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INH prophylaxis for tuberculin-positive persons
IIDN1 Infectious Discascs Ncwslcttcr Editor-in-Chief V i n c e n t A. Fulglniti, M.D.
Regular Contributors E. Russell Alexander, M.D. C. George Ra); M.D. H. R o b e r t H a r r i s o n , M.D:: Allan D. F r i e d m a n , M.D. J a m e s E J o n e s , M.D. K e n n e t h J . Ryan, M.D. Mary Fried, Ph.D.
Volume
INH P R O P H Y L A X I S
FOR TUBERCULIN-POSITIVE
It may seem unusual, and even incongruous, to review a r t i c l e s p u b l i s h e d 20-24 years ago in this "up-to-date" newsletter. However, I do so because of recent discussion at a n a t i o n a l m e e t i n g and locally w h i c h led me to believe that the use of INH in tuberculin-positive i n d i v i d u a l s is m i s u n d e r s t o o d . Frank M o u n t and Shirley Ferebee with many c o l l a b o r ~ t o r s u n d e r t o o k a study in 1955 which changed our thinking and management of t u b e r c u l o s i s in children. (i, 2) They e s t a b l i s h e d a c o l l a b o r a t i v e study under the aegis of the Public Health Service involving 32 pediatricians, several U.S. cities,
INH P r o p h y l a x i s for T u b e r c u l i n Positive Persons M o x a l a c t a m a n d Cefotaxime: Possible I n d i c a t i o n s in P e d i a t r i c s U n d e r s t a n d i n g and M a n a g i n g F e v e r Instructive Case Report I n t e r n a t i o n a l and N a t i o n a l N o t e s
33 34 35 37 38
i, N~nfoer
5, 1982
PERSONS
Toronto, San Juan, P u e r t o Rico and M e x i c o City, and 2750 children. Any child <3 years old with a >5 mm PPD (intermediate - 5TU) was eligible. C h i l d r e n older than 3 years old also had to have x-ray e v i d e n c e c o n s i s t e n t with 1 ~ tuberculosis. All symptomatic children were excluded. One-half of subjects entering the study were treated with isoniazid (INH); the o t h e r s an identical placebo; the choice was random and no one knew who was g e t t i n g which. Each child had a t h o r o u g h examination, chest x-ray, and repeat t u b e r c u l i n test. Monthly physical e x a m i n a t i o n s were performed for 1 year and x - r a y s of the chest o b t a i n e d at i, 3, 6, and 12 months after initiation of the study. In the second and third years of observation, occasional e x a m i n a t i o n and y e a r l y x-rays and PPD tests were performed. The data d e r i v e d from this study are vast, but I will only summarize the salient f e a t u r e s to my theme. i. A d e f i n i t e c o m p l i c a t i o n of 1 ~ infection occurred in only 2 of 1394 children receivingisoniazid (cervical spine osteo and pulmonary disease with effusion). In contrast,
Vie,~Tsexpressed within are the responsibility of the authors. Every effort has been made to ensure the accuracy of the information. The publisher, however, must" disclaim any responsibility or liability. Readers are advised to check the product information sheet of each drug prior to administration.
InfectiousDiseasesNewsletter is published monthly by Elsevier Science Publishing Co., Inc., 52 Vanderbilt Avenue, New York, NY 10017. Editorial correspondence: Vincent A. Fulginiti, Arizona Health SciencesCenter, Tucson, AZ 85724. Subscription correspondence: Elsevier Science Publishing Co., Inc., 52 Vanderbilt Avenue, New York, NY 10017. Personal subscription: $42.00 for 12 issues per year. Library subscription: $84.00 for 12 issues plus one bound volume per year. Prices include postage and handling. Add $I0.00 for delivery (airmail) outside the United States. 9 1982 by ElsevierScience Publishing Co., Inc.
