Clinical standards for the diagnosis, treatment and prevention of TB infection.

BACKGROUND: Tuberculosis (TB) preventive therapy (TPT) decreases the risk of developing TB disease and its associated morbidity and mortality. The aim of these clinical standards is to guide the assessment, management of TB infection (TBI) and implementation of TPT.METHODS: A panel of global experts in the field of TB care was identified; 41 participated in a Delphi process. A 5-point Likert scale was used to score the initial standards. After rounds of revision, the document was approved with 100% agreement.RESULTS: Eight clinical standards were defined: Standard 1, all individuals belonging to at-risk groups for TB should undergo testing for TBI; Standard 2, all individual candidates for TPT (including caregivers of children) should undergo a counselling/health education session; Standard 3, testing for TBI: timing and test of choice should be optimised; Standard 4, TB disease should be excluded prior to initiation of TPT; Standard 5, all candidates for TPT should undergo a set of baseline examinations; Standard 6, all individuals initiating TPT should receive one of the recommended regimens; Standard 7, all individuals who have started TPT should be monitored; Standard 8, a TBI screening and testing register should be kept to inform the cascade of care.CONCLUSION: This is the first consensus-based set of Clinical Standards for TBI. This document guides clinicians, programme managers and public health officers in planning and implementing adequate measures to assess and manage TBI.

Rates and risk factors for nephrotoxicity and ototoxicity among tuberculosis patients in Tbilisi, Georgia.

SETTING: Treatment of multidrug-resistant tuberculosis (MDR-TB) is lengthy and utilizes second-line anti-TB drugs associated with frequent adverse drug reactions (ADRs).OBJECTIVE: To evaluate the prevalence of and risk factors for ADRs among patients with MDR- and extensively drug-resistant TB (XDR-TB).DESIGN: A retrospective chart review of patients initiating treatment for M/XDR-TB in 2010-2012 in Tbilisi, Georgia.RESULTS: Eighty (54%) and 38 (26%) of 147 patients developed nephrotoxicity per RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) classification and ototoxicity, respectively. Twenty-five (17%) patients required permanent interruption of injectables due to an ADR. Median hospital stay, total treatment duration and number of regimen changes were higher among those with nephrotoxicity and/or ototoxicity, compared to those without (P < 0.01). Multinomial logistic regression analysis identified increasing age (per year) as a risk factor for nephrotoxicity (aOR 1.08, 95%CI 1.03-1.12) and for both, nephro- and ototoxicity (aOR 1.11, 95%CI 1.05-1.17). Low baseline creatinine clearance (CrCl) was a significant risk factor for developing nephrotoxicity (aOR 1.05, 95%CI 1.02-1.07).CONCLUSION: Second-line injectable drug-related ADRs are common among M/XDR-TB patients. Patients with increasing age and low baseline CrCl should be monitored closely for injectable-related ADRs. Notably, our findings support WHO's latest recommendations on introduction of injectable free anti-TB treatment regimens.

Smoking behavior and beliefs about the impact of smoking on anti-tuberculosis treatment among health care workers.

SETTING: Tuberculosis (TB) health care facilities throughout Georgia. OBJECTIVE: To describe smoking behaviors among health care workers (HCWs) at TB facilities and determine HCWs' knowledge and beliefs regarding the impact of tobacco use on anti-tuberculosis treatment. DESIGN: Cross-sectional survey from May to December 2014 in Georgia. Adult HCWs (age 18 years) at TB facilities were eligible. We administered a 60-question anonymous survey about tobacco use and knowledge of the effect of smoking on anti-tuberculosis treatment. RESULTS: Of the 431 HCWs at TB facilities who participated, 377 (87.5%) were female; the median age was 50 years (range 20-77). Overall, 59 (13.7%) HCWs were current smokers and 35 (8.1%) were past smokers. Prevalence of current smoking was more common among physicians than among nurses (18.6% vs. 7.9%, P < 0.0001). Among HCWs, 115 (26.7%) believed smoking does not impact anti-tuberculosis treatment, and only 25.3% of physicians/nurses received formal training in smoking cessation approaches. Physicians who smoked were significantly more likely to believe that smoking does not impact anti-tuberculosis treatment than non-smoking physicians (aOR 5.11, 95%CI 1.46-17.90). CONCLUSION: Additional education about the effect of smoking on TB treatment outcomes is needed for staff of TB health care facilities in Georgia. Nurses and physicians need more training about smoking cessation approaches for patients with TB.

Impact of gyrB and eis Mutations in Improving Detection of Second-Line-Drug Resistance among Mycobacterium tuberculosis Isolates from Georgia.

The country of Georgia has a high burden of multi- and extensively drug-resistant tuberculosis (XDR-TB). To evaluate whether mutations in gyrB and eis genes increased the sensitivity of detection of phenotypic resistance to ofloxacin and kanamycin or capreomycin compared to use of the first-generation MTBDRsl assay alone, which tests for mutations in gyrA and rrs genes, a retrospective study of stored Mycobacterium tuberculosis isolates was performed. All isolates underwent DNA sequencing of resistance-determining regions. Among 112 M. tuberculosis isolates with DNA extraction data, targeted sequencing was successfully performed for each gene as follows: for gyrA, 98% sensitivity; for gyrB, 96%; for rrs, 93%; for the eis gene and its promoter, 93%. The specificity and hence the positive predictive value of gyrA and gyrB mutations for detecting ofloxacin resistance were 100%. The addition of gyrB mutations increased the sensitivity of phenotypic ofloxacin resistance detection by 13% (75% to 88%). All rrs resistance-conferring mutations were A1401G, and this mutation had low sensitivity (40% and 18%) and high specificity (95% and 100%) in predicting phenotypic capreomycin and kanamycin resistance, respectively. The eis C-14T mutation increased the sensitivity of phenotypic kanamycin resistance detection by 9% (18% to 27%) and was found solely in kanamycin phenotypic resistance isolates. Our data showed that the inclusion of eis C-14T and gyrB mutations in addition to rrs and gyrA mutations improves the sensitivity of detection of phenotypic ofloxacin and kanamycin resistance, respectively.

