Evolution and emergence of multidrug-resistant Mycobacterium tuberculosis in Chisinau, Moldova.

The evolution and emergence of drug-resistant tuberculosis (TB) has been studied extensively in some contexts, but the ecological drivers of these two processes remain poorly understood. This study sought to describe the joint evolutionary and epidemiological histories of a novel multidrug-resistant Mycobacterium tuberculosis strain recently identified in the capital city of the Republic of Moldova (MDR Ural/4.2), where genomic surveillance of drug-resistant M. tuberculosis has been limited thus far. Using whole genome sequence data and Bayesian phylogenomic methods, we reconstruct the stepwise acquisition of drug resistance mutations in the MDR Ural/4.2 strain, estimate its historical bacterial population size over time, and infer the migration history of this strain between Eastern European countries. We infer that MDR Ural/4.2 likely evolved (via acquisition of rpoB S450L, which confers resistance to rifampin) in the early 1990s, during a period of social turmoil following Moldovan independence from the Soviet Union. This strain subsequently underwent substantial population size expansion in the early 2000s, at a time when national guidelines encouraged inpatient treatment of TB patients. We infer exportation of this strain and its isoniazid-resistant ancestral precursor from Moldova to neighbouring countries starting as early as 1985. Our findings suggest temporal and ecological associations between specific public health practices, including inpatient hospitalization of drug-resistant TB cases from the early 2000s until 2013, and the evolution of drug-resistant M. tuberculosis in Moldova. These findings underscore the need for regional coordination in TB control and expanded genomic surveillance efforts across Eastern Europe.

Cutaneous tuberculosis overview and current treatment regimens.

Tuberculosis is one of the oldest diseases known to humankind and it is currently a worldwide threat with 8-9 million new active disease being reported every year. Among patients with co-infection of the human immunodeficiency virus (HIV), tuberculosis is ultimately responsible for the most deaths. Cutaneous tuberculosis (CTB) is uncommon, comprising 1-1.5% of all extra-pulmonary tuberculosis manifestations, which manifests only in 8.4-13.7% of all tuberculosis cases. A more accurate classification of CTB includes inoculation tuberculosis, tuberculosis from an endogenous source and haematogenous tuberculosis. There is furthermore a definite distinction between true CTB caused by Mycobacterium tuberculosis and CTB caused by atypical mycobacterium species. The lesions caused by mycobacterium species vary from small papules (e.g. primary inoculation tuberculosis) and warty lesions (e.g. tuberculosis verrucosa cutis) to massive ulcers (e.g. Buruli ulcer) and plaques (e.g. lupus vulgaris) that can be highly deformative. Treatment options for CTB are currently limited to conventional oral therapy and occasional surgical intervention in cases that require it. True CTB is treated with a combination of rifampicin, ethambutol, pyrazinamide, isoniazid and streptomycin that is tailored to individual needs. Atypical mycobacterium infections are mostly resistant to anti-tuberculous drugs and only respond to certain antibiotics. As in the case of pulmonary TB, various and relatively wide-ranging treatment regimens are available, although patient compliance is poor. The development of multi-drug and extremely drug-resistant strains has also threatened treatment outcomes. To date, no topical therapy for CTB has been identified and although conventional therapy has mostly shown positive results, there is a lack of other treatment regimens.

Resistance patterns among multidrug-resistant tuberculosis patients in greater metropolitan Mumbai: trends over time.

