Long-term evaluation of clinical success and safety of omadacycline in nontuberculous mycobacteria infections: a retrospective, multicenter cohort of real-world health outcomes.

Infections due to nontuberculous mycobacteria (NTM) continue to increase in prevalence, leading to problematic clinical outcomes. Omadacycline (OMC) is an aminomethylcycline antibiotic with FDA orphan drug and fast-track designations for pulmonary NTM infections, including Mycobacteroides abscessus (MAB). This multicenter retrospective study across 16 U.S. medical institutions from January 2020 to March 2023 examined the long-term clinical success, safety, and tolerability of OMC for NTM infections. The cohort included patients aged ≥18 yr, who were clinically evaluable, and` had been treated with OMC for ≥3 mo without a previous diagnosis of cystic fibrosis. The primary outcome was 3 mo clinical success, with secondary outcomes including clinical improvement and mortality at 6- and 12 mo, persistence or reemergence of infection, adverse effects, and reasons for OMC utilization. Seventy-five patients were included in this analysis. Most patients were female (48/75, 64.0%) or Caucasian (58/75, 77.3%), with a median (IQR) age of 59 yr (49-67). Most had NTM pulmonary disease (33/75, 44.0%), skin and soft tissue disease (19/75, 25.3%), or osteomyelitis (10/75, 13.3%), and Mycobacterium abscessus (60/75, 80%) was the most commonly isolated NTM pathogen. The median (IQR) treatment duration was 6 mo (4 - 14), and the most commonly co-administered antibiotic was azithromycin (33/70, 47.1%). Three-month clinical success was observed in 80.0% (60/75) of patients, and AEs attributable to OMC occurred in 32.0% (24/75) of patients, leading to drug discontinuation in 9.3% (7/75).

Risk factors for mortality and progression to severe COVID-19 disease in the Southeast region in the United States: A report from the SEUS Study Group.

OBJECTIVE: Identify risk factors that could increase progression to severe disease and mortality in hospitalized SARS-CoV-2 patients in the Southeast region of the United States. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, retrospective cohort including 502 adults hospitalized with laboratory-confirmed COVID-19 between March 1, 2020, and May 8, 2020 within 1 of 15 participating hospitals in 5 health systems across 5 states in the Southeast United States. METHODS: The study objectives were to identify risk factors that could increase progression to hospital mortality and severe disease (defined as a composite of intensive care unit admission or requirement of mechanical ventilation) in hospitalized SARS-CoV-2 patients in the Southeast United States. RESULTS: In total, 502 patients were included, and 476 of 502 (95%) had clinically evaluable outcomes. The hospital mortality rate was 16% (76 of 476); 35% (177 of 502) required ICU admission and 18% (91 of 502) required mechanical ventilation. By both univariate and adjusted multivariate analyses, hospital mortality was independently associated with age (adjusted odds ratio [aOR], 2.03 for each decade increase; 95% confidence interval [CI], 1.56--2.69), male sex (aOR, 2.44; 95% CI, 1.34-4.59), and cardiovascular disease (aOR, 2.16; 95% CI, 1.15-4.09). As with mortality, risk of severe disease was independently associated with age (aOR, 1.17 for each decade increase; 95% CI, 1.00-1.37), male sex (aOR, 2.34; 95% CI, 1.54-3.60), and cardiovascular disease (aOR, 1.77; 95% CI, 1.09-2.85). CONCLUSIONS: In an adjusted multivariate analysis, advanced age, male sex, and cardiovascular disease increased risk of severe disease and mortality in patients with COVID-19 in the Southeast United States. In-hospital mortality risk doubled with each subsequent decade of life.

Increased Frequency of Memory CD4+ T-Cell Responses in Individuals With Previously Treated Extrapulmonary Tuberculosis.

