Factors Contributing to the High Prevalence of Multidrug- Resistant/Rifampicin-Resistant Tuberculosis: A Study From Russia

Background: Rapidly growing prevalence of multidrug-resistant/Rifampicin-resistant tuberculosis (MDR/RR-TB; resistance to Isoniazid and Rifampicin/Isolated resistance to Rifampicin) is putting in jeopardy the WHO End TB strategy. This study aimed to identify factors contributing to the high prevalence of MDR/RR-TB in Khabarovsk krai region of Russia.Methods: A cross-sectional retrospective study was conducted. Clinical, demographic and drug susceptibility testing data on 1440 patients were analyzed. Factors associated with MDR/RR-TB were identified through logistic regression analysis, along with in-depth interviews with eight patients, five healthcare managers and five doctors.Findings: 618 patients (42.9%) were identified with MDR/RR-TB. Patients with a history of imprisonment were 16.53 times (95% CI 5.37 to 50.88,) more likely to have MDR/RR-TB, whereas re-treatment patients were 2.82 times (95% CI 2.16 to 3.66) more likely to have MDR/RR-TB. Other influencing factors included presence of disability (AOR is 2.32, 95% CI 1.38 to 3.89) and cavitary disease (AOR is 1.76, 95% CI 1.37 to 2.25). Poor knowledge, progressive tiredness of prolonged TB treatment and inability to hospitalize infectious patients without their consent were perceived by the interviewees as major influencing factors. Conclusions: Incarceration and treatment history, regardless of outcome, were identified as major factors influencing MDR/RR-TB prevalence. It is essential for TB care system to eliminate legal loopholes, which deprive doctors of means to enforce quarantine procedures and epidemiological surveillance on infected patients, former and current inmates. In addition, increasing people’s awareness of TB, early detection and appropriate treatment of patients with TB are needed for successfully combating MDR/RR-TB.

Efficacy of fluoroquinolones as substitutes for ethambutol or rifampin in the treatment of Mycobacterium avium complex pulmonary disease according to radiologic types

Objective: During the treatment of Mycobacterium avium complex pulmonary disease (MAC-PD), ethambutol or rifampin is often discontinued because of adverse events. This study investigated the treatment outcomes when later-generation fluoroquinolones substitute ethambutol or rifampin in MAC-PD treatment based on the radiologic type. Methods: Between 2006 and 2019, patients who initiated standard treatment and whose treatment duration was ≥1 year were retrospectively identified at a tertiary referral center in South Korea, including 178 patients with cavitary disease (fibrocavitary and cavitary nodular bronchiectatic types) and 256 patients with noncavitary nodular bronchiectatic (NC-NB) type. We compared the microbiologic cure at 1 year between the patients who maintained the initial regimen and those who replaced ethambutol or rifampin with fluoroquinolones (moxifloxacin or levofloxacin). Results: The overall microbiologic cure rate of the 178 patients with cavitary disease was 71.3%. Among these, the microbiologic cure rates of the 16 patients who substituted fluoroquinolones for ethambutol were lower than those of the 156 patients who maintained three-drug oral antibiotics with aminoglycoside (37.5% vs. 74.4%, respectively; P = 0.007), which was statistically significant in multivariate analysis. The outcomes of the six patients receiving fluoroquinolones as an alternative to rifampin were similar to that of those continuing the initial regimen. The microbiologic cure rate of the patients with the NC-NB type receiving daily or intermittent oral three-drug therapy was similar regardless of maintaining the initial therapy or replacing ethambutol or rifampin with fluoroquinolones. Conclusions: In cavitary MAC-PD, substituting ethambutol with fluoroquinolones resulted in inferior patient outcomes.

