Isoniazid-resistant Tuberculosis Research Articles

Phenotypic Detection of Rifampicin and Isoniazid Resistance Pattern of Mycobacterium Tuberculosis Auramine Positive Isolates in Mtata, South Africa

Background: The increase prevalence of Isoniazid (INH) and Rifampicin (RIF) resistant Tuberculosis (TB) has become a significant challenge for TB control for over 10 years. Aim: The study assessed the phenotypic detection of rifampicin (RIF) and isoniazid (INH) resistant pattern of Mycobacteria tuberculosis among patients attending hospitals in Mtata, South Africa. Methodology: Three hundred and fifty (350) patients age between 10-80 years attending Nelson Mandela Hospital Mtata were recruited for the study. Ethical approval was obtained from the Ethics Committee of Nelson Mandela Hospital Mtata. Sputum specimens were investigated employing Auramin fluorescence microscopy technique. Drug susceptibility testing (DST) was carried out using cultural technique and conventional drugs susceptibility testing method. Results: Result showed that 28.6% of the isolates were positive on culture. For INH testing, 27% were sensitive, 68% were resistant where as 5% had lost viability to INH. For RIF, 28% were sensitive, 69% were resistant and 3% had lost viability to RIF. The rural settlers has 55% INH resistance and 26% RIF resistance while in urban area 35% and 25% were resistance to RIF and INH respectively. Conclusion: Result from this study showed that INH and RIF resistance were very high among the patients attending Nelson Mandela Hospital and other treatment centers in Mtata, South Africa.

Is a 6-month Treatment for Isoniazid-resistant Tuberculosis Effective?

The objective: to compare treatment efficacy and relapse rates in patients with isoniazid-resistant tuberculosis treated with 9- and 6-month courses of chemotherapy.Subjects and Methods. A retrospective cohort study was conducted. The period from 2010 to 2015 was evaluated. The cases of tuberculosis registered on the territory of Arkhangelsk Region were studied. In 2010-2013, all patients with isoniazid-resistant tuberculosis (n = 130) in the region received a 9-month course of treatment. From 2014 to 2015, the duration of treatment for isoniazid-resistant tuberculosis in the region was reduced from 9 to 6 months. The patients (n = 54) received short-course treatment: aminoglycoside or polypeptide (2 months), rifampicin, pyrazinamide, fluoroquinolone, and ethambutol.There was no statistically significant difference in treatment outcomes of isoniazid-resistant tuberculosis between two regimens: The outcome of effective treatment made 76.2% for the 9-month regimen and 74.1% for the 6-month regimen. The relapse rate per 100 person-years was 0.7 (95% CI 0.1-1.9) for the 9-month regimen and 1.9 (95% CI 0.2-6.7) for the 6-month regimen. This study confirmed the need to decrease the duration of treatment for isoniazid-resistant tuberculosis to 6 months.

Time to start of tuberculosis treatment in penitentiary system of Kyrgyz Republic: A retrospective cohort study.

BackgroundTuberculosis burden among the incarcerated population is generally higher than that of general population. Early diagnosis and prompt initiation of treatment are key strategies to contain disease transmission. The aim of this study was to determine the time to treatment initiation among inmates with new smear or Xpert MTB/RIF positive pulmonary tuberculosis and explore risk factors associated with delayed treatment initiation in prison settings.MethodsWe conducted a retrospective cohort study using routine health care data from prison settings in Kzrgyz Republic on new pulmonary tuberculosis patients confirmed by smear microscopy or GeneXpert MTB/RIF during 2014–2019. We computed delay in start of treatment—days from specimen collection to treatment initiation—for exposure variables. We dichotomized treatment delay using 10-day cut-off point,and used logistic regression to identify factors associated with treatment delay.ResultsAmong 406 cases included into analysis, the median delay to treatment initiation was 7 days [IQR: 2–16 days]. Using 10-day cut-off, 189 (46.6%) patients had delayed treatment initiation. Treatment delay was negatively associated with smear positivity [adjusted OR (aOR) = 0.44, 95% CI 0.29–0.68] compared to smear negative patients, while patients with isoniazid resistant (aOR = 2.61, 95%CI 1.49–4.56) and rifampicin resistant tuberculosis (aOR = 4.14, 95%CI 2.56–6.77) had increased delay compared to patients who were sensitive for both rifampicin and isoniazid.ConclusionTimely diagnosis and effective treatment remain the cornerstone of TB control program populations in the general and in prison settings in particular. Prison authorities need to address all potential areas of delay in TB diagnosis and treatment to strengthen their TB control efforts so that prisons remain free of TB for detainees, prison staff and visitors. These include improved supply of TB drugs, early detection of TB cases and improved collaboration with the health authorities outside the prison system.

