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The underlying cause of tuberculosis (TB) treatment failure is still largely unknown. A 1 H NMR approach was applied to identify and quantify a subset of TB drugs and drug metabolites: ethambutol (EMB), acetyl isoniazid (AcINH), isonicotinic acid, pyrazinamide (PZA), pyrazinoic acid and 5-hydroxy-pyrazinoic acid, from the urine of TB patients. Samples were collected before, during (weeks one, two and four) and after standardised TB treatment. The median concentrations of the EMB and PZA metabolites were comparable between the samples from patients with eventually cured and failed treatment outcomes. The INH metabolites showed comparatively elevated concentrations in the treatment failure patients during and after treatment. Variation in INH metabolite concentrations couldn't be associated with the varying acetylator genotypes, and it is therefore suggested that treatment failure is influenced more so by other conditions, such as environmental factors, or individual variation in other INH metabolic pathways., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: Twelve weekly doses of rifapentine and isoniazid (3HP regimen) are recommended for TB preventive therapy in children with TB infection. However, they present with variability in the pharmacokinetic profiles. The current study aimed to develop a pharmacokinetic model of rifapentine and isoniazid in 12 children with TB infection using NONMEM., Methods: Ninety plasma and 41 urine samples were collected at Week 4 of treatment. Drug concentrations were measured using a validated HPLC-UV method. MassARRAY® SNP genotyping was used to investigate genetic factors, including P-glycoprotein (ABCB1), solute carrier organic anion transporter B1 (SLCO1B1), arylacetamide deacetylase (AADAC) and N-acetyl transferase (NAT2). Clinically relevant covariates were also analysed., Results: A two-compartment model for isoniazid and a one-compartment model for rifapentine with transit compartment absorption and first-order elimination were the best models for describing plasma and urine data. The estimated (relative standard error, RSE) of isoniazid non-renal clearance was 3.52 L·h-1 (23.1%), 2.91 L·h-1 (19.6%), and 2.58 L·h-1 (20.0%) in NAT2 rapid, intermediate and slow acetylators. A significant proportion of the unchanged isoniazid was cleared renally (2.7 L·h-1; 8.0%), while the unchanged rifapentine was cleared primarily through non-renal routes (0.681 L·h-1; 3.6%). Participants with the ABCB1 mutant allele had lower bioavailability of rifapentine, while food prolonged the mean transit time of isoniazid., Conclusions: ABCB1 mutant allele carriers may require higher rifapentine doses; however, this must be confirmed in larger trials. Food did not affect overall exposure to isoniazid and only delayed absorption time., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

We assessed adherence in an infant tuberculosis prevention trial in Kenya with a urine isoniazid metabolite-detecting dipstick. Ninety-seven infants had 155 assays performed; 77 (49.7%) were found to be positive despite caregiver-reported adherence. Positive assays were associated with maternal secondary education, HIV suppression and no reported missed doses in past 3 days, suggesting caregiver education and self-medication use influenced infant adherence.

Objectives: Tuberculosis preventive therapy for people living with HIV is effective, widely recommended, and increasingly prescribed, but completion rates are less than ideal, and adherence is not typically monitored. We sought to quantify adherence to isoniazid preventive therapy using a urine metabolite assay., Design: Two cross-sectional surveys., Setting: Rio de Janeiro, Brazil, 2008-2009; and Northwest Province, South Africa, 2018-2019., Participants: Two hundred and three Brazilian and 93 South African patients attending HIV clinics with active prescriptions for isoniazid preventive therapy MAIN OUTCOME MEASURES:: Self-reported isoniazid adherence, paired with semiquantitative measurement of urine isoniazid metabolites., Results: By self-report, 90% of patients [95% confidence interval (CI) 86-93%] reported having taken a dose of isoniazid on the day of enrollment or the preceding day, and 91% (95% CI 87-94%) reported missing an average of one dose or fewer per week. By urine testing, only 65% (95% CI 59-70%) of all patients, and 69% (95% CI 63-74%) of those who reported having taken isoniazid on the current or preceding day, had detectable urine metabolites (expected in 95% of patients at 24 h). Longer time since starting preventive therapy was independently associated with a negative urine test for isoniazid metabolites (adjusted prevalence ratio 1.11 per month of isoniazid, 95% CI 1.05-1.18)., Conclusion: Adherence to isoniazid preventive therapy among patients with HIV in Brazil and South Africa is inadequate, is overestimated by self-report, and declines with time on treatment. Shorter regimens for TB preventive therapy may improve adherence and completion, but adherence support for all patients may be necessary.

Herein, we report a novel composite fabricated via embedding rod-like Co based metal-organic framework (Co-MOF-74) crystals into MC matrix for the first time. The introduction of MC astricts the size of Co-MOF-74 crystals, enlarges the pore size and improves the electrical conductivity, which lead to the good electrochemical properties of the composite. The fabricated sensor based on Co-MOF-74@MC exhibits superior electrocatalytic activity toward the reduction of pyrazinamide (PZA) and the oxidation of isonicotinyl hydrazide (INZ). Under optimized conditions, the sensor shows two linear ranges from 0.3 to 46.5 μM and 46.5-166.5 μM with a high sensitivity of 7.2 μA μM -1  cm -2 and a detection limit of 0.21 μM for the determination of PZA. The electroanalytical sensing of INZ also gives two linear ranges of 0.15-1.55 μM and 1.55-592.55 μM with a detection limit of 0.094 μM. The mechanism involved was also discussed, briefly. The sensor is assessed toward the detection of PZA and INZ in human serum and urine samples. Recovery values varied from 97.08 to 103.20% for PZA sensing and 96.67-102.90% for INZ sensing, revealing the promising practicality of sensor for PZA and INZ detection., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Population level variation of drug metabolism phenotype (DMP) has great implications in treatment outcome, drug-related side effects, and resistance development. In this study, we used a gas chromatography-time of flight-mass spectrometry (GC-TOF-MS)-based untargeted urine metabolomics approach to understand the DMP of a tuberculosis (TB) patient cohort (n= 20) from Tripura, a state in the northeastern part of India. Urine samples collected at different postdose time points (2 h, 6 h, 12 h, 24 h, 36 h, and 48 h) from these newly diagnosed TB patients receiving first-line anti-TB drugs were analyzed, and we have successfully detected three of the four first-line drugs,viz, isoniazid (INH), ethambutol (ETB), and pyrazinamide (PZA). The majority of their known metabolites, acetyl-isoniazid (AcINH), isonicotinic acid (INA), isonicotinuric acid (INTA), 2,2'-(ethylenediimino)-dibutyric acid (EDBA), 5-hydroxypyrazinamide (5OH-PZA), pyrazinoic acid (POA), and 5-hydroxypyrazinoic acid (5OH-POA), were also detected. Analyzing the variation in abundances of drugs and their known metabolites and calculating the metabolic ratios in these samples, we offer comprehensive DMP information on this small patient cohort that represents Tripura, India. The majority (75%) of these patients are found to be slow acetylators of INH. The average metabolic ratios of POA/PZA and 5OH-POA/POA are 3.16 ± 3.03 and 6.09 ± 6.15, respectively. Employing correlation analysis of the metabolomics metadata and a manual prediction of drug catabolism, we have proposed 2-aminobutyric acid (AABA) as a novel metabolite of ETB. These observations indicate the usefulness of GC-MS-based metabolomics to characterize the DMP at a population level and also to identify novel drug metabolites., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

