INH Prophylaxis Research Articles

Tuberculosis chemoprophylaxis using a liquid isoniazid-methadone admixture for drug users in methadone maintenance.

Tuberculosis is common in drug users, although compliance with therapy may be difficult in this population. To evaluate an approach to enhancing compliance with tuberculosis chemoprophylaxis in drug users enrolled on methadone maintenance utilizing an isoniazid (INH)-methadone admixture. A prospective cohort study. A drug treatment program in New Haven, Connecticut, USA. Opioid-dependent drug users enrolled in methadone maintenance. Liquid isoniazid was mixed into subjects' daily dose of methadone. Vitamin B6 was given to subjects for self-administration. Number of eligible subjects, reasons for not starting therapy, number starting therapy, proportion completing therapy and median duration of INH therapy were calculated. Thirty-nine subjects were eligible for INH chemoprophylaxis: 34 (87%) received INH mixed directly in their methadone and five (13%) had their INH consumption supervised by a nurse. Among these subjects, 72% (28/39) completed therapy. Among the 11 subjects who discontinued INH, discharge from the methadone maintenance program was the most common reason--73% (8/11). Thus, among the 31 subjects who were not discharged from methadone maintenance, 90% (28/31) successfully completed INH prophylaxis. The median duration of therapy was 182 days. Tuberculosis chemoprophylaxis using a liquid isoniazid-methadone admixture appears to be an effective approach to enhancing compliance with this therapy in methadone-maintained drug users.

Tuberculin Test Conversion among Employees of a Tertiary Care Hospital in Riyadh, Saudi Arabia

The objective of this study was to determine the tuberculin skin test conversion rate, as well as the course and outcome of the converters, among employees of a tertiary care hospital. The study is a retrospective, cohort descriptive study undertaken at the King Faisal Specialist Hospital and Research Centre, in Riyadh, Saudi Arabia. The study was undertaken over a four-year period from 1993 to 1996, and the subjects were employees who had annual screening PPD skin tests. The outcome measures skin test conversion, prophylactic treatment with isoniazid (INH), side effects, and development of clinical tuberculosis. A total of 6883 tuberculin skin tests were performed during the study period. The mean annual conversion rate was 1.55%. About 78% of the converters received INH prophylaxis, but only 75% of those who started chemoprophylaxis completed the course. The side effects of INH treatment were found in 23% of those on treatment, and one of the converters developed clinically active tuberculosis during the study period. At the King Faisal Specialist Hospital and Research Centre, the mean annual tuberculin skin test conversion rate among employees is similar to that found in other studies, but compliance to oral isoniazide prophylaxis is low. There is a need to develop strategies to improve compliance.

ISONIAZID DOES NOT AFFECT BIOAVAILABITY OF CYCLOSPORINE IN RENAL TRANSPLANT RECIPIENTS

627 The incidence of tuberculosis is increasing worldwide. Transplant recipients are particularly predisposed to develop tuberculosis and Isoniazid (INH) is used in most anti-tubercular therapeutic and prophylactic protocols. Cyclosporine (CyA) bioavailability increases on concomitant use of drugs that inhibit hepatic cytochrome P-450 enzymes. There are reports expressing concern regarding the use of INH in patients treated concomitantly with CyA. Seven renal transplant recipients receiving CyA (SANDIMMUN NEORAL) in a dose of 3.9-5.7 mg/kg/day and requiring concomitant INH prophylaxis (300 mg/day) against tuberculosis were studied. Acetylation status was assessed before inclusion in the study protocol and only slow acetylators were studied. Whole blood CyA levels at 0,1,2,4,6 and 8 hours of last dose were estimated by RIA on days 0 and 14 of starting INH and total CyA exposure (AUC) and CyA clearance calculated. The pharmacokinetic parameters before and after INH administration are shown in the Table:TableEven after post INH Cmin, Cmax, Tmax, AUCs and CyA clearance values were adjusted for INH levels, the differences in the above pre and post INH parameters did not reach statistical significance. There was also no statistically significant correlation between INH levels and changes in Cmin, Cmax, Tmax. AUCs and CyA clearance before and after administration of INH. There was no significant change in the serum creatinine levels before (1.49±0.49 mg/dl) and after INH administration (1.44±0.53 mg/dl, p>0.05). There were no episodes of CyA toxicity or acute rejection during and upto 4 weeks of starting INH. We conclude that concomitant administration of INH and CyA is safe and is not associated with any appreciable alterations in bioavailability of CyA.

Tuberculosis after renal transplantation: experience of one Turkish centre.

