December 1975
1015
The Journal o f P E D I A T R I C S
Rifampin in tuberculous meningitis
TUBERCULOUS MENINGITIS was a frequent and
invariably fatal disease three decades ago. The average duration of the disease from onset of symptoms to death was 1989 days? With the advent of streptomycin in the late forties it became possible to save a few patients. Administration of streptomycin by the intrathecal route was recommended and as a result deafness occurred in about 50% of the survivors. When isoniazid became available in 1952, the outcome of therapy improved. Streptomycin by the intrathecal route was discontinued, and the incidence of deafness among the survivors decreased sharply. Other neurologic sequelae continued to occur according to the stage of the disease at the onset of treatment. Since 1959 isoniazid has been extensively used as a chemoprophylactic agent among household contacts of tuberculous patients and among children with positive tuberculin reactions. The incidence of tuberculous meningitis in developed countries has diminished to the extent that many recently trained pediatricians have never seen a case. The disease is usually not suspected in its first stage characterized by such nonspecific manifestations as fever, personality changes, and vomiting. Diagnosis is often delayed until the patient has reached the second stage, in which neck rigidity and other neurologic signs appear. Sometimes the diagnosis is not made until the last and the third stage in which the patient becomes comatose. Occasionally the diagnosis is missed while the patient is alive, and he becomes the subject of a clinicopathologic exercise? Each successive stage is associated with increasing mortality and sequelae among survivors. In the Bellevue series of 1952 the mortality rate for patients initially treated in the first stage was only 9.5%; in the second stage it was 26%, and in the third stage it rose to 84%.' These results of therapy of tuberculous meningitis have not changed significantly since 1952. The mortality continues to range between 10 and 50% and the incidence of permanent sequelae continues to be high? Rifampin (Rifampicin, Rifadin, Rimactane) was developed and initially tested in Italy in 1963. Because of its effectiveness against Mycobacterium tuberculosis its usefulness in improving the results of therapy of tubercu-
lous meningitis loomed as an exciting possibility. Ideally, double-blind prQspective studies should have been carried out comparing various regimens in adequate numbers of patients. This was not done for various reasons. Some investigators no longer treated a sufficiently large number of patients with tuberculous meningitis to conduct a properly controlled study; others who treated many patients either did not have the drug available to them or, if they did, were not willing to withhold it from their patients for the sake of a study. Important information about the effectiveness of rifampin in tuberculous meningitis appears in this issue of THE JOURNALin the paper by Visudhiphan and Chiemchanya. They compared patients See related article, p. 983.
treated between 1970 and 1972 with a "standard regimen" (streptomycin 20-40 mg/kg/day, isoniazid 20 mg/kg/day, and para-aminosalicylic acid 250 mg/kg/day) with patients treated between 1972 and 1974 with a "rifampin regimen" (isoniazid 20 mg/kg/day in 2 or 3 doses and rifampin 15 mg/kg/day in one daily dose before breakfast). The setting, characteristics of the patients, and age groups were comparable. The results were superior with the rifampin regimen. Four of the 13 patients in the standard regimen died, whereas only one of the 19 in the rifampin regimen died. Only three patients of the 13 treated with the standard regimen were spared significant neurologic sequelae, while 12 of 19 in the rifampin group were spared and none were deaf. The average duration of hospitalization in the rifampin group was only 3V2 weeks, ie, 589 weeks less than that of the standard regimen. These results cannot be readily explained by chance or bias. Patients with tuberculous meningitis treated with the standard regimen in a given setting respond in a fairly consistent manner. The low case fatality rate and the low incidence of sequelae reported by the investigators from Bangkok in the rifampin-treated patients would ordinarily be expected among patients predominantly diagnosed and treated in the first stage of the disease. The clinical
VoL 87, No. 6, part 1, pp. 1015-1017
1016
Editor's column
