Modification of Recurrent Otitis Media by Short-term Sulfonamide Therapy Clark W. Biedel, MD
\s=b\Alternating cases of upper respiratory infection (URI) occurring within two months of an episode of otitis media were treated with either sulfonamides or decongestants. One hundred three cases of uncomplicated URI were treated with sulfonamide and 98 with decongestant. When adjusted for possible recrudescence rather than recurrence the rate was 4/71 (5.6%) and 15/76 (20%) in the treated and control groups, respectively. This difference is significant (P < .001) and suggests that intermittent prophylactic treatment can modify the recurrence rate of otitis media in children. (Am J Dis Child 132:681-683, 1978) acute otitis media is a and frequently recurring illness that may endanger hearing. In the patient who has recently recov¬ ered from an episode of otitis media a new upper respiratory infection (URI) often results in recurrent otitis. With the advent of the chemotherapeutic agents and antibiotics, hope of effective prophylaxis of the bacterial complications of viral illnesses flared, sputtered, and died. Multiple studies1-1
In childhood, common
From the
Department of Pediatrics,
Universi-
ty of Washington School of Medicine, Seattle. Reprint requests to 245 Fourth St Bldg, Bremerton, WA 98310 (Dr Biedel).
confirmed that complications follow¬ ing viral respiratory disease were not prevented and antibiotic toxicity and superinfection with resistant bacteria were
constant
phylactic
dangers. However, pro¬ directed against
measures
certain bacteria are successful. Two examples are the control of recurrent streptococcal infections in patients with acute rheumatic fever and con¬ trol of gonococcal ophthalmia. Long-term prophylactic therapy in recurrent or chronic urinary tract infection also has become a recom¬ mended pattern of treatment.' Since the pathogenesis of recurrent otitis media is believed to be related to defects in Eustachian tube function3 involving either obstruction of venti¬ lation and drainage or excessive reflux of nasopharyngeal contents, the parallel with urinary tract disease is apparent. In addition, the common bacteria of otitis media (Pneumococ-
Haemophilus influenzae, Streptococcus:'K) are relatively susceptible to cus,
antibiotic
measures.
et alv treated Eskimo children with sulfamethoxypyridazine for a period of nine months, with a 56% reduction in the incidence of draining ears. Maynard et al" conducted a double-blind study
In
Alaska, Ensign
Downloaded From: http://archpedi.jamanetwork.com/ by a Michigan State University User on 06/17/2015
using continuous ampicillin prophy¬ laxis for a period of one year in Eski¬ mo children, with an overall 47% reduction in episodes of otorrhea and a 67% reduction where medication compliance was good. Perrin et al" used sulfisoxazole over a period of six winter months in a double-blind study of 54 children who previously had experienced an increased incidence of otitis media. There were four cases of otitis in the treatment period com¬ pared to 21 in the control period, a reduction of 81%. Many pediatricians have attempted to modify the recurrences of otitis with their own empiric routines. This study is a test of one such program in
primary care pediatrie practice. Using a low-cost sulfonamide rather than a broad-spectrum antibiotic, and limiting medication to short periods on a specific basis, we hoped to lessen a
the amount of medication used and thus lessen reactions and the oppor¬ tunity for the development of resist¬ ant organisms. We theorized that the residual edema of the mucosa or lymphoid tissue obstructing the Eustachian tube would subside if reinfec¬ tion could be prevented for a period of six to eight weeks following an episode of otitis. This should allow a
Table 1—Sex and Age Distribution of Study Groups No. (%) of Patients
Boys
Girls
Age
0-6
mo
6-12 mo 1-2 yr 3-4 yr 5-9 yr
>10yr
Chemo-
Decon-
therapy (N = 103) 48 (47) 55 (53)
gestant (N = 98) 44 (45) 54 (55)
4
(4) 14(14) 36(35) 23(22) 24 (23) 2(2)
Table 2.—Recurrences of Otitis With New URI Sulfonamide Group Cases of Otitis
(6) (16) 26(27) 18(18) 25 (26) 7(7) 6 16
Weeks After Initial Otitis 2-8 Total
return to normal function and lessen the likelihood of recurrent episodes.