Extrapulmonary TB (EPTB) occurs with increased frequency in persons with underlying immunodeficiency. Even after recovery from acute illness, differences in immune phenotype and activation persist. Studies defining characteristics of immune responses after recovery from extrapulmonary TB may provide insights into factors that increase TB risk. We performed two case-control studies (in the United States and Brazil) among HIV-seronegative adults with previous EPTB (n = 9; 25), previous pulmonary TB (n = 7; 25), latent M. tuberculosis (Mtb) infection (n = 11; 25), and uninfected TB contacts (n = 10; 25). We assessed the frequency of dual CD4+ interferon-γ and tumor necrosis factor-α responses after stimulation with overlapping Mtb peptides from ESAT-6 or CFP-10, or gamma-irradiated Mtb H37Rv, proliferative responses to Mtb antigens, T-regulatory cell (Treg) frequency and phenotype. In both study populations, individuals with prior EPTB had the highest frequency of intracellular cytokine-producing cells in response to Mtb antigens (p < 0.05; p <.0001). Persons with prior EPTB in Brazil had the highest levels of CD4 proliferation to Mtb antigens (p < 0.0001), and the highest expression of CD39 on Tregs (p < 0.0001). Individuals with treated EPTB maintained high frequencies of Mtb-specific memory responses and active Treg cells, suggesting that susceptibility to EPTB occurs despite the ability to develop and maintain enhanced adaptive immune responses.

Increased vitamin D receptor expression from macrophages after stimulation with M. tuberculosis among persons who have recovered from extrapulmonary tuberculosis.

BACKGROUND: Independent of HIV infection, extrapulmonary TB (EPTB) risk is increased in women, persons of black race or foreign birth, and by genetic variants in vitamin D receptor (VDR), interleukin-1 beta (IL-1ß), and toll-like receptor (TLR)-2; functional correlates are unclear. We evaluated macrophage expression of VDR, TLR2, cathelicidin, and TNF-α, and production of IL-1ß in HIV-seronegative persons with previous EPTB, previous pulmonary TB, latent M. tuberculosis infection, and uninfected TB contacts. Persons with previous pleural TB were excluded due to enhanced immune responses at the site of disease. METHODS: Macrophages were stimulated with TLR-2 agonist M. tuberculosis lipoprotein (LpqH), live and gamma-irradiated M. tuberculosis. RESULTS: M. tuberculosis - infected macrophages from persons with previous EPTB had increased VDR expression (29.17 relative value unit increase in median expression vs. uninfected contacts, after adjusting for foreign-born status; P = 0.02). Macrophages from persons with previous EPTB had a 38.88 µg/mL increase in median IL-1ß production after stimulation with LpqH compared to uninfected contacts (P = 0.01); the effect was similar (44.99 µg/mL) but not statistically significant after controlling for foreign-born status. Median 25-hydroxyvitamin D levels were low but not significantly different between groups. CONCLUSIONS: There was increased macrophage expression of VDR after stimulation with live M. tuberculosis in persons with previous extrapulmonary TB. If post-treatment VDR expression reflects expression prior to disease, it may identify persons at risk for extrapulmonary TB.

Type of Treatment Supporters in Successful Completion of Tuberculosis Treatment: A Retrospective Cohort Study in Pakistan.

BACKGROUND: The World Health Organization has recommended a patient-centered approach to tuberculosis drug administration. A central element of the patient-centered strategy is the use of treatment supporters to evaluate and elevate adherence to the treatment regimen and to address poor adherence when it occurs. This study was led to determine the part of various treatment supporters in the successful completion of treatment. METHOD: This study was conducted in two locales of Sindh, Hyderabad and Mirpurkhas. Information gathered included age, gender, regions, sort of treatment supporters (relatives, community and health facility workers) and treatment outcomes. RESULTS: Of the 773 patients incorporated into the study, 86.8% picked a family supporter, 7.63% selected community worker and 5.56% chose health facility worker as their treatment supporter. Women and younger patients were more likely to prefer that family members supervise their treatment. Treatment achievement rates among the patients regulated by the three kinds of treatment supporters, were not altogether unique in relation to each other (p=0.23 Chi square). CONCLUSION: The study demonstrates that TB patients ought to be urged to pick the supporter of their inclination as selection of treatment supporter outside the health system does not adversely affect TB treatment outcomes in limited resource settings.

Tuberculosis Meningitis.

