A neglected research approach to prevent acquired drug resistance when treating new tuberculosis patients.

The occurrence of significant drug resistance in many countries, coupled with known problems in delivering directly observed therapy (DOT), calls for a re-examination of tuberculosis (TB) treatment delivery strategies. Electronic medication monitors, devices that determine when medication is removed from containers, and videophone-based strategies are being introduced to determine if they can effectively differentiate 1) patients who are adequately adherent to self-administered treatment (SAT), 2) less reliable patients who could be successfully treated with SAT if given more intensive counseling and 3) patients who require DOT. The adherence record could be used in deciding on compensatory longer treatment when poor adherence occurs. The time saved not giving DOT to all patients could be used to retrieve defaulters. Together these components constitute a monitor-based strategy. The program could be extended to supervise the adherence of private patients to medication provided by trained and subsidized pharmacies with the physicians or, when necessary, health departments managing poorly adherent patients. When patients move, the device could transfer essential data to the new care giver. To obtain optimal results, the requirements for the best possible devices and procedures for dealing with poor adherence need to be carefully evaluated.

Preventing drug-resistant tuberculosis with a fixed dose combination of isoniazid and rifampin.

SETTING: Los Angeles County Department of Health Services. OBJECTIVE: To determine how well a self-administered fixed dose combination of isoniazid and rifampin (CombinedHR) prevents acquired drug resistance to Mycobacterium tuberculosis despite treatment interruptions. DESIGN: Self-administered CombinedHR was given to approximately 75% of patients and directly observed therapy or separate drugs to 25%. Three quarters of the patients completed the prescribed treatment. We determined 1) how many patients had two drug-susceptible cultures 3 or more months apart as a measure of drug-susceptible failure or relapse, 2) how many patients whose initial culture was drug-susceptible had a subsequent drug-resistant culture as a measure of acquired drug resistance, and 3) what treatment regimen was taken by each patient who developed acquired drug resistance. RESULTS: Among 5337 drug-susceptible tuberculosis patients who were known or presumed to be human immunodeficiency virus (HIV) negative, 152 (2.84%) treatment failures or relapses occurred, of which 25 (0.47%) developed acquired drug resistance. Among approximately 4000 cases taking CombinedHR and primarily CombinedHR, drug resistance occurred in only eight cases (0.2%), and a total of 12 cases (0.3%) when patients with indeterminate treatment histories were added. CONCLUSIONS: Treatment with self-administered CombinedHR results in minimal acquired drug resistance in HIV-seronegative tuberculosis cases despite modest rates of incomplete treatment.

Managing medication compliance of tuberculosis patients in Haiti with medication monitors.

SETTING: A tuberculosis clinic in Haiti using self-administered medication. OBJECTIVE: To determine if medication monitors could be used along with directly observed therapy in developing countries to help solve the problem of compliance with medication. DESIGN: Patients were randomized into three groups: Group A took medication from medication monitors and were given counseling based on the monitor record; Group B took medication from medication monitors, but the record was not available for counseling; and Group C took medication from simple containers. RESULTS: Good monitor records in the first 11 weeks predicted less default from treatment (P < 0.01), and better compliance (P < 0.01) in the last 9 months. Counseling based on the monitor record appeared to reduce treatment abandonment by about half. CONCLUSION: This study suggests that medication monitoring of self administered treatment would be useful in settings where directly observed therapy cannot be delivered for the entire duration of treatment, especially in rural areas, by 1) identifying poor compliance early in therapy, 2) reducing the frequency of clinic visits for patients with good monitor records who live excessive distances from the clinic, 3) counseling patients about their monitor record to improve treatment completion rates, and 4) lengthening the duration of therapy when poor compliance is found.

Medication monitors to treat tuberculosis. A supplement to directly observed therapy.

The use of directly observed therapy (DOT) for nearly all cases of pulmonary tuberculosis (TB) is being widely promoted by the Centers for Disease Control, but its implementation is being resisted by many health professionals. Consequently, less than half of the patients in major metropolitan health departments were given DOT in 1996. The usual justification for "universal" DOT instead of selective DOT is the well-known difficulty in differentiating between patients who are reliable in taking medication from those who are not. Devices called medication monitors, which record when medication is removed from a container, were shown to be effective in determining the reliability of TB patients in taking medication in the 1960s but were cumbersome to use. Since then several improved, convenient to use, electronic medication monitors have been introduced and further improvements can be anticipated. These increasingly practical medication monitors need to be studied as a supplement to DOT in order to make selective DOT an effective alternative to "universal" DOT in managing the medication compliance problem when treating TB.

Fixed-dose combinations of antituberculous medications to prevent drug resistance.

