Case-control study of vitamin D status and adult multidrug-resistant pulmonary TB.

BACKGROUND: India has the highest prevalence of multidrug-resistant TB (MDR-TB) globally. Vitamin D deficiency is potentially an important risk factor for MDR-TB.METHODS: We conducted a case-control study of 90 newly diagnosed adult MDR-TB cases, 180 household controls and 82 non-household controls in Mumbai, India. Serum 25-hydroxyvitamin D (25(OH)D), anthropometry, clinical status and history, dietary data and sociodemographic data were collected from each participant. Interferon-gamma release assay (IGRA) was also performed in controls to assess latent TB. Multivariable regression was performed to estimate associations between 25(OH)D vs. case status and IGRA positivity.RESULTS: Mean participant age was 33.8 ± 12.0 years; 72.8% had 25(OH)D <20 ng/ml. Mean 25(OH)D was significantly (P < 0.05) lower in cases (12.5 ± 7.9) than both household (17.5 ± 11.2) and non-household controls (16.4 ± 9.1). In multivariable models, 25(OH)D concentration was inversely associated with MDR-TB case status among cases and household controls (OR 0.95 per 1 ng/ml, 95% CI 0.92-0.99; P = 0.015), and among cases and non-household controls (OR 0.94 per 1 ng/ml, 95% CI 0.89-1.00; P = 0.033); 53.6% of controls were IGRA-positive. 25(OH)D status was not associated with IGRA positivity.CONCLUSION: Vitamin D status was independently associated with MDR-TB case status. Research should evaluate the effectiveness of vitamin D supplementation in prevention and adjunctive treatment of MDR-TB.

Presumptive treatment of multidrug-resistant tuberculosis in household contacts.

SETTING: Multidrug-resistant tuberculosis (MDR-TB) is a growing global health threat that often requires presumptive treatment in the absence of drug susceptibility testing (DST) results. OBJECTIVE: To compare two approaches to the treatment of MDR-TB contacts with no DST results who develop TB disease. DESIGN: We conducted a retrospective cohort study of adults treated for TB disease who were contacts of patients living with MDR-TB. Subjects had been treated according to one of two presumptive treatment strategies: 1) regimens containing exclusively first-line drugs, and 2) regimens that included both first- and second-line drugs that were adjusted if and when DST results became available. The primary endpoint was a composite of death and treatment failure. RESULTS: Household contacts of MDR-TB patients who developed TB disease and were treated with first-line regimens were significantly more likely to experience unfavorable end-of-treatment outcomes than those treated with presumptive MDR-TB regimens (RR 2.88, 95%CI 1.24-6.68). CONCLUSION: Household contacts of MDR-TB patients who develop TB disease but have no DST results should receive regimens containing second-line drugs selected based on the infecting strain of the index patient. Regimens containing only first-line anti-tuberculosis drugs significantly increase the risk of unfavorable outcomes.

Rate of cyp51A mutation in Aspergillus fumigatus among lung transplant recipients with targeted prophylaxis.

OBJECTIVES: The most common mechanism of azole (itraconazole and voriconazole) resistance in Aspergillus fumigatus is a mutation at the cyp51A locus. The aim of our study was to determine the rate of cyp51A mutations in lung transplant recipients (LTR) undergoing targeted antifungal prophylaxis with 12 weeks of voriconazole. METHODS: We conducted a prospective study that included 22 LTR with A. fumigatus between October 2008 and November 2011. Of those, 10 LTR were colonized with A. fumigatus and 12 had invasive pulmonary aspergillosis. RESULTS: Four patients were found to have A. fumigatus isolates with a cyp51A mutation, two had colonization and two had invasive pulmonary aspergillosis. The remaining 18 LTR had WT cyp51A A. fumigatus isolates. All A. fumigatus isolates (except one due to mixed growth) were tested for antifungal susceptibility. A total of nine LTR were exposed to azoles prior to A. fumigatus isolation for a median duration of 249 (IQR 99-524) days. Azole exposure preceded the isolation of two mutant isolates and seven WT isolates. None of the cyp51A mutant isolates conferred phenotypic resistance to azoles. CONCLUSIONS: Targeted antifungal prophylaxis in LTR did not lead to cyp51A resistance mutations in this cohort. Data on larger cohorts who receive universal antifungal prophylaxis are needed.

Totally drug-resistant tuberculosis and adjunct therapies.

The first cases of totally drug-resistant (TDR) tuberculosis (TB) were reported in Italy 10 years ago; more recently, cases have also been reported in Iran, India and South Africa. Although there is no consensus on terminology, it is most commonly described as 'resistance to all first- and second-line drugs used to treat TB'. Mycobacterium tuberculosis (M.tb) acquires drug resistance mutations in a sequential fashion under suboptimal drug pressure due to monotherapy, inadequate dosing, treatment interruptions and drug interactions. The treatment of TDR-TB includes antibiotics with disputed or minimal effectiveness against M.tb, and the fatality rate is high. Comorbidities such as diabetes and infection with human immunodeficiency virus further impact on TB treatment options and survival rates. Several new drug candidates with novel modes of action are under late-stage clinical evaluation (e.g., delamanid, bedaquiline, SQ109 and sutezolid). 'Repurposed' antibiotics have also recently been included in the treatment of extensively drug resistant TB. However, because of mutations in M.tb, drugs will not provide a cure for TB in the long term. Adjunct TB therapies, including therapeutic vaccines, vitamin supplementation and/or repurposing of drugs targeting biologically and clinically relevant molecular pathways, may achieve better clinical outcomes in combination with standard chemotherapy. Here, we review broader perspectives of drug resistance in TB and potential adjunct treatment options.