Assessment of Pattern of Drug-resistant TB and Associated Factors in Rewa, Madhya Pradesh, India

Background and aims: The emergence and spread of drug-resistant strains of Mycobacterium tuberculosis are greatly complicating tuberculosis (TB) control efforts in many countries. In India, in 2018, out of 2.4 million notified cases of TB, there were an estimated 66359 and 3,882 laboratory-confirmed cases of multi-drug resistant tuberculosis (MDR-TB) and extensively drug-resistant TB (XDR-TB) respectively. The main objective of this study was to assess pattern of drug-resistant tuberculosis (DR-TB) and factors associated with it in Rewa district of Madhya Pradesh, India. Methods: This descriptive-analytical cross-sectional study was carried out at a tertiary care center in Rewa district from March 1, 2019, to February 29, 2020 (12 months). Taking the census method into account, all of 186 DR-TB cases registered at District Tuberculosis Centre (DTC), Rewa district, with the age of 18 years and above were included in the study. All the patients were interviewed thoroughly using a pre-tested, pre-validated, and reliable pro forma which included information regarding socio-demographic profile and history of TB. For statistical analysis, chi-square test (with/without Yate’s correction) was applied and a P value less than 0.05 was considered statistically significant. Results: In the present study, 71.6% and 28.4% of the cases were reported to be male and female, respectively. Additionally, 78.4% of the study subjects belonged to the age group of less than 45 years. Besides, rifampicin-resistant TB (RR-TB) was found to be the most prevalent type (56.4%), followed by isoniazid-resistant TB (HR-TB) (13.4%), and mixed pattern (12.4%) of DR-TB. Conclusion: DR-TB was more commonly observed in males of the economically productive age group (45 years and below), which can affect the social and economic development of individual, society, and nation.

Identification of S315T mutation in katG gene using probe-free exclusive mismatch primers for a rapid diagnosis of isoniazid-resistant Mycobacterium tuberculosis by real-time loop-mediated isothermal amplification

We developed a LAMP-based technique that employs primers that carry base mismatches to specifically detect the katG (S315T) SNP associated with isoniazid resistance in tuberculosis (TB). Antibiotic resistance in TB is still predominantly determined by the standard drug susceptibility testing that lacks sensitivity, and often requires a weeks-long effort of manual labor and extensive laboratory resources. Advanced real-time PCR techniques are highly efficient for detecting these drug-resistant SNPs, yet their accessibility is limited in TB-endemic regions due to prohibitive instrumental costs and a lack of highly-trained personnel. The isothermal assay described herein was optimized for fluorescence detection on the real-time PCR system. Its ability to discriminate the S315T mutant from wild-type katG without using the melting curve analysis has granted its adaptation into an end-point detection format performed on a hand-held potentiostat device through rapid electrochemical detection. Our technique exhibited the statistical sensitivity and specificity of 100% (95% CI: 98% − 100%) and 96% (95% CI: 87% − 99%), respectively, based on the validation with 218 tuberculosis isolates collected from patients performed under real-time detection mode. The versatility of analysis of this assay has unprecedently allowed the determination of a key INH-resistant associated SNP to be diagnosed without relying on detection probes or the melting curve analysis as often required by standard real-time PCR.

Prevalences of levofloxacin resistance and pncA mutation in isoniazid-resistant Mycobacterium tuberculosis in Hong Kong.

In 2018, the World Health Organization recommended a 6-month treatment regimen that included levofloxacin and pyrazinamide for isoniazid-resistant Mycobacterium tuberculosis without rifampicin resistance (Hr-TB). Susceptibility testing for both drugs is not routinely performed for Hr-TB in Hong Kong. This study examined the prevalences of levofloxacin and pyrazinamide resistances in Hr-TB and explored associated risk factors. All Hr-TB isolates archived during 2018 were retrieved. Isolates were de-duplicated to identify unique cases. Levofloxacin susceptibility testing was performed using the MGIT 960 System; pncA gene sequencing was used as a surrogate indicator of pyrazinamide susceptibility. Previous laboratory records for each case were analysed. In total, 160 phenotypic Hr-TB cases were identified from among 3411 patients with tuberculosis (4.7%). Among these, 157 were analysed, revealing 0.6% (n=1) levofloxacin resistance and 4.5% (n=7) pyrazinamide resistance, respectively. Independent risk factors associated with pncA mutations included history of tuberculosis in the affected patient and isoniazid poly-resistance (ie, double and triple resistances), but not mono-resistance. For Hr-TB in Hong Kong, levofloxacin resistance is rare and pyrazinamide resistance-associated pncA mutations are uncommon. Routine susceptibility testing for these drugs is not indicated unless related risk factors are identified.

