Correspondence
Drug Malabsorption and Resistant Tuberculosis in HIV-Infected Patients
N Engl J Med 1995; 332:336-337February 2, 1995
- Article
To the Editor:
Directly observed therapy for tuberculosis has been advocated as a way to improve compliance and control the emergence of drug resistance.1,2 We recently cared for two patients with human immunodeficiency virus (HIV) infection who were receiving therapy under direct observation when they relapsed with drug-resistant isolates of Mycobacterium tuberculosis, presumably due to subtherapeutic drug levels caused by malabsorption.
Patient 1, a 30-year-old man, began receiving directly observed therapy in December 1993; his therapy consisted of isoniazid (300 mg), rifampin (600 mg), and pyrazinamide (800 mg) daily for ileocecal and pulmonary tuberculosis. At that time tuberculosis isolates from sputum and stool were susceptible to all drugs tested. In April 1994, after four months of observed therapy, he was found to have a new cavitary pulmonary lesion. Sputum cultures grew M. tuberculosis resistant to rifampin but still sensitive to isoniazid, pyrazinamide, ethambutol, and streptomycin.
Patient 2, a 51-year-old man, was given a diagnosis of pulmonary tuberculosis in 1993. He received isoniazid (300 mg), rifampin (600 mg), pyrazinamide (1.5 g), and ethambutol (1.5 g) daily under direct supervision in a homeless shelter. After 10 months of continuous therapy, a new right-upper-lobe infiltrate appeared. His initial isolate of M. tuberculosis had been sensitive to all first-line drugs, but in April 1994 an isolate from sputum was resistant to both isoniazid and rifampin, while remaining sensitive to pyrazinamide, ethambutol, and streptomycin.
Serum levels of antimycobacterial drugs from both patients measured two hours after oral administration were assayed at the National Jewish Center for Immunology and Respiratory Medicine.2 The results are shown in Table 1Table 1
Concentrations of Antituberculous Drugs in Two Patients..Serum samples were also obtained from Patient 2 at the time of an oral dose of 600 mg of rifampin and 400 mg of isoniazid at steady state and 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours thereafter. Isoniazid was undetectable in all samples except the one obtained at 2 hours, when the concentration was 0.43 μg per milliliter. Rifampin was undetectable at 0, 0.5, 1, and 1.5 hours; the concentration was 0.42 μg per milliliter at 2 hours, 3.01 μg per milliliter at 4 hours, 1.37 μg per milliliter at 6 hours, 1.07 μg per milliliter at 8 hours, and 0.58 μg per milliliter at 12 hours. The peak rifampin level was seen at 4 hours rather than 2 hours, but it remained subtherapeutic. Patient 1 had no clinical evidence of malabsorption, but Patient 2 had chronic diarrhea and a subnormal result on a D-xylose–absorption test, believed to be due to HIV enteropathy.
Although malabsorption of antituberculous medication has been described in HIV-infected patients,3,4 therapeutic drug monitoring is not widely practiced. These patients could have acquired another strain of M. tuberculosis, 5 but the temporal sequence argues against this, and they had no known contact with patients infected with drug-resistant tuberculosis.
These cases demonstrate that drug malabsorption may contribute to the emergence of acquired drug resistance, as some have theorized.3 In addition to the use of directly observed therapy to ensure compliance, we advocate routine screening of antimycobacterial-drug levels in HIV-infected patients with tuberculosis, particularly those with advanced HIV disease. Still at issue, however, is the timing of such screening relative to dosing, since our data with regard to rifampin suggest that delayed absorption, in addition to malabsorption, may occur in HIV-infected patients.
5 ReferencesKalpana B. Patel, Pharm.D.
Romelle Belmonte, M.D.
Helen M. Crowe, M.D.
Hartford Hospital, Hartford, CT 06102-50371
Initial therapy for tuberculosis in the era of multidrug resistance: recommendations of the Advisory Council for the Elimination of Tuberculosis
Medline2
Weis SE ,Slocum PC ,Blais FX , et al. The effect of directly observed therapy on the rates of drug resistance and relapse in tuberculosis. N Engl J Med 1994;330:1179-1184
Full Text | Web of Science | Medline3
Peloquin CA ,MacPhee AA ,Berning SE . Malabsorption of antimycobacterial medications. N Engl J Med 1993;329:1122-1123
Full Text | Web of Science | Medline4
Berning SE ,Huitt GA ,Iseman MD ,Peloquin CA . Malabsorption of antituberculosis medications by a patient with AIDS. N Engl J Med 1992;327:1817-1818
Full Text | Web of Science | Medline5
Horn DL ,Hewlett D Jr ,Haas WH , et al. Superinfection with rifampin-isoniazid-streptomycin-ethambutol (RISE)-resistant tuberculosis in three patients with AIDS: confirmation by polymerase chain reaction fingerprinting. Ann Intern Med 1994;121:115-116
Web of Science | Medline
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