A simple and sensitive UPLC-MS/MS assay was developed and validated for rapid determination of thiosemicarbazide derivative of isoniazid (TSC-INH), a potent anti-candidal agent in rat plasma, tissues, urine and feces. All biological samples were prepared by protein precipitation method using celecoxib as an internal standard (IS). Chromatographic separation was achieved on Acquity BEH™ C18 (50×2.1 mm, 1.7 μm) column using gradient mobile phase of acetonitrile and water (containing 0.1% formic acid) at flow rate of 0.3 mL/min. The MRM transitions were monitored at m/z 305.00→135.89 for TSC-INH and m/z 380.08→316.03 for IS in ESI negative mode. All validation parameter results were within the acceptable range described in guideline for bioanalytical method validation. The pharmacokinetic study showed that the compound TSC-INH was orally active with 66% absolute bioavailability in rats. It was rapidly absorbed with peak plasma concentration of 1985.92 ng/mL achieved within 1 h after single oral dose (10 mg/kg) administration. TSC-INH exhibited rapid distribution across the body with highest levels in liver and lungs. Penetration in brain tissues suggests that TSC-INH crossed the blood brain barrier. Only 5.23% of the orally administered drug was excreted as unconverted form in urine and feces implying that TSC-INH was metabolized extensively before excretion. With the preliminary knowledge of in vivo pharmacokinetics and disposition properties, this study will be beneficial for further development of compound TSC-INH in future studies., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The sampling of study included 185 examined workers. Out of them 90 work at "Opitnii zavod Neftekhim" (67 females and 23 males) and 95--at "Kaustik" (64 females and 31 males) from various workshops of the given enterprises. To determine biochemical indicators samples of blood, saliva and urine were collected. The study was carried out in concordance with ethic principles of the Helsinki world medical association declaration, 2008 ed. with receiving written consent of patient to participate in study.

Based on the oxidation of acridine yellow by permanganate in basic medium, a new chemiluminescence system was developed for the sensitive determination of some important drugs. The remarkable inhibiting effect of fluvoxamine, ceftriaxone and isoniazid on this reaction was applied to their detection. A possible mechanism was proposed for this system based on chemiluminescence emission wavelengths and experimental observations. Under optimum conditions, calibration graphs were obtained for 1 × 10(-9) to 1 × 10(-6) mol/L of fluvoxamine; 2 × 10(-8) to 8 × 10(-6) mol/L of ceftriaxone and 5 × 10(-8) to 4 × 10(-5) mol/L of isoniazid. This proposed method was satisfactorily used in the determination of these drugs in pharmaceutical samples and human urine and serum., (Copyright © 2014 John Wiley & Sons, Ltd.)

A simple and sensitive electrochemical method has been proposed for the determination of isoniazid (INZ). For the first time, rhodium (Rh) modified glassy carbon electrode (GCE) has been employed for the determination of INZ by linear sweep voltammetry technique (LSV). Compared with the unmodified electrode, the proposed Rh modified electrode provides strong electrocatalytic activity toward INZ with significant enhancement in the anodic peak current. Scanning electron microscopy (SEM) and field emission scanning electron microscopy (FESEM) results reveal the morphology of Rh particles. With the advantages of wide linearity (70-1300μM), good sensitivity (0.139μAμM(-1)cm(-2)) and low detection limit (13μM), this proposed sensor holds great potential for the determination of INZ in real samples. The practicality of the proposed electrode for the detection of INZ in human urine and blood plasma samples has been successfully demonstrated using LSV technique. Through the determination of INZ in commercially available pharmaceutical tablets, the practical applicability of the proposed method has been validated. The recovery results are found to be in good agreement with the labeled amounts of INZ in tablets, thus showing its great potential for use in clinical and pharmaceutical analysis., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The Arkansas colorimetric method monitors adherence to isoniazid (INH) by the detection of INH metabolites in urine. Urine samples 4 h after INH administration in 31 human immunodeficiency virus infected children receiving daily or thrice weekly INH preventive therapy were Arkansas test-positive for 29/31 (94%), while acetylisoniazid (AcINH) was detected in 30/31 (97%) using mass spectrometry. At 24, 48 and 72 h, only 78%, 23% and 0 samples, respectively, were Arkansas-positive, while INH or AcINH was detected in respectively 94%, 69% and 33%. The Arkansas test reliably predicted INH ingestion at a clinic visit 4 h after morning doses, but did not perform well at 24 h.

Background: Good adherence to treatment is crucial to control tuberculosis (TB). Efficiency and feasibility of directly observed therapy (DOT) under routine program conditions have been questioned. As an alternative, Médecins sans Frontières introduced self-administered therapy (SAT) in several TB programs. We aimed to measure adherence to TB treatment among patients receiving TB chemotherapy with fixed dose combination (FDC) under SAT at the Homa Bay district hospital (Kenya). A second objective was to compare the adherence agreement between different assessment tools., Methods: We conducted a cross-sectional survey amongst a series of new TB patients receiving 6 months of standard TB chemotherapy with FDC under SAT. Adherence was assessed at home with urine testing for Isoniazid (INH), pill count, interviewer-administered questionnaire and visual analogue scale (VAS)., Results: In November 2008 and in June 2009, 212 of 279 eligible patients were assessed for adherence. Overall, 95.2% [95%CI: 91.3-97.7] of the patients reported not having missed a tablet in the last 4 days. On the VAS, complete adherence was estimated at 92.5% [95%CI: 88.0-95.6]. INH urine test was positive for 97.6% [95%CI: 94.6-99.2] of the patients. Pill count could be assessed among only 70% of the interviewed patients. Among them, it was complete for 82.3% [95%CI: 75.1-88.1]. Among the 212 surveyed patients, 193 (91.0%) were successfully treated (cured or treatment completed). The data suggest a fair agreement between the questionnaire and the INH urine test (k = 0.43) and between the questionnaire and the VAS (k = 0.40). Agreement was poor between the other adherence tools., Conclusion: These results suggest that SAT, together with the FDC, allows achieving appropriate adherence to antituberculosis treatment in a high TB and HIV burden area. The use of a combination of a VAS and a questionnaire can be an adequate approach to monitor adherence to TB treatment in routine program conditions.