1400. Pretomanid in the Treatment of Patients with Tuberculosis in the United States: the Bedaquiline, Pretomanid and Linezolid (BPaL) Accelerated Monitoring (BAM) Project

Background In August 2019 the U.S. FDA approved pretomanid as part of a 6-month all-oral BPaL (bedaquiline, pretomanid, and linezolid) regimen for treating pulmonary extensively drug-resistant (XDR) or treatment-intolerant or nonresponsive multidrug-resistant (MDR) tuberculosis (TB). In the study supporting approval, 89% of patients had a favorable outcome, and all reported ≥ 1 adverse event. We describe the reported use of BPaL in the United States. Methods Using the 2020 CDC Report of a Verified Case of Tuberculosis (RVCT) MDR TB supplemental form, TB programs and providers submitted data for patients who began taking BPaL between Aug 1, 2019 and May 1, 2020, for retrospective descriptive analysis. Results Programs and providers reported 17 TB patients aged a mean of 41 years (range 23–76) who received BPaL: 11 (65%) were male; 15 (88%) were non-U.S. born; 15 (88%) had pulmonary TB disease only; two (12%) had both pulmonary and extrapulmonary disease. Of all patients, 16 had Mycobacterium tuberculosis isolated from sputum and 7 (44%) had cavitary disease. The preliminary drug susceptibilities were 8 MDR patterns, 8 pre-XDR, and 1 unreported. Three patients received BPaL as their only treatment; six first received treatment for drug-susceptible TB, and eight received other regimens for MDR TB before BPaL. Eleven (65%) patients had ≥ 1 side effect reported during any TB treatment, including peripheral neuropathy (n=5), depression (n=4), vestibular dysfunction (n=3), and vision changes (n=3). Timing related to specific TB drug use was not reported. Sixteen (94%) patients received less than the approved initial dose of 1200 mg linezolid daily, and 15 (88%) patients underwent monitoring of linezolid exposure. All 16 patients with M. tuberculosis in initial sputa converted to negative culture results within 6 months of starting treatment. At 12 months after BPaL initiation, all patients had completed treatment, without TB recurrences or deaths reported. Conclusion In the early period after FDA approval, most U.S. patients received BPaL off-label with an initial linezolid dose lower than the approved 1200mg yet still achieved good outcomes. Most reported patients underwent some monitoring of linezolid exposure. Monitoring of BPaL use is important and should continue. Disclosures All Authors: No reported disclosures

Immune Correlates of Non-Necrotic and Necrotic Granulomas in Pulmonary Tuberculosis: A Pilot Study

A granuloma, a pathologic hallmark of tuberculosis (TB), is a complex cellular structure that develops at the site of Mycobacterium tuberculosis (Mtb) infection and is comprised of different immune cell types. Severe pulmonary TB in humans is characterized by the presence of heterogeneous granulomas, ranging from highly cellular to solid/non-necrotic and necrotic lesions, within the lungs. The host-Mtb interactions within the granulomas dictate the containment of Mtb infection or its progression into a necrotic, cavitary disease. However, the immune environment in various granulomas is poorly understood. The myeloid-derived suppressor cells (MDSCs) are key immune cells that regulate the protective versus permissive host responses against Mtb infection. However, their contexture within the lung granulomas remains unclear. In this study, using single and multiplex immunohistochemical staining, we analyzed the distribution of MDSCs, macrophages, CD4+ T cells and their immunometabolic and effector function states in the solid/non-necrotic and necrotic granulomas in patients with active pulmonary TB. We found increased MDSCs with elevated expression of immunosuppressive molecules in the solid/non-necrotic granulomas. In contrast, cells in the solid and necrotic granulomas produced similar levels of IL-6 and IL-10. Our findings suggest that MDSCs are present in solid/non-necrotic granuloma, which may play an essential role in the progression into a necrotic lesion, thus exacerbating disease pathology and transmission.

