Ethionamide Population Pharmacokinetic Model and Target Attainment in Multidrug-Resistant Tuberculosis

Ethionamide (ETA), an isonicotinic acid derivative, is part of the multidrug-resistant tuberculosis (MDR-TB) regimen. The current guidelines have deprioritized ETA because it is potentially less effective than other agents. Our aim was to develop a population pharmacokinetic (PK) model and simulate ETA dosing regimens in order to assess target attainment. This study included subjects from four different sites, including healthy volunteers and patients with MDR-TB. The TB centers included were two in the United States and one in Bangladesh. Patients who received ETA and had at least one drug concentration reported were included. The population PK model was developed, regimens with a total of 1,000 to 2,250 mg daily were simulated, and target attainment using published MICs and targets of 1.0-log kill and resistance suppression was assessed with the Pmetrics R package. We included 1,167 ethionamide concentrations from 94 subjects. The final population model was a one-compartment model with first-order elimination and absorption with a lag time. The mean (standard deviation [SD]) final population parameter estimates were as follows: absorption rate constant, 1.02 (1.11) h(-1); elimination rate constant, 0.69 (0.46) h(-1); volume of distribution, 104.16 (59.87) liters; lag time, 0.43 (0.32) h. A total daily dose of 1,500 mg or more was needed for >= 90% attainment of the 1.0-log kill target at a MIC of 1 mg/liter, and 2,250 mg/day led to 80% attainment of the resistance suppression target at a MIC of 0.5 mg/liter. In conclusion, we developed a population PK model and assessed target attainment for different ETA regimens. Patients may not be able to tolerate the doses needed to achieve the pre-defined targets supporting the current recommendations for ETA deprioritization

Association between diabetes mellitus and multi-drug-resistant tuberculosis:a protocol for a systematic review and meta-analysis

INTRODUCTION: Multi-drug-resistant tuberculosis (MDR-TB) has emerged as a challenge to global tuberculosis (TB) control and remains a major public health concern in many countries. Diabetes mellitus (DM) is an increasingly recognized comorbidity that can both accelerate TB disease and complicate its treatment. The aim of this study is to summarize available evidence on the association of DM and MDR-TB among TB patients and to provide a pooled estimate of risks. METHODS: All studies published in English before October 2016 will be searched using comprehensive search strings through PubMed, EMBASE, Web of Science, and WHO Global Health Library databases which have reported the association of DM and MDR-TB in adults with TB (age > =15). Two authors will independently collect detailed information using structured data abstraction form. The quality of studies will be checked using Newcastle-Ottawa Scale for cohort and case-control studies and the Agency for Healthcare Research and Quality tool for cross-sectional studies. Heterogeneity between included studies will be assessed using the I(2) statistic. We will check potential publication bias by visual inspection of the funnel plot and Egger's regression test statistic. We will use the random effects model to compute a pooled estimate. DISCUSSION: Increases in the burden of non-communicable diseases and aging populations are changing the importance of different risk factors for TB, and the profile of comorbidities and clinical challenges for people with TB. Although classic risk factors and comorbidities such as overcrowding, under-nutrition, silicosis, and HIV infection are crucial to address, chronic conditions like diabetes are important factors that impair host defenses against TB. Thus, undertaking integrated multifaceted approach is remarkably necessary for reducing the burden of DM and successful TB treatment outcome. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016045692

Performance of computed tomography versus chest radiography in patients with pulmonary tuberculosis with and without diabetes at a tertiary hospital in Riyadh, Saudi Arabia

Yosra M Alkabab,1 Mushira A Enani,2 Nouf Y Indarkiri,3 Scott K Heysell1 1Department of Medicine, Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, USA; 2Department of Infectious Diseases, King Fahad Medical City, 3Department of Family Medicine, Prince Sultan Military Medical City, Riyadh, Saudi Arabia Background: Prior research suggests that diabetes mellitus (DM) is associated with increasing risk for developing cavitary lung disease in patients with pulmonary tuberculosis (TB). Additionally, chest computed tomography (CT) scan may be more sensitive than chest X-ray in detecting cavitary disease in such patients. The aim of this study was to compare the performance of chest CT to chest X-ray in detecting cavitary lung disease and to compare the frequency of cavities between TB patients with DM and without DM.Patients and methods: We conducted a retrospective cohort study at King Fahad Medical City, Riyadh, Saudi Arabia, from January 2004 to December 2015. We included patients aged 18 years and older with a positive sputum culture for Mycobacterium tuberculosis, and their medical charts were reviewed from admission to discharge.Results: Of the 133 patients who met the inclusion criteria, 38 (28.6%) patients were known to have DM and were compared with 95 (71.4%) patients without DM. DM patients with glycated hemoglobin (HbA1c) >6.5% had significantly more cavitary lesions when compared to all patients (with or without DM) with HbA1c <6.4% and/or random blood sugar <200 mg/dL. Furthermore, CT was able to detect lung cavities in 58.8% of the patients who had negative chest X-ray findings for cavities.Conclusion: The presence of lung cavities was significantly associated with the presence of DM and levels of HbA1c in patients with pulmonary TB. CT scan in those with normal radiography increased the detection of cavities. Keywords: diabetes, pulmonary tuberculosis, lung cavities, computed tomograph