Background: Poor adherence to isoniazid (INH) preventive therapy (IPT) is an impediment to effective control of latent tuberculosis (TB) infection. TB patients who smoke are at higher risk of latent TB infection, active disease, and TB mortality, and may have lower adherence to their TB medications. The objective of our study was to validate IsoScreen and SmokeScreen (GFC Diagnostics, UK), two point-of-care tests for monitoring INH intake and determining smoking status. The tests could be used together in the same individual to help identify patients with a high-risk profile and provide a tailored treatment plan that includes medication management, adherence interventions, and smoking cessation programs., Methodology/principal Findings: 200 adult outpatients attending the TB and/or the smoking cessation clinic were recruited at the Montreal Chest Institute. Sensitivity and specificity were measured for each test against the corresponding composite reference standard. Test reliability was measured using kappa statistic for intra-rater and inter-rater agreement. Univariate and multivariate logistic regression models were used to explore possible covariates that might be related to false-positive and false-negative test results. IsoScreen had a sensitivity of 93.2% (95% confidence interval [CI] 80.3, 98.2) and specificity of 98.7% (94.8, 99.8). IsoScreen had intra-rater agreement (kappa) of 0.75 (0.48, 0.94) and inter-rater agreement of 0.61 (0.27, 0.90). SmokeScreen had a sensitivity of 69.2% (56.4, 79.8), specificity of 81.6% (73.0, 88.0), intra-rater agreement of 0.77 (0.56, 0.94), and inter-rater agreement of 0.66 (0.42, 0.88). False-positive SmokeScreen tests were strongly associated with INH treatment., Conclusions: IsoScreen had high validity and reliability, whereas SmokeScreen had modest validity and reliability. SmokeScreen tests did not perform well in a population receiving INH due to the association between INH treatment and false-positive SmokeScreen test results. Development of the next generation SmokeScreen assay should account for this potential interference.

One of the most effective and widely used antituberculosis (anti-TB) drugs is isoniazid (INH), a prodrug activated via oxidation that forms an adduct with NAD(+) to inhibit NADH-dependent targets of Mycobacterium tuberculosis, such as enoyl-acyl carrier protein reductase (InhA). The metabolic by-products and potentially toxic intermediates resulting from INH therapy have been identified through a large body of work. However, an INH-NAD adduct or structures related to this adduct have not been identified in specimens from human TB patients or animal models of TB. Analyses by mass spectrometry of urine collected from TB patients in a study conducted by the NIAID-funded Tuberculosis Research Unit identified 4-isonicotinoylnicotinamide (C(12)H(9)N(3)O(2)) as a novel metabolite of INH therapy. This compound was formed by M. tuberculosis strains in a KatG-dependent manner but could also be produced by mice treated with INH independent of an M. tuberculosis infection. Thus, the 4-isonicotinoylnicotinamide observed in human urine samples is likely derived from the degradation of oxidized INH-NAD adducts and provides direct evidence of host INH activation.

Background: Participant non-adherence and loss to follow-up can compromise the validity of clinical trial results. An assessment of these issues was made in a 3-year tuberculosis prevention trial among HIV-infected adults in Botswana., Methods and Findings: Between 11/2004-07/2006, 1995 participants were enrolled at eight public health clinics. They returned monthly to receive bottles of medication and were expected to take daily tablets of isoniazid or placebo for three years. Non-adherence was defined as refusing tablet ingestion but agreeing to quarterly physical examinations. Loss to follow-up was defined as not having returned for appointments in ≥60 days. Between 10/2008-04/2009, survey interviews were conducted with 83 participants identified as lost to follow-up and 127 identified as non-adherent. As a comparison, 252 randomly selected adherent participants were also surveyed. Multivariate logistic regression analysis was used to identify associations with selected risk factors. Men had higher odds of being non-adherent (adjusted odds ratio (AOR), 2.24; 95% confidence interval [95%CI] 1.24-4.04) and lost to follow-up (AOR 3.08; 95%CI 1.50-6.33). Non-adherent participants had higher odds of reporting difficulties taking the regimen or not knowing if they had difficulties (AOR 3.40; 95%CI 1.75-6.60) and lower odds associated with each year of age (AOR 0.95; 95%CI 0.91-0.98), but other variables such as employment, distance from clinic, alcohol use, and understanding study requirements were not significantly different than controls. Among participants who were non-adherent or lost to follow-up, 40/210 (19.0%) reported that they stopped the medication because of work commitments and 33/210 (15.7%) said they thought they had completed the study., Conclusions: Men had higher odds of non-adherence and loss to follow-up than women. Potential interventions that might improve adherence in trial participants may include:targeting health education for men, reducing barriers, clarifying study expectations, educating employers about HIV/AIDS to help reduce stigma in the workplace, and encouraging employers to support employee health., Trial Registration: ClinicalTrials.gov NCT00164281.

Isoniazid (INH) is a first-line drug for tuberculosis control; the side effects of INH are thought to be associated with its metabolism, and this study was designed to globally characterize isoniazid metabolism. Metabolomic strategies were used to profile isoniazid metabolism in humans. Eight known and seven novel INH metabolites and hydrazones were identified in human urine. The novel products included two hydroxylated INH metabolites and five hydrazones. The two novel metabolites were determined as 2-oxo-1,2-dihydro-pyridine-4-carbohydrazide and isoniazid N-oxide. Five novel hydrazones were produced by condensation of isoniazid with keto acids that are intermediates in the metabolism of essential amino acids, namely, leucine and/or isoleucine, lysine, tyrosine, tryptophan, and phenylalanine. This study enhances our knowledge of isoniazid metabolism and disposition and may offer new avenues for investigating INH-induced toxicity.