Elsevier Biomedical
ISSN 0278-2316
IDINDN
1 (5) 33-40 (1982)
34 Infectious Diseases Newsletter
among 1356 children receiving placebo, 31 developed a definite complication (p < 0.000001) (8 CNS, 4 miliary, 6 skeletal, 9 effusion, 1 tonsillitis, and 3 conjunctivitis). 2. Among placebo recipients, the two significant risk factors were age and extent of initial x-ray disease. 3. Complications were not just suppressed by the year of INH; in the two years after INH was discontinued, complications did not occur. 4. Progression of initial pulmonary disease related to INH therapy or not was more difficult to a s s e s s . . T h e r e were 76 children who had definite adverse changes during the first year; 30 had received IN~I and 46 placebo. When rates were compared the trend favored INH but was not significant. Thus what Mount and Ferebee definitely showed for the first time in a controlled trial was that one year of INH reduced extrapulmonary complications. They suggested that already existing pulmonary disease might be benefited (i.e., lack of adverse progression) but did not demonstrate it. Although a number of studies have been done since, this massive controlled trial remains at the foundation of our preventive efforts with INH. (3) When we administer INH to a tuberculin positive, asymptomatic, chest x-ray negative individual, we are attempting to prevent extrapulmonary spread, presumably hematogenous, from a pulmonary focus too small to be seen in the roentgenogram. Other studies extended the risk beyond early childhood to our present position that any person with newly discovered o__rr converted positive PPD reaction 10 mm, less than 35 years old, be treated for one year with INH. Of course, the person should be asymptomatic with a negative chest x-ray. It is important to recognize that: (i) if a person is symptomatic or has positive pulmonary findings on x-ray, treatment, not prophylaxis is indicated; (2) we have no way to distinguish atypical disease from tuberculosis; some persons will be treated unnecessarily; (3) careful follow-up is essential; INH prophylaxis does not guarantee suppression of all disease. The dose of INH is entirely empiric. (4) Mount and Ferebee used 4-6 mg/kg/day. Others have had failures with 2-3 times that amount. Today, 10-20 mg/kg/day in a single dose (maximum 500 mg/kg) is usually recommended. This higher dose is intended to blur any distinction between rapid-excreters of
9
INH and those who sustain adequate levels at lower doses. Vincent A. Fulginiti, M.D. Professor and Head Department of Pediatrics Arizona Health Sciences Center References i. Mount, FW and Ferebee, SH, Preventive effects of isoniazia in the treatment of primary tuberculosis in children. New Engl J Med 265:713-721, 1961. 2. A United States Public Health Service Tuberculosis Prophylaxis Trial, Prophylactic effects of isoniazid on primary tuberculosis in children. Amer Rev Tubercul Pulmon Dis 76:942-963, 1957. 3. Curry, FJ, Prophylactic effect of isoniazid in young tuberculin reactors. New Engl J Med 277:562, 1967. 4. Vivien, JN, et al., Recent studies on isoniazid. Adv Tubercul Res 18:149, 1972.
MOXALACTAM AND CEFOTAXIME: INDICATIONS IN PEDIATRICS
POSSIBLE
Moxalactam and cefos are two new, recently released beta-lactam antibiotics that appear to have an increased spectrum of activity against gram-negative bacilli. These drugs have greater activity against coliform bacilli, Haemophilus influenzae species, Pseudomonas species, and gonococci than previously available cephalosporins. In addition, moxalactam has been shown to have good cerebrospinal fluid penetration. Although pediatric use of these drugs has been appropriately limited and cautious, there are currently three possible circumstances in which moxalactam and cefotaxime may be of particular use. i. Gram-Negative Neonatal Meningitis The percentage of coliforms causing this illness that are resistant to ampicillin and to chloramphenicol is increasing. The aminoglycosides do not penetrate cerebrospinal fluid well, and chloramphenicol is bacteriostatic only even with sensitive organisms. Thus our therapeutic options have been somewhat limited. Moxalactam is highly active in vitro against strains isolated from neonates with meningitis, and in one study achieved good cerebrospinal fluid levels (mean 30% of serum) when given intravenously. Preliminary clinical
by Elsevier Science Publishin~ Co.. Inc.