In this study, renal transplant recipients with tuberculosis of different organs, were retrospectively analysed with respect to prevalence, outcome and drug toxicity. In 520 patients, 22 (4.2%) tuberculosis of various organs was diagnosed. The time interval between transplantation and diagnosis of tuberculosis was 44.4 +/- 33.5 (range 3-111) months. In 18 (82%) of the patients, tuberculosis was detected after the first year of transplantation. The most common form was pleuro/pulmonary tuberculosis (54%), and other localizations included jejunum, liver, bone, and urogenital tract. Sixteen of the 22 patients responded favourably to the treatment and maintain excellent allograft function, whereas six patients (27.2%) died. Toxic hepatitis was seen in four (18%) patients, and one case was complicated with acute hepatocellular failure due to isoniazide (INH). However, of the 23 patients at risk of tuberculosis who had had INH prophylaxis for 1 year, neither tuberculosis, nor hepatotoxicity was observed. Tuberculosis is a common infection of renal transplant recipients in developing countries. The peak incidence is after the first year of transplantation and mortality is considerable. Hepatoxicity is a considerable risk of treatment, possibly as a result of additive toxic effects of immunosuppressive drugs.

Tuberculosis infection and anergy in hemodialysis patients.

Patients on hemodialysis are at increased risk for developing active tuberculosis (TB) after primary infection. Although this increased risk is well documented, the prevalence of TB infection, as indicated by a positive tuberculin skin test (TST), is not well described. End-stage renal disease is also known to be a risk factor for skin test anergy, but the rate of anergy in hemodialysis patients is unclear. We sought to identify rates of anergy and TST positivity in patients at four hemodialysis units in St Louis, Missouri, from June 1996 through August 1996. Data obtained from patients and medical records included age, years on hemodialysis, medical history, and basic laboratory data. Patients without a history of TB or a positive TST had a TST with Tubersol, as well as candida and tetanus controls, placed by the Mantoux method. Tests were read 48 hours later. Of the patients enrolled at these units, 307 of 331 (93%) were evaluated. Patients had a mean age of 58 years (range, 19 to 91 years) and had been on hemodialysis for a mean of 3.7 years (range, 1 week to 18.7 years). Blacks made up 81% of the population. A history of a positive TST was obtained from 24 patients (8%), and an additional seven (2%) had a history of active TB. Of the 276 patients tested, 93 did not respond to either control antigen, but five of these patients had a positive TST, leaving 88 (32%) anergic. Anergy was related to age, immunosuppressive drug use, and the reagents used, but not to urea reduction ratio. Positive TSTs were found in 17 of 188 of nonanergic patients (9%) (6% of all tested patients). Overall, 48 of 307 patients (16%) had a positive TST or history of TB. TB or a positive TST was associated with liver disease and peptic ulcer disease, but not socioeconomic status. All 17 newly identified TST-positive patients received chest radiographs. No new cases of active TB were found. Only two of 17 of these patients (12%) were started on isoniazid (INH) prophylaxis. We identified high rates of TST positivity and anergy in the hemodialysis patients tested. Hemodialysis patients should receive regular TST screening, and INH prophylaxis needs to be more strongly encouraged. Studies are ongoing to define the rate of TST conversion over time.

Isoniazid preventive therapy for pulmonary tuberculosis sequelae: Which patients up to which age?

Setting: Preventive therapy with isoniazid (INH) is usually recommended for all patients with pulmonary fibrotic lesions compatible with previous tuberculosis (TB). Objective: To determine the optimal strategy between a 6- to 12-month course of prophylactic INH and therapeutic abstention in different age groups and in patients with severe coexisting diseases that limit life expectancy, such as chronic heart failure (CHF) or chronic obstructive pulmonary disease (COPD). Design: A Markov decision analysis model that balances the risk of developing active TB against TB-related mortality, the risk of INH-related hepatitis, and INH-related death. Results: In all groups of patients, prophylactic INH clearly reduced the number of deaths from TB, whereas very few cases died from INH-related toxicity. However, because INH-related deaths occur early, and TB-related deaths occur early or late, the gain in life expectancy was small. Particularly for patients with short survival such as those older than 80 years and those with CHF or COPD, the average gain in life expectancy provided by prophylactic INH did not exceed one week. Conclusions: Our analysis confirms that prophylactic INH is beneficial to all cohort groups of patients. However, in the case of very old age or severe disease, the gain in life expectancy is minimal. In these cases, the decision to give INH prophylaxis should be tailored on an individual basis with special consideration given to the patient and his environment.

Perspective: Preventive Isoniazid Therapy and the Liver

The preventive use of isoniazid (INH) has been controversial since 1975, but official agencies continue to advocate the procedure. Cost-effectiveness and risk benefit studies of preventive INH use have come to conflicting conclusions. A review of eight such studies indicates an increasing tendency to minimize INH hepatotoxicity and to disregard the declining tuberculosis morbidity and mortality in countries in which INH prophylaxis has not been widely adopted. We report three cases of fatal INH-associated hepatitis that illustrate that this complication of preventive INH use remains a serious problem. Current recommendations that encourage wide use of preventive INH therapy are unwise because they inflict a risk of fatal hepatitis on compliant adults and older children who have little danger of tuberculosis while being difficult to deliver to the alcohol- and drug-addicted persons whose risk is high. Health departments and physicians should severely restrict preventive INH therapy.

