Impact of Prior Tuberculosis Treatment With New/Companion Drugs on Clinical Outcomes in Patients Receiving Concomitant Bedaquiline and Delamanid for Multidrug- and Rifampicin-Resistant Tuberculosis.

BACKGROUND: There are scarce data on the clinical outcomes of persons retreated with new/companion anti-tuberculosis (TB) drugs for multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB). We sought to evaluate the efficacy and safety of bedaquiline and delamanid containing regimens among patients with and without prior exposure to the new/companion drugs (bedaquiline, delamanid, linezolid, clofazimine, and fluoroquinolones). METHODS: We conducted a retrospective cohort study among patients with pulmonary MDR/RR-TB in Georgia who received bedaquiline and delamanid combination as a part of a salvage regimen from November 2017 to December 2020 in a programmatic setting. RESULTS: Among 106 persons with a median age of 39.5 years, 44 (41.5%) were previously treated with new/companion TB drugs. Patients with prior exposure to new/companion drugs had higher rates of baseline resistance compared to those without exposure to new/companion TB drugs (bedaquiline 15.2% vs 1.8%, linezolid 22.2% vs 16.7%). Sputum culture conversion rates among patients exposed and not exposed to new/companion drugs were 65.9% vs 98.0%, respectively (P < .001). Among patients with and without prior new/companion TB drug use, favorable outcome rates were 41.0% and 82.3%, respectively (P < .001). Treatment adherence in 32 (30.2%) patients was ≤80%. Five of 21 patients (23.8%) who had a baseline and repeat susceptibility test had acquired bedaquiline resistance. QTC/F prolongation (>500 ms) was rare (2.8%). CONCLUSIONS: Prior exposure to new/companion TB drugs was associated with poor clinical outcomes and acquired drug resistance. Tailoring the TB regimen to each patient's drug susceptibility test results and burden of disease and enhancing adherence support may improve outcomes.

Clinical Outcomes Among Patients With Drug-resistant Tuberculosis Receiving Bedaquiline- or Delamanid-Containing Regimens.

BACKGROUND: Bedaquiline and delamanid are newly available drugs for treating multidrug-resistant tuberculosis (MDR-TB); however, there are limited data guiding their use and no comparison studies. METHODS: We conducted a prospective, observational study among patients with MDR-TB in Georgia who were receiving a bedaquiline- or delamanid-based treatment regimen. Monthly sputum cultures, minimal inhibitory concentration testing, and adverse event monitoring were performed. Primary outcomes were culture conversion rates and clinical outcomes. Targeted maximum likelihood estimation and super learning were utilized to produce a covariate-adjusted proportion of outcomes for each regimen. RESULTS: Among 156 patients with MDR-TB, 100 were enrolled and 95 were receiving a bedaquiline-based (n = 64) or delamanid-based (n = 31) regimen. Most were male (82%) and the median age was 38 years. Rates of previous treatment (56%) and cavitary disease (61%) were high. The most common companion drugs included linezolid, clofazimine, cycloserine, and a fluoroquinolone. The median numbers of effective drugs received among patients on bedaquiline-based (4; interquartile range [IQR], 4-4) and delamanid-based (4; IQR, 3.5-5) regimens were similar. Rates of acquired drug resistance were significantly higher among patients receiving delamanid versus bedaquiline (36% vs 10%, respectively; P < .01). Adjusted rates of sputum culture conversion at 2 months (67% vs 47%, respectively; P = .10) and 6 months (95% vs 74%, respectively; P < .01), as well as more favorable clinical outcomes (96% vs 72%, respectively; P < .01), were higher among patients receiving bedaquiline versus delamanid. CONCLUSIONS: Among patients with MDR-TB, bedaquiline-based regimens were associated with higher rates of sputum culture conversion, more favorable outcomes, and a lower rate of acquired drug resistance versus delamanid-based regimens.

Clinical outcomes among patients with tuberculous meningitis receiving intensified treatment regimens.