BACKGROUND: While the high burden of multidrug-resistant tuberculosis (MDR-TB) itself is a matter of great concern, the emergence and rise of advanced forms of drug-resistance such as extensively drug-resistant TB (XDR-TB) and extremely drug-resistant TB (XXDR-TB) is more troubling. The aim of this study was to investigate the trends over time of patterns of drug resistance in a sample of MDR-TB patients in greater metropolitan Mumbai, India. METHODS: This was a retrospective, observational study of drug susceptibility testing (DST) results among MDR-TB patients from eight health care facilities in greater Mumbai between 2005 and 2013. We classified resistance patterns into four categories: MDR-TB, pre-XDR-TB, XDR-TB and XXDR-TB. RESULTS: A total of 340 MDR-TB patients were included in the study. Pre-XDR-TB was the most common form of drug-resistant TB observed overall in this Mumbai population at 56.8% compared to 29.4% for MDR-TB. The proportion of patients with MDR-TB was 39.4% in the period 2005-2007 and 27.8% in 2011-2013, while the proportion of those with XDR-TB and XXDR-TB was changed from 6.1% and 0% respectively to 10.6% and 5.6% during the same time period. During the same periods, the proportions of patients with ofloxacin, moxifloxacin and ethionamide resistance significantly increased from 57.6% to 75.3%, from 60.0% to 69.5% and from 24.2% to 52.5% respectively (p<0.05). DISCUSSION: The observed trends in TB drug-resistance patterns in Mumbai highlight the need for individualized drug regimens, designed on the basis of DST results involving first- and second-line anti-TB drugs and treatment history of the patient. A drug-resistant TB case-finding strategy based on molecular techniques that identify only rifampicin resistance will lead to initiation of suboptimal treatment regimens for a significant number of patients, which may in turn contribute to amplification of resistance and transmission of strains with increasingly advanced resistance within the community.

[Outcomes of treatment of chemotherapy drugs different manufacturers tuberculosis patients with multiple drug resistance].

The article is devoted to studying the effectiveness of treatment of tuberculosis (TB) patients with multidrug-resistant TB drugs 2 number of different manufacturers. To assess the effectiveness of treatment of second-line drugs were taken to study two groups of patients: Group 1 - 164 patients who received anti-TB drugs from the Global Fund and Group 2 174 patients who received anti-TB drugs for the national program. Comparative evaluation showed high efficiency second-line drugs from the Global Fund, as evidenced by the high level of 95,8 % abacillation in a short time in this patient group.

What's in a name? The future of drug-resistant tuberculosis classification.

Due to a recent resurgence in tuberculosis research focused on drug development, several new antituberculosis drugs are in the pipeline, and the standard of care for tuberculosis might soon change. If new drugs replace the current first-line treatment, then existing classifications of resistance, including multidrug-resistant and extensively drug-resistant tuberculosis, might become less relevant. When much needed new drugs reach the market, a new classification system for resistance might need to be devised to describe resistance to these novel agents. Many options for such a system exist, each with its own inherent benefits and challenges. The adoption of new terminology for resistance should be guided by outcomes data from clinical trials in progress, and should be accompanied by increased support for drug susceptibility testing in developing countries to be clinically useful. Consideration of these issues now will hopefully help foster an informed approach to the classification of drug-resistant tuberculosis in the era of new drugs.

A two-step strategy for molecular typing of multidrug-resistant Mycobacterium tuberculosis clinical isolates from Poland.

Tuberculosis (TB) continues to be one of the most challenging public health problems in the world. An important contributor to the global burden of the disease is the emergence and spread of drug-resistant and particularly multidrug-resistant Mycobacterium tuberculosis strains (MDR), defined as being resistant to at least isoniazid and rifampicin. In recent years, the introduction of different DNA-based molecular typing methods has substantially improved the knowledge of the epidemiology of TB. The purpose of this study was to employ a combination of two PCR-based genotyping methods, namely spoligotyping and IS6110-Mtb1/Mtb2 PCR to investigate the clonal relatedness of MDR M. tuberculosis clinical isolates recovered from pulmonary TB patients from Poland. Among the 50 isolates examined, 28 (56%) were clustered by spoligotyping, whereas IS6110-Mtb1/Mtb2 PCR resulted in 16 (32%) clustered isolates. The isolates that clustered in both typing methods were assumed to be clonally related. A two-step strategy consisting of spoligotyping as a first-line test, performed on the entire pool of isolates, and IS6110-Mtb1/Mtb2 PCR typing as a confirmatory subtyping method, performed only within spoligotype-defined clusters, is an efficient approach for determining clonal relatedness among M. tuberculosis clinical isolates.

Drug resistance patterns in pulmonary tuberculosis.