Regular Contributors E. Russell Alexander, M.D. C. George Ra); M.D. H. R o b e r t H a r r i s o n , M.D:: Allan D. F r i e d m a n , M.D. J a m e s E J o n e s , M.D. K e n n e t h J . Ryan, M.D. Mary Fried, Ph.D.
Volume
INH P R O P H Y L A X I S
FOR TUBERCULIN-POSITIVE
It may seem unusual, and even incongruous, to review a r t i c l e s p u b l i s h e d 20-24 years ago in this "up-to-date" newsletter. However, I do so because of recent discussion at a n a t i o n a l m e e t i n g and locally w h i c h led me to believe that the use of INH in tuberculin-positive i n d i v i d u a l s is m i s u n d e r s t o o d . Frank M o u n t and Shirley Ferebee with many c o l l a b o r ~ t o r s u n d e r t o o k a study in 1955 which changed our thinking and management of t u b e r c u l o s i s in children. (i, 2) They e s t a b l i s h e d a c o l l a b o r a t i v e study under the aegis of the Public Health Service involving 32 pediatricians, several U.S. cities,
INH P r o p h y l a x i s for T u b e r c u l i n Positive Persons M o x a l a c t a m a n d Cefotaxime: Possible I n d i c a t i o n s in P e d i a t r i c s U n d e r s t a n d i n g and M a n a g i n g F e v e r Instructive Case Report I n t e r n a t i o n a l and N a t i o n a l N o t e s
33 34 35 37 38
i, N~nfoer
5, 1982
PERSONS
Toronto, San Juan, P u e r t o Rico and M e x i c o City, and 2750 children. Any child <3 years old with a >5 mm PPD (intermediate - 5TU) was eligible. C h i l d r e n older than 3 years old also had to have x-ray e v i d e n c e c o n s i s t e n t with 1 ~ tuberculosis. All symptomatic children were excluded. One-half of subjects entering the study were treated with isoniazid (INH); the o t h e r s an identical placebo; the choice was random and no one knew who was g e t t i n g which. Each child had a t h o r o u g h examination, chest x-ray, and repeat t u b e r c u l i n test. Monthly physical e x a m i n a t i o n s were performed for 1 year and x - r a y s of the chest o b t a i n e d at i, 3, 6, and 12 months after initiation of the study. In the second and third years of observation, occasional e x a m i n a t i o n and y e a r l y x-rays and PPD tests were performed. The data d e r i v e d from this study are vast, but I will only summarize the salient f e a t u r e s to my theme. i. A d e f i n i t e c o m p l i c a t i o n of 1 ~ infection occurred in only 2 of 1394 children receivingisoniazid (cervical spine osteo and pulmonary disease with effusion). In contrast,
Vie,~Tsexpressed within are the responsibility of the authors. Every effort has been made to ensure the accuracy of the information. The publisher, however, must" disclaim any responsibility or liability. Readers are advised to check the product information sheet of each drug prior to administration.
InfectiousDiseasesNewsletter is published monthly by Elsevier Science Publishing Co., Inc., 52 Vanderbilt Avenue, New York, NY 10017. Editorial correspondence: Vincent A. Fulginiti, Arizona Health SciencesCenter, Tucson, AZ 85724. Subscription correspondence: Elsevier Science Publishing Co., Inc., 52 Vanderbilt Avenue, New York, NY 10017. Personal subscription: $42.00 for 12 issues per year. Library subscription: $84.00 for 12 issues plus one bound volume per year. Prices include postage and handling. Add $I0.00 for delivery (airmail) outside the United States. 9 1982 by ElsevierScience Publishing Co., Inc.