Multidrug-Resistant Tuberculosis in U.S.-Bound Immigrants and Refugees.

RationaleApproximately two-thirds of new cases of tuberculosis (TB) in the United States are among non–U.S.-born persons. Culture-based overseas TB screening in U.S.-bound immigrants and refugees has substantially reduced the importation of TB into the United States, but it is unclear to what extent this program prevents the importation of multidrug-resistant TB (MDR-TB).ObjectivesTo study the epidemiology of MDR-TB in U.S.-bound immigrants and refugees and to evaluate the effect of culture-based overseas TB screening in U.S.-bound immigrants and refugees on reducing the importation of MDR-TB into the United States.MethodsWe analyzed data of immigrants and refugees who completed overseas treatment for culture-positive TB during 2015–2019. We also compared mean annual number of MDR-TB cases in non–U.S.-born persons within 1 year of arrival in the United States between 1996–2006 (when overseas screening followed a smear-based algorithm) and 2014–2019 (after full implementation of a culture-based algorithm).ResultsOf 3,300 culture-positive TB cases identified by culture-based overseas TB screening in immigrants and refugees during 2015–2019, 122 (3.7%; 95% confidence interval [CI], 3.1–4.1) had MDR-TB, 20 (0.6%; 95% CI, 0.3–0.9) had rifampicin-resistant TB, 382 (11.6%; 95% CI, 10.5–12.7) had isoniazid-resistant TB, and 2,776 (84.1%; 95% CI, 82.9–85.4) had rifampicin- and isoniazid-susceptible TB. None were diagnosed with extensively drug-resistant TB. All 3,300 persons with culture-positive TB completed treatment overseas; of 70 and 11 persons who were treated overseas for MDR-TB and rifampicin-resistant TB, respectively, none were diagnosed with TB disease at postarrival evaluation in the United States. Culture-based overseas TB screening in U.S.-bound immigrants and refugees prevented 24.4 MDR-TB cases per year from arriving in the United States, 18.2 cases more than smear-based overseas TB screening. The mean annual number of MDR-TB cases among non–U.S.-born persons within 1 year of arrival in the United States decreased from 34.6 cases in 1996–2006 to 19.5 cases in 2014–2019 (difference of 15.1; P < 0.001).ConclusionsCulture-based overseas TB screening in U.S.-bound immigrants and refugees substantially reduced the importation of MDR-TB into the United States.

Isoniazid or rifampicin preventive therapy with and without screening for subclinical TB: a modeling analysis

BackgroundShort-course, rifamycin-based regimens could facilitate scale-up of tuberculosis preventive therapy (TPT), but it is unclear how stringently tuberculosis (TB) disease should be ruled out before TPT use.MethodsWe developed a state-transition model of a TPT intervention among two TPT-eligible cohorts: adults newly diagnosed with HIV in South Africa (PWH) and TB household contacts in Pakistan (HHCs). We modeled two TPT regimens—4 months of rifampicin [4R] or 6 months of isoniazid [6H]—comparing each to a reference of no intervention. Before initiating TPT, TB disease was excluded either through symptom-only screening or with additional radiographic screening that could detect subclinical TB but might limit access to the TPT intervention. TPT’s potential curative effects on both latent and subclinical TB were modeled, as were both acquisitions of resistance and prevention of drug-resistant disease. Although all eligible individuals received the screening and/or TPT interventions, the modeled TB outcomes comprised only those with latent or subclinical TB that would have progressed to symptomatic disease if untreated.ResultsWhen prescribed after only symptom-based TB screening (such that individuals with subclinical TB were included among TPT recipients), 4R averted 45 active (i.e., symptomatic) TB cases (95% uncertainty range 24–79 cases or 40–89% of progressions to active TB) per 1000 PWH [17 (9–29, 43–94%) per 1000 HHCs]; 6H averted 37 (19–66, 52–73%) active TB cases among PWH [13 (7–23, 53–75%) among HHCs]. With this symptom-only screening, for each net rifampicin resistance case added by 4R, 12 (3–102) active TB cases were averted among PWH (37 [9–580] among HHCs); isoniazid-resistant TB was also reduced. Similarly, 6H after symptom-only screening increased isoniazid resistance while reducing overall and rifampicin-resistant active TB. Screening for subclinical TB before TPT eliminated this net increase in resistance to the TPT drug; however, if the screening requirement reduced TPT access by more than 10% (the estimated threshold for 4R among HHCs) to 30% (for 6H among PWH), it was likely to reduce the intervention’s overall TB prevention impact.ConclusionsAll modeled TPT strategies prevent TB relative to no intervention, and differences between TPT regimens or between screening approaches are small relative to uncertainty in the outcomes of any given strategy. If most TPT-eligible individuals can be screened for subclinical TB, then pairing such screening with rifamycin-based TPT maximizes active TB prevention and does not increase rifampicin resistance. Where subclinical TB cannot be routinely excluded without substantially reducing TPT access, the choice of TPT regimen requires weighing 4R’s efficacy advantages (as well as its greater safety and shorter duration that we did not directly model) against the consequences of rifampicin resistance in a small fraction of recipients.

