Correspondence

Malabsorption of Antimycobacterial Medications

N Engl J Med 1993; 329:1122-1123October 7, 1993

Article

To the Editor:

Malabsorption of antimycobacterial drugs has been reported in one person with AIDS coinfected with Mycobacterium tuberculosis and 26 patients with AIDS coinfected with M. avium complex1-3. We report an additional 32 instances of drug malabsorption in people with AIDS, all but one of whom had tuberculosis.

We reviewed the serum concentrations of antimycobacterial drugs in all samples submitted to our laboratory between January 1 and July 31, 1993 (approximately 1100 assays). Serum concentrations were determined primarily by high-performance liquid chromatography or gas chromatography. All assays were extensively validated and were specific for the drugs of interest in the presence of the various other drugs commonly taken by people with AIDS. Normal ranges were established on the basis of values in the literature, pharmacokinetic studies, and more than four years of clinical experience. Quality control was routinely performed. All assay values more than 10 percent below the normal ranges for concentrations measured two hours after a dose were tabulated according to patient. Health care workers provided the time of the dose and the blood drawing for all samples.

Many patients were prospectively monitored for possible malabsorption. Others were monitored when they had no clinical and bacteriologic responses to appropriate treatment. Samples were sent from medical centers around the country. There was no way to derive incidence data from review of these samples. Several of the 31 patients with human immunodeficiency virus (HIV) and M. tuberculosis coinfections had multidrug-resistant isolates of M. tuberculosis. One patient was infected with M. haemophilum. Patients' serum concentrations were below the expected ranges for the following 10 drugs: ciprofloxacin, clofazimine, cycloserine, ethambutol, ethionamide, isoniazid, ofloxacin, aminosalicylic acid, pyrazinamide, and rifampin4. To our knowledge, all doses of aminosalicylic acid were given as standard tablets, not as granules of a new drug (Paser granules, Jacobus Pharmaceutical, Princeton, N.J.).

Most of the serum concentrations in these patients (74 of 105 measurements, or 70 percent) were below normal. In particular, 19 of 20 measurements of rifampin and 12 of 17 measurements of ethambutol were below normal. Between one and seven drugs were assayed per patient. In each patient, a median of 75 percent of the drugs tested were malabsorbed. Malabsorption of a particular drug did not indicate whether other drugs would be malabsorbed.

We are determining the patient characteristics associated with an increased risk of malabsorption of antimycobacterial drugs. Given the nearly uniform occurrence of malabsorption in the study of patients with AIDS who were infected with M. avium complex, low CD4 counts may be one marker for malabsorption2,3. We do not know whether this is true for patients with AIDS who are infected with M. tuberculosis. Prospective trials should define the scope and clinical impact of this problem and the potential need for intravenous antimycobacterial regimens. Second-line antimycobacterial drugs, such as cycloserine and ethionamide, are far less potent than isoniazid and rifampin. Therefore, patients being treated for multidrug-resistant tuberculosis may be at particular risk for poor therapeutic responses if drug malabsorption occurs1. In addition, absorption of only one drug in a multidrug regimen may select for further drug resistance. Drug malabsorption should be suspected in patients who adhere to therapy, but who fail to respond appropriately. Patients with HIV and coinfection with M. tuberculosis should be screened for drug malabsorption before treatment failure, because of the potentially severe consequences of such failure5.

Charles A. Peloquin, Pharm.D.
Allan A. MacPhee, Ph.D.
Shaun E. Berning, Pharm.D.
National Jewish Center for Immunology and Respiratory Medicine, Denver, CO 80206

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   David P Holland, Carol D Hamilton, Amy C Weintrob, John J Engemann, Ellen R Fortenberry, Charles A Peloquin, Jason E Stout. (2009) Therapeutic Drug Monitoring of Antimycobacterial Drugs in Patients with Both Tuberculosis and Advanced Human Immunodeficiency Virus Infection. Pharmacotherapy 29:5, 503-510
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