characteristics described for the rifampin-treated patients indicate that most were in the second or third stages of tuberculous meningitis. One might ask whether the inferior results obtained with the standard regimen could have been related to a high prevalence of primary isoniazid resistance in Thailand. This is a possibility which cannot be ruled out. But a high prevalence of isoniazid resistance should have had an adverse effect upon both groups. It might also be asked whether the two groups had comparable degrees of tuberculin allergy, nutrition, and other tuberculous or nontuberculous disease. All the answers are not available. Superior results with rifampin-isoniazid therapy can be explained by the known antimicrobial effectiveness of the combination." One might also speculate that the immunosuppressive effects of rifampin could play a beneficial role. Rifampin is known to penetrate the cerebrospinal fluid barrier in adequate concentrations and these are higher in patients with tuberculous meningitis than in normal persons? Arteritis of the pial vessels and block to the cerebrospinal fluid circulation by the thick exudate present in the base of the brain characterize the pathology of tuberculous meningitis. ~It is not inconceivable that, if rifampin does affect cellular immunity, it might affect the inflamatory changes which are responsible for the pathology of meningeal tuberculosis. It must be emphasized, however, that until more is known about cell-mediated immunity and rifampin, the possibility of such effect at this time is entirely speculative? Until the results of a controlled study become available, if it is ever done, one must decide now whether rifampin should be included in the therapy of tuberculous meningitis. Some investigators already do so?. 7 The information now available supports its use in patients with second and third stage of tuberculous meningitis and in those in the first stage of the disease who do not respond promptly to the standard regimen. Patients who harbor or are suspected of harboring isoniazid-resistant mycobacteria should receive three or four antituberculous agents including isoniazid, rifampin, and others such as streptomycin, pyrazinamide, and ethambutoL If pyrazinamide is administered, it probably should be accompanied by streptomycin. Fox and Mitchison 8 describe isoniazid and rifampin as "complete" bactericidal drugs against the entire population of M. tuberculosis; streptomycin, as active in tissues with an alkaline pH; pyrazinamide, as active in an acid pH. Therefore, streptomycin and pyrazinamide are said to be one-half bactericidal each and only together are considered to form a single bactericidal drug? Rifampin has many side effects which must be taken
The Journal of Pediatrics December 1975
into consideration? Its immunosuppressive effect so far has not been shown to have important clinical significance. TM Its allergic and immunologic reactions are more serious. These are more common when the drug is adnainistered intermittently. Purpura and other hemorrhagic manifestations with or without thrombocytopenia may rarely occur. Rifampin may affect the pharmacologic action of other drugs given simultaneously. It inhibits the activity of Coumarin anticoagulants. In women receiving contraceptives, breakthrough bleeding and pregnancy may occur. Other medications such as para-aminosalycilic acid and barbiturates inhibit the intestinal absorption of rifampin. Rifampin inhibits the absorption of methadone so that withdrawal symptoms may appear in addicts, n Other side effects include fever, orange-red staining of urine, feces, saliva, sputum, tears, and sweat; uric acid elevation; abdominal distress, nausea, vomiting, diarrhea, flatulence, leukopenia, confusion, lassitude, difficulty in concentration, dizziness, numbness, and hepatitis?- 1~The latter may be severe or mild and self-limited despite continuation of the drug. In mice teratogenic effects have been noted. Insufficient information is available about the dose and side effects of rifampin in children. 13 The data available suggest that the drug is well tolerated by children but more information is necessary about the pharmacology of rifampin in infants and children. Information is needed about blood, tissue, and cerebrospinal fluid concentrations, side effects, and interaction with other drugs. Of special interest would be long-term follow-up of treated children from the standpoint of diseases related to the mechanisms of immunologic surveillance. The results of such studies may not become available for many years. In the meantime, rifampin should not be withheld from infants and children in whom the drug may be life-saving or valuable in preventing serious neurologic sequelae.
Jos( E. Sifontes, M.D. Department of Pediatrics University of Puerto Rico School of Medicine San Juan, Puerto Rico 00936 REFERENCES
1. Lincoln EM, and Sifontes JE: Tuberculous meningitis in children, Med Clin N Amer, Philadelphia-London, March 1953, WB Saunders Company, pp 345-362. 2. Case records of the Massachusetts General Hospital: Case 19-1974, N Engl J Med 290:1130, 1974. 3. Vaughan III VC, McKay RJ, and Nelson WE: Nelson textbook of pediatrics, Philadelphia, 1975, WB Saunders Company, pp 639-640. 4. Newman R, Doster BE, Murray F J, and Ferebee-Woolpert S: Rifampin in initial treatment of pulmonary tuberculo-
Volume 87 Number 6, part 1
5.