The potential of a multiplex high-throughput molecular assay for early detection of first and second line tuberculosis drug resistance mutations to improve infection control and reduce costs: a decision analytical modeling study.

BACKGROUND: Molecular resistance detection (MRD) of resistance to second-line anti-tuberculous drugs provides faster results than phenotypic tests, may shorten treatment and allow earlier separation among patients with and without second-line drug resistance. METHODS: In a decision-analytical model we simulated a cohort of patients diagnosed with TB in a setting where drug resistant TB is highly prevalent and requires initial hospitalization, to explore the potential benefits of a high-throughput MRD-assay for reducing potential nosocomial transmission of highly resistant strains, and total costs for diagnosis of drug resistance, treatment and hospitalization. In the base case scenario first-line drug resistance was diagnosed with WHO-endorsed molecular tests, and second-line drug resistance with culture and phenotypic methods. Three alternative scenarios were explored, each deploying high-throughput MRD allowing either detection of second-line mutations in cultured isolates, directly on sputum, or MRD with optimized markers. RESULTS: Compared to a base case scenario, deployment of high-throughput MRD reduced total costs by 17-21 %. The period during which nosocomial transmission may take place increased by 15 % compared to the base case if MRD had currently reported suboptimal sensitivity and required cultured isolates; increased by 7 % if direct sputum analysis were possible including in patients with smear-negative TB, and reduced by 24 % if the assay had improved markers, but was still performed on cultured isolates. Improved clinical sensitivity of the assay (additional markers) by more than 35 % would be needed to avoid compromising infection control. CONCLUSIONS: Further development of rapid second-line resistance testing should prioritize investment in optimizing markers above investments in a platform for direct analysis of sputum.

A comparison of the Xpert(®) MTB/RIF and GenoType(®) MTBDRplus assays in Georgia.

Few studies have directly compared the performance of rapid molecular diagnostic tests for tuberculosis (TB). We found that the commercially available molecular diagnostic tests Xpert(®) MTB/RIF and GenoType(®) MTBDRplus both provided timely and accurate results compared to conventional phenotypic tests in detecting TB and rifampicin resistance.

Diabetes mellitus is associated with cavities, smear grade, and multidrug-resistant tuberculosis in Georgia.

SETTING: National tuberculosis (TB) treatment facility in the country of Georgia. OBJECTIVE: To determine the prevalence of diabetes mellitus (DM) and pre-DM among patients with TB using glycosylated-hemoglobin (HbA1c), and to estimate the association between DM and clinical characteristics and response to anti-tuberculosis treatment. DESIGN: A cohort study was conducted from 2011 to 2014 at the National Centre for TB and Lung Disease in Tbilisi. Patients aged ⩾ 35 years with pulmonary TB were included. HbA1c was used to define DM (⩾ 6.5%), pre-DM (⩾ 5.7-6.4%), and no DM (<5.7%). Interviews and medical chart abstraction were performed. Regression analyses estimated associations between DM and 1) baseline TB characteristics and 2) anti-tuberculosis treatment outcomes. RESULTS: A total of 318 newly diagnosed patients with TB were enrolled. The prevalence of DM and pre-DM was 11.6% and 16.4%, respectively. In multivariable analyses, patients with TB-DM had more cavitation (adjusted OR [aOR] 2.26), higher smear grade (aOR 2.37), and more multidrug-resistant TB (MDR-TB) (aOR 2.27) than patients without DM. The risk of poor anti-tuberculosis treatment outcomes was similar among patients with and those without DM (28.1% vs. 23.6%). CONCLUSION: DM and pre-DM were common among adults with newly diagnosed pulmonary TB in Tbilisi, Georgia, and DM was associated with more clinical symptoms, and MDR-TB, at presentation.

Performance of the MTBDRsl assay in Georgia.

SETTING: The country of Georgia has a high burden of multi- (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB). OBJECTIVE: To assess the performance of the GenoType® MTBDRsl assay in the detection of resistance to kanamycin (KM), capreomycin (CPM) and ofloxacin (OFX), and of XDR-TB. DESIGN: Consecutive acid-fast bacilli smear-positive sputum specimens identified as MDR-TB using the MTBDRplus test were evaluated with the MTBDRsl assay and conventional second-line drug susceptibility testing (DST). RESULTS: Among 159 specimens, amplification was adequate in 154 (97%), including 9 of 9 culture-negative and 2 of 3 contaminated specimens. Second-line DST revealed that 17 (12%) Mycobacterium tuberculosis isolates were XDR-TB. Compared to DST, the MTBDRsl had 41% sensitivity and 98% specificity in detecting XDR-TB and 81% sensitivity and 99% specificity in detecting OFX resistance. Sensitivity was low in detecting resistance to KM (29%) and CPM (57%), while specificity was respectively 99% and 94%. Median times from sputum collection to second-line DST and MTBDRsl results were 70-104 vs. 10 days. CONCLUSION: Although the MTBDRsl assay had a rapid turnaround time, detection of second-line drug resistance was poor compared to DST. Further genetic mutations associated with resistance to second-line drugs should be included in the assay to improve test performance and clinical utility.