Diabetes-related tuberculosis in the Middle East: an urgent need for regional research

Objectives: Diabetes mellitus (DM) triples the risk of tuberculosis (TB) disease, complicates TB treatment, and increases the risk of a poor TB outcome. As DM prevalence is increasing across the Middle East, this review was performed to identify regional gaps in knowledge and research priorities for DM/TB. Methods: Online databases were searched for studies published from Middle East countries on DM and TB and the studies summarized based on topic and major findings. Studies included had a principle hypothesis related to both diseases, or described TB patients with individual data on DM. Results: Fifty-nine studies from 10 countries met search criteria. No published studies were found from Lebanon, Bahrain, Syria, Jordan, Cyprus, or the United Arab Emirates. DM prevalence among TB patients was high, but varied considerably across studies. The vast majority of studies were not specifically designed to compare DM/TB and non-DM/TB patients, but many suggested worse treatment outcomes for DM/TB, in accordance with reports from other regions. Conclusions: Opportunity exists for the regional study of bidirectional screening, management strategies for both DM and TB diseases, and whether such efforts could take place through the integration of services

Ultrasound-guided core biopsy in the diagnostic work-up of tuberculous lymphadenitis in Saudi Arabia, refining the diagnostic approach. Case series and review of literature

Summary: Objective: Tuberculous cervical lymphadenitis is the most common presentation of extrapulmonary tuberculosis (TB) in Saudi Arabia and worldwide. Obtaining a tissue biopsy for culture and histopathology is frequently needed to establish the diagnosis. The available diagnostic tools include excisional surgical biopsy, fine needle aspiration (FNA) and ultrasound-guided core lymph node biopsy. We present a single center experience of the use of ultrasound-guided core lymph node biopsy as a diagnostic tool for tuberculous lymphadenitis. Methods: A retrospective review of the interventional radiology database for all of the patients with cervical lymphadenopathy undergoing ultrasound-guided core biopsy at King Abdulaziz Medical City-Riyadh, Saudi Arabia from January 1 2008 to December 30 2011. The data were the patient demographics, clinical characteristics, biopsy method and pathological and clinical diagnoses. Results: Five cases underwent ultrasound-guided cervical lymph node biopsy during the study period. A total of 55 cases underwent excisional cervical lymph node biopsy in the same period. The age of the patients who underwent the core biopsy ranged from 18 to 76 years old. All of the biopsies were performed as one-day surgery, and all of the patients were discharged on the same day with no complications. The final diagnosis was confirmed in all of the cases (100%); with tuberculosis being the diagnosis in four of the five cases (80%), and one case being diagnosed as lymphoma. Conclusion: Ultrasound-guided core biopsy is an underutilized procedure in our hospital and could be a very valuable asset in the diagnostic algorithm of tuberculous lymphadenitis in Saudi Arabia. The widespread use of the procedure would positively affect patient care, providing earlier diagnosis and treatment. Keywords: Ultrasound-guided biopsy, Ultrasound-guided core biopsy, Ultrasound-guided lymph node biops

Fixed-dose combination associated with faster time to smear conversion compared to separate tablets of anti-tuberculosis drugs in patients with poorly controlled diabetes and pulmonary tuberculosis in Qatar

Abstract Background Diabetes is associated with increased risk of tuberculosis (TB) treatment failure, death, and relapse compared to patients without diabetes. Current TB regimens are available as fixed dose combination (FDC) and separate tablets (ST), in which using the former is purported to make it easier to adhere and complete treatment. So far there are no studies assessing the performance of FDC compared to ST in diabetic patients with pulmonary TB. Methodology A retrospective cohort study was conducted, and included eight hospitals in Qatar in which patients diagnosed with pulmonary TB received rifampin, isoniazid, pyrazinamide, and ethambutol (as FDC or ST) given as directly observed therapy. Sputum smears for acid fast bacilli were tested weekly. We included patients admitted between December 2012 and December 2015, ≥18 years old, diagnosed with TB with pretreatment positive sputum smears, and having diabetes. Patients with Mycobacterium tuberculosis that was resistant to any first-line drug were excluded. Blood glucose was monitored closely and controlled to < 180 md/dL using oral hypoglycemic agents and/or insulin. We assessed the effectiveness of TB regimens by comparing time to confirmed negative smears between those treated with FDC or ST, and the impact of adding metformin. Results 103 patients met inclusion criteria. Mean age and body mass index were 45.6 ± 9.1 years and 22.1 ± 3.6 kg/m2, respectively. Fifty-four (52%) patients received the FDC. There was no difference between groups in baseline characteristics and sputum bacillary loads. Patients prescribed FDC showed faster times to sputum smear conversion compared to ST (32 ± 19 vs. 46 ± 31 days, p = 0.01). The difference was greater among patients with pretreatment bacillary load of 3+ (FDC 36.6 ± 19.5 vs. ST 56.1 ± 28.8, p = 0.008). Receipt of metformin≥2000 mg/day altered the difference in time to smear conversion (FDC 30.7 ± 13.4 vs. ST 62 ± 35.5, p = 0.016), which was of greatest difference in those with pretreatment bacillary load 3+ and who received metformin≥2000 mg/day (FDC 36 ± 12.1 vs. ST 92.2 ± 26 days, p = 0.001). Conclusion Patients with diabetes and prescribed FDC showed faster smear conversion during treatment for pulmonary TB compared to ST which was more pronounced in those with 3+ bacillary load pretreatment and which appeared to be modified by higher dose metformin

