John A. Sbarbaro

A 62-Dose, 6-Month Therapy for Pulmonary and Extrapulmonary Tuberculosis: A Twice-Weekly, Directly Observed, and Cost-Effective Regimen

STUDY OBJECTIVEnTo evaluate the efficacy and toxicity of a 62-dose, four-drug, 6-month, and directly observed regimen for treatment of pulmonary and extrapulmonary tuberculosis.nnnDESIGNnAn open, nonblinded clinical trial, with intended follow-up of patients for 36 months after the completion of therapy.nnnSETTINGnA metropolitan tuberculosis clinic in a public health department.nnnPATIENTSnFrom March 1981 through April 1989, we enrolled 160 patients with suspected or known tuberculosis; 35 of these patients were excluded from the analysis.nnnINTERVENTIONSnIsoniazid, rifampin, pyrazinamide, and streptomycin were administered daily for 2 weeks; these drugs were then given in higher doses twice weekly for 6 weeks, followed by isoniazid and rifampin twice weekly for 6 weeks, followed by isoniazid and rifampin twice weekly for 18 weeks. A total of 62 doses were administered, and all therapy was directly observed by a nurse or an outreach worker.nnnMEASUREMENTS AND MAIN RESULTSnOf the 125 evaluable patients, 101 (81%) had pulmonary tuberculosis, 7 (6%) had both pulmonary and extrapulmonary involvement, and 17 (13%) had extrapulmonary disease only. Seventy-one (57%) patients had a history of recent alcoholism. There were two relapses (1.6% +/- 2.2%), occurring 6 and 56 months after the completion of therapy. The time at which sputum samples became culture negative in pulmonary patients ranged from 1 to 19 weeks (median, 4.6 weeks); 40% +/- 9.6% of patients were culture-negative after 4 weeks of therapy, 75% +/- 8.5% after 8 weeks, 94% +/- 4.7% after 12 weeks, 97% +/- 3.3% after 16 weeks, and 100% after 20 weeks. Adverse drug reactions included hyperuricemia (greater than 178 mumol/L [3 mg/dL] above normal) secondary to pyrazinamide in 80 patients (64%), twofold or greater elevations of aspartate aminotransferase in 21 patients (17%), 1.5-fold or greater elevations of alkaline phosphatase in 33 patients (27%), cutaneous abnormalities in 8 patients (6%), nausea in five patients (4%), and dizziness in 1 patient (1%).nnnCONCLUSIONSnThis 62-dose, largely twice-weekly tuberculosis treatment regimen is efficacious and relatively nontoxic and is especially useful for patients in whom directly observed therapy is indicated.

Promoting adherence to treatment for tuberculosis: the importance of direct observation

Since 1993, WHO has recommended a strategy through which national governments can meet their responsibility to treat patients and to prevent the spread of tuberculosis (TB). Four of the major elements of the strategy, which came to be known as DOTS, were political commitment by governments, improved laboratory services, a continuous supply of good-quality drugs, and a reporting system to document the progress (and failure) of treatment for individual patients and of the programme. The fifth element, effective case management via direct observation of treatment by an independent and trained third party, was a response to decades of reports documenting the failure of patients to complete treatment. Put simply: direct observation of treatment is an integral and essential component of DOTS. WHO has reported that more than 30 million patients with TB have been treated with its five-element DOTS strategy, resulting in cure rates of > 80% and default rates of < 10%. 1 WHO’s recently announced Global Plan to Stop TB highlights the need to expand DOTS through “standardized treatment, under proper case management conditions, including directly observed treatment to reduce the risk of acquiring drug resistance, and support of patients to increase adherence to treatment and chance of cure”. 2 However, the value of the direct observation component of DOTS has been questioned in a recent systematic review, in which it was suggested that direct observation of treatment is unnecessary and disrespectful of patients. 3 Both self-administered treatment and treatment observation by a family member have been proposed as acceptable alternatives. We challenge the validity of these assertions.

Can We Influence Prescribing Patterns

A variety of programming techniques and methods of training have been employed to change physician behavior. Didactic continuing medical education lectures and clinical guidelines have had minimal impact, although endorsement of national professional guidelines by local opinion leaders appears to have a positive influence on the impact of professional guidelines. Interactive, hands-on workshops, performance reporting, and peer/patient feedback are also effective. Changing prescribing habits has been equally difficult. Drug utilization letters involving both pharmacist and physician have more impact than do letters sent only to the physician. Academic detailing, when properly executed, has been consistently effective. When combined with these strategies, closed formularies become a powerful tool in changing prescribing behavior.