6.
7. 8.
9.
sis--a US Public Health Service Tuberculosis Therapy Trial, Am Rev Respir Dis 109:216, 1974. Pilheu JA, Maglio F, Pleuz AD, De Hardie NM, and Iannello JA: Rifampicina en meningitis tuberculosa, An C~itedra Patologia Clin Tuberculosis 23:98, 1969. Graber CD, Patrick CC, and Galphin RL: Light chain proteinuria and cellular mediated immunity in rifampin treated patients with tuberculosis, Chest 67:408, 1975. Farmer TW: Pediatric neurology, Hagerstown, 1975, Harper & Row, Publishers, pp 268-272. Fox W, and Mitchison DA: Short-course chemotherapy for pulmonary tuberculosis, Am Rev Respir Dis 111:845, 1975. Council on Drugs: Evaluation of a new antituberculous agent--Rifampin (Rifadin, Rimactane), JAMA 220:414, 1972.
Editor's column
1017
10. Goldstein RA, Hun Ang U, and Janicki BW: Rifampin and immune responses in tuberculosis, Am Rev Respir Dis 111:949, 1975. 11. Kreek M J, Garfield JW, Gutjahr CL, Bowen D, and Field F: Rifampin-methadone relationship. 2 Rifampin effects on plasma concentration, metabolism and excretion of methadone, Am Rev Respir Dis 111:926, 1975. 12. Schewer PJ, Summerfield JA, Lal S, and Sherlock S: Rifampicin hepatitis. A clinical and histological study, Lancet 1:421, 1974. 13. Casteels-Van Daele M, Igodt-Ameye L, Corbeel L, and Elckels R: Hepatotoxicity of rifampicin, and isoniazid in children, J PEDIATR86:739, 1975.
1015
The Journal o f P E D I A T R I C S
Rifampin in tuberculous meningitis
TUBERCULOUS MENINGITIS was a frequent and
invariably fatal disease three decades ago. The average duration of the disease from onset of symptoms to death was 1989 days? With the advent of streptomycin in the late forties it became possible to save a few patients. Administration of streptomycin by the intrathecal route was recommended and as a result deafness occurred in about 50% of the survivors. When isoniazid became available in 1952, the outcome of therapy improved. Streptomycin by the intrathecal route was discontinued, and the incidence of deafness among the survivors decreased sharply. Other neurologic sequelae continued to occur according to the stage of the disease at the onset of treatment. Since 1959 isoniazid has been extensively used as a chemoprophylactic agent among household contacts of tuberculous patients and among children with positive tuberculin reactions. The incidence of tuberculous meningitis in developed countries has diminished to the extent that many recently trained pediatricians have never seen a case. The disease is usually not suspected in its first stage characterized by such nonspecific manifestations as fever, personality changes, and vomiting. Diagnosis is often delayed until the patient has reached the second stage, in which neck rigidity and other neurologic signs appear. Sometimes the diagnosis is not made until the last and the third stage in which the patient becomes comatose. Occasionally the diagnosis is missed while the patient is alive, and he becomes the subject of a clinicopathologic exercise? Each successive stage is associated with increasing mortality and sequelae among survivors. In the Bellevue series of 1952 the mortality rate for patients initially treated in the first stage was only 9.5%; in the second stage it was 26%, and in the third stage it rose to 84%.' These results of therapy of tuberculous meningitis have not changed significantly since 1952. The mortality continues to range between 10 and 50% and the incidence of permanent sequelae continues to be high? Rifampin (Rifampicin, Rifadin, Rimactane) was developed and initially tested in Italy in 1963. Because of its effectiveness against Mycobacterium tuberculosis its usefulness in improving the results of therapy of tubercu-
lous meningitis loomed as an exciting possibility. Ideally, double-blind prQspective studies should have been carried out comparing various regimens in adequate numbers of patients. This was not done for various reasons. Some investigators no longer treated a sufficiently large number of patients with tuberculous meningitis to conduct a properly controlled study; others who treated many patients either did not have the drug available to them or, if they did, were not willing to withhold it from their patients for the sake of a study. Important information about the effectiveness of rifampin in tuberculous meningitis appears in this issue of THE JOURNALin the paper by Visudhiphan and Chiemchanya. They compared patients See related article, p. 983.
