuberculosis. Currently, the World Health Organization (WHO) guidelines recommend the treatment of Hr-TB with rifampicin, ethambutol, pyrazinamide, and levofloxacin for 6 months. The susceptibility profiles of Hr-TB clinical isolates, especially when they are co-resistant to second-line drugs, are critical in the selection of the appropriate treatment regimen to prevent treatment failure. This study highlights the susceptibility profiles of the WHO-recommended treatment regimen in Hr-TB clinical isolates from a tertiary care hospital in Thailand and the concordance and importance of using the phenotypic drug susceptibility testing or genotypic drug susceptibility testing for accurate and comprehensive interpretation of results.

Mutation Characteristics of inhA and katG Genes in Isoniazid-Resistant Mycobacterium Tuberculosis Patients in Xinjiang

Objective: To analyze the mutation characteristics of inhA and katG genes in isoniazid-resistant Mycobacterium tuberculosis in Xinjiang. Methods: The katG and inhA in 148 strains of isoniazid-resistant Mycobacterium tuberculosis were amplified through fluorescence quantitative PCR, and the amplified products were sequenced and compared. Results:The inhA gene mutation rate of 148 strains of isoniazid-resistant mycobacterium tuberculosis was 13.51% (20/148), among which the inhA gene mutation rate among patients of Han, Uygur, and Kazakh ethnicity were 15.87%, 13.21%, and 17.65%, respectively. There was no significant difference in the inhA mutation rate among nationalities (c2 = 2.897, P &gt; 0.05). The mutation rate of the katG gene was 84.46% (125/148), among which the mutation rates of patients of Han, Uyghur, and Kazak ethnicities were 82.54%, 84.91%, and 76.47%, respectively. The Hui and other ethnic groups were all affected by the katG gene mutation. There was no significant difference in the mutation rate of the katG gene among different ethnicities (c2 = 3.772, P &gt; 0.05). The mutation rates of the inhA gene in southern Xinjiang, northern Xinjiang, and other provinces were 18.60%, 9.28%, and 37.50%, respectively. The mutation rates of the inhA gene in different regions were statistically different (c2 = 6.381, P &lt; 0.05). There was no significant difference in the inhA mutation rate between patients from southern and northern Xinjiang (c2 = 2.214, P &gt; 0.05) and between southern Xinjiang and other provinces (c2 =1.424, P &gt; 0.05). However, the mutation rate of the inhA gene in patients from other provinces was higher than that in northern Xinjiang (c2 = 5.539, P &lt; 0.05). The mutation rates of the katG gene in southern Xinjiang, northern Xinjiang, and other provinces were 81.40%, 87.63%, and 62.50%, respectively. There was no significant difference in the mutation rates of the katG gene among different regions (c2 = 3.989, P &gt; 0.05). Conclusion: katG gene mutation was predominant in isoniazid-resistant tuberculosis patients in Xinjiang Uygur Autonomous Region, and inhA and katG gene mutation were no different among different ethnic groups.

Tailored treatment for tuberculosis in transgender individuals: a call for a patient-centered approach from a large Italian cohort.

Tuberculosis (TB) diagnosis and management in special populations remain challenging. Data about TB and transgender individuals is scarce, and strategies aimed at reducing the TB burden in this at-risk group are needed. We conducted an observational monocentric study from a national reference center for TB, including transgender individuals with active TB in a low-TB burden country (Italy), over 34 years (1990-2023). Sixty-six transgender males and two transgender females (median age 30 years, interquartile range 26-38 years, 65 migrants) were included. Most patients (38/66, 57.6%) lived in poor social conditions. 65.2% (43/66) of patients were people living with HIV. Multidrug- and rifampicin-resistant tuberculosis and isoniazid-resistant TB were diagnosed in five (7.6%) and three (4.5%) patients, respectively. The overall treatment success rate was 72.7% (48/66 patients), with differences observed according to social conditions. Our study highlights the need for a tailored approach to increase treatment success in this at-risk population.

Treatment outcomes of retreated patients with isoniazid/rifampicin resistant pulmonary tuberculosis.