PURPOSE OF REVIEW: As the most severe form of tuberculosis (TB), TB meningitis disproportionately affects developing countries and results in significant morbidity and mortality. In this report, we review recent updates in the epidemiology, diagnosis, and management of TB meningitis. RECENT FINDINGS: Young children and people living with HIV continue to be at highest risk for TB meningitis. Early diagnosis remains challenging, especially since conventional diagnostic tests have sub-optimal sensitivity and specificity. Recently, nucleic acid amplification testing emerged as the preferred diagnostic modality due to its rapid turnaround time and high specificity. Several recent studies have assessed the optimal treatment for TB meningitis. While the benefit of treatment intensification, by increasing rifampin dosing or adding a fluoroquinolone, is unclear, a growing body of evidence suggests that steroids confer a survival advantage, particularly in patients with mild disease. Additionally, TB meningitis management is further complicated by high rates of HIV co-infection. Recent data suggest that unlike other forms of TB, early initiation of antiretroviral therapy in patients with TB meningitis is associated with higher rates of adverse reactions, without improved survival. TB meningitis continues to be a significant problem worldwide. Despite recent advances, more studies are warranted to improve early disease detection and optimize therapy.

25-Hydroxyvitamin D levels after recovery from tuberculosis: insights into pathogenesis.

OBJECTIVE: 25-Hydroxyvitamin D [25(OH)D] levels after recovery from tuberculosis (TB) may reflect pre-morbid levels and therefore provide insight into pathogenesis. We assessed 25(OH)D levels after recovery from TB disease, and compared to levels in persons without TB disease. METHODS: Case-control study. Cases were persons who had recovered from culture-confirmed Mycobacterium tuberculosis disease. Controls were persons without TB disease. Total 25(OH)D was measured from stored plasma specimens using liquid chromatography-mass spectrometry. RESULTS: 29 persons with prior TB disease and 36 controls were included. Median 25(OH)D levels were 24.7 ng/mL (IQR, 18.3-34.1) in prior TB disease, and 33.6 ng/mL (IQR, 26.2-42.4) in controls (Mann-Whitney; P = 0.01). Multivariable linear regression analysis showed that black race (adjusted mean difference [ß] = -8.3 ng/mL; 95% CI -14.5, -2.2; P < 0.01), enrollment in winter (ß = -10.4 ng/mL; 95% CI -17.0, -3.8; P < 0.01) and prior TB disease (ß = -5.8 ng/mL; 95% CI -11.4, -0.3; P = 0.05) were associated with lower 25(OH)D levels. CONCLUSIONS: Persons who had recovered from TB disease had lower 25(OH)D levels compared to controls without TB disease, after adjusting for important confounders. Larger, longitudinal studies are needed to further characterize the possible role of low 25(OH)D in the pathogenesis of TB disease and TB recurrence after recovery.

Abnormal immune responses in persons with previous extrapulmonary tuberculosis in an in vitro model that simulates in vivo infection with Mycobacterium tuberculosis.

Persons with previous extrapulmonary tuberculosis have reduced peripheral blood mononuclear cell cytokine production and CD4(+) lymphocytes compared to persons with previous pulmonary tuberculosis or latent tuberculosis infection, but specific defects related to Mycobacterium tuberculosis infection of macrophages have not been characterized. The objective of this study was to further characterize the in vitro immune responses to M. tuberculosis infection in HIV-seronegative persons with previous extrapulmonary tuberculosis. Peripheral blood mononuclear cells were isolated from HIV-seronegative persons with previous extrapulmonary tuberculosis (n = 11), previous pulmonary tuberculosis (n = 21), latent M. tuberculosis infection (n = 19), and uninfected tuberculosis contacts (n = 20). Experimental conditions included M. tuberculosis-infected macrophages cultured with and without monocyte-depleted peripheral blood mononuclear cells. Concentrations of interleukin 1ß (IL-1ß), IL-4, IL-6, CXCL8 (IL-8), IL-10, IL-12p70, IL-17, CCL2 (monocyte chemoattractant protein 1), tumor necrosis factor alpha (TNF-α), and gamma interferon (IFN-γ) were measured by multiplex cytokine array. When M. tuberculosis-infected macrophages were cocultured with monocyte-depleted peripheral blood mononuclear cells, IFN-γ (P = 0.01), TNF-α (P = 0.04), IL-10 (P < 0.001), and IL-6 (P = 0.03) exhibited similar continua of responses, with uninfected persons producing the lowest levels, followed by extrapulmonary tuberculosis cases, pulmonary tuberculosis controls, and persons with latent M. tuberculosis infection. A similar pattern was observed with CXCL8 (P = 0.04), IL-10 (P = 0.02), and CCL2 (P = 0.03) when monocyte-depleted peripheral blood mononuclear cells from the four groups were cultured alone. Persons with previous extrapulmonary tuberculosis had decreased production of several cytokines, both at rest and after stimulation with M. tuberculosis. Our results suggest that persons who develop extrapulmonary tuberculosis have a subtle global immune defect that affects their response to M. tuberculosis infection.