Predictors of sputum culture conversion among patients treated for multidrug-resistant tuberculosis.

OBJECTIVE: To identify predictors of initial sputum culture conversion, estimate the usefulness of persistent positive cultures at different time points in predicting treatment failure, and evaluate different definitions of culture conversion for predicting failure among patients with multidrug-resistant tuberculosis (MDR-TB) in five countries, 2000-2004. METHODS: Predictors of time to conversion were identified using multivariate Cox proportional hazards regression modeling. Receiver operating characteristic curves were plotted to visualize the effect of using different definitions of 'culture conversion' on the balance between sensitivity and specificity. RESULTS: Overall, 1209/1416 (85%) of patients with baseline positive cultures converted in a median of 3.0 months (interquartile range 2.0-5.0). Independent predictors of less likely conversion included baseline positive smear (hazard ratio [HR] 0.60, 95%CI 0.53-0.68), resistance to pyrazinamide (HR 0.82, 95%CI 0.70-0.96), fluoroquinolones (FQs; HR 0.65, 95%CI 0.51-0.83) or thioamide (HR 0.83, 95%CI 0.71-0.96), previous use of FQs (HR 0.71, 95%CI 0.60-0.83), poor outcome of previous anti-tuberculosis treatment (HR 0.69, 95%CI 0.54-0.88) and alcoholism (HR 0.74, 95%CI 0.63-0.87). The maximum combined sensitivity (84%) and specificity (94%) in predicting treatment failure was based on lack of culture conversion at month 9 of treatment, assuming conversion is defined as five consecutive negative cultures. CONCLUSION: Patients with identified risk factors were less likely to achieve sputum culture conversion during MDR-TB treatment.

Programmatic management of multidrug-resistant tuberculosis: models from three countries.

BACKGROUND: Although multidrug-resistant tuberculosis (MDR-TB) is a major global health problem, there is a gap in programmatic treatment implementation. METHODS: This study describes MDR-TB treatment models in three countries--Peru, Russia and Lesotho-- using qualitative data collected over a 13-year period. RESULTS: A program analysis is presented for each country focusing on baseline medical care, initial implementation and program evolution. A pattern analysis revealed six overarching themes common to all three programs: 1) importance of baseline assessments, 2) early identification of key collaborators, 3) identification of initial locus of care, 4) minimization of patient-incurred costs, 5) targeted interventions for vulnerable populations and 6) importance of technical assistance and funding. Site commonalities and differences in each of these areas were analyzed. CONCLUSIONS: It is recommended that all programs providing MDR-TB treatment address these six areas during program development and implementation.

'Sputnik': a programmatic approach to improve tuberculosis treatment adherence and outcome among defaulters.

SETTING: A novel patient-centered tuberculosis (TB) treatment delivery program, 'Sputnik', was introduced for patients at high risk of treatment default in Tomsk City, Russian Federation. OBJECTIVE: To assess the effects of the Sputnik intervention on patient default rates. DESIGN: We analyzed the characteristics of patients referred to the program, treatment adherence of Sputnik program enrollees before and during the intervention, and final outcomes for all patients referred to the Sputnik program. RESULTS: For patients continuing their existing regimens after referral to the program (n = 46), mean adherence to treatment increased by 56% (from 52% of prescribed doses prior to enrolment to 81%). For patients initiating new regimens after referral ( n = 5), mean adherence was 83%. Mean adherence for patients with multidrug-resistant TB (MDR-TB; n = 38) was 79% and for all others (n = 13) it was 89%. The cure rate was 71.1% for patients with MDR-TB, 60% for all others and 68% in the program overall. CONCLUSION: The Sputnik intervention was successful in reducing rates of treatment default among patients at high risk for non-adherence.

Feline immunodeficiency virus vectors persistently transduce nondividing airway epithelia and correct the cystic fibrosis defect.

Several problems limit the application of gene transfer to correct the cystic fibrosis (CF) Cl(-) transport defect in airway epithelia. These include inefficient transduction with vectors applied to the apical surface, a low rate of division by airway epithelial cells, failure of transgene expression to persist, and immune responses to vectors or vector-encoded proteins. To address these issues, we used a feline immunodeficiency virus-based (FIV-based) vector. FIV vector formulated with a calcium chelator transduced fully differentiated, nondividing human airway epithelia when applied to the apical surface. FIV-based vector encoding the cystic fibrosis transmembrane conductance regulator cDNA corrected the Cl(-) transport defect in differentiated CF airway epithelia for the life of the culture (>3 months). When this approach was applied in vivo, FIV vector expressing beta-galactosidase transduced 1-14% of adult rabbit airway epithelia. Transduced cells were present in the conducting airways, bronchioles, and alveoli. Importantly, gene expression persisted, and cells with progenitor capacity were targeted. FIV-based lentiviral vectors may be useful for the treatment of genetic lung diseases such as CF. This article may have been published online in advance of the print edition.