MULTIPLE RETREATMENT DRUG REGIMENS FOR PULMONARY TUBERCULOSIS*

Robert F. Johnston, H. William Harris, Ralph A. Knight, Alfred Dufour and John B. Waller, Jr.

Department of Medicine, Woman’s Medical College of Pennsylvania and the Henry R . Landis State Hospital for

Tuberculosis, Philadelphia, Pa.

This is a preliminary report of our experience with multiple “retreatment” drug regimens, utilizing single daily doses of each drug in patients with far- advanced pulmonary tuberculosis and organisms resistant to primary drugs. The drug regimens were designed so as to expose the population of tubercle bacilli simultaneously to “peak” concentrations of antituberculous agents. Most of the patients in this study received ethambutol. TABLE 1 outlines the purpose and plan of the study. Extensive use was made of drug susceptibility tests in order to find the most effective program for each patient. All drugs were given in single daily doses and in a time sequence so the peak drug levels of each would occur simultaneously. Usually this was accomplished by giving the parenteral drug two hours after the entire daily dose of oral drugs had been administered.

TABLE 2 indicates the duration, extent and bacterial drug resistance of the caws treated. In all patients, the disease was cavitary and far advanced, and in 14 of 15 the organisms showed some degree of isoniazid resistance.

TABLE 3 shows the treatment regimens used. The number is large, for in each case an effort was made to select drugs which on the basis of history and laboratory studies seemed most appropriate. There were 14 different regimens, 12 of these containing 3 drugs. Ten of the 14 regimens contained ethambutol, 7 ethionamide and 6 kanamycin.

FIGURE 1 indicates the current bacteriologic status of the study patients. At the initiation of treatment, all were repeatedly positive by culture. After four months of treatment, 27 per cent remained positive. Ten patients have now been followed for nine months or longer and seven (70 per cent) remained negative by culture.

TABLE 4 summarizes the toxic drug reactions encountered. I n the 14 pa- tients receiving ethambutol, we have detected no toxicity. All received 25 mg./ kg. for a t least six months before the dose was reduced to 15 mg.1 kg. One patient became pregnant while receiving 25 mg./ kg. When the pregnancy was discovered a t the end of the third month, the dose was reduced to 15 mg./kg. A male infant has recently been delivered which on initial examination ap- pears normal. An additional 17 patients not reported in this paper have received ethambutol for four months or less and have evidenced no definite

*Supported in part by United States Public Health Service Grant AI-05311 83 1

832 Annals New Y ork Academy of Sciences

TABLE 1 RETREATMENT PROTOCOL

Purpose: Design retreatment regimens to expose tubercle bacilli simultaneously to “peak” concentrations of antituberculous drugs.

Plan: 1. Select patients with positive sputum whohdve either failed to respond o r have demonstrated in vitvo resistance to primary drugs.

2. Perform complete drug susceptibility tests.

3. Choose retreatment drug regimenby utilizing history and results of susceptibility tests.

4. Determine time of occurrence of “peak” blood level after administration of each drug.

5. Give drugs so that “peak” level of each drug occurs at the same time.

TABLE 2 DURATION, EXTENT AND DRUG RESISTANCE OF TREATED CASES

AVERAGE DURATION . . . . . . . . . . . . . . . 7.9 YEARS.

MEDIAN DURATION. . . . . . . . . . . . . . . . . 9 YEARS.

EXTENT OF DISEASE . . . . . . . . . . . . . . . 15/15 FAR-ADVANCED.

DRUG RESISTANCE

ISOMAZID RESISTANT. . . . . . . . . . . . .14/15 STREPTOMYCIN RESISTANT . . . . . . . . 6/15 PARA-AMINOSALICYLATE RESISTANT. .12/15

TABLE 3 DRUG REGIMENS

EMB-ETA-KM EMB-CS-VM E MB-INH-KM EMB-CS-SM EMB-CS-KM EMB-CS-ETA EMB-PZA-KM ETA-INH-KM EMB-KM ETA-PAS-VM EMB-ETA-VM ETA-CS-SM EMB-INH-VM ETA-SM

14 Di ffe Yen t Regimens

12/14 3 DRUGS 10/14 EMB

7/14 ETA 6/14 KM

Johnston et al.: Multiple Retreatment Drug Regimens 833

834 Annals New Y ork Academy of Sciences

TABLE 4 DRUG TOXICITY

Dmg Reaction

EMB.. . . . . . . . . 0/14 KM. . . . . . . . . . . 6/10 Hearing loss by audiometry.

2/10 Significant hearing loss. l O / l O Pain and induration at injection site.

ETA. . . . . . . . . . 6/10 Anorexia, nausea. VM. . . . . . . . . . . 1/4 Hearing loss by audiometry CS.. . . . . . . . . . 0/5 SM . . . . . . . . . . . 0/4 INH . . . . . . . . . . 0/3 P Z A . . . . . . . . . . 0/1 P A S . . . . . . . . . . 0/1

toxicity. Another patient has received 1200 grams of ethambutol over a two year period without toxicity. Six of ten patients receiving kanamycin in doses ranging from 0.5 to 1.0 grams per day showed hearing loss by audiometry. In two of these, the loss appeared to be clinically significant. All receiving kanamycin have complained of pain and induration at the injection sites. Six of ten patients receiving ethionamide noted anorexia and nausea, but it has been necessary to stop the drug in only one case. One of four patients receiving viomycin 0.5 grams daily had hearing loss by audiometry.

In summary, preliminary results indicate that multiple drug retreatment regimens utilizing single daily doses of drugs are effective in the treatment of tuberculosis resistant to the primary drugs. We have encountered no toxicity with ethambutol but are not able to assess its therapeutic effectiveness spe- cifically from this study.