Active tuberculosis in children who received INH chemoprophylaxis

Twelve children who developed active tuberculosis even after receiving isoniazid (INH) chemoprophylaxis were seen at Tokyo Metropolitan Children's Hospital from 1982 through 1991. All cases received INH more than 9 mg/kg/day, except for one case in which the amount of INH administered at the referring hospital was unknown and Streptomycin was administered together with INH. The age of starting INH prophylaxis ranged from 2 months to 13 years, and the age at which clinical symptoms and/or laboratory evidences of active tuberculosis were first manifested ranged from 4 months to 18 years. Five patients developed active tuberculosis after the completion of chemoprophylaxis and patients during chemoprophylaxis, with the first presentation ranging from primary complex (seven), chronic pulmonary tuberculosis (two), tuberculous meningitis (two), and tuberculous pleuritis (one). None of the Mycobacterium tuberculosis resistant to INH was isolated. Reviewing these patients, eleven cases had at least one of the following factors: (1) age less than two years old (2) infectious sources expectorated more Mycobacterium tuberculosis (3) delay in starting INH. Above factors should be considered in initiating INH chemoprophylaxis and subsequent follow-up of the patients.

Extraordinary examinations in tuberculous prevalence areas and family contact examinations

A survey was made on the actual state of performance of extraordinary examinations done in high tuberculosis prevalence areas and those of family contact examinations of the index cases of tuberculosis during the period between April 1986 and November 1987 in Chiba Prefecture. The results are as follows: (1) Forty-eight extraordinary examinations were performed by 19 public health centers. (2) By these extraordinary examinations, 22 additional tuberculous patients were detected and 143 persons were indicated INH prophylaxis. There were 2 cases of mass tuberculosis infection: from which 19 patients and 140 persons for chemoprophylaxis were detected. (3) Out of 18 extraordinary examinations done for contacts of cases from danger groups, one was done actually for unnecessary case. As to tuberculin tests, they were not performed in 2 groups, and in another case, the test subjects were inappropriate. (4) The examination rate of family members of index cases was as high as 95.4%, whereas the performance of tuberculin tests was not satisfactory, especially as regards to the younger populations. The total performance rate of the tests was 29.0%, and the rate in those below 19 years of age was 56.5%, and the rate in those below 29 was 42.9%. (5) There were 6 families with tuberculosis, which included 14 patients. It is considered that in extraordinary examinations, appropriate setting of subjects and tuberculin tests for younger persons are important; in family contacts examination, tuberculin tests for younger persons are indispensable.

Mycobacterial Disease: Epidemiology, Diagnosis, Treatment, and Prevention

TB is common in the setting of HIV-induced immunosuppression, especially among demographic groups with a high background prevalence of tuberculous infection. It is often the first (sentinel) infectious disease to appear, extrapulmonary and disseminated disease is common, the chest x-ray picture is frequently atypical, and the tuberculin skin test is often falsely negative. It therefore requires a high index of suspicion and an aggressive diagnostic approach to avoid missing HIV-related tuberculous disease, which is communicable from man to man by the aerosol route and which appears to be highly treatable with conventional anti-TB drugs. Identification and INH prophylaxis of tuberculous-infected, HIV-seropositive persons is likely to be very important in the prevention of tuberculous disease. MAI is also a very common pathogen that frequently produces extrapulmonary and disseminated disease among patients with AIDS. In contrast to TB, AIDS-related MAI disease occurs more uniformly among the AIDS risk groups, occurs late among the HIV-related infections, and is not effectively treated with current drug regimens.

Two-Stage Skin Testing for Tuberculosis in a Domiciliary Population

We scheduled two-stage skin testing for tuberculosis with Candida and mumps controls on 618 residents of our domiciliary unit at the Veterans Administration Medical Center, Johnson City, Tennessee. Of the 618 residents in the unit, 30 (4.8%) were not available for evaluation, 77 (13%) had a prior history of active tuberculosis or positive skin test, and 1 resident refused testing. Of these 510 patients who received first-step testing with purified protein derivative (PPD), 153 (30%) had greater than to 10 mm induration. Those patients with less than 10 mm induration had a repeat PPD 2 wk later. Fifty-nine (19.2%) of the 307 patients who received a second PPD had a booster response. A total of 50.9% of the residents had evidence of tuberculosis exposure by skin testing. There were no differences between patients with significant and nonsignificant reactions when comparing age, length of stay, functional status evaluated by Karnofsky scale, or number of underlying diseases. Second test conversion occurred in 4.3% of those patients who had been in the unit for less than 1 month and in 36% of those who had been residents for a period of 3 to 6 months (p less than 0.05). Regardless of the size of the initial reading, it is important to perform a two-stage PPD in residents of chronic care facilities who have a negative first test. INH prophylaxis should be considered in patients admitted to chronic care facilities such as the domiciliary when they have significant Mantoux reactions.

