More Tailored Approaches to Tuberculosis Treatment and Prevention.

Recent advances in the treatment of tuberculosis (TB) have led to improvements unprecedented in our lifetime. Decades of research in developing new drugs, especially for multidrug-resistant TB, have created not only multiple new antituberculous agents but also a new approach to development and treatment, with a focus on maximizing the benefit to the individual patient. Prevention of TB disease has also been improved and recognized as a critical component of global TB control. While the momentum is positive, it will take continued investment at all levels, especially training of new dedicated TB researchers and advocates around the world, to maintain this progress.

Resistance and Susceptibility to Mycobacterium tuberculosis Infection and Disease in Tuberculosis Households in Kampala, Uganda.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major public health problem. Household contact studies identify children and adults along the spectrum from Mtb exposure to disease. In the Kawempe Community Health Study (conducted in Kampala, Uganda), 872 culture-confirmed pulmonary TB cases and their 2,585 contacts were enrolled during 2002-2012 and followed for up to 2 years each. Risk factors identified by time-to-event analysis for secondary TB differed among children, women, and men. Younger age (P = 0.0061), human immunodeficiency virus (HIV) (P = 0.0002), thinness (P = 0.01), absent bacille Calmette-Guérin vaccination (P = 0.002), and epidemiologic risk score (P < 0.0001) were risks for children. For women, risks were HIV (P < 0.0001), thinness (World Health Organization criteria; P < 0.0001), and epidemiologic risk score (P = 0.003). For men, HIV (P = 0.0007) and low body mass index (P = 0.008) resulted in faster progression to TB. Tuberculin skin testing (TST) identified contacts with Mtb infection and those with persistently negative TST. Risks for faster time to Mtb infection were identified, and included age (P = 0.0007), baseline TST induration (P < 0.0001), and epidemiologic risk score (P < 0.0001) only in children. Those with persistently negative TST comprised 10% of contacts but had no unique epidemiologic characteristics among adults. The burden of Mtb infection and disease is high in TB households, and risk factors for progression from exposure to infection and disease differ among children, women, and men.

Sulfamethoxazole susceptibility of Mycobacterium tuberculosis isolates from HIV-infected Ugandan adults with tuberculosis taking trimethoprim-sulfamethoxazole prophylaxis.

Additional drugs are needed for the treatment of multidrug-resistant tuberculosis (TB). Sulfamethoxazole has been shown to have in vitro activity against Mycobacterium tuberculosis; however, there is concern about resistance given the widespread use of trimethoprim-sulfamethoxazole prophylaxis among HIV-infected patients in sub-Saharan Africa. Thirty-eight of 40 Mycobacterium tuberculosis isolates (95%) from pretreatment sputum samples from Ugandan adults with pulmonary TB, including HIV-infected patients taking trimethoprim-sulfamethoxazole prophylaxis, were susceptible with MICs of ≤38.4 µg/ml.

Capturing Recent Mycobacterium tuberculosis Infection by Tuberculin Skin Test vs. Interferon-Gamma Release Assay.

Reductions in tuberculosis (TB) incidence require identification of individuals at high risk of developing active disease, such as those with recent Mycobacterium tuberculosis (Mtb) infection. Using a prospective household contact (HHC) study in Kampala, Uganda, we diagnosed new Mtb infection using both the tuberculin skin test (TST) and interferon-gamma release assay (IGRA). Our study aimed to determine if the TST adds additional value to the characterization of IGRA converters. We identified 13 HHCs who only converted the IGRA (QFT-only converters), 39 HHCs who only converted their TST (TST-only converters), and 24 HHCs who converted both tests (QFT/TST converters). Univariate analysis revealed that TST-only converters were older. Additionally, increased odds of TST-only conversion were associated with older age (p = 0.02) and crowdedness (p = 0.025). QFT/TST converters had higher QFT quantitative values at conversion than QFT-only converters and a bigger change in TST quantitative values at conversion than TST-only converters. Collectively, these data indicate that TST conversion alone likely overestimates Mtb infection. Its correlation to older age suggests an "environmental" boosting response due to prolonged exposure to environmental mycobacteria. This result also suggests that QFT/TST conversion may be associated with a more robust immune response, which should be considered when planning vaccine studies.