Clinical Relevance of Rifampicin-Moxifloxacin Interaction in Isoniazid-Resistant/Intolerant Tuberculosis Patients.

Moxifloxacin is an attractive drug for the treatment of isoniazid-resistant rifampicin-susceptible tuberculosis (TB) or drug-susceptible TB complicated by isoniazid intolerance. However, co-administration with rifampicin decreases moxifloxacin exposure. It remains unclear whether this drug-drug interaction has clinical implications. This retrospective study in a Dutch TB center investigated how rifampicin affected moxifloxacin exposure in patients with isoniazid-resistant or -intolerant TB. Moxifloxacin exposures were measured between 2015 and 2020 in 31 patients with isoniazid-resistant or -intolerant TB receiving rifampicin, and 20 TB patients receiving moxifloxacin without rifampicin. Moxifloxacin exposure, i.e., area under the concentration-time curve (AUC0-24h), and attainment of AUC0-24h/MIC > 100 were investigated for 400 mg moxifloxacin and 600 mg rifampicin, and increased doses of moxifloxacin (600 mg) or rifampicin (900 mg). Moxifloxacin AUC0-24h and peak concentration with a 400 mg dose were decreased when rifampicin was co-administered compared to moxifloxacin alone (ratio of geometric means 0.61 (90% CI (0.53, 0.70) and 0.81 (90% CI (0.70, 0.94), respectively). Among patients receiving rifampicin, 65% attained an AUC0-24h/MIC > 100 for moxifloxacin compared to 78% of patients receiving moxifloxacin alone; this difference was not significant. Seven out of eight patients receiving an increased dose of 600 mg moxifloxacin reached the target AUC0-24h/MIC > 100. This study showed a clinically significant 39% decrease in moxifloxacin exposure when rifampicin was co-administered. Moxifloxacin dose adjustment may compensate for this drug-drug interaction. Further exploring the impact of higher doses of these drugs in patients with isoniazid resistance or intolerance is paramount.

Differentiated Approaches to Chemotherapy of Respiratory Tuberculosis in Children Exposed to Isoniazid Resistant Tuberculosis

The objective of the study: evaluation of the results of differentiated approaches to chemotherapy of respiratory tuberculosis in children exposed to isoniazid resistant tuberculosis. Subjects and Methods. 57 children aged 2-12 years were enrolled in the study (the median age made 8 years) all children suffered from active respiratory tuberculosis and received conservative therapy only All children were exposed to isoniazid resistant tuberculosis. Patients were divided into two groups. Group 1 received standard chemotherapy regimen 2: 5 anti-tuberculosis drugs (TB drugs) in the intensive phase and 4 TB drugs in the continuation phase (5 TB drugs/4 TB drugs) for disseminated processes (25 patients); Group 2 - 32 patients who received individualized regimens: 4 TB drugs/3 TB drugs for the limited disease (14 patients); 3 TB drugs for the whole course of chemotherapy for minor forms (18 patients). The combination of TB drugs was based on the susceptibility of the index case. Results. Treatment outcomes in all children were classified as effective treatment. The intensive phase of chemotherapy made 4.2 ± 0.3 months in Group 1 and 2.8 ± 0.2 months in Group 2, p t < 0.05. The total duration of chemotherapy in Group 1 made 9.9 ± 0.3 months, and in Group 2 was 6.8 ± 0.2 months, p t < 0.05. Conclusion. The use of individual regimens of anti-tuberculosis chemotherapy consisting of the fewer number of drugs and with a shorter duration of treatment, does not impair effectiveness of chemotherapy of respiratory tuberculosis in case of the limited disease and minor lesions in children exposed to isoniazid resistant tuberculosis.

