Diagnosis of tuberculosis through breath test:A systematic review

Background: Breath tests may diagnose tuberculosis (TB) through detecting specific volatile organic compounds produced by Mycobacterium tuberculosis or the infected host. Methods: To estimate the diagnostic accuracy of breath test with electronic-nose and other devices against culture or other tests for TB, we screened multiple databases until January 6, 2019. Findings: We included fourteen studies, with 1715 subjects in the analysis. The pooled sensitivity and specificity of electronic-nose were 0.93 (95% to 0.82-0.97) and 0.93 (95% to 0.82-0.97), respectively, and no heterogeneity was found. The sensitivity and specificity of other breath test devices ranged from 0.62 to 1.00, and 0.11 to 0.84, respectively. Interpretation: The low to moderate evidence of these studies shows that breath tests can diagnose TB accurately, however, to give a real-time test result, additional development is needed. Research should also focus on sputum smear negative TB, children, and the positioning of breath testing in the diagnostic work flow. (C) 2019 The Authors. Published by Elsevier B.V

Impact of food intake on pharmacokinetics(PK) of first-line tuberculosis drugs in treatment-naive patients

Background: In treatment naive TB patients, the impact of food intake on the PK data of 1st line TB drugs is unknown in the early phase of treatment. Objectives: To assess impact of food intake on PK of isoniazid(INH), Rifampisin(RIF),pyrazinamide(PZA)and ethambutol(EMB) in treatment-naive TB patients. Methods: Randomized, cross-over trial in 20 patients. Subjects were administered INH, RIF, and EMB iv and PZA orally on day 1,and Fixed Drug Combination of all four on day 2&3 either while fasting or along with a high carbohydrate meal. Full PK curves were collected, and assayed by Liquid Chromatography-tandem Mass Spectrometry. Results: mean age was 41.8(SD=20)yrs, mean body mass index 17.48(SD=2.6)kg/m2. The PK data was shown in Conclusions: In treatment naive TB patients, concomitant food intake substantially influenced PK of TB drugs. Area under the curve(AUC0-24,),maximum concentration(Cmax ) and bioavailability decreased significantly when drugs were taken with food. The impact of the differences found in drug exposure on treatment efficacy and tolerability should be evaluated in a randomized prospective study. (Table Presented)

Sensitivity and specificity of an electronic nose in diagnosing pulmonary tuberculosis among patients with suspected tuberculosis

OBJECTIVE: To investigate the potency of a hand-held point-of-care electronic-nose to diagnose pulmonary tuberculosis (PTB) among those suspected of PTB. METHODS: Setting: Lung clinics and Dr. Sardjito Hospital, Yogyakarta, Indonesia. Participants: patients with suspected PTB and healthy controls. Sampling: 5 minutes exhaled breath. Sputum-smear-microscopy, culture, chest-radiography, and follow-up for 1.5-2.5 years, were used to classify patients with suspected PTB as active PTB, probably active PTB, probably no PTB, and no PTB. After building a breath model based on active PTB, no PTB, and healthy controls (Calibration phase), we validated the model in all patients with suspected PTB (Validation phase). In each variable (sex, age, Body Mass Index, co-morbidities, smoking status, consumption of alcohol, use of antibiotics, flu symptoms, stress, food and drink intake), one stratum's Receiver Operating Characteristic (ROC)-curve indicating sensitivity and specificity of the breath test was compared with another stratum's ROC-curve. Differences between Area-under-the-Curve between strata (p<0.05) indicated an association between the variable and sensitivity-specificity of the breath test. Statistical analysis was performed using STATA/SE 15. RESULTS: Of 400 enrolled participants, 73 were excluded due to extra-pulmonary TB, incomplete data, previous TB, and cancer. Calibration phase involved 182 subjects, and the result was validated in 287 subjects. Sensitivity was 85% (95%CI: 75-92%) and 78% (95%CI: 70-85%), specificity was 55% (95%CI: 44-65%) and 42% (95%CI: 34-50%), in calibration and validation phases, respectively. Test sensitivity and specificity were lower in men. CONCLUSION: The electronic-nose showed modest sensitivity and low specificity among patients with suspected PTB. To improve the sensitivity, a larger calibration group needs to be involved. With its portable form, it could be used for TB screening in remote rural areas and health care settings

Impact of food on the pharmacokinetics of first-line anti-TB drugs in treatment-naive TB patients: a randomized cross-over trial