We evaluated the accuracy of a point-of-care test designed to measure adherence to isoniazid (INH) preventive therapy in a hospital setting in Rio de Janeiro, Brazil. Patients on treatment with daily INH and patients not receiving INH were included. Sensitivity and specificity of the test were 84%/98% at the first minute, and 95%/98% at the fifth minute, respectively. Among smokers, sensitivity and specificity was reduced (80%/89% at the fifth minute, respectively), but only 17% smoked. This test accurately detected INH metabolites 24h following directly observed INH intake, though sensitivity and specificity may be compromised by tobacco smoke exposure.

The Arkansas method (AM) for isoniazid (INH) metabolite detection is a relatively inexpensive, simple, objective measure of adherence. The purpose of the study was to explore whether variations in urine sample handling and storage will produce accurate assay outcomes. Participants were a convenience sample of 28 adults and adolescents prescribed INH for latent tuberculosis infection. Participants provided one sample to test effects of the following: mixing processes; durations at room temperature, in a refrigerator, or frozen; and effects of freeze/thaw cycles on AM outcomes. No manipulations had a discernible impact on outcomes with concordant positive rates from 85% to 100%. Concordance rates of manipulated samples did not appear to differ from rates of norm samples. Results suggest that urine samples can withstand a variety of manipulations in both handling and storage without affecting the accuracy of AM assay results. These findings have important implications for providers of treatment and researchers and provide the impetus for both to examine the potential of using the AM of INH metabolite testing as a measure of medication adherence.

A sensitive voltammetric method for trace measurements of isoniazid (INZ) in synthetic human urine sample is described. The method is based on its electroreduction at -0.98V vs. Ag/AgCl on screen-printed carbon electrode (SPCE) modified with poly-l-histidine (PH). A film of good adherence on SPCE and electrocatalytic properties was obtained coating the electrode by histidine monomer electropolymerization process (SPCE/EPH). The electrochemical behavior of the modified SPCE was investigated by cyclic, linear sweep (LSV), differential pulse (DPV), square-wave voltammetry (SWV), and electrochemical impedance spectroscopy (EIS). Limits of detection of 5.0x10(-7) mol L(-1), 1.7x10(-7) mol L(-1) and 2.5x10(-7) mol L(-1) were estimated from LSV, DPV and SWV determinations, respectively. The method was successfully applied to the determination of INZ in human urine samples., (2009 Elsevier B.V. All rights reserved.)

Isoniazid (INH) reacted with p-dimethylaminobenzaldehyde (DABD) in the presence of trichloroacetic acid to give isonicotinylhydrazone (INZ) having lambda(max) 365nm. Cloud point extraction (CPE) is carried out to extract INH and IHZ in aqueous solutions using surfactant poly(ethylene glycol) 4000 (PEG4000), respectively. Langmuir model is used to study the adsorption behaviors of the two solutes on micelles of PEG4000. A linear correlation is found between variation of PEG4000 concentration required for feed concentration of the two solutes and used to predict PEG4000 concentration required for extracting INH and IHZ in CPE procedure. The results calculated show that, for a desired recovery level of 90%, only can IHZ be sufficiently extracted by PEG4000. In this experiment, the feed concentration of PEG4000 is defined by above-mentioned correlation, and the effects of other operating parameters, e.g., concentration of salt, pH and centrifugation time on extraction of PEG4000-IHZ system have also been studied in detail. The proposed CPE method coupled with HPLC-UV system is successfully used for the determination of INH in urine sample.

Setting: A South African hospital serving gold mine employees., Objective: To determine the sensitivity and specificity of the Arkansas method for detecting isoniazid (INH) metabolites among South African adults and to examine the effect of smoking status on positive results., Design: Urine specimens were collected from in-patients taking INH as part of tuberculosis treatment at 6, 12 and 24 h after a directly observed 300 mg oral dose. As a control group, a single urine specimen was collected from surgical in-patients not taking INH. Specimens were tested for INH using a commercially available dipstick., Results: A total of 153 patients on INH and 60 controls were recruited. The sensitivity of the test was 93.3% (95%CI 88.1-96.8) at 6 h post INH, 93.4% (95%CI 88.2-96.8) at 12 h and 77% (95%CI 69.1-83.7) at 24 h. The specificity of the test was 98.3% (95%CI 91.1->99.9). There was no association between smoking status and colour change of positive results., Conclusions: This test is a useful method of monitoring adherence to TB treatment or preventive therapy among South Africans. However, it is less than 100% sensitive, especially with increasing time post dose, which should be taken into consideration when interpreting results for individual patients.

Background & Objective: AIDS and its associated gastrointestinal complications may impair the absorption of anti-tuberculosis (TB) drugs. Impaired absorption of anti-TB drugs could lead to low drug exposure, which might contribute to acquired drug resistance and reduced effectiveness of anti-TB treatment. The aim of this study was to obtain information on the status of absorption of rifampicin (RMP) and isoniazid (INH) in asymptomatic HIV- positive individuals, who are less immunocompromised. The D-xylose absorption test was also carried out to assess the absorptive capacity of intestive., Methods: The absorption of RMP, INH and D-xylose was studied in 15 asymptomatic HIV-positive individuals with CD4 cell counts>350 cells/mm3 and 16 healthy volunteers, after oral administration of single doses of RMP (450 mg), INH (300 mg) and D-xylose (5 g). Urine was collected up to 8 h after drug administration. Percentage dose of the drugs and their metabolites and D-xylose excreted in urine were calculated., Results: A significant reduction in the urinary excretion of INH and D-xylose in HIV-positive persons compared to healthy volunteers was observed. The per cent dose of RMP and its metabolite, desacetyl RMP was also lower in HIV-positive persons compared to healthy volunteers, but this difference was not statistically significant., Interpretation & Conclusion: Decreased urinary excretion of D-xylose and INH are suggestive of intestinal malabsorption in HIV-positive individuals. HIV infection could cause malabsorption of anti-TB drugs even at an early stage of the disease. The clinical implications of these findings need to be confirmed in larger studies.

In this paper, molecularly imprinted polymer (MIP) of isoniazid is synthesized through thermal radical copolymerization of metharylic acid (MAA) and ethylene glycol dimethacrylate (EGDMA) in the presence of isoniazid template molecules. A novel flow injection chemiluminescence sensor for isoniazid determination is developed by packing the isoniazid-MIP into the flow cell as recognition elements. Isoniazid could be selectively adsorbed by the MIPs and the adsorbed isoniazid was sensed by its great enhancing effect on the weak CL reaction between luminol and periodate which were mixed in the flow cell. The enhanced CL intensity is linear in the range 2x10(-9) to 2x10(-7) g/mL and the detection limit is 7x10(-10) g/mL (3sigma) isoniazid with a relative standard deviation 2.8% (n=9) for 8x10(-8) g/mL. The sensor is reversible and reusable. It has a great improvement in sensitivity and selectivity for CL analysis. As a result, the sensor has been successfully applied to determination of isoniazid in human urine. At the same time, the binding characteristic of the polymer to isoniazid was evaluated by batch method and the dynamic method, respectively.