The treatment of tuberculosis requires at least two drugs to retard the development of drug resistance. Unfortunately, patients may take only one drug (monotherapy) when more than one is prescribed. Fixed-dose combinations with two or more antituberculous drugs in one capsule or tablet are available to prevent this. In the United States, these drugs are Rifamate (Marion Merrell Dow), which contains isoniazid plus rifampin, and Rifater (Marion Merrell Dow), which contains isoniazid plus rifampin and pyrazinamide. Because these preparations make monotherapy impossible, they are clearly preferable to individual drugs. In the United States in 1993, however, only 15% to 18% of rifampin was sold in the form of fixed-dose combinations. To correct this deficiency, fixed-dose combinations should be widely promoted and accepted as a primary way to prevent drug-resistant tuberculosis. There are two caveats regarding these preparations. First, many fixed-dose combinations, especially those in developing countries, achieve inadequate blood levels of one or more of the component drugs, especially rifampin. Our recommendations apply only to preparations with proven bioavailability. Second, because the name Rifamate is similar to the name rifampin, mistakes in prescribing and dispensing can result in the patient receiving rifampin alone when Rifamate is intended. A name change from Rifamate to a highly distinctive name such as Rif-Isoniazid is needed to prevent such occurrences.

Twenty isoniazid-associated deaths in one state.

Twenty deaths from isoniazid-associated hepatitis are known to have occurred in California over a 14-yr period in persons ranging in age from 5 to 73 yr. Because no comprehensive survey was carried out, more such deaths probably occurred. With one exception, the patients were not seen or contacted monthly throughout the course of treatment. However, in 16 patients where the information was known, eight were seen by a member of the group giving the isoniazid (INH) within 30 days prior to the patients presenting with hepatitis. In 12 of 17 cases, symptoms were present for 7 days or more before the patient presented for medical care. In at least 35% of cases where the information was known, a management error occurred, usually failing to immediately stop INH when the patient presented with symptoms. The duration of treatment before hepatitis developed varied from 9 to 53 wk. Four of the 20 patients had cholelithiasis or a history of cholelithiasis. With one possible exception, no excessive alcohol use was noted. Concomitant acetaminophen, barbiturate, and tetracycline use occurred in several cases. There were no deaths in Orientals. Sixteen of the 20 deaths occurred in women who had started to receive INH between the ages of 15 and 55. Four of these women began receiving INH during pregnancy and continued it postpartum. Eight deaths occurred in persons starting INH before 35 yr of age. The continued occurrence of INH-associated deaths suggests that indications and precautions for INH preventive treatment be carefully reconsidered.

Treatment of disease due to Mycobacterium intracellulare.

During eleven and one-half years, 122 patients with M. intracellulare disease were treated at National Jewish Hospital and Research Center, Denver, Colorado. Of the 81 patients treated with multiple drug chemotherapy, 63 (78%) were considered to be treatment successes. On follow-up (averaging 55 months) 40 of the 63 patients had remained clinically stable or improved and 12 had grown worse. Ten of these 63 patients had relapsed. Of the 63 patients considered to be treatment successes, 23 (36.5%) had died during follow-up, mostly of pulmonary disease. Of the 18 patients who failed to respond to chemotherapy, 2 were later successfully treated with surgery, 5 patients were clinically worsening, and 8 (44%) had died during a follow-up period averaging 43 months. A group of 41 patients had indeterminate results with chemotherapy. Eight had died while in the hospital. Follow-up information after an average of 43 months indicated that 9 patients became treatment successes (5 with chemotherapy, 4 with surgery), 12 were clinically stable or improving, and an additional 13 had died for a total of 21 deaths (51%). The overall success of treatment in the 122 patients was 61%. Fifty-two (43%) died during the study. Many patients will respond to drug therapy and remain clinically well for years. Because of the potential seriousness of this disease in some patients, multiple drug chemotherapy should be used.

Should isoniazid be used in retreatment of tuberculosis despite acquired isoniazid resistance?

The use of high-dose isoniazid in retreatment regimens for tuberculosis, despite acquired isoniazid resistance, could possibly improve therapeutic results if all or part of the organisms were resistant to only low concentrations of that drug. Furthermore, organisms resistant to low concentrations of isoniazid have been shown, on occasion, to be resistant to 2 of the retreatment drugs, ethionamide and pyrazinamide, whereas higher degrees of isoniazid resistance are associated with susceptibility to these drugs. Use of high-dose isoniazid might improve results in retreatment with ethionamide and pyrazinamide by eliminating any organisms with low degrees of isoniazid resistance that have associated ethionamide and pyrazinamide resistance. Two clinical trials concerning this topic have been reported. A controlled retreatment trial with various combinations of ethionamide, cycloserine, and pyrazinamide with and without conventional "low" doses of isoniazid (300 mg per day) showed no benefit when isoniazid was added. However, a noncontrolled trial using ethionamide and pyrazinamide with and without high doses of isoniazid, 1 to 1.5 g per day, showed marked benefit with the added isoniazid. In view of these conflicting data, the use of high-dose isoniazid in retreatment regimens needs further study, which could probably be carried out in the developing countries.