The Role of Risk Factors in the Development of Tuberculosis in Children Exposed to Rifampicin Resistant Tuberculosis

The objective: to identify factors of a higher risk to develop tuberculosis in children exposed to tuberculosis cases resistant or sensitive to rifampicin.Subjects 161 children under 6 years old exposed to tuberculosis in their families were enrolled in the retrospective study. The children were divided into 2 groups: Group 1 (n = 92) – children free of TB; Group 2 (n = 69) – children ill with TB. In each group, two subgroups were identified: those with index cases susceptible to rifampicin (RS) 1A (n = 40) and 2A (n = 43) and those with index cases resistant to rifampicin (RR) 1Б (n = 52) and 2Б (n = 26).Results. Exposure to isoniazid resistant tuberculosis increases the risk of TB in the child by 12 times, on the opposite, drug resistance to rifampicin provides no impact on the risk to develop tuberculosis. If the child is exposed to 2 cases of tuberculosis and more, the risk to develop tuberculosis increases by 2-14 times. BCG vaccination of the child exposed to tuberculosis reduces the risk to develop tuberculosis by 2-13 times.

Diagnostic Performance of Line Probe Assay for the Diagnosis of Rifampicin and Isoniazid ‎Resistant Tuberculosis in a Resource-Poor Country ‎

Background and study aim: The use of LPA is still new in Nigeria and only available in TB reference laboratories. In this ‎study, the performance of LPA version 2.0 was evaluated for the detection of resistant to first-line ‎anti-TB drugs‎‎‎. Patients and Methods: ‎We evaluated the performance of LPA version 2.0 for the detection of rifampicin (RIF) and ‎isoniazid (INH) resistance. Sputum samples from 223 participants were subjected to phenotypic ‎drug susceptibility testing (PDST) and LPA. Statistical analyses included calculation of sensitivity, ‎specificity, positive and negative predictive values. Cross tabulation was done along the kappa test ‎to measure the degree of agreement between PDST and LPA. P-Value > 0.05 was considered ‎significant‎.‎ Results: The overall sensitivity and specificity of 89.6% (95% C.I 82.5-94.5%) and 65.4% (95% C.I 44.3-‎‎82.7%) for detection of RIF resistance; for INH they were 76.6 (95% C.I 67.5-84.5%) and 76.7% ‎‎(95% C.I 49.5-82.6%); and for MDR-TB, they were 67.0% (95% C.I 56.4-76.5%) and 72.0% ‎‎(95% C.I 57.6-83.7%). The kappa values were 0.53 (0.001), 0.38 (p = 0.000) and 0.36 (p = 0.000) ‎for the detection of RIF, INH and MDR-TB. There was moderate agreement between PDST and ‎LPA for detection of RIF (κ = 0.57; P = 0.0001), INH (κ = 0.44; P = 0.0001), MDR-TB (κ = 0.43; ‎P = 0.001)‎‎. Conclusion: The Line probe assay has good sensitivity and specificity for detecting rifampicin and isoniazid. ‎However, the overall performance is moderate; this should be considered when interpreting the ‎assay’s results‎‎‎‎.

Treatment Outcomes of Isoniazid-Resistant (Rifampicin Susceptible) Tuberculosis Patients in Uzbekistan, 2017-2018.

Tuberculosis patients “resistant to isoniazid and susceptible to rifampicin (Hr-TB)” remain neglected, despite a high burden and poor outcomes. The World Health Organization (WHO) recommends a 6 month regimen consisting of levofloxacin, rifampicin, ethambutol, and pyrazinamide (LRZE) to treat Hr-TB. In contrast, Uzbekistan uses a 9 month regimen (LRZE plus a second-line injectable in the first 3 months). We aimed to assess the treatment outcomes of this novel regimen among Hr-TB patients treated in two regions of Uzbekistan (Fergana and Bukhara) in 2017–2018. We conducted a cohort study involving secondary analysis of routine surveillance data. Of 132 Hr-TB patients, 105 (80%) were successfully treated. Death was the predominant unsuccessful outcome (13, 10%) followed by “treatment failure” (10, 8%) and “lost to follow-up” (4, 2%). High treatment success is an indicator of the potential effectiveness of the novel regimen and adds to the limited global evidence on this issue. However, the sample size was small and there was no comparison group. Since the study was conducted in two regions of Uzbekistan only, the findings have limited generalizability. We recommend future research using an adequate sample size and an appropriate study design (randomized controlled trial or prospective cohort with a control group receiving the WHO-recommended regimen).