Background: Tuberculosis (TB) is the most common opportunistic infection in HIV-infected adults in developing countries. Isoniazid (INH) is recommended for treatment of latent TB infection, however non-adherence is common. The purpose of this study was to apply in-house prepared isoniazid (INH) urine test strips in a clinical setting, and identify predictors of positive test results in an adherence questionnaire in HIV-infected adults taking INH for prevention of TB., Methods: Cross-sectional study of adherence using a questionnaire and urine test strips for detection of INH metabolites at two hospitals in Pietermaritzburg, South Africa. Participants were aged at least 18 years, HIV positive, and receiving INH for prevention of tuberculosis disease. Univariate and multivariate analyses are used to identify factors relevant to adherence., Results: 301 consecutive patients were recruited. 28% of participants had negative urine tests. 32 (37.2%, 95% CI25.4, 45.0) of the 86 patients who received INH from peripheral pharmacies said the pharmacy had run out of INH at some time, compared with central hospital pharmacies (p = 0.0001). In univariate analysis, a negative test was associated with self-reported missed INH doses (p = 0.043). Each 12-hour increment since last reported dose increased the likelihood of a negative test by 34% (p = 0.0007). Belief in INH safety was associated with a positive test (p = 0.021). In multivariate analysis, patients who believed INH is important for prevention of TB disease were more likely to be negative (p = 0.0086)., Conclusion: Adequate drug availability at peripheral pharmacies remains an important intervention for TB prevention. Key questions may identify potentially non-adherent patients. In-house prepared urine tests strips are an effective and cheap method of objectively assessing INH adherence, and could be used an important tool in TB control programs.

This investigation retrospectively assessed inexpensive non-invasive qualitative methods to monitor the ingestion of anti-tuberculosis drugs isoniazid, rifampicin and rifapentine. Results showed that commercial test strips detected the isoniazid metabolites isonicotinic acid and isonicotinylglycine as efficiently as the isonicotinic acid method in 150 urine samples. The presence of rifamycins in urine samples (n=1085) was detected by microbiological assay techniques and the sensitivity compared to the n-butanol extraction colour test in 91 of these specimens. The proportions detected by the two methods were significantly different and the sensitivity of the n-butanol procedure was only 63.8% (95% CL 51.2-76.4%) as compared to that of the superior microbiological method. Final validation (n=691) showed that qualitative assays measure isoniazid and rifamycin ingestion with an efficiency similar to high-performance liquid chromatography. The qualitative procedures may therefore be valuable in clinical trials and in tuberculosis clinics to confirm drug ingestion.

Background: Adherence with therapy is a wide spectrum of behavior rather than a categorical state. While extreme nonadherence is readily apparent, it is rare compared to lesser degrees of nonadherence, which are difficult to predict., Aims: To compare the accuracy of doctor, nurse, and patient prediction of adherence with antituberculous therapy with urine isoniazid levels., Methods: A prospective, blinded clinical study was conducted, comparing adherence to antituberculous therapy as reported by patients, doctors, and nurses with urine isoniazid levels. We studied 173 patients with active tuberculosis (TB) recruited over 3 years in two TB clinics in Victoria, Australia. Adherence was defined as six random urine isoniazid (INH) levels being >0. Blinded assessment of adherence was completed by doctors, nurses, and patients. Lid opening and closing of computerized pill bottles were measured in a random subsample., Results: Of 173 patients, the rate of nonadherence was 24% (41/173) by urine INH, 54% (93/173) by patient self-report, 11% (19/173) by doctor assessment, and 7% (12/173) by nurse assessment. The sensitivity of prediction of nonadherence was 76% for patient self-report, 24% for doctor assessment, and 19% for nurse assessment. The 10 patients who used computerized pill bottles were all (100%) noncompliant at some stage., Conclusion: Nonadherence is common and poorly predicted by doctors and nurses, even those with extensive experience in treating TB. Contrary to popular belief, patient self-report is more reliable than doctor or nurse assessment of nonadherence. As clinicians, asking patients about adherence may be more valuable than attempting to judge for ourselves.

Background: In the fight against the global tuberculosis epidemic, it is essential to ensure that patients adhere to the treatment prescribed. As the treatment is given for a minimum of 6 months it is common for patients not to take their drugs regularly. Strategies are therefore needed to assess adherence to treatment. One established method is to examine the patient's urine for the presence of drug metabolites. A rapid point-of-care test would overcome some of the drawbacks associated with currently available methods., Method: A rapid, safe point-of-care test for isoniazid metabolites (IsoScreen, Surescreen Diagnostics Limited, Derby, UK) has been developed and used to help assess adherence to treatment in a busy clinic for tuberculosis patients in South London., Results: Urine samples were examined from 191 patients receiving isoniazid, usually in combination with rifampicin and other anti-tuberculous drugs. Isoscreen was positive in 93.2% of patients, suggesting that 6.8% might be poorly adhering to treatment. By contrast, examining the same urine samples for evidence of rifampicin ingestion gave positive results in only 43.5%, due to the fact that this test is only positive for a few hours after drug ingestion., Conclusion: IsoScreen has been shown to provide a rapid and safe point-of-care test, which contributes to the detection of non-adherence in patients with tuberculosis.

Isoniazid, pyridine-4-carboxylic acid hydrazide, is an antituberculosis-agent, which is used to prevent the development of clinical tuberculosis. A validated square-wave adsorptive cathodic stripping voltammetric procedure for the trace determination of the bulk drug at the hanging mercury drop electrode (HMDE) has been developed. Under the optimized conditions, (accumulation potential=-0.9 V, accumulation time=50-300 s, scan increment=8 mV, pulse-amplitude=25 mV, frequency=120 Hz and acetate buffer at pH 5.5) isoniazed generated two irreversible cathodic peaks. The first peak current showed a linear dependence with the drug concentration over the range 5 x 10(-10)-21 x 0(-6) M. The mean percentage recoveries, based on the average of five replicate measurements, for 7 x 10(-9) and 5 x 10(-8) M isoniazid were 97.71+/-2.93 and 99.76+/-0.77, respectively. The achieved limits of detection (LOD) and quantitation (LOQ) were 1.18 x 10(-10) and 3.93 x 10(-10) M isoniazid, respectively. The procedure was applied to the assay of the drug in tablets (Isocid and T.B. Zide), spiked human serum and urine with mean percentage recoveries of 97.81+/-1.49, 97.45+/-2.09, and 97.08+/-1.06, respectively. The limits of detection of 1.47 x 10(-9) and 2.4 x 10(-8) M, and quantitation of 4.9 x 10(-9) and 8 x 10(-8) M drug in human serum and urine, respectively, were achieved. The mean values of the various pharmackinetic parameters of isoniazid (C(max), T(max), t(1/2), AUC, and K(e)), estimated from analysis of plasma of two volunteers by means of the proposed procedure were similar to literature values.