About 8% of TB cases worldwide are estimated to have rifampicin-susceptible, isoniazid-resistant tuberculosis (Hr-TB), ranging from 5 to 11% regions. However, Hr-TB has not received much attention while comparing to be given high priority to the management of rifampicin-resistant tuberculosis (RR-TB). This study aimed to compare the differences of treatment effects for Hr-TB and RR-TB, so as to intensify the treatment and management of Hr-TB. A retrospective study was used to collect bacteriologically positive retreated patients with isoniazid/rifampicin resistant pulmonary tuberculosis, who were conducted at 29 tuberculosis control institutions in China from July 2009 to June 2021. We assessed effectiveness and safety of retreated patients with isoniazid/ rifampicin resistant pulmonary tuberculosis. A total of 147 with either positive smear or cultures were enrolled, and 80 cases were in Hr-TB group and 67 cases were in RR-TB group. There was no significant difference in terms of age, sex, body mass, type of retreatment and comorbid diabetes between the two groups (P > 0.05). The rate of number of lesions involving lung fields ≥ 3 in Hr-TB group 75.9% (60/79) was significantly higher than RR-TB group 56.7% (38/67) (χ2 = 6.077, P = 0.014). There was no statistically significant difference (P = 0.166) with regard to the treatment outcomes of the two groups, the cure rates were 54.7% (41/75) and 53.6% (30/56), respectively, and the failure rate in Hr-TB group 22.7% (17/75) was 10% higher than RR-TB group 10.7% (6/56). The rate of negative sputum smear at the end of the second month (65.7%) in the Hr-TB group was significantly lower than that in the RR-TB group (85.7%) (P = 0.025). There were no significant differences in the incidences of serious adverse reactions and chest X-ray changes between the two groups (P > 0.05). During the 5-year follow-up, recurrence in the Hr-TB group (7 cases, 14.9%) was no significantly lower than that in the RR-TB group (4 cases, 11.8%) (P = 0.754). The treatment of retreated Hr-TB patients was difficult and could be statistically similar or considerably worse than RR-TB. It's urgent to conduct further evaluation of the treatment status quo to guide the guideline development and clinical practice of Hr-TB patients.

Assessing Treatment Efficacy and Determinants of Outcome in Isoniazid Mono-resistant Tuberculosis Patients: A Prospective Observational Study in Gujarat

Introduction: There is a high number of isoniazid-resistant tuberculosis (TB) in India; estimates imply that over 25% of TB patients there are isoniazid-resistant. Hence, the study aimed to evaluate the effectiveness of therapy for patients with isoniazid-mono-resistant TB and the negative effects of the H-mono-resistant TB Regime. Materials and Methods: It was a hospital-based prospective observational study from September 2021 to August 2022. Hence, 100 patients diagnosed with isoniazid mono-resistance TB enrolled in this study. After obtaining the prior informed consent of all patients willing to approve the collection and publication of their data, including extensive clinical history and radiological, microbiological, and biochemical investigations, this study included all diagnosed cases of isoniazid mono-resistant TB. A descriptive statistical analysis was done for continuous and categorical variables. Differences in characteristics between participants were tested with logistic regression and cross-tabulation. P &lt;0.05 was considered significant. Results: Among 100 patients participated, their mean age was 50.8 ± 3.2 years. About 72 (72%) participants have successful treatment outcomes (cure). Only about 25 (25%) patients had minor adverse drug reactions. Body mass index (16.6 [3.6–74]), substance addiction history (9.5 [3.3–26.9]), previous history of TB (9 [3.3–24.0]), type of lesion (5.3 [1.6–17]), and extent of the lesion (2.6 [1.03–6.07]) in chest X-ray were associated statistically with the treatment outcome. Conclusion: The findings suggest that the H-mono-resistance regime is generally well-tolerated, with only a small percentage of patients experiencing nonserious adverse drug reactions, and the overall successful treatment outcome in H-mono patients was 72%. The study also highlights the importance of monitoring drug resistance patterns, particularly for levofloxacin and moxifloxacin, and the need for effective treatment regimens for isoniazid mono-resistant pulmonary TB.

