Epidemiological analyses of tuberculosis in Archangelsk, Russia and implementation of a rapid assay for detection of resistance in this high burden setting

Tuberculosis [TB] is a major problem in Russia, particularly regarding multidrug-resistant tuberculosis [MDR-TB]. Rapid drug susceptibility testing methods are therefore needed. To perform epidemiological analyses of TB in the Archangelsk region and to evaluate the molecular method GenoType [registered sign] MTBDRplus in this type of setting. Clinical and microbiological data of all TB patients in Archangelsk were collected in 2010. Smear-positive sputa were analysed by MTBDRplus and Bactec MGIT 960. The number of TB cases was 812 [incidence 65/105] and among these patients, 151 cases were registered in the penitentiary system [incidence 1162/105]. Most patients were men, 94% had pulmonary TB and 22% were relapses. Out of all cases, 341 [42%] were smear positive and thus contagious and 176 [22%] had MDR-TB, among which one had extensively drug resistant tuberculosis [XDR-TB]. Furthermore, two TB patients had strains being resistant to rifampicin, but susceptible to isoniazid. The number of cases being both contagious and MDR-TB was 128 representing 15.8% of all TB cases [incidence 10.2/105]. Among these 128 TB patients 37 were relapses representing 25.7% of all the relapse cases. The results of MTBDRplus and Bactec MGIT analyses corresponded in 98.8%. In Archangelsk many TB patients had contagious MDR-TB thus being hazardous in society and relapsing pulmonary TB was common. The TB situation in the prisons was particularly severe. The analyses showed furthermore that MTBDRplus is of major value in this setting

Tentative susceptibility testing breakpoint for the neuroleptic drug thioridazine, a treatment option for multiband extensively drug resistant tuberculosis

New drugs against multi-[MDR] and extensively drug [XDR] resistant tuberculosis are urgently needed. While new candidate drugs are being developed, reinvestigation of already approved drugs available for other indications could be of value. The objective of this study is to determine tentative drug susceptibility testing strategies and breakpoints for thioridazine, a well-known and well-tolerated neuroleptic drug, which has been shown to be effective against drug resistant tuberculosis both in vitro and in vivo. By testing the minimal inhibitory concentration [MIC] on Middlebrook 7H10 media, the wild-type distribution of thioridazine was established for Mycobacterium tuberculosis [n = 51] and this distribution was compared to the MICs of M/XDR strains [n = 67]. A tentative epidemiological cut off [ECOFF] of thioridazine at 16 mg/L was suggested. Even though such concentrations are not clinically achievable in serum, thioridazine is concentrated intracellularly and concentrations of only 0.1 mg/L has been shown to kill M. tuberculosis residing inside cells. MICs above the wild-type [MIC > 16 mg/L] were found in 4/67 [6%] of the M/XDR strains suggesting that resistance mechanisms against thioridazine may already be present in resistant clinical strains. In view of the difficulties obtaining clinical outcome data for single drugs in the case of tuberculosis since combination therapy is mandatory, the tentative ECOFF may be considered a tentative clinical breakpoint, but the findings should be validated by others. The data from this study strengthens the use of thioridazine as a treatment option for M/XDR tuberculosis, although its proper place in the therapeutic arsenal should ideally be confirmed in clinical trials.