Accuracy of pharmacy and coded-diagnosis information in identifying tuberculosis in patients with rheumatoid arthritis.

PURPOSE: Previous studies suggest that disease-modifying anti-rheumatic drugs (DMARDs) increase tuberculosis (TB) risk. The accuracy of pharmacy and coded-diagnosis information to identify persons with TB is unclear. METHODS: Within a cohort of rheumatoid arthritis (RA) patients (2000-2005) enrolled in Tennessee Medicaid, we identified those with potential TB using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD9-CM) diagnosis codes and/or pharmacy claims. Using the Tennessee TB registry as the gold standard for identification of TB, we estimated the sensitivity, specificity, predictive values, and the respective 95% confidence intervals for each TB case-ascertainment strategy. RESULTS: Ten of 18,094 RA patients had confirmed TB during 61,461 person-years of follow-up (16.3 per 100,000 person-years). The sensitivity and positive predictive value (PPV) and respective 95% confidence intervals were low for confirmed TB based on ICD9-CM codes alone (60.0% (26.2-87.8) and 1.3% (0.5-2.9)), pharmacy data alone (20% (2.5-55.6) and 4.1% (0.5-14.3)), and both (20% (2.5-55.6) and 25.0% (3.2-65.1)). CONCLUSIONS: Algorithms that use administrative data alone to identify TB have a poor PPV that results in a high false positive rate of TB detection.

Increased frequency of regulatory T cells and T lymphocyte activation in persons with previously treated extrapulmonary tuberculosis.

Extrapulmonary tuberculosis may be due to underlying immune compromise. Immunosuppressive regulatory T cells (Treg cells), and CD4(+) T lymphocytes in general, are important in the host immune response to Mycobacterium tuberculosis. We evaluated T lymphocytes from patients after recovery from extrapulmonary tuberculosis, which may reflect conditions before M. tuberculosis infection. A case-control study was conducted among HIV-uninfected adults with previously treated extrapulmonary tuberculosis and 3 sets of controls: (i) subjects with previously treated pulmonary tuberculosis, (ii) close tuberculosis contacts with M. tuberculosis infection, and (iii) close tuberculosis contacts with no infection. Monocyte-depleted peripheral blood mononuclear cells (PBMC-M) were stained for CD4(+) CD25(hi) CD127(low) FoxP3(+) cell (Treg cell) and T lymphocyte activation. Both characteristics were compared as continuous variables between groups with the Kruskal-Wallis test. There were 7 extrapulmonary tuberculosis cases, 18 pulmonary tuberculosis controls, 17 controls with M. tuberculosis infection, and 18 controls without M. tuberculosis infection. The median Treg cell proportion was highest among persons with previous extrapulmonary tuberculosis (1.23%) compared to subjects with pulmonary tuberculosis (0.56%), latent M. tuberculosis infection (0.14%), or no M. tuberculosis infection (0.20%) (P = 0.001). The median proportion of CD4(+) T lymphocytes that expressed the activation markers HLA-DR and CD38 was highest for CD4(+) T lymphocytes from persons with previous extrapulmonary tuberculosis (0.79%) compared to subjects with pulmonary tuberculosis (0.44%), latent M. tuberculosis infection (0.14%), or no M. tuberculosis infection (0.32%) (P = 0.005). Compared with controls, persons with previously treated extrapulmonary tuberculosis had the highest Treg cell frequency, but also the highest levels of CD4(+) T lymphocyte activation. Immune dysregulation may be a feature of individuals at risk for extrapulmonary tuberculosis.