Successful Use of Rifamycin-Sparing Regimens for the Treatment of Active Tuberculosis in Lung Transplant Recipients.

Tuberculosis is an important opportunist infection that can complicate the posttransplant course of solid-organ transplant recipients. Lung transplant recipients are at higher risk of tuberculosis after transplant than are other solid-organ transplant recipients. Significant drug-drug interactions between antituberculous medications, especially rifampin, and immunosuppressant medications render treatment in this patient population especially challenging. Data on the management of tuberculosis in lung transplant recipients with rifamycin-sparing regimens are so far limited. Therefore, we evaluated the incidence, clinical features, treatment, and outcomes of active tuberculosis in lung transplant patients from a single center in Riyadh, Saudi Arabia. Cases of active tuberculosis in lung transplant recipients diagnosed between January 2005 and December 2017 at our center were included. Data on patient demographics, clinical presentations, diagnosis, treatment regimens, and outcomes were collected. Seven of 133 lung transplant recipients (5.3%) were diagnosed with active tuberculosis during the study period, corresponding to an incidence rate of 2147/100 000 person-years. Patients were diagnosed at median time of 94 days posttransplant. Fever and weight loss were the most common presenting symptoms. All patients were initially treated with a regimen consisting of isoniazid, ethambutol, pyrazinamide, and moxifloxacin. Isoniazid was later substituted with rifabutin in 2 patients with isoniazid-resistant tuberculosis. All patients were treated for a total of 9 to 12 months, without any adverse event-related interruptions. All patients were alive at 12 months after the diagnosis of tuberculosis. There was no evidence of relapse in any of the patients after a median of 32 (range, 9-51) months of follow-up after treatment. Rifamycin-sparing regimens appear to be safe and highly efficacious in the treatment of active tuberculosis in lung transplant recipients.

Isoniazid Preventive Therapy for Prevention of Tuberculosis Among People Living with HIV in Ethiopia: A Systematic Review of Implementation and Impacts

Background: Tuberculosis (TB) is a major cause of morbidity and mortality in people living with HIV (PLWHIV). Isoniazid preventive therapy (IPT) prevents TB in PLWHIV, but estimates of its effects and actual implementation vary across countries. We reviewed studies that examined the impact of IPT on PLHIV and the factors influencing its implementation in Ethiopia. Methods: We searched PubMed/MEDLINE, Embase, and Cochrane Central Register of Clinical Controlled Trials from their inception to 01 April 2021 for studies of any design that examined the impact of IPT on PLHIV and the factors influencing its implementation. The protocol was registered in PROSPERO, ID: CRD42021256579. Result: Of the initial 546 studies identified, 13 that enrolled 12,426 participants: 12,364 PLHIV and 62 HIV clinical care providers, were included. PLHIV who were on IPT, independently or simultaneously with ART, were less likely to develop TB than those without IPT. IPT interventions had a significant association with improved CD4 count and reduced all-cause mortality. IPT was less effective in people with advanced HIV infection. The major factors influencing IPT implementation and uptake were stock-outs, fear of developing isoniazid-resistant TB, patient’s refusal and non-adherence, and improper counseling and low commitment of HIV clinical care providers. Conclusion: IPT alone or in combination with ART significantly reduces the incidence of TB and mortality in PLHIV in Ethiopia than those without IPT. There needs a realistically attainable system in place to meet the Ethiopian National TB guideline of offering IPT to all HIV-infected individuals who are unlikely to have active TB. More research on safety is needed, especially on women with HIV who receive a combination of IPT and ART. Funding Information: This review did not receive specific funding. T.M. was supported in part by the Fogarty International Center and National Institute of Allergy and Infectious Diseases of the US National Institutes of Health under Award Number D43TW009127. Declaration of Interests: We declare that they have no competing interests.