Emergence of bedaquiline-resistance in a high-burden country of tuberculosis

RationaleBedaquiline has been classified as a Group A drug for the treatment of multidrug-resistant tuberculosis (MDR-TB) by the World Health Organization, however globally emerging resistance threatens the effectivity of novel MDR-TB treatment regimens.ObjectivesWe analysed pre-existing and emerging bedaquiline resistance in bedaquiline-based MDR-TB therapies, and risk factors associated with treatment failure and death.MethodsIn a cross-sectional cohort study, we employed patient data, whole genome sequencing (WGS) and phenotyping of Mycobacterium tuberculosis complex (MTBC) isolates. We could retrieve baseline isolates from 30.5% (62/203) of all MDR-TB patients who received bedaquiline between 2016 and 2018 in the Republic of Moldova. This includes 26 patients for whom we could also retrieve a follow-up isolate.Measurements and Main ResultsAt baseline, all MTBC isolates were susceptible to bedaquiline. Among 26 patients with available baseline and follow-up isolates, 4/26 (15.3%) patients harbored strains which acquired bedaquiline resistance under therapy, while 1/26 (3.8%) patients was re-infected with a second bedaquiline resistant strain. Treatment failure and death were associated with cavitary disease (p=0.011), and any additional drug prescribed in the bedaquiline containing regimen with WGS-predicted resistance at baseline (p=0.012, OR 1.92 per unit increase, 95%CI 1.15–3.21).ConclusionsMDR-TB treatments based on bedaquiline require a functional background regimen to achieve high cure rates and to prevent the evolution of bedaquiline resistance. Novel MDR-TB therapies with bedaquiline require timely and comprehensive drug resistance monitoring.

Study on Prevalence of Adverse Drug Reactions and Drug-Drug Interactions and Co-Morbid Conditions of Patients Suffering from Tuberculosis

Background: Tuberculosis is the oldest common infectious disease affecting not only lungs but several organs in a human body. Its caused by the bacteria Mycobacterium tuberculosis. Tuberculosis exposure is through lungs. This disease has co-morbid conditions. The basic treatment according to WHO is with Isoniazid, Rifampicin, Pyrazinamide, Ethambutol, but these drugs may lead to adverse drug reactions and drug interactions. Objective: To determine the adverse effects and drug-drug interactions post administration of anti-tubercular drugs and to determine the influence of drugs on their co-morbid conditions of patients suffering from tuberculosis in Aster Prime Hospital. Methods: The patient’s prescriptions of total 110 were collected from the outpatient and in-patient Pulmonology department. These were noted in the data collection form and the comparative study was done by evaluating the number of male and female affected with Tuberculosis, common drug-drug interaction with respective drug, adverse drug reaction followed by the common co-morbid condition occurring with TB and the effect of drugs on co-morbidities Results: The prevalence of tuberculosis in 110 patients was found to be more in females by 12% than males. The co-morbid conditions found with tuberculosis were Hypertension, diabetes, pleural effusion, hepatitis, cavitary disease and respiratory failure. The least common comorbidities were chronic obstructive pulmonary disease (COPD), gastritis, and stroke and chronic kidney disease (CKD) and ulcerative colitis. The total adverse effect found in the 62 patients (56.36%) and the patients with no adverse drug reactions were 48 (43.63%) The percentage of total drug-drug interactions found in the patients were 44% (n=48) and the percentage of patients with no interactions were 56% (n=62). Conclusion: Health care workers play an important role and considered as a vital group for tuberculosis awareness activities to increase competence in TB management and compliance with national guidelines. Interventions address a combination of varying influences on behaviour, focusing on specific gaps identified to improve their impact.

Treatment outcomes of patients with multidrug and extensively drug-resistant tuberculosis in Zhejiang, China

Background The aim of this study was to assess the treatment outcomes of multidrug and extensively drug-resistant tuberculosis (M/XDR-TB) in Zhejiang, China and to evaluate possible risk factors associated with poor outcomes of M/XDR-TB. Methods Two-hundred-and-sixty-two patients having M/XDR-TB who received the diagnosis and treatment at nine referral hospitals from 1 January 2016 to 31 December 2016 in Zhejiang, China were included. All patients received second-line regimens recommended by WHO under the DOTS-Plus strategy. Results Among the 262 patients, the treatment success rate was 55.34% (n = 145) with 53.44% (n = 140) cured and 1.91% (n = 5) who completed treatment, 62 (23.66%) failed, 27 (10.31%) died, 16 (6.11%) defaulted and 12 (4.58%) transferred out. Forty (64.52%) of the 62 M/XDR-TB patients who failed treatment were due to adverse effects in the first 10 months of treatment. Eighteen patients (6.37%) had XDR-TB. Treatment failure was significantly higher among patients with XDR-TB at 50% than that among patients with non-XDR-TB at 21.72% (P = 0.006). Failure outcomes were associated with a baseline weight less than 50 kg (OR, 8.668; 95% CI 1.679–44.756; P = 0.010), age older than 60 years (OR, 9.053; 95% CI 1.606–51.027; P = 0.013), hemoptysis (OR, 8.928; 95% CI 1.048–76.923; P = 0.045), presence of cavitary diseases (OR, 10.204; 95% CI 2.032–52.631; P = 0.005), or treatment irregularity (OR, 47.619; 95% CI 5.025–500; P = 0.001). Conclusion Treatment outcomes for M/XDR-TB under the DOTS-Plus strategy in Zhejiang, China were favorable but still not ideal. Low body weight (< 50 kg), old age (> 60 years), severe symptoms of TB including cavitary disease, hemoptysis and irregular treatment were independent prognostic factors for failure outcomes in patients with M/XDR-TB.