Elsevier Biomedical
ISSN 0278-2316
IDINDN
1 (5) 33-40 (1982)
34 Infectious Diseases Newsletter
among 1356 children receiving placebo, 31 developed a definite complication (p < 0.000001) (8 CNS, 4 miliary, 6 skeletal, 9 effusion, 1 tonsillitis, and 3 conjunctivitis). 2. Among placebo recipients, the two significant risk factors were age and extent of initial x-ray disease. 3. Complications were not just suppressed by the year of INH; in the two years after INH was discontinued, complications did not occur. 4. Progression of initial pulmonary disease related to INH therapy or not was more difficult to a s s e s s . . T h e r e were 76 children who had definite adverse changes during the first year; 30 had received IN~I and 46 placebo. When rates were compared the trend favored INH but was not significant. Thus what Mount and Ferebee definitely showed for the first time in a controlled trial was that one year of INH reduced extrapulmonary complications. They suggested that already existing pulmonary disease might be benefited (i.e., lack of adverse progression) but did not demonstrate it. Although a number of studies have been done since, this massive controlled trial remains at the foundation of our preventive efforts with INH. (3) When we administer INH to a tuberculin positive, asymptomatic, chest x-ray negative individual, we are attempting to prevent extrapulmonary spread, presumably hematogenous, from a pulmonary focus too small to be seen in the roentgenogram. Other studies extended the risk beyond early childhood to our present position that any person with newly discovered o__rr converted positive PPD reaction 10 mm, less than 35 years old, be treated for one year with INH. Of course, the person should be asymptomatic with a negative chest x-ray. It is important to recognize that: (i) if a person is symptomatic or has positive pulmonary findings on x-ray, treatment, not prophylaxis is indicated; (2) we have no way to distinguish atypical disease from tuberculosis; some persons will be treated unnecessarily; (3) careful follow-up is essential; INH prophylaxis does not guarantee suppression of all disease. The dose of INH is entirely empiric. (4) Mount and Ferebee used 4-6 mg/kg/day. Others have had failures with 2-3 times that amount. Today, 10-20 mg/kg/day in a single dose (maximum 500 mg/kg) is usually recommended. This higher dose is intended to blur any distinction between rapid-excreters of
9
INH and those who sustain adequate levels at lower doses. Vincent A. Fulginiti, M.D. Professor and Head Department of Pediatrics Arizona Health Sciences Center References i. Mount, FW and Ferebee, SH, Preventive effects of isoniazia in the treatment of primary tuberculosis in children. New Engl J Med 265:713-721, 1961. 2. A United States Public Health Service Tuberculosis Prophylaxis Trial, Prophylactic effects of isoniazid on primary tuberculosis in children. Amer Rev Tubercul Pulmon Dis 76:942-963, 1957. 3. Curry, FJ, Prophylactic effect of isoniazid in young tuberculin reactors. New Engl J Med 277:562, 1967. 4. Vivien, JN, et al., Recent studies on isoniazid. Adv Tubercul Res 18:149, 1972.
MOXALACTAM AND CEFOTAXIME: INDICATIONS IN PEDIATRICS
POSSIBLE
Moxalactam and cefos are two new, recently released beta-lactam antibiotics that appear to have an increased spectrum of activity against gram-negative bacilli. These drugs have greater activity against coliform bacilli, Haemophilus influenzae species, Pseudomonas species, and gonococci than previously available cephalosporins. In addition, moxalactam has been shown to have good cerebrospinal fluid penetration. Although pediatric use of these drugs has been appropriately limited and cautious, there are currently three possible circumstances in which moxalactam and cefotaxime may be of particular use. i. Gram-Negative Neonatal Meningitis The percentage of coliforms causing this illness that are resistant to ampicillin and to chloramphenicol is increasing. The aminoglycosides do not penetrate cerebrospinal fluid well, and chloramphenicol is bacteriostatic only even with sensitive organisms. Thus our therapeutic options have been somewhat limited. Moxalactam is highly active in vitro against strains isolated from neonates with meningitis, and in one study achieved good cerebrospinal fluid levels (mean 30% of serum) when given intravenously. Preliminary clinical
by Elsevier Science Publishin~ Co.. Inc.