Bedaquiline in the treatment regimen of multidrugresistant tuberculosis (clinical observation)

Current trials are underway to design chemotherapy regimens that include bedaquiline to treat children with rifampicin and isoniazid resistant mycobacterium tuberculosis. This clinical observation is interesting from the viewpoint of experience of the potential effective and safe use of the new anti-tuberculosis drug bedaquiline (Sirturo) in children under 12 years of age, as the publications of clinical trials of the drug use in children is limited. The female patient was diagnosed with primary tuberculosis complex complicated by infusional pleurisy based on the epidemiological anamnesis (family contact with tuberculosis patients), immunodiagnostic tests – a positive ATR-test result (Diaskin-test), pathological changes in the lung tissue and intrathoracic lymph nodes found on the chest CT scans. The diagnosis was confirmed by detection of MBT in pleural effusion by PCR and liquid culture method (BACTEC MGIT-960), which are resistant to isoniazid and rifampicin (multidrug resistance, MDR). The girl was enrolled in a clinical trial and treated according to chemotherapy regimen IV including a new anti-tuberculosis drug, which she received for 6 months. There was a positive clinical and X-ray dynamics of the tuberculosis process with minimal residual changes throughout the entire course of chemotherapy followed by confirmed clinical cure of TB (after 24-month follow-up). Based on the example of this clinical observation, it can be concluded that bedaquiline is safe and showed good clinical efficacy in the chemotherapy regimen to treat MDR MBT in children under 12 years of age.

Rapid and Simple Detection of Isoniazid-Resistant Mycobacterium tuberculosis Utilizing a DNA Chromatography-Based Technique.

Despite the availability of anti-tuberculosis drugs, the treatment of tuberculosis has been complicated by drug-resistant tuberculosis. The early detection of drug resistance makes early treatment possible. However, the available tools are mainly for rifampicin resistance detection, and the existing isoniazid resistance detection method is expensive, highly technical, and complicated, making it unsustainable for use in developing nations. This study aimed to develop a simple, rapid, and low-cost diagnostic kit for isoniazid-resistant tuberculosis using the single-stranded tag hybridization method to target an isoniazid resistance-conferring mutation. Specificity and sensitivity were assessed using DNA extracted from 49 isoniazid-resistant and 41 isoniazid-susceptible Mycobacterium tuberculosis clinical isolates cultured in mycobacterial growth indicator tubes. Positive signals were observed on mutant and wild-type lines with 100% sensitivity and specificity compared with Sanger sequencing results. In contrast, no positive signal was observed for non-tuberculosis mycobacteria. The detection limit of this method was 103 CFU or less. The STH-PAS system for isoniazid-resistant M. tuberculosis detection developed in this study offers a better alternative to conventional phenotypic isoniazid resistance determination, which will be of both clinical and epidemiological significance in resource-limited nations.

Isoniazid resistance profile and associated levofloxacin and pyrazinamide resistance in rifampicin resistant and sensitive isolates/from pulmonary and extrapulmonary tuberculosis patients in Pakistan: A laboratory based surveillance study 2015-19

Pakistan is among top five high burden countries for tuberculosis and drug resistant TB. Among rifampicin sensitive new pulmonary TB (PTB), prevalence of isoniazid resistance is 8.3% (95%CI: 7.0-10.7) and resistance to fluoroquinolone is higher (11·1%, 95%CI: 7·8-14·3) than isoniazid resistance. Five year retrospective data (2015-2019) of drug susceptibility testing (DST) for Mycobacterium tuberculosis isolates, performed using recommended phenotypic (pDST) and/or genotypic (gDST) methods was analyzed stratified by rifampicin results for isoniazid resistance profiles and associated levofloxacin and pyrazinamide resistance. DST data was analyzed from 11045 TB patients. Isolates were tested using pDST (87%), gDST (92%) and both methods (79.5%). For both rifampicin and isoniazid, a significant difference (P < .001) was noted between resistance detected by pDST and gDST. Among isolates, tested by both methods (8787), 49% were resistant to rifampicin and 51.7% to isoniazid with discordance in resistant results of 15.8% for each, with 13.2% (570) of rifampicin resistance reported sensitive by pDST and 14.2% (660) of isoniazid resistance missed by gDST. Estimated isoniazid resistance among rifampicin sensitive new PTB, extrapulmonary TB and previously treated PTB was 9.8% (95%CI: 8.7-11.1), 6.8% (95%CI: 5.4-8.5) and 14.6% (95%CI: 11.8-17.9) respectively. Significant differences were reported between the genotypic profile of isoniazid resistance associated with rifampicin-resistant and sensitive isolates including detectable mutations (87% vs 71.6%), frequency of inhA (7.6% and 30.2%) and katG mutations (76.1% vs 41.2%) respectively. Among rifampicin resistant and sensitive isolates, a significantly higher level of resistance to levofloxacin and pyrazinamide was seen associated with isoniazid resistance. There are risks and many challenges in implementing WHO recommended treatment for isoniazid resistant tuberculosis. The laboratory based surveillance can complement random surveys in country specific planning for TB diagnostics and appropriate treatment regimens.