Mortality in rheumatoid arthritis patients with pulmonary nontuberculous mycobacterial disease: A retrospective cohort study

Objective The aim of this study was to compare long-term mortality following diagnosis of pulmonary nontuberculous mycobacterial (NTM) disease between patients with and without rheumatoid arthritis (RA) and to evaluate predictive factors for death outcomes. Methods We reviewed the electronic medical records of all patients who were newly diagnosed with pulmonary NTM disease at participating institutions between August 2009 and December 2018. Patients were followed until death, loss to follow-up, or the end of the study. Taking into consideration the presence of competing risks, we used the cumulative incidence function with Gray’s test and Fine-Gray regression analysis for survival analysis. Results A total of 225 patients (34 RA patients and 191 non-RA controls) were followed, with a mean time of 47.5 months. Death occurred in 35.3% of RA patients and 25.7% of non-RA patients. An exacerbation of pulmonary NTM disease represented the major cause of death. The estimated cumulative incidence of all-cause death at 5 years was 24% for RA patients and 23% for non-RA patients. For NTM-related death, the 5-year cumulative incidence rate was estimated to be 11% for RA patients and 18% for non-RA patients. Gray’s test revealed that long-term mortality estimates were not significantly different between patient groups. Fine-Gray regression analysis showed that the predictive factors for NTM-related death were advanced age (adjusted hazards ratio 7.28 [95% confidence interval 2.91–18.20] for ≥80 years and 3.68 [1.46–9.26] for 70–80 years vs. <70 years), male sex (2.40 [1.29–4.45]), Mycobacterium abscessus complex (4.30 [1.46–12.69] vs. M. avium), and cavitary disease (4.08 [1.70–9.80]). Conclusions RA patients with pulmonary NTM disease were not at greater risk of long-term mortality compared with non-RA patients. Rather, advanced age, male sex, causative NTM species, and cavitary NTM disease should be considered when predicting the outcomes of RA patients with pulmonary NTM disease.

Molecular detection of Mycobacterium tuberculosis from buccal swabs among adult in Peru

Tuberculosis (TB) diagnosis relies on a sputum sample, which cannot be easily obtained from all symptomatic patients. Mycobacterium tuberculosis DNA can be detected from oral swabs, a noninvasive, safe alternative sample type; however, reported sensitivities have been variable and likely depend on sample collection, processing procedures and host characteristics. We analyzed three buccal swab samples from 123 adults with culture-confirmed TB in Lima, Peru. We compared the sensitivity and specificity of two sample collection devices (OmniSwab and EasiCollect FTA cards) and examined factors associated with detection. DNA was extracted with a commercially available kit and detected via real-time PCR IS6110 amplification. Overall sensitivity for buccal samples was 51% (95% Confidence Interval [CI] 42–60%). Specificity from a single sample among healthy controls was 96.7% (95% CI 83–99.9%). Positive sputum smear and cavitary disease, correlates of disease burden, were associated with detection via buccal swab. Although we observed higher sensitivities with the Omniswab samples, this appeared to be due primarily to differences in patient characteristics (e.g., cavitary disease). Overall, our findings support the potential for a buccal sample-based TB assay. Future work should focus on assay optimization and streamlining the assay workflow.