Tuberculosis screening in alcoholics and drug addicts.

To ascertain the value of screening for tuberculosis in the New York City (NYC) alcoholic and drug abusing welfare population, 2,641 clients were interviewed, and 970 (36.7%) of them met preestablished criteria for alcohol or drug abuse. The prevalence of active tuberculosis was 0.91%, which is 28 times the age-matched NYC rate. Screening only those persons with a positive PPD and a cough substantially increased the yield of active tuberculosis to 7.2%, or 225 times the NYC rate. The prevalence of a positive tuberculin skin test was 32.4%, or 1.5 times greater than the age-matched NYC rate. Treatment or prophylaxis for tuberculosis was required in 128 or 13.2% of the screened population. Seventy thousand NYC welfare clients are routinely evaluated for medical illness each year. This study predicts that in 1 yr this subpopulation could yield 239 clients with active tuberculosis and 3,181 requiring INH prophylaxis. Screening for tuberculosis in the alcoholic and drug abusing welfare clients is therefore urgently recommended.

Severe Febrile Reaction to Isoniazid

A case of severe febrile reaction to INH is described. The patient had a mild febrile reaction two weeks following INH prophylaxis. Isoniazid was discontinued. Two weeks later and on rechallenge with INH she developed a severe febrile reaction with protracted hypotension. An initial mild febrile reaction to INH is a warning sign that rechallenge can result in a life-threatening situation.

Amphotericin--how safe and effective?

Over a period of 35 days beginning July 23, 1984, the Infection Control Section of the Nassau Hospital, a 535-bed community teaching institution received reports of an unusually high number of PPD tuberculin skin test conversions among employees from Employee Health Service personnel.The first case involved a registered nurse who, upon receiving a routine annual Mantoux skin test on July 23, converted from the previous year's negative reaction to a significant reaction (20 mm induration) with a greater than normal area of erythema. When she reported this to her private medical doctor prior to beginning INH prophylaxis, she was retested by the physician. This test was read as nonreactive.

Intentional isoniazid overdosage among southwestern American Indians.

A 30-month study explored the degree to which self-destructive behavior compromised tuberculosis therapy and prophylaxis among southwestern American Indians. The frequency of isoniazid (INH) overdosage paralleled the extent of INH usage in each tribe and the entent to which INH was perscribed for each tuberculosis category. The authors recommend the careful selection of patients for INH prophylaxis, the dispensing of small amounts at short intervals, the close monitoring of patient compliance with the prescribed drug regimen, and, possiblly, the dispensing of individually wrapped tablets to inhibit the impulsive ingestion of massive amounts of the drug.

Newborn Infants of Tuberculous Mothers, Further Comment

In their recent article, Avery and Wolfsdorf discussed INH prophylaxis of infants of tuberculous mothers and stated, "The unusual reactions of infants to many pharmacologic agents, with respect to absorption and excretion, have necessitated great care in matters of dosage and indications in infancy." The Committee on Drugs commented, in the same issue, that the pharmacology of INH has not been systematically studied in the newborn infant. We have been studying the characteristics of the hepatic enzyme which catalyzes the acetylation of INH and sulfonamides.

TUBERCULIN TESTING IN THE YOUNG

The child with a positive tuberculin reaction or uncomplicated primary tuberculosis rarely has symptoms. Since INH prophylaxis for one year will practically always prevent the severe forms of tuberculosis, early diagnosis is essential. An annual or biennial tuberculin test is recommended, and is always indicated when there has been known contact with a tuberculous adult. The Mono-Vacc test is a satisfactory screening device.

Tuberculosis and Pregnancy

As tuberculosis (TB) is prevalent all over the world and affects all ages, its management during pregnancy and lactation is of special importance. It affects the health of both mother and the infants. There are many constraints in the diagnosis of TB in pregnancy including hazards of radiography. Treatment of tuberculosis requires a careful selection of drugs and avoiding agents, which are unsafe during pregnancy. Untreated TB cases risk to both mother and infant. Most of the antituberculosis drugs are secreted in breast milk but the concentrations are sub-therapeutic. INH prophylaxis is a serious consideration for infants born to mothers with active pulmonary TB. Congenital TB, although rare, is a definite entity and needs to be recognized.