Pathomorphosis of chemoresistant tuberculosis

Objective — to study the profile of the MTB resistance and the results of treatment in patients with pulmonary tuberculosis with different profile of the MTB resistance and a history of previous treatment.Materials and methods. A retrospective cohort study was conducted. The total number of patients included in the study — 1162 patients with multidrug-resistant pulmonary tuberculosis, including pre- and extensively resistance of the MTB, who began treatment on the basis of the SI «National Institute of Phthisiology and Pulmonology named after F.G. Yanovsky of the NAMS of Ukraine» (Institute) and 9560 — on the basis of KZ «Dnepropetrovsk Regional Clinical Treatment and Prevention Association DOR» during 2006—2017.Results and discussion. Over the last 13 years, there has been a trend towards an increase of primary resistance of fluoroquinolones (including advanced resistance) both according to Institute and Dnipropetrovsk region data: at a minimum frequency in 2006 (0 %) to almost 30,0 % in 2019, against the background of a decrease in the proportion of patients with MDR TB without resistance of fluoroquinolones (from 60,0 to 40,0 %), isoniazid-resistant tuberculosis, rifampicin-resistant tuberculosis and the risks of MDR TB. Un favorable trend — since 2017, the number of patients with MDR and XDR TB has almost equalized. According to the results of treatment in Dnipropetrovsk region, the extremely low efficiency of treatment was maintained from 2009 to 2013 inclusively due «lost to follow-up» — 20,5—26,9 % and «died of other causes» — 9,6—20,5 %, against the background of the same number of «treatment failed» and «died from tuberculosis» from year to year, with the subsequent reduction of the level of separation with the expansion of social support of patients in the outpatient phase of treatment. Immunodeficiency (TB/HIV co-infection) is not the main factor in reducing efficiency: the proportion of HIV deaths has remained unchanged over the past 10 years.Conclusions. All the studied trends are a modern pathomorphosis of tuberculosis in Ukraine, which indicates the urgent need to adopt a new, different from the previous, strategy to combat tuberculosis, which should include: the introduction of completely different regimens of antimycobacterial therapy of short duration and mandatory before treatment.

A retrospective cohort study of isoniazid-resistant tuberculosis treatment outcomes and isoniazid resistance-associated mutations in eastern China from 2013 to 2018

ObjectivesThe current situation of isoniazid-resistant, rifampicin-susceptible tuberculosis (Hr-TB) and associated genetic factors is not clear in China. MethodsA retrospective cohort study was conducted from 2013 to 2018 in Jiangsu Province, China. Phenotypic Hr-TB were identified by drug susceptibility testing on Lowenstein–Jensen medium and using a Mycobacterium Growth Indicator Tube 960 (MGIT 960) system, and mutations in the katG 315 codon and inhA promoter nucleotides –8, –15 and –16 were determined by GenoType MTBDRplus and sequencing. All of the Hr-TB patients enrolled were followed up until June 2019. ResultsA total of 1416 smear-positive sputum samples were collected, of which 57 were excluded due to the presence of nontuberculous mycobacteria. Finally, 63/1359 (4.6%) were determined as Hr-TB. After follow-up, 11 Hr-TB patients (17.5%) showed an unfavourable outcome, of whom 5 (7.9%) relapsed, 4 (6.3%) had treatment failure and 2 (3.2%) died. A total of 52 isolates (82.5%) were detected with either katG 315 or inhA promoter nucleotide –8, –15 or –16 mutations, whereas no canonical mutations were found in 8 isolates (12.7%); 3 isolates failed in mutation detection. TB history was found to be associated with unfavourable outcomes for Hr-TB (odds ratio = 6.13, 95% confidence interval 1.05–35.82; P = 0.04). However, mutations in katG 315 and the inhA promoter region were not found to be associated with Hr-TB unfavourable outcomes (P = 0.15). ConclusionUnfavourable outcomes for Hr-TB are serious in eastern China, especially for previously treated patients. Meanwhile, current genetic determination of Hr-TB is inadequate.