SETTING: National Center for Tuberculosis and Lung Diseases (NCTLD), Tbilisi, Georgia.OBJECTIVE: To determine clinical outcomes of patients with tuberculous meningitis (TBM) treated with an intensified regimen including a fluoroquinolone (FQ) and an injectable agent.DESIGN: Prospective cohort of patients aged ≥16 years initiating treatment for TBM at the NCTLD from January 2018 to December 2019. Treatment outcomes and neurologic disability at 1, 6 and 12 months after treatment initiation were assessed.RESULTS: Among 77 patients with median follow-up time of 363 days (IQR 269-374), 97% received a FQ, 62% an injectable agent, 44% linezolid and 39% a carbapenem. Fifty-seven patients (74%) successfully completed treatment, 2 (2.6%) had treatment failure, 6 (7.8%) died, and the remainder (12%) were lost to follow up. Among 11 patients treated for multidrug-resistant TBM, the median follow-up time was 467 days and one patient (8%) died. Regarding neurologic outcomes, 14/76 (18%) patients had Modified Rankin Scores of 0 at baseline, improving to 85% (56/66) and 94% (47/50) at 6 and 12 months, respectively.CONCLUSION: Intensified multidrug treatment regimens including a FQ and an injectable agent in all patients and newly implemented drugs in patients with multidrug-resistant TBM resulted in low mortality and favorable neurologic outcomes.

Linezolid use for drug-resistant tuberculosis in Georgia: a retrospective cohort study.

SETTING: Data on the long-term use of linezolid (LZD) in the treatment of drug-resistant pulmonary tuberculosis (DR-PTB) are limited.OBJECTIVE: To assess safety, tolerability and efficacy of LZD-containing regimens for the treatment of DR-PTB in the country of Georgia.DESIGN: A retrospective study was conducted among DR-PTB patients receiving LZD 600 mg/day as part of newly implemented regimens (bedaquiline or delamanid, repurposed and second-line drugs) from July 2014 to October 2015 in programmatic conditions and following WHO recommendations.RESULTS: One hundred mostly male (82%) patients with a median age of 33 years received LZD. Most patients (77%) had previously been treated for TB; 57% had extensively drug-resistant TB. The median duration of LZD use was 503 days (interquartile range 355-616). LZD-associated adverse events occurred in 12 patients, leading to discontinuation in 4 (2 each due to peripheral neuropathy and cytopenias), and dose reduction to 300 mg/day in 6 cases (4 due to peripheral neuropathy and 2 for cytopenias). Almost all patients (95%) achieved culture conversion and 79% had a successful treatment outcomes.CONCLUSION: Treatment regimens including lengthy LZD use showed fairly good safety and tolerability and were associated with high rates of culture conversion and favorable outcomes.

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.

A survey of the tuberculosis physician workforce in the country of Georgia.

SETTING: A well-trained and sufficient tuberculosis (TB) workforce is essential for disease control, especially in an era of newly implemented diagnostics and medications. However, there are few reports on the status of the TB workforce in many endemic countries. OBJECTIVE: To evaluate the demographics, salary, career satisfaction, and attitudes towards the field of TB among the physician TB workforce in the country of Georgia. DESIGN: A cross-sectional study of physicians in the current Georgian National TB Programme (NTP) using an anonymous 31-item questionnaire. RESULTS: Among 184 NTP physicians countrywide, 142 (77%) were contacted and 138 (75%) completed questionnaires. The median age was 56 years (interquartile range 50-64); most (81%) were female. The monthly salary from TB work was USD205 for 50% of respondents. Nearly half (47%) received an additional salary from another source. Many physicians (65%) indicated that they were satisfied with their work, but over half (55%) were unsatisfied with reimbursement. While most physicians (78%) were concerned about the lack of interest in TB, only 36% would recommend a career in TB care. CONCLUSION: While the current TB workforce in Georgia finds their work fulfilling, an ageing workforce, low salaries and perceived lack of interest in the field are a matter of concern for future TB control.

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.

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.

[Use of echocardiography in diagnosing heart failure in the acute stage of myocardial infarct]. / Primenenie ékhokardiografii dlia diagnostiki serdechnoi nedostatochnosti v ostrom periode infarkta miokarda.

