CHEMOTHERAPY OF MILIARY TUBERCULOSIS AND TUBERCULOUS MENINGITIS

Abstract

Two combinations of drugs were compared in a cooperative study of 32 children with acute hematogenous miliary tuberculosis treated at seven different pediatric centers under a common protocol. Eighteen children were given intramuscular streptomycin with oral para-aminosalicylic acid and promizole®; 14 children were given streptomycin and para-aminosalicylic acid without promizole®. A one year follow-up of this small group showed no significant differences in the results due to the use of promizole®. However, 5 of 10 children treated initially with a streptomycin dose of 20 mg./kg. intramuscularly twice a day were either dead or had developed meningitis, while only 2 of 22 children treated with a 50 mg. dose died, one of these having developed meningitis. Twenty-six of the original 32 patients were alive 12 months after the start of treatment. Relapse of miliary disease was not encountered during the first year of this study. The optimum duration of treatment is still uncertain. The combination of para-aminosalicylic acid with streptomycin may be assumed to delay the emergence of streptomycin-resistant organisms in miliary and meningeal diseases just as it does in pulmonary tuberculosis. Thus, a six month or even one year course of streptomycin can now be considered feasible. Although some patients may have been treated longer than necessary, the observation that three patients developed meningitis at 110, 125 and 130 days of study suggests that treatment should be relatively long. A child who survives miliary tuberculosis only to develop tuberculous meningitis has received little real benefit from therapy. As the over-all mortality in miliary tuberculosis is lowered, the prevention of meningitis in the survivors becomes an increasingly important goal. Disturbing side effects of promizole® therapy were less frequent among the patients reported here than among other reported groups. The daily dose, however, was small in comparison with the amounts recommended by Lincoln. Ninety-three children with tuberculous meningitis, 23 of whom also had miliary tuberculosis, were observed for a period of one year while under treatment with a combination of tuberculostatic agents. Half the patients were given intramuscular streptomycin, intrathecal streptomycin, and para-aminosalicylic acid and promizole® by mouth. The remainder received an identical regimen except that promizole® was omitted. Forty-two patients (45%) survived the first year; 24 of these had no serious sequelae from the disease. No differences were noted in the course of the disease among those who received promizole® and those who did not, and the one year survival rates in the two groups were practically identical. Revision of the streptomycin dosage, which took place after the study had been in progress seven months, produced results which appear to justify the change. An intramuscular streptomycin dose of 50 mg./kg. twice daily to a maximum of 1.5 gm. twice daily was apparently more effective than 20 mg./kg. twice daily. Lincoln whose results in childhood meningitis are the most successful yet reported and the British Medical Research Council both depend on a regimen which includes intrathecal streptomycin. The investigators in this study favor its use and had no unusual difficulty with it. Relapse occurred in eight children, all of whom survived the first year. A poorer prognosis was noted in infants, in nonwhites, and in patients with miliary tuberculosis. The most common toxic effects were due to streptomycin, which caused vestibular damage in a large number of patients, but the capacity of children to compensate for this dysfunction is so great that this risk is minor in the face of the otherwise hopeless outcome. Streptomycin may have been partially responsible for marked hearing loss in six. Para-aminosalicylic acid and promizole® act less rapidly than streptomycin. They are easily administered and rarely produce significant toxicity even when given over extended periods. They appear to reinforce the effect of streptomycin, and para-aminosalicylic acid at least postpones the emergence of streptomycin resistance. Their use appears to decrease the likelihood of relapse. Finally, their daily use at home maintains the patient's awareness that he requires prolonged medical supervision and brings him back for examination when his drug supply needs replenishing. The use of these drugs with streptomycin in tuberculous meningitis is recommended.