Objectives: We sought to determine the efficacy of coaching Latino adolescents with latent tuberculosis infection to adhere to isoniazid treatment., Methods: Participants (n = 286) were randomly assigned to adherence coaching, attention control, or usual care groups. Adherence was measured via interviews and validated with urine assays., Results: Coaching resulted in significant increases in adherence compared with attention and usual care groups. Bicultural adolescents were more likely to be adherent than those most or least acculturated. Age and risk behavior were negatively related to adherence., Conclusions: Coaching can increase Latino adolescents' adherence to treatment for latent tuberculosis infection and should contribute to tuberculosis control for adolescents at high risk of contracting the disease.

Setting: A randomised, controlled clinical trial of the effectiveness of a family-based programme of directly observed treatment (DOT) for tuberculosis., Methods: TB patients seen in Victoria, Australia, were randomly allocated to DOT observed by a family member (FDOT), or to standard supervised but non-observed therapy (ST). The outcome measure was compliance, measured by blinded testing of isoniazid levels in urine. An intention-to-treat analysis was used., Results: Of 173 patients, 87 were allocated to FDOT and 86 to ST. Only 58% in the FDOT group were able to receive FDOT, the major reason being living alone and not having a family member to observe treatment. The rate of non-compliance was 24% (41/173), with no significant difference between FDOT (22/87) and ST (19/86). No clinical or socio-demographic variable predicted compliance., Conclusions: We were unable to demonstrate a benefit of FDOT in an urban, industrialised country setting. FDOT may be more appropriate in developing countries, where extended family support is often available and the burden of TB is much higher. Poor compliance and the difficulty in predicting non-compliance shown in this study highlights the need for DOT for all TB patients.

Study Objective: To apply the Arkansas color method in order to evaluate drug compliance and factors that can predict treatment adherence in patients being treated for latent tuberculosis infection (LTBI) with a single daily dose of isoniazid (INH)., Design: Prospective study of adherence of 105 patients aged 1 to 75 years who were treated with a single daily dose of INH for LTBI., Interventions: Patients or their parents were interviewed regarding parameters that may affect compliance. Urine samples were collected and tested for INH metabolites with the Arkansas color method., Results: Nonadherence to treatment was found in 28.5% of patients. There was no statistically significant correlation among the following parameters: gender; age; diagnosis; mode of administration (self or parents); duration of treatment; dose of INH per weight; or interval since last intake of dose. Twenty-six patients were randomly checked for treatment adherence on two separate visits, and nonadherent patients were informed immediately and their condition was fully explained to them. Five of six patients who were nonadherent in the first visit and were examined twice became adherent in the second visit. Three of 20 patients who were adherent in the first visit became nonadherent., Conclusion: Almost one third of the patients who received LTBI treatment with INH were nonadherent to treatment. No factor was found to predict adherence. The Arkansas method can be used by the family physician and is a simple, immediate method to follow-up patients with LTBI who are treated with INH.

Patient compliance should be ensured in an effective tuberculosis control programme. We measured patient compliance by detecting antituberculous drugs in the urine of 237 outpatients receiving one to three antituberculous drugs. Positive controls were 20 hospitalised patients, supervised to receive isoniazid (INH), rifampicin (RIF) and pyrazinamide (PZA), and negative controls were not on any drugs. Among the 237 study patients, only 67% were found to be taking the appropriate treatment and 8% had taken none. We conclude that a remarkable number of patients (33%) were non-compliant with treatment. The detection of antituberculous drugs in the urine is a quick, simple and inexpensive means of measuring adherence to treatment. Unless directly observed therapy (DOT) is adopted, we recommend routine urine testing for antituberculous drugs to identify defaulting patients.

Setting: Mulago Hospital, Kampala, Uganda., Objective: To evaluate the usefulness of urine dipsticks for monitoring adherence to anti-tuberculosis chemotherapy., Design: In-house urine dipsticks for detection of isoniazid (INH) metabolites were compared to commercial test strips. The value of n-butanol to detect rifampicin was compared to coloration of the urine. Non-adherence was assessed through a questionnaire and reviews of the Mulago Hospital TB register., Results: Urine was obtained from 236 patients (127 adults and 109 children) on daily chemotherapy. Using commercial test strips as standard, the sensitivity of in-house urine dipsticks was 99.5% and specificity was 96.4%. The sensitivity and the specificity of n-butanol and of coloration of urine to detect rifampicin were low (64.0% and 54.9%, and 85.5% and 64.8%, respectively). Fifty patients (21.2%) admitted non-adherence to treatment during the previous month. An additional 15 (6.8%) were detected through urine testing. Of 911 patients in the TB register of Mulago Hospital who had started treatment in the first 3 months of 2000, 39.7% did not complete their treatment. Two-thirds of these had discontinued treatment in the first 2 months., Conclusion: In-house INH test strips are as effective as commercially available strips for detecting isoniazid in the urine. They are a simple tool for monitoring adherence. Adherence to anti-tuberculosis chemotherapy as determined by the use of isoniazid test strips and review of the TB register showed poor compliance. Tests for rifampicin are less sensitive and specific.

For the purpose of more accurate and rapid analysis of isoniazid in body fluid samples, a reversed-phase high performance liquid chromatographic (HPLC) method was developed. Vanillin, being as a derivatizing reagent, was added to the plasma and urine samples when they were pretreated. Isoniazid and vanillin reacted to form isonicotinoyl hydrazone which was separated and detected. The pretreatment method of sample, the linear range, the precision, and the recovery of isoniazid were investigated by using human's plasma and urine spiked with standard isoniazid. The linear range was 0.2 mg/L- 12.0 mg/L (for plasma, r =0.999 6; for urine, r = 0.999 4). The detection limit was 0.2 mg/L. The intra-day and inter-day precisions of assay for isoniazid were 2.3% - 2.6% and 3.8% - 4.0% (n = 5) for plasma, 1.3% - 4.0% and 2.1% - 3.9% (n = 5) for urine respectively. The average recoveries of isoniazid were from 96.5% to 99.8% in plasma and from 96.3% to 99.4% in urine. The HPLC method has been used to investigate the concentration of isoniazid in the volunteer's plasma. The quantitative analysis of isoniazid in plasma was not interfered by impurities, the metabolites of isoniazid and the derivatizing reagent residue. This analytical method for isoniazid is sensitive, rapid and convenient. It is suitable for the analysis of toxics in forensic samples, the detection of drug concentration in clinical medicines and pharmacokinetic studies.