treated between 1970 and 1972 with a "standard regimen" (streptomycin 20-40 mg/kg/day, isoniazid 20 mg/kg/day, and para-aminosalicylic acid 250 mg/kg/day) with patients treated between 1972 and 1974 with a "rifampin regimen" (isoniazid 20 mg/kg/day in 2 or 3 doses and rifampin 15 mg/kg/day in one daily dose before breakfast). The setting, characteristics of the patients, and age groups were comparable. The results were superior with the rifampin regimen. Four of the 13 patients in the standard regimen died, whereas only one of the 19 in the rifampin regimen died. Only three patients of the 13 treated with the standard regimen were spared significant neurologic sequelae, while 12 of 19 in the rifampin group were spared and none were deaf. The average duration of hospitalization in the rifampin group was only 3V2 weeks, ie, 589 weeks less than that of the standard regimen. These results cannot be readily explained by chance or bias. Patients with tuberculous meningitis treated with the standard regimen in a given setting respond in a fairly consistent manner. The low case fatality rate and the low incidence of sequelae reported by the investigators from Bangkok in the rifampin-treated patients would ordinarily be expected among patients predominantly diagnosed and treated in the first stage of the disease. The clinical
VoL 87, No. 6, part 1, pp. 1015-1017
1016
Editor's column
characteristics described for the rifampin-treated patients indicate that most were in the second or third stages of tuberculous meningitis. One might ask whether the inferior results obtained with the standard regimen could have been related to a high prevalence of primary isoniazid resistance in Thailand. This is a possibility which cannot be ruled out. But a high prevalence of isoniazid resistance should have had an adverse effect upon both groups. It might also be asked whether the two groups had comparable degrees of tuberculin allergy, nutrition, and other tuberculous or nontuberculous disease. All the answers are not available. Superior results with rifampin-isoniazid therapy can be explained by the known antimicrobial effectiveness of the combination." One might also speculate that the immunosuppressive effects of rifampin could play a beneficial role. Rifampin is known to penetrate the cerebrospinal fluid barrier in adequate concentrations and these are higher in patients with tuberculous meningitis than in normal persons? Arteritis of the pial vessels and block to the cerebrospinal fluid circulation by the thick exudate present in the base of the brain characterize the pathology of tuberculous meningitis. ~It is not inconceivable that, if rifampin does affect cellular immunity, it might affect the inflamatory changes which are responsible for the pathology of meningeal tuberculosis. It must be emphasized, however, that until more is known about cell-mediated immunity and rifampin, the possibility of such effect at this time is entirely speculative? Until the results of a controlled study become available, if it is ever done, one must decide now whether rifampin should be included in the therapy of tuberculous meningitis. Some investigators already do so?. 7 The information now available supports its use in patients with second and third stage of tuberculous meningitis and in those in the first stage of the disease who do not respond promptly to the standard regimen. Patients who harbor or are suspected of harboring isoniazid-resistant mycobacteria should receive three or four antituberculous agents including isoniazid, rifampin, and others such as streptomycin, pyrazinamide, and ethambutoL If pyrazinamide is administered, it probably should be accompanied by streptomycin. Fox and Mitchison 8 describe isoniazid and rifampin as "complete" bactericidal drugs against the entire population of M. tuberculosis; streptomycin, as active in tissues with an alkaline pH; pyrazinamide, as active in an acid pH. Therefore, streptomycin and pyrazinamide are said to be one-half bactericidal each and only together are considered to form a single bactericidal drug? Rifampin has many side effects which must be taken