The authors studied prognostic criteria and early diagnosis of cardiac insufficiency during the acute period of myocardial infarction. 44 patients with macrofocal myocardial infarction were examined during the acute phase. Phase analysis of time intervals of the cardiac cycle and a number of integral indices reflecting the contractile and pumping function of the myocardium came under scrutiny. It is established that the indices can be used for the diagnosis of circulatory insufficiency in the acute period of myocardial infarction and also for prognosis of the severity of the disease.

[Assessment of myocardial contractility by the sector scanning of myocardial infarct patients]. / Otsenka sokratimosti miokarda metodom sektoral'nogo skanirovaniia u bol'nykh infarktom miokarda.

A comparative assessment of left-ventricular myocardial contractility in patients with myocardial infarction was made using sector scanning and ventriculographic techniques. Eight patients were investigated within 2-4 hours of the infarction, and twenty patients, on days 20-25 of the disease. Ultimate diastolic, ultimate systolic and stroke volumes were calculated, as was the expulsion fraction, using the mono- and biplane method and modified formula 5/6 AL. Ventriculography was the testing method. Sector scanning is shown to be one of the most informative methods of myocardial contractility assessment in patients with myocardial infarction; the formula 5/6 AL appears to yield the best information when left-ventricular volumes are computed.

[Hypermyoglobinemia and creatine phosphokinase MB activity as signs of combined myocardial lesion and acute cerebral circulatory disorder]. / Gipermioglobinemiia i aktivnost' kreatinfosfokinazy MB kak priznaki sochetaniia porazheniia miokarda i ostrogo narusheniia mozgovogo krovoobrashcheniia.

In order to detect simultaneous damage to the myocardium in cerebral stroke the authors radioimmunoassayed myoglubin and activity of the heart fraction of creatine phosphokinase MB (CP K MB) in the blood serum of 22 patients. Hypermyoglobinemia and elevated activity of CP K MB were revealed in almost all cases of hemorrhagic stroke (15 patients) whereas in patients with ischemic stroke they were identified far less frequently. Thus, hypermyoglobinemia and the activity of CP K MB correlate with the macro- and microscopic picture of myocardial damage and may serve as its diagnostic criteria when both the clinical picture and ECG findings prove uninformative.

[State of humoral immunity in epilepsy patients]. / Sostoianie gumoral'nogo immuniteta u bol'nykh épilepsiei.

The results of examining the content of immunoglobulins and determining the presence of organ-specific anti-encephalic antibodies in the serum of patients with epilepsy of vascular and non-vascular genesis give one grounds to regard the lowered level of the immunoglobulins as a state of the immune system characteristic of epilepsy and as a factor in whose presence an epileptic seizure starts and develops. The lowering of the immunoglobulin level and the presence of anti-encephalic antibodies mainly against the thalamus in epileptic patients is, undoubtedly, of an importance for disclosing certain links of the disease pathogenesis. It is quite probably, that the data obtained are reflecting one more manifestation of the combined affection of the immunocompetent and the nervous systems.

[2-dimensional echocardiography in the diagnosis of heart aneurysms]. / Dvukhmernaia ékhokardiografiia v diagnostike anevrizm serdtsa.

The authors observed 157 patients with the myocardial infarction, of them 88 were in the acute phase of the disease. They compared different noninvasive methods of diagnosis of aneurysms. They believe that the method of sectoral scanning is the best. The mono-dimensional echocardiography is effective in detecting apical aneurysms. Dynamic echocardiography is essential for early detection of cardiac aneurysms. Taking of the apical section of the heart is to be preferred.

[Prognostic significance of the area of myocardial lesion and the status of the coronary bed during restoration of work capacity in patients with a complicated course of acute myocardial infarction]. / Prognosticheskoe znachenie ploshchadi porazheniia miokarda i sostoianiia koronarnogo rusla pri vosstanovlenii trudosposobnosti bol'nykh s oslozhnennym techeniem ostrogo perioda infarkta miokarda.