This study examined the validity of the Arkansas urine test. One hundred ninety-four adolescents submitted an unannounced urine specimen monthly (for 6 to 8 months). Duplicate specimens were blindly tested with high agreement (kappa >90%). Sensitivity and specificity were estimated. In 68% of test runs, adolescents recalled taking INH within 24 hr of specimen collection. For recall intervals of 24, 48, and 72 hr, sensitivity was 87, 85, and 83%, respectively. Females were less likely to test positive when INH was taken within the previous 24 hr (sensitivity 84 versus 92% males). Specificity was 57, 91, and 95% at 24, 48, and 72 hr, respectively. The Arkansas urine test was practical to use, and results correlated well with self-reported adherence to INH for treatment of latent tuberculosis infection (LTBI), over several months of follow-up. The test may be useful as part of an adherence-monitoring program when used in conjunction with self-reported measures.

The objective of this study was to develop a new simplified method using thin-layer chromatography (TLC) for determining isoniazid (INH) compliance in patients receiving antituberculosis chemotherapy. TLC was performed on silica gel plates using a standard solution of INH and acetylisoniazid (AcINH) and ethyl acetate-methanol (70:30 v/v) as the developing solvent. The spots of compound were detected by iodine. In the human study, fractional urine samples were collected over 24 hours from 4 healthy human subjects genotyped for NAT2* and to whom 400 mg of INH were administered orally. These samples were used for TLC analysis. The results of TLC were compared with those of high-performance liquid chromatography (HPLC). This method indicated good separation between INH and AcINH in standard solutions. The detection limits for INH and AcINH (applied volume; 20 microl of standard solution) were 2.2 nmole and 5 nmole, respectively, as detected by iodine. In the human study, the INH spot in urine was not detected on the TLC plate, except in one sample over the 0- to 4-hour period from 1 volunteer. However, the AcINH spot was detected in all urine samples from all volunteers. The total experimental time from application of the urine sample to analysis on TLC was 30 minutes. The results suggest that this method for detecting AcINH on TLC is an excellent, convenient, and simple method for determining INH compliance in patients receiving standard antituberculosis chemotherapy regimen or INH preventative therapy, regardless of the patient's NAT2* genotype.

Salivary and urinary excretion and plasma-saliva concentration ratios of isoniazid (INH) in the absence and presence of ciprofloxacin (CP) were investigated in healthy female volunteers. Results obtained indicated an absorption form of interaction between INH and CP. This led to delay in gastric emptying and onset of absorption of INH in the upper part of the gastrointestinal tract, resulting in a corresponding delay in the onset of salivary and urinary excretion of the drugs. There was a 1-hour reduction in the time to attain peak saliva concentration of INH (tmax), an insignificant difference in peak saliva concentration (Cmax), and a significant (P = 0.05) increase in AUC(0-24h) of INH in the presence of CP. Cumulative amount of INH excreted in the urine increased approximately 38% in the presence of CP. The calculated plasma-saliva concentration ratios of INH were reduced in the presence of CP and were slightly lower than the experimental values. This indicates increased amount of the drug secreted into saliva in the presence of CP and possible buccal partitioning of the drug. Overall, results of the current study indicate that CP delayed the onset but not the extent of INH absorption. Therefore, concurrent administration of the two drugs was considered relatively safe, and the absorption interaction that may have occurred may not be of reasonable clinical consequence.

Setting: In sub-Saharan Africa, tuberculosis (TB) has increased over the last two decades due to the human immunodeficiency virus pandemic. In Malawi, 20630 new TB patients were notified to the National Tuberculosis Programme in 1996, a fourfold increase since 1986. Due to this increase in cases and lack of resources (both human and monetary) it is becoming more difficult to ensure directly observed treatment (DOT) in the TB wards., Methods: In Ntcheu district, Malawi, a new TB regimen was introduced from April 1996 in which patients received supervised treatment by either a health worker or a guardian (i.e., family member). Adherence to the different treatment options was measured by form checks, tablet counts, and tests for detecting isoniazid in the urine. Adherence was measured at 2, 4 and 8 weeks after onset of TB treatment., Results: Overall adherence rate was 95-96%. Inpatients showed the highest adherence rates. Patients on guardian-based DOT (GB-DOT) (n = 35) showed 94% adherence, while patients on health centre based DOT (n = 40) showed more non-adherent behaviour: 11% according to monitoring forms, 14% according to tablet counts and 16% according to urine tests., Discussion: The results suggest that decentralised care is a feasible option for anti-tuberculosis treatment and that guardians can supervise TB treatment just as well as health workers during the intensive phase of TB treatment.

Setting: The perceived need for simple, non-invasive methods of assessing the relative bioavailability of rifampicin in fixed-dose combination (FDC) anti-tuberculosis formulations., Objective: To compare the performance of methods based on urinary excretion data with those utilising plasma concentration-time profiles to assess the relative bioavailability of rifampicin in combined and single-drug formulations., Design: A two-period randomised crossover bioequivalence study in healthy male volunteers with a 1 week washout period between treatments. Plasma rifampicin concentrations were measured at 0, 1, 2, 4, 6 and 8 hours after each drug administration using a high performance liquid chromatography (HPLC) method. The rifampicin and desacetylrifampicin content of complete urinary collections made from 0-4 and 4-8 hours after dosage were determined using both the HPLC and a much simpler colorimetric procedure., Results: There was good agreement between the relative bioavailability of the formulations using plasma and urinary excretion data, although the precision of the urinary-based estimates was slightly less than those derived from the plasma findings. There was also good agreement between the HPLC and colorimetric estimates of the combined urinary excretion of rifampicin plus desacetylrifampicin., Conclusions: Urinary excretion data may be used for ongoing quality control to confirm that commercial combined rifampicin-containing formulations that were initially shown to be satisfactory continue to be so.