OBJECTIVE: To determine the resistance patterns of mycobacterium tuberculosis (MTB) isolates among category I and II patients of pulmonary tuberculosis. METHODS: This cross sectional study was conducted at the Department of Medicine, Liaquat University of Medical and Health Sciences Jamshoro, from November 2008 to September 2009. Patients were divided into category I and II. The sputa were collected, stained with Ziehl-Nielsen (Z-N) staining and ultimately inoculated on Lowenstein-Jensen (L-J) media for six weeks. Out of 890 pulmonary tuberculosis (PTB) patients, the growth was obtained in 285 cases. The Drug sensitivity testing (DST) for Isoniazid (INH), Rifampicin (RIF), Ethambutol (EMB) Pyrazinamide (PZA) and Streptomycin (SM) were performed. The data was analyzed on SPSS 10.0. A p-value of <0.05 was taken as significant. RESULT: Out of 285 cases, 176 (61.75%) were male and 109 (38.24%) female. The mean age was 37 +/- 19.90 years. The DST showed drug sensitive and drug resistant isolates in 80 (28.05%) and 205 (71.92%) cases respectively (p=0.001). The drug resistant tuberculosis (DR-TB) rates for individual drugs; INH, RIF, EMB, PZA and SM were 51,22%, 15.4%, 13.33%, 9%12, and 3.85% respectively (p=0.03). The MDR-TB isolates were detected in 120 (42.10%) cases, including 5 (5.88%) in category I and 115 (57.50%) in category II patients (p=0.0001). CONCLUSION: Drug resistant and multidrug resistant tuberculosis was observed mainly in category II patients. However, primary MDR was also observed in category I patients and reflects dissemination of MDR cases within the community.

Species spectrum of nontuberculous mycobacteria isolated from clinical specimens in Kuwait.

Specific identification of mycobacteria is of clinical relevance since treatment varies according to the Mycobacterium species causing infection. All mycobacterial isolates are currently identified as M. tuberculosis (MTB) or nontuberculous mycobacteria (NTM) based on p-nitro-alpha-acetylamino-beta-hydroxypropiophenone (NAP) test, and the species spectrum of NTM-causing infections in Kuwait remains unknown. This study identified all NTM strains isolated in Kuwait from 1 October 2003 to 31 March 2004 to the species level. The mycobacteria were cultured from various clinical specimens using the BACTEC 460 TB system and NAP test was performed to differentiate MTB from NTM strains. The INNO-LiPA MYCOBACTERIA v2 assay (LiPA) was used for species-specific identification of NTM strains and some randomly selected MTB strains. The LiPA results for selected isolates were confirmed by DNA sequencing of the 16S-23S internal transcribed spacer region. A total of 325 isolates of Mycobacterium species originating from 305 individual patients were recovered during the study period, with 307 and 18 isolates identified as MTB and NTM, respectively. The LiPA correctly identified all 18 MTB isolates analyzed. Seven different NTM species were identified among 18 NTM isolates originating from 14 patients, with M. fortuitum causing the majority of NTM infections in Kuwait. One patient was infected with two NTM species. Rapid species-specific identification of NTM may help with appropriate treatment regimens for proper patient management.

Classification of drug-resistant tuberculosis in an epidemic area.

BACKGROUND: Traditionally, patients with drug-resistant tuberculosis are classified as having acquired drug-resistant or primary drug-resistant disease on the basis of a history of previous tuberculosis treatment. Only cases of primary drug resistance are assumed to be due to transmission of drug-resistant strains. METHODS: This descriptive study of 63 patients with drug-resistant tuberculosis assessed the relative contribution of transmission of drug-resistant strains in a high-incidence community of Cape Town, South Africa, by restriction-fragment length polymorphism (RFLP). The RFLP results were compared with the results obtained by traditional classification methods. FINDINGS: According to RFLP definitions, 52% (33 cases) of drug-resistant tuberculosis was caused by transmission of a drug-resistant strain. The proportion of cases due to transmission was higher for multidrug-resistant (64%; 29 cases) than for single-drug-resistant (no cases) tuberculosis. By the clinical classification, only 18 (29%) patients were classified as having primary drug-resistant tuberculosis (implying transmission). The clinical classification was thus misleading in 25 patients. INTERPRETATION: The term acquired drug resistance includes patients infected with strains that truly acquired drug resistance during treatment and patients who were initially infected with or reinfected with a drug-resistant strain. This definition could lead to misinterpretation of surveillance studies, incorrect evaluation of tuberculosis programmes, and delayed diagnosis and treatment of patients with multidrug-resistant disease. The clinical term acquired drug resistance should be replaced with the term "drug resistance in previously treated cases", which includes cases with drug resistance due to true acquisition as well as that due to transmitted drug-resistant strains.