Simulation of Conditions and Results of Implementation of Short-Course Treatment Regimes in Tuberculosis Patients

The objective: to study the conditions of implementation of short-course (4 and 9 months) treatment regimens in tuberculosis patients and simulate their impact on the frequency of early treatment interruption (ETI) by patients.Subjects and Methods. Data on the treatment duration from enrollment to chemotherapy interruption in 8,029 tuberculosis patients were studied. Data were obtained from the Federal Register of Tuberculosis Cases for 2020. Of these, 3,379 patients were treated with regimens for susceptible or suspected susceptible tuberculous mycobacteria excluding isoniazid resistant tuberculosis, and 4,650 patients received regimens for rifampicin-resistant tuberculous mycobacteria.Results. The median duration of treatment from onset to ETI was 124 (95% CI 120-128) days in 3,379 patients, 224 (95% CI 215-233) days in 4,650 patients, or 170 (95% CI 157-181) days if there was a history of treatment interruption. Simulation of ETI terms when short-course chemotherapy regimens were introduced has shown that we can expect a 2-fold decrease in the proportion of patients who interrupted chemotherapy among patients with preserved/suspected susceptibility of tuberculous mycobacteria, and 1.3-1.7-fold decrease among patients with confirmed/presumed drug resistance of tuberculous mycobacteria at least to rifampicin.

Efficacy of Various Approaches to Treatment of Patients with Isoniazid Resistant Pulmonary Tuberculosis

The objective: to evaluate the efficacy of chemotherapy regimens for isoniazid resistant pulmonary tuberculosis (Hr-TB): short-course regimen consisting of 4 components (non-injection) and the regimen consisting of 5 components (standard regimen).Subjects and Methods. Medical records of 292 pulmonary tuberculosis patients with resistance to isoniazid were retrospectively studied. In 89 patients (Group A), the regimen containing rifampicin, pyrazinamide, ethambutol, and levofloxacin was used – a 4-component non-injection regimen (180±20 doses). In 203 patients (Group B), the regimen containing rifampicin, pyrazinamide, ethambutol, levofloxacin, and amikacin/kanamycin was used - a 5-component standard regimen (270 doses).Results. The efficacy of treatment of isoniazid resistant pulmonary tuberculosis was similar, while a short-term 4-component (non-injection) regimen is 4.5 times less expensive versus the standard 5-component regimen. Treatment success made 88.8% and 88.2% respectively, p&gt;0.05.

Assess the Diagnostic Accuracy of GeneXpert to Detect Mycobacterium tuberculosis and Rifampicin-Resistant Tuberculosis among Presumptive Tuberculosis and Presumptive Drug Resistant Tuberculosis Patients

GeneXpert MTB/RIF is a rapid molecular diagnostic tool capable of simultaneously detecting Mycobacterium tuberculosis and rifampicin resistance. This study aimed to assess the diagnostic precision of GeneXpert MTB/RIF assay to detect pulmonary and extrapulmonary tuberculosis and evaluate the performance for detecting of rifampicin resistance. Of 37,695 samples, 7156 (18.98%) were tuberculosis-positive, and 509 (7.11%) were rifampicin-resistant. The sensitivity, specificity, positive predictive value, negative predictive value, disease prevalence, and accuracy of the GeneXpert MTB/RIF assay for pulmonary tuberculosis were 99.87% (95%CI: 99.75–99.94), 99.92% (95%CI: 99.88–99.95), 99.71% (95%CI: 99.54–99.82), 99.97% (95%CI: 99.93–99.98), 21.38% (95%CI: 20.92–21.86), and 99.91% (95%CI: 99.87–99.94), respectively. For extrapulmonary tuberculosis, the sensitivity, specificity, PPV, NPV, disease prevalence, and accuracy of GeneXpert MTB/RIF assay accounted for 99.45% (95%CI: 98.73–99.82), 99.84% (95%CI: 99.73–99.92), 98.70% (95%CI: 97.73–99.25), 99.93% (95%CI: 99.84–99.97), 10.64% (95%CI: 9.99–11.31), and 99.80% (95%CI: 99.68–99.88), respectively. Despite its high sensitivity for detecting tuberculosis and rifampicin resistance, GeneXpert MTB/RIF had contradictory results for 20.5% of cases among patients with smear-negative results and 54.9% of cases among patients with a high risk of multidrug-resistant tuberculosis. Of 46% fluoroquinolone-resistant cases, 16.56% (26/157) were multidrug-resistant tuberculosis isolates, and 4.02% (20/498) were isoniazid-resistant, a characteristic distribution leading to about 17.2% of fluoroquinolone-resistance events and relevant marker gyr-A mutations in MDR tuberculosis isolates. Further, our study indicated that increased fluoroquinolone resistance among rifampicin-resistant and isoniazid-resistant tuberculosis endangers the success of newly endorsed MDR-TB regimens.