An improved high-voltage electric field isolating joint and small detection cell have been carefully designed and fabricated. The joint possesses short steady time, high electric conductance efficiency and high performance. The cell is convenient to install and remove the capillaries with and without the joint, as well as to fix, adjust and insert the microelectrode into the detection capillary. Using the joint and the cell, an analytical method for determination of ofloxacin (Oflx) and pasiniazid (Ipa) in urine by capillary electrophoresis with on-column amperometric detection was developed. The calibration lines were linear in the range of 10-100 mg l-1 of Oflx and 1.0-50 mg l-1 of Ipa, respectively. The detection limits were 8.5 mg l-1 of Oflx and 0.80 mg l-1 of Ipa. Their recovery ranged from 101 to 104%. The accuracy and intra-day and inter-day reproducibility of Oflx and Ipa were determined with satisfactory results. This method was successfully used for determining Oflx and Ipa in human urine.

The effects of pefloxacin (PFC), a fluoroquinolone antibiotic, on the urinary and salivary concentrations of Isoniazid (INH) were investigated in six healthy female volunteers 19 to 30 years of age. The presence of PFC increased the rate and extent of INH absorption and the rate of its excretion in the urine and saliva. There was an increase in the excretion rate constant (K) and a reduction in the half-life (t1/2) of INH in the presence of PFC. Four of the volunteers had t(1/2) values in the range of 1.55 to 2.43 hours and were considered to be fast acetylators, whereas two subjects with a t(1/2) in the range of 3.36 to 4.41 hours were considered to be slow acetylators. Concurrent administration of INH and PFC may lead to an increased INH toxicity based on the results of the present study.

Setting: The present study assesses bioavailability indices for rifampicin, isoniazid and pyrazinamide when administered to healthy volunteers separately or in a fixed triple-drug formulation, Rifater 125 SCT., Objective: To compare the pharmacokinetics of rifampicin, isoniazid and pyrazinamide based on their blood concentrations up to 12 hours with the proportions of the doses of the drugs and their metabolites excreted in urine up to 12 hours, and to assess the bioavailability indices for the free and fixed triple drug formulations., Design: An open cross-over study was conducted in 18 healthy volunteers with normal hepatic and renal functions to whom the drug combinations were administered in free and fixed dose formulations a week apart, to the same subject., Results: Concentrations of the three drugs/metabolites were assessed in blood and urine. The results indicated the absence of negative pharmacokinetic interactions between the drugs when administered in both the free and the new fixed triple drug formulation., Conclusion: Human bioavailability studies provide direct straightforward information, particularly when studying compounds such as rifampicin and other major anti-tuberculosis drugs. The results of the present study indicate that the pharmacokinetic properties of rifampicin, isoniazid and pyrazinamide as assessed after individual and combined administration do not change when combined in a single pharmaceutical preparation. The bioavailability indices calculated based on plasma concentrations and urinary levels for all three drugs compared well.

Separation and determination of capreomycin (Cp), ofloxacin (Oflx) and pasiniazide (Ipa) in urine by high-performance capillary electrophoresis (HPCE) with 280 nm detection have been studied systematically. The calibration lines were linear in the range of 0.5 approximately 50 mg 1(-1), and the detection limits (S/N = 3) were 0.15, 0.20 and 0.10 mg 1(-1) for Cp, Oflx and Ipa, respectively. The recoveries for these materials from urine were higher than 93.5%. The accuracy and intra- and inter- day reproducibility of Cp, Oflx and Ipa were determined with satisfactory results. This method was successfully used for determining Cp. Oflx and Ipa in human urine.

The effects of drug concentration in internal aqueous phase of stabilized w/o/w emulsion and additives in oleaginous phase on release characteristics of isoniazid were investigated. The release was significantly effected by both of the formulation variables. The release was enhanced initially with increasing concentration of drug in internal aqueous phase followed by a steady release at high concentration of isoniazid. The release declined substantially in the presence of aluminum tristearate, cetostearyl alcohol, and cholesterol, and it increased with egg lecithin and oleic acid in oily phase. The bioavailability was increased with a multiple-emulsion formulation.

Compliance with tuberculosis preventive therapy in a randomized placebo-controlled trial in 2736 HIV-infected Ugandans was measured using urinary isoniazid metabolite testing, clinic attendance, and self-report. Overall, 77% of urine tests were positive, subjects kept 85% of their scheduled visits while on therapy, and 69% reportedly never forgot to take their medication. Different strategies were used for constructing three composite compliance indices in active arms: (1) an unweighted index of the summed scores on scaled compliance measures; (2) a weighted index using weights obtained from a survey of experts on tuberculosis; and (3) a statistically weighted index using principal components analysis. Composite indices were evaluated for reliability, validity, and practical utility. Understanding of the regimen, study arm, subsequent follow-up, tuberculosis status, and urine spot-check result were associated with composite compliance scores. The unweighted index in this study performed as well as the weighted indices.

Aim: To determine the prevalence of non-compliance with tuberculosis treatment at Freegold Mines., Objectives: 1. To establish the rates of attendance and collection of anti-tuberculosis drugs. 2. To determine prevalence of non-compliance by means of urine tests., Design: A cross-sectional study conducted over 2 weeks at mine medical stations., Method: Urine samples were collected from tuberculosis patients 3 hours after drug ingestion. Non-compliance was established by testing these samples for rifampicin and/or isoniazid (INH) metabolites. Non-compliance was defined as a negative urine test result for these drugs in participants whose treatment regimens included one or both. Daily attendance and collection of drugs statistics are recorded in the medical station tuberculosis register. The patient rate of adherence was calculated as the observed number of days on which medication had been collected over the expected treatment days in a given period., Results: Urine test results showed an overall prevalence of non-compliance of 14.6 +/- 3.3%. The study showed that non-compliance with tuberculosis treatment was underestimated by the surveillance data. The rate of non-adherence with treatment established from the formal surveillance procedure was 0.2%. The poor response rate of patients was found to be a major problem and fewer than 40% per day returned to bring urine specimens. The mean prevalences of non-compliance established by rifampicin and INH tests were 19.5 +/- 5.3% and 9.8 +/- 3.9%, respectively, and these were significantly different (Chi 2 = 7.44; P < 0.05). The proportion of false-positive results for INH and rifampicin urine tests were 21% (11/53) and 35% (17/48), respectively, showing that some patients were taking the wrong treatment., Conclusions: It is clear that attendance at the clinics does not accurately reflect compliance. Both programme compliance (dispensing of the correct treatment) and patient compliance need to be improved. This has important implications for the new national tuberculosis control policy adopted by the South African government that stresses the importance of directly observed therapy, short-course (DOTS) and a patient-centred approach.