The Journal of Pediatrics December 1975
into consideration? Its immunosuppressive effect so far has not been shown to have important clinical significance. TM Its allergic and immunologic reactions are more serious. These are more common when the drug is adnainistered intermittently. Purpura and other hemorrhagic manifestations with or without thrombocytopenia may rarely occur. Rifampin may affect the pharmacologic action of other drugs given simultaneously. It inhibits the activity of Coumarin anticoagulants. In women receiving contraceptives, breakthrough bleeding and pregnancy may occur. Other medications such as para-aminosalycilic acid and barbiturates inhibit the intestinal absorption of rifampin. Rifampin inhibits the absorption of methadone so that withdrawal symptoms may appear in addicts, n Other side effects include fever, orange-red staining of urine, feces, saliva, sputum, tears, and sweat; uric acid elevation; abdominal distress, nausea, vomiting, diarrhea, flatulence, leukopenia, confusion, lassitude, difficulty in concentration, dizziness, numbness, and hepatitis?- 1~The latter may be severe or mild and self-limited despite continuation of the drug. In mice teratogenic effects have been noted. Insufficient information is available about the dose and side effects of rifampin in children. 13 The data available suggest that the drug is well tolerated by children but more information is necessary about the pharmacology of rifampin in infants and children. Information is needed about blood, tissue, and cerebrospinal fluid concentrations, side effects, and interaction with other drugs. Of special interest would be long-term follow-up of treated children from the standpoint of diseases related to the mechanisms of immunologic surveillance. The results of such studies may not become available for many years. In the meantime, rifampin should not be withheld from infants and children in whom the drug may be life-saving or valuable in preventing serious neurologic sequelae.
Jos( E. Sifontes, M.D. Department of Pediatrics University of Puerto Rico School of Medicine San Juan, Puerto Rico 00936 REFERENCES
1. Lincoln EM, and Sifontes JE: Tuberculous meningitis in children, Med Clin N Amer, Philadelphia-London, March 1953, WB Saunders Company, pp 345-362. 2. Case records of the Massachusetts General Hospital: Case 19-1974, N Engl J Med 290:1130, 1974. 3. Vaughan III VC, McKay RJ, and Nelson WE: Nelson textbook of pediatrics, Philadelphia, 1975, WB Saunders Company, pp 639-640. 4. Newman R, Doster BE, Murray F J, and Ferebee-Woolpert S: Rifampin in initial treatment of pulmonary tuberculo-
Volume 87 Number 6, part 1
5.
6.
7. 8.
9.
sis--a US Public Health Service Tuberculosis Therapy Trial, Am Rev Respir Dis 109:216, 1974. Pilheu JA, Maglio F, Pleuz AD, De Hardie NM, and Iannello JA: Rifampicina en meningitis tuberculosa, An C~itedra Patologia Clin Tuberculosis 23:98, 1969. Graber CD, Patrick CC, and Galphin RL: Light chain proteinuria and cellular mediated immunity in rifampin treated patients with tuberculosis, Chest 67:408, 1975. Farmer TW: Pediatric neurology, Hagerstown, 1975, Harper & Row, Publishers, pp 268-272. Fox W, and Mitchison DA: Short-course chemotherapy for pulmonary tuberculosis, Am Rev Respir Dis 111:845, 1975. Council on Drugs: Evaluation of a new antituberculous agent--Rifampin (Rifadin, Rimactane), JAMA 220:414, 1972.
Editor's column
1017
10. Goldstein RA, Hun Ang U, and Janicki BW: Rifampin and immune responses in tuberculosis, Am Rev Respir Dis 111:949, 1975. 11. Kreek M J, Garfield JW, Gutjahr CL, Bowen D, and Field F: Rifampin-methadone relationship. 2 Rifampin effects on plasma concentration, metabolism and excretion of methadone, Am Rev Respir Dis 111:926, 1975. 12. Schewer PJ, Summerfield JA, Lal S, and Sherlock S: Rifampicin hepatitis. A clinical and histological study, Lancet 1:421, 1974. 13. Casteels-Van Daele M, Igodt-Ameye L, Corbeel L, and Elckels R: Hepatotoxicity of rifampicin, and isoniazid in children, J PEDIATR86:739, 1975.