Discordance between genotypic and phenotypic methods for the detection of rifampicin and isoniazid resistant Mycobacterium tuberculosis and the correlation with patient treatment outcomes

BackgroundAccurate drug susceptibility testing (DST) of Mycobacterium tuberculosis (MTB) is essential for proper patient management. We investigated discordance between genotypic (Xpert MTB/RIF and MTBDRplus) and phenotypic (MGIT 960) methods for the detection of rifampicin (RIF) and isoniazid (INH) resistant MTB and its correlation with patient treatment outcomes in Jimma, Southwest Oromia, Ethiopia. MethodsA retrospective study was conducted on 57 stored MTB isolates with known Xpert RIF resistance status (45 RIF resistant and 12 RIF susceptible) at Jimma University Mycobacteriology Research Center from November 2, 2021, to December 28, 2022. We did MTBDRplus and phenotypic DST (using the Mycobacterial Growth Indicator Tube (MGIT) system). The Xpert and MTBDRplus results were compared using phenotypic DST as a reference standard method. The treatment outcome was determined as per national guideline. The discordance between the genotypic and phenotypic DST was calculated using GraphPad software. ResultsAmong the 57 MTB isolates, six (10.5 %) had discordant results between the two DST methods. Xpert yielded five discordant results for RIF when compared with phenotypic DST (kappa coefficient (κ) = 0.76, 95 % confidence interval 0.56–0.96). The MTBDRplus compared with phenotypic DST gave three discordant results for RIF (κ = 0.86, 95 % confidence interval 0.71–1.00) and three for INH (κ = 0.86, 95 % confidence interval 0.70–1.00). Compared with Xpert, MTBDRplus yielded lower discordance with phenotypic DST for RIF. Out of six patients with discordant results, three had unfavorable outcomes while the other three were cured. Of the three patients with unfavorable outcomes, only one patient has received an inappropriate treatment regimen. There was no correlation between unfavorable outcomes and incorrect treatment regimens due to discordant results (Χ2 = 0.404; P = 0.525). ConclusionsDiscordance between genotypic and phenotypic DST for RIF or INH occurred in 10.5 % of isolates. Only one patient with discordant results has received an inappropriate treatment regimen, resulting in an unfavorable outcome. The impact of parallel use of rapid molecular assay with phenotypic DST on patient treatment outcomes requires further study.

Isoniazid-Resistant Tuberculosis - A Series of Clinical Cases

Abstract The emergence of M. tuberculosis strains resistant to Isoniazid (INH) and Rifampicin (RIF), the two most potent drugs of first-line anti-TB treatment is termed multidrug drug-resistant TB (MDR-TB). Multidrug-resistant tuberculosis has been a severe medical and epidemic problem worldwide. We present a series of clinical cases consisting of two patients diagnosed with isoniazid-resistant tuberculosis. Histopathological examination supports the diagnosis of tuberculous granulomas. The pathology molecular examination revealed the presence of Isoniazid-resistant Mycobacterium tuberculosis 1, 2 via the following mutation c.947G&gt;A; p. Gly316Asp. Isoniazid-resistance is associated with mutations in the furA-katG and fabG1-inhA operons and in the ahpC gene. 64% of the isoniazid-resistance phenotypes were associated with the kat G 315 mutation worldwide. The second most common mutation is inhA-15, reported in 19% of the Isoniazid-resistant isolates. The significant association between the two mutations, inhA c-15 and kat G 315 respectively, and the high-level resistance is of interest in the interpretation of current and future molecular diagnostic testing, as an early prediction of the level of Isoniazid-resistance is essential to decide the benefit of high-dose Isoniazid use.