PATIENTS AND METHODS The patients were all from the author's pediatrie practice and had just recovered from an episode of acute otitis media. The diagnosis of acute otitis, both initially and made on the basis of in the drum asso¬ ciated with distortion of normal landmarks and evidence of fluid on pneumatic otoscopy. (Without tympanocentesis and culture, clinical diagnosis is only about 70% accu¬ rate.) Those patients who were diagnosed as having serous otitis were not included in the study. Since all examinations were done by the same physician, the criteria were constant for all patients so that any diagnostic errors would apply equally to treatment and control patients. Recovery was considered to be complete when eardrum landmarks had returned to normal on physical examination, and there was normal mobility of the tympanic membrane on pneumatic otoscopy and/or a normal screening audiogram with the tritone audiometer. As each patient recovered from the attack of otitis, the pattern of the clinical investigation was explained to the parent and consent for participation obtained. Each parent was instructed to call the office promptly in the event of any sign of a new URI during the two months follow¬ ing recovery from the otitis so that appro¬ priate treatment could be prescribed. When parents reported symptoms typical of the "common cold" no further criteria were required. If unusual symptoms were reported or the patient had a history of allergic disease, decision to treat was made on the basis of additional telephone histo¬ ry, actual examination, or even nasal smears for eosinophilia. The precise cause of the respiratory symptoms was not always possible to determine, but the same
on
recurrence,
Decongestant Group
was
inflammatory changes
-
Episodes of URI 32
Episodes
No.
71 103
criteria were applied to both patient groups. Patients were placed alternately in the treatment and control groups as the reports of symptoms were received. The only exception to strict alternation of treatment groups occurred when siblings were involved in a single telephone call, at which time the same medication was prescribed for each sibling involved. Those patients in the treatment group were given sulfisoxazole or trisulfapyrimidines in a dosage of 100 to 130 mg/kg/24 hr or sulfamethoxazole in a dosage of 55 mg/kg/24 hr. Sulfisoxazole was used for 90% of the patients. Since we recognized that most parents on their own initiative will treat a URI in their child with some type of decongestant, we gave the control patients a proprietary decongestant in recommended dosage. In all cases, treat¬ ment was prescribed for a minimum of six days and for the total duration of more extended respiratory symptoms. In the event of any earache or suspected loss of hearing during the course of the respiratory infection, the child was always examined. A clinical otitis occurring during treatment for a URI with either sulfona¬ mide or decongestant or within six days of the conclusion of treatment was defined as an episode of recurrent otitis. When bacte¬ rial complications other than otitis oc¬ curred during the URI and were verified by examination, culture, and/or roentgenography, the patient was treated with appropriate antibiotics and excluded from the study group for that episode. This pattern of short-term treatment was continued for each episode of URI that occurred during the eight-week period of this study. Some children were therefore treated more than once, but not necessarily in the same treatment group. Strong emphasis on completing the prescribed course of treatment has always been part of the education of patients in this practice, and the actual amount of
Downloaded From: http://archpedi.jamanetwork.com/ by a Michigan State University User on 06/17/2015
12
5.6 7.8
of URI 22 76 98
15 22
32 20 22
medication taken is always verified when a is reexamined at the end of a treated illness. No attempt was made, however, to determine actual compliance in completing the prophylactic medication. Some obvious episodes of noncompliance became apparent and will be discussed later. As Maynard et als demonstrated, poor compliance tends to decrease the effectiveness of prophylaxis and would lessen the difference between the treat¬ ment and control groups.
patient
RESULTS
One hundred twenty-nine children involved in 233 episodes of URI that fulfilled the protocol criteria. were
Thirty-two patients had acute bacteri¬ al complications requiring antibiotics.
One hundred three trials with sulfon¬ amide prophylaxis (the treatment group) and 98 trials with decongestants (the control group) were carried out in uncomplicated URL Analysis of the two groups (Table 1) showed no significant difference in the age and sex distribution. There were eight cases of recurrent otitis in the total treatment group (7.8%) (Table 2) and 22 cases in the control group (22%). In reviewing the results, it was suggested that those cases of otitis occurring in the first week after conclusion of treatment of the original otitis media might be a recrudescence of an incompletely treated infection and should not be included. Accordingly, only those re¬ currences beginning after the first week of observation were considered in the final statistical analysis. Those cases occurring in the second to eighth week of observation consti¬ tute the adjusted group. Of the 76
episodes of URI that were treated with decongestant, there were 15
of recurrent otitis media (20%), whereas the 71 cases of URI treated with sulfonamides were followed by only four episodes of otitis (5.6%). This 71% reduction in incidence is highly
cases
significant (P < .001).
COMMENT
The incidence of otitis in the treated group, 5.6%, is very close to the figure of 7.4% reported by Perrin et al.9 The control group had an inci¬ dence of 20%, less than the 38.4% reported by Perrin et al, but each patient of their group was followed up for six months compared to our study period of two months. One of the major problems in any prophylactic program is compliance. Of the four cases of recurrent otitis in the treatment group, three are of spe¬ cial interest. One mother gave the medication in half dosage, and anoth¬ er discontinued the medication as soon as the URI symptoms had ceased and did not give all the prescribed medi¬ cine. A third mother failed to report a continuing URI; the otitis appeared
four
days after the termination of therapy that should have been contin¬
ued. These represent one of the mech¬ anisms of failure of any treatment
regimen.
The charts of the 129 children involved were reviewed 2xk years after completion of the original study. One hundred fifteen children were still under continuing care. Because of the apparent success