Fixed-dose combination associated with faster time to smear conversion compared to separate tablets of anti-tuberculosis drugs in patients with poorly controlled diabetes and pulmonary tuberculosis in Qatar

Background: Diabetes is associated with increased risk of tuberculosis (TB) treatment failure, death, and relapse compared to patients without diabetes. Current TB regimens are available as fixed dose combination (FDC) and separate tablets (ST), in which using the former is purported to make it easier to adhere and complete treatment. So far there are no studies assessing the performance of FDC compared to ST in diabetic patients with pulmonary TB. Methodology: A retrospective cohort study was conducted, and included eight hospitals in Qatar in which patients diagnosed with pulmonary TB received rifampin, isoniazid, pyrazinamide, and ethambutol (as FDC or ST) given as directly observed therapy. Sputum smears for acid fast bacilli were tested weekly. We included patients admitted between December 2012 and December 2015, ?18years old, diagnosed with TB with pretreatment positive sputum smears, and having diabetes. Patients with Mycobacterium tuberculosis that was resistant to any first-line drug were excluded. Blood glucose was monitored closely and controlled to &lt;180 md/dL using oral hypoglycemic agents and/or insulin. We assessed the effectiveness of TB regimens by comparing time to confirmed negative smears between those treated with FDC or ST, and the impact of adding metformin. Results: 103 patients met inclusion criteria. Mean age and body mass index were 45.6?9.1years and 22.1?3.6kg/m 2 , respectively. Fifty-four (52%) patients received the FDC. There was no difference between groups in baseline characteristics and sputum bacillary loads. Patients prescribed FDC showed faster times to sputum smear conversion compared to ST (32?19 vs. 46?31days, p=0.01). The difference was greater among patients with pretreatment bacillary load of 3+ (FDC 36.6?19.5 vs. ST 56.1?28.8, p=0.008). Receipt of metformin?2000mg/day altered the difference in time to smear conversion (FDC 30.7?13.4 vs. ST 62?35.5, p=0.016), which was of greatest difference in those with pretreatment bacillary load 3+ and who received metformin?2000mg/day (FDC 36?12.1 vs. ST 92.2?26days, p=0.001). Conclusion: Patients with diabetes and prescribed FDC showed faster smear conversion during treatment for pulmonary TB compared to ST which was more pronounced in those with 3+ bacillary load pretreatment and which appeared to be modified by higher dose metformin. ? 2018 The Author(s)

Differentiating transient from persistent diabetic range hyperglycemia in a cohort of people completing tuberculosis treatment in Dhaka, Bangladesh.

BACKGROUND: In recent non-pandemic periods, tuberculosis (TB) has been the leading killer worldwide from a single infectious disease. Patients with DM are three times more likely to develop active TB and poor treatment outcomes. Single glycemic measurements at TB diagnosis may inaccurately diagnose or mischaracterize DM severity. Data are limited regarding glycemic dynamics from TB diagnosis through treatment. METHODS: Prospective study of glycemia dynamics in response to TB treatment measured glycosylated haemoglobin (HbA1c) in patients presenting to TB screening centres in Bangladesh to determine the prevalence and risk factors of hyperglycemia before and at TB treatment completion. RESULTS: 429 adults with active TB disease were enrolled and divided into groups based on history of DM and initial HbA1c range: normoglycemia, prediabetes, and DM. DM was diagnosed in 37%. At treatment completion,14(6%) patients from the normoglycemia and prediabetes groups had HbA1c>6.5%, thus increasing the prevalence of DM to 39%. The number needed to screen to diagnose one new case of DM at TB diagnosis was 5.7 and 16 at treatment completion in the groups without DM. Weight gain>5% at treatment completion significantly increased the risk of hyperglycemia in the groups without DM at TB diagnosis (95% CI 1.23-26.04, p<0.05). CONCLUSION: HbA1c testing prior to and at TB treatment completion found a high prevalence of prediabetes and DM, including a proportion found at treatment completion and commonly in people with a higher percentage of weight gain. Further longitudinal research is needed to understand the effects of TB disease and treatment on insulin resistance and DM complications