Disseminated Mycobacterium chelonae infection in a patient receiving an epidermal growth factor receptor inhibitor for advanced head and neck cancer.

We report a case of disseminated cutaneous Mycobacterium chelonae infection in a patient with head and neck cancer on salvage chemotherapy, including the epidermal growth factor receptor inhibitor cetuximab. Mycobacterium chelonae should be considered in the differential diagnosis of cutaneous infections in cancer patients receiving epidermal growth factor receptor inhibitors.

Drug-Resistant Tuberculosis: A Glance at Progress and Global Challenges.

Multidrug-resistant Mycobacterium tuberculosis remains a major public health threat; its management poses a significant economic burden. Treatment requires a programmatic approach with access to laboratory services, second-line medications, and adequate clinical resources. In recent years, we have seen rapid developments in diagnostic techniques with whole genome sequencing-based drug susceptibility prediction now in reach, an array of new drugs that transform treatment regimens to purely oral formulations, and a steady stream of multinational trials that inform us about most efficient combinations. Our hope is that the current momentum keeps the ambitious goal to end tuberculosis in 2030 in reach.

Identification of Host Proteins Predictive of Early Stage Mycobacterium tuberculosis Infection.

The objective of this study was to identify blood-based protein biomarkers of early stage Mycobacterium tuberculosis (Mtb) infection. We utilized plasma and serum specimens from TB patients and their contacts (age≥12) enrolled in a household contact study in Uganda. In the discovery phase cross-sectional samples from 104 HIV-uninfected persons classified as either active TB, latent Mtb infection (LTBI), tuberculin skin test (TST) converters, or persistent TST-negative were analyzed. Two hundred eighty-nine statistically significant (false discovery rate corrected p<0.05) differentially expressed proteins were identified across all comparisons. Proteins associated with cellular immunity and lipid metabolism were induced early after Mtb infection. One hundred and fifty-nine proteins were selected for a targeted mass spectrometry assay. A set of longitudinal samples from 52 TST-negative subjects who converted to TST-positive or remained TST-negative were analyzed, and multivariate logistic regression was used to identify unique protein panels able to predict TST conversion with cross-validated AUC>0.85. Panel performance was confirmed with an independent validation set of longitudinal samples from 16 subjects. These candidate protein biomarkers may allow for the identification of recently Mtb infected individuals at highest risk for developing active TB and most likely to benefit from preventive therapy.

Drug-Resistant Tuberculosis: Challenges and Progress.

Antimicrobial resistance is a natural evolutionary process, which in the case of Mycobacterium tuberculosis is based on spontaneous chromosomal mutations, meaning that well-designed combination drug regimens provided under supervised therapy will prevent the emergence of drug-resistant strains. Unfortunately, limited resources, poverty, and neglect have led to the emergence of drug-resistant tuberculosis throughout the world. The international community has responded with financial and scientific support, leading to new rapid diagnostics, new drugs and regimens in advanced clinical development, and an increasingly sophisticated understanding of resistance mechanisms and their application to all aspects of TB control and treatment.

Incubation time of Mycobacterium tuberculosis complex sputum cultures in BACTEC MGIT 960: 4weeks of negative culture is enough for physicians to consider alternative diagnoses.

We retrospectively analyzed time to detection of 3747 positive MGIT sputum cultures at a laboratory in a country with heavy burden of tuberculosis. Ninety-nine percent of diagnostic cultures turned positive within 28days, suggesting that physicians may consider alternative diagnoses if sputum cultures remain negative after 4weeks of incubation.