Drug-resistant tuberculosis in Naples, 2008-2013

Background. Drug-resistant tuberculosis (TB) is an important threat in industrialized countries, but low information is known from Southern Italy. Here, we present the results of a retrospective study on TB cases diagnosed in 2008-2013 in Naples, the biggest city in the South of Italy. Methods. Six hundred ninety Mycobacterium tuberculosis strains were isolated at the Ospedali dei Colli of Naples, and resistance to first-line and second-line drugs was determined. Results. Multidrug-resistant (MDR) TB increased from 2008 to 2013, with most strains being isolated from migrants arriving from 41 countries. Overall MDR-TB rate was 4.5%: Italian-born persons, 2.2%; Romania, 7.5%; Former Soviet Union countries (Ukraine, Russia, Armenia, Georgia), 22.4%; all other foreign countries, 2.0%. Resistance of MDR strains to second-line drugs was high against kanamycin, ofloxacin, capreomycin. Conclusions. MDR-TB increased in 2008-13 and was mostly observed in migrants, indicating the need to intensify diagnosis and treatment of these populations in Naples

TARGETING DORMANT BACILLI TO FIGHT TUBERCULOSIS

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), which kills about 2 million people annually. Furthermore, 2 billion people worldwide are latently infected with this organism, with 10% of them reactivating to active TB due to re-growth of nonreplicating (dormant) Mtb residing in their tissues. Because of the huge reservoir of latent TB it is important to find novel drugs/drug combinations killing dormant bacilli (microaerophiles, anaerobes and drug-tolerant persisters) surviving for decades in a wide spectrum of granulomatous lesions in the lungs of TB patients. Antibiotic treatment of drug-susceptible TB requires administration of isoniazid, rifampin, pyrazinamide, ethambutol for 2 months, followed by isoniazid and rifampin for 4 months. To avoid reactivation of dormant Mtb to active pulmonary TB, up to 9 months of treatment with isoniazid is required. Therefore, a strategy to eliminate dormant bacilli needs to be developed to shorten therapy of active and latent TB and reduce the reservoir of people with latent TB. Finding drugs with high rate of penetration into the caseous granulomas and understanding the biology of dormant bacilli and in particular of persister cells, phenotypically resistant to antibiotics, will be essential to eradicate Mtb from humans. In recent years unprecedented efforts have been done in TB drug discovery, aimed at identifying novel drugs and drug combinations killing both actively replicating and nonreplicating Mtb in vitro, in animal models and in clinical trials in humans

Fighting tuberculosis by drugs targeting nonreplicating Mycobacterium tuberculosis bacilli

Current tuberculosis (TB) treatment requires 6 months of combination therapy with isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol for active TB and 9 months of INH or 3 months of rifapentine (RFP) + INH for latent TB. The lungs of patients with active and latent TB contain heterogeneous mixtures of cellular and caseous granulomas harboring Mycobacterium tuberculosis bacilli ranging from actively replicating (AR) to nonreplicating (NR), phenotypically drug-resistant stages. Several in vitro models to obtain NR cells were reported, including exposure to hypoxia, nutrient starvation, acid + nitric oxide, and stationary phase. Overall, these models showed that RIF, RFP, PA-824 (PA), metronidazole (MZ), bedaquiline (BQ), and fluoroquinolones were the most active drugs against NR M. tuberculosis. In hypoxia at pH 5.8, some combinations killed AR plus NR cells, as shown by lack of regrowth in liquid media, whereas in hypoxia at pH 7.3 (the pH of the caseum), only RIF and RFP efficiently killed NR bacilli while several other drugs showed little effect. In conventional mouse models, combinations containing RFP, BQ, PA, PZA, moxifloxacin, sutezolid, linezolid, and clofazimine sterilized animals in ≤2 months, as shown by lack of viable bacilli in lung homogenates after 3 months without therapy. Drugs were less effective in C3HeB/FeJ mice forming caseous granulomas. Overall, in vitro observations and in vivo studies suggest that the search for new TB drugs could be addressed to low lipophilic molecules (e.g., new rpoB inhibitors with clogP < 3) killing NR M. tuberculosis in hypoxia at neutral pH and reaching high rates of unbound drug in the caseum

Tuberculosis in migrants from 106 countries to Italy, 2008-2014

In migrants coming to Italy from 106 countries, MDR-TB was high from the former Soviet Union and low from Africa http://ow.ly/WZDb