The effect of heart failure and acute left-ventricular aneurysm on the recovery of working capacity was assessed with reference to the size of necrotic focus and the extent of coronary arterial involvement in 117 patients with acute myocardial infarction. The size of necrotic focus and magnitude of coronary arterial affection were shown to be the principal determinants of heart failure in acute myocardial infarction. The presence of heart failure and acute left-ventricular aneurysm in combination with multiple coronary-arterial lesions is an adverse predictive sign in the assessment of the severity of acute myocardial infarction and the recovery of patients' working capacity. On the contrary, the presence of a local aneurysm in combination with an isolated coronary-arterial lesion should not be regarded as an unequivocal indicator of disability.

[Effect of physical training with reference to anaerobic threshold on the indicators of exercise tolerance and restoration of work capacity in patients after myocardial infarction]. / Vliianie fizicheskikh trenirovok s uchetom anaérobnogo poroga na pokazateli tolerantnosti i vosstanovlenie trudosposobnosti u bo'lnykh, perenesshikh infarkt miokarda.

In patients who had sustained myocardial infarction including that of complicated history, the anaerobic threshold was defined to choose the optimum intensity of physical training. The latter were also examined for effects on exercise tolerance. It was ascertained that measuring physical exercise by heart rate at the level of the anaerobic threshold made it possible to choose the optimal conditions for the aerobic supply of metabolic demands during physical training. Applying physical training under aerobic conditions greatly increases exercise tolerance, prevents recurrent myocardial infarctions and plays an important role in the secondary prevention of coronary heart disease.

[Study of prevalence and structure of cerebrovascular disorders in different regions of the USSR based on simultaneous epidemiological examinations]. / Rasprostranennost' i struktura tserebrovaskuliarnykh zabolevanii v razlichnykh regionakh SSSR po dannym adnomomentnogo épidemio- logicheskogo issledovaniia.

The authors describe the data of the screenings of the representative random samples from the open male population aged 20 to 54 years, carried out in accordance with the common program in 6 cities of this country. The prevalence of definite cases of cerebrovascular diseases (CVD) ranged from 7.7% in Moscow to 12% in Irkutsk. As to the structure of cerebrovascular injuries, the initial manifestations of brain blood supply insufficiency accounted for 68%. The prevalence of CVD turned out to be the greatest in Western Siberia, the least in the European region. The transcaucasian republics occupy an intermediate position.

[Diagnosis of impairment of segmental myocardial contractility during the acute phase of infarction using sector scanning]. / Diagnostika narushenii segmentarnoi sokratimosti miokarda v ostreishei faze infarkta metodom sektoral'nogo skanirovaniia.

The paper is concerned with sector scanning for early diagnosis of acute myocardial infarction. A total of 157 patients were examined within the first 2 to 6 hours after transmural infarction. The segments of the left ventricle which are mostly affected in infarctions of different sites were defined. Application of two-dimensional echocardiography permitted an earlier detecting of the segmental disorders and the extent of the focus of lesion as compared with the ECG. The method appeared particularly informative in the diagnosis of conduction impairment and repeated lesions of the left ventricular myocardium. It has been demonstrated that involvement of over 65% of left ventricular segments is an unfavourable sign from the standpoint of the disease prognosis.

Left ventricular contractility related to the state of the coronary bed.

The authors studied total and segmental contractility of the left ventricular (LV) myocardium in patients with acute myocardial infarction with single and multiple coronary artery (CA) disease. The group included 75 patients with acute transmural myocardial infarction; coronary arteriography was performed in 56 of them. All patients underwent echocardiography (sector scanning), on the basis of which total (ejection fraction) and segmental parameters (segmental ejection fraction, fraction of segmental wall shortening, velocity of change of segmental area, velocity of change in segmental wall thickness) of LV contractility were calculated. Patients with single CA affection display only a moderate decrease in total ejection fraction, and an insignificant number of complications of myocardial infarction. Segmental contractility data showed severe hyperkinesis of the intact segments of the left ventricle. Multiple CA disease is associated with a marked decrease in both total and segmental contractility of the LV myocardium, and there is no hyperkinesis of the intact segments of the heart.