Concomitant food intake influences pharmacokinetics of first-line anti-TB drugs in healthy volunteers. However, in treatment-naive TB patients who are starting with drug treatment, data on the influence of food intake on the pharmacokinetics are absent. This study aimed to quantify the influence of food on the pharmacokinetics of isoniazid, rifampicin, ethambutol and pyrazinamide in TB patients starting anti-TB treatment. A prospective randomized cross-over pharmacokinetic study was conducted in treatment-naive adults with drug-susceptible TB. They received isoniazid, rifampicin and ethambutol intravenously and oral pyrazinamide on day 1, followed by oral administration of these drugs under fasted and fed conditions on two consecutive days. Primary outcome was the bioavailability while fasting and with concomitant food intake. This study was registered with clinicaltrials.gov identifier NCT02121314. Twenty subjects completed the study protocol. Absolute bioavailability in the fasted state and the fed state was 93% and 78% for isoniazid, 87% and 71% for rifampicin and 87% and 82% for ethambutol. Food decreased absolute bioavailability of isoniazid and rifampicin by 15% and 16%, respectively. Pyrazinamide AUC(0-24) was comparable for the fasted state (481 mg center dot h/L) and the fed state (468 mg center dot h/L). Food lowered the maximum concentrations of isoniazid, rifampicin and pyrazinamide by 42%, 22% and 10%, respectively. Time to maximum concentration was delayed for isoniazid, rifampicin and pyrazinamide. The pharmacokinetics of ethambutol were unaffected by food. Food decreased absolute bioavailability and maximum concentration of isoniazid and rifampicin, but not of ethambutol or pyrazinamide, in treatment-naive TB patients. In patients prone to low drug exposure, this may further compromise treatment efficacy and increase the risk of acquired drug resistance

Population Pharmacokinetic Modelling and Limited Sampling Strategies for Therapeutic Drug Monitoring of Pyrazinamide in Patients with Tuberculosis

Pyrazinamide is one of the first-line antituberculosis drugs. The efficacy of pyrazinamide is associated with the ratio of 24-h area under the concentration–time curve (AUC24) to MIC. The objective of this study was to develop and validate a limited sampling strategy (LSS) based on a population pharmacokinetic (popPK) model to predict AUC24. A popPK model was developed using an iterative two-stage Bayesian procedure and was externally validated. Using data from 20 treatment-naive adult tuberculosis (TB) patients, a one compartment model with transit absorption and first-order elimination best described pyrazinamide pharmacokinetics and fed state was the only significant covariate for absorption rate constant (ka). External validation, using data from 26 TB patients, showed that the popPK model predicted AUC24 with a slight underestimation of 2.1%. LSS were calculated using Monte Carlo simulation (n = 10,000). External validation showed LSS with time points 0 h, 2 h, and 6 h performed best with RMSE of 9.90% and bias of 0.06%. Food slowed absorption of pyrazinamide, but did not affect bioavailability, which may be advantageous in case of nausea or vomiting in which food can be used to diminish these effects. In this study, we successfully developed and validated a popPK model and LSS, using 0 h, 2 h, and 6 h postdose samples, that could be used to perform therapeutic drug monitoring (TDM) of pyrazinamide in TB patients

Population Pharmacokinetic Modelling and Limited Sampling Strategies for Therapeutic Drug Monitoring of Pyrazinamide in Patients with Tuberculosis

Pyrazinamide is one of the first-line antituberculosis drugs. The efficacy of pyrazinamide is associated with the ratio of 24-h area under the concentration-time curve (AUC24) to MIC. The objective of this study was to develop and validate a limited sampling strategy (LSS) based on a population pharmacokinetic (popPK) model to predict AUC24. A popPK model was developed using an iterative two-stage Bayesian procedure and was externally validated. Using data from 20 treatment-naive adult tuberculosis (TB) patients, a one compartment model with transit absorption and first-order elimination best described pyrazinamide pharmacokinetics and fed state was the only significant covariate for absorption rate constant (ka). External validation, using data from 26 TB patients, showed that the popPK model predicted AUC24 with a slight underestimation of 2.1%. LSS were calculated using Monte Carlo simulation (n = 10,000). External validation showed LSS with time points 0 h, 2 h, and 6 h performed best with RMSE of 9.90% and bias of 0.06%. Food slowed absorption of pyrazinamide, but did not affect bioavailability, which may be advantageous in case of nausea or vomiting in which food can be used to diminish these effects. In this study, we successfully developed and validated a popPK model and LSS, using 0 h, 2 h, and 6 h postdose samples, that could be used to perform therapeutic drug monitoring (TDM) of pyrazinamide in TB patients