Black race, sex, and extrapulmonary tuberculosis risk: an observational study.

BACKGROUND: Extrapulmonary tuberculosis is likely a marker of underlying immune compromise. Our objective was to determine race and sex differences in extrapulmonary tuberculosis risk in order to identify the optimal population in which to assess for host factors associated with extrapulmonary tuberculosis. METHODS: We performed an observational study of all tuberculosis cases reported to the Tennessee Department of Health, January 1, 2000 to December 31, 2006. We compared the incidence of extrapulmonary tuberculosis by race and sex. We also examined risk factors associated with extrapulmonary disease among all persons with tuberculosis. RESULTS: Extrapulmonary tuberculosis incidence per 100,000 population was 5.93 in black men, 3.21 in black women, 1.01 in non-black men, and 0.58 in non-black women. Among those with tuberculosis, black women were most likely to have extrapulmonary disease (38.6%), followed by black men (28.1%), non-black women (24.6%) and non-black men (21.1%). In multivariate logistic regression among persons with tuberculosis, black women (OR 1.82 (95% CI 1.24-2.65), p = 0.002), black men (OR 1.54 (95% CI 1.13-2.09, p = 0.006), foreign birth (OR 1.55 (95% CI 1.12-2.14), p = 0.009), and HIV infection (OR 1.45 (95% CI 0.99-2.11), p = 0.06) were associated with extrapulmonary tuberculosis. CONCLUSIONS: Black men and black women had the highest incidence of extrapulmonary tuberculosis, and high odds of extrapulmonary disease among persons with tuberculosis. These data suggest that factors in addition to tuberculosis exposure contribute to extrapulmonary tuberculosis risk in blacks.

Alcohol use and clinical manifestations of tuberculosis.

OBJECTIVES: Excess alcohol use represents a significant challenge in tuberculosis control. Whether alcohol use enhances transmission of Mycobacterium tuberculosis is not known. METHODS: We analyzed North Carolina, USA surveillance data for all adult (>14 years) tuberculosis cases reported 1994-2006 (N = 5556). RESULTS: The prevalence of excess alcohol use among tuberculosis cases declined from 27.3% in 1994 to 17.9% in 2006. Cases with excess alcohol use were more likely to have pulmonary tuberculosis compared with cases without excess alcohol use (92.5% vs. 77.2%, p < 0.0001). Among pulmonary cases, excess alcohol use was associated with cavities on chest radiograph (36.8% vs. 28.2%, p < 0.0001) and positive acid-fast sputum smears (65.9% vs. 45.8%, p < 0.0001). CONCLUSIONS: Although excess alcohol use is becoming less prevalent among tuberculosis cases in North Carolina, cases who use excess alcohol had clinical features associated with greater infectiousness, and represent a significant public health problem.

Alcohol use and clinical manifestations of tuberculosis.

OBJECTIVES: Excess alcohol use represents a significant challenge in tuberculosis control. Whether alcohol use enhances transmission of Mycobacterium tuberculosis is not known. METHODS: We analyzed North Carolina, USA surveillance data for all adult (> 14 years) tuberculosis cases reported 1994-2006 (N = 5556). RESULTS: The prevalence of excess alcohol use among tuberculosis cases declined from 27.3% in 1994 to 17.9% in 2006. Cases with excess alcohol use were more likely to have pulmonary tuberculosis compared with cases without excess alcohol use (92.5% vs. 77.2%, p < 0.0001). Among pulmonary cases, excess alcohol use was associated with cavities on chest radiograph (36.8% vs. 28.2%, p < 0.0001) and positive acid-fast sputum smears (65.9% vs. 45.8%, p < 0.0001). CONCLUSIONS: Although excess alcohol use is becoming less prevalent among tuberculosis cases in North Carolina, cases who use excess alcohol had clinical features associated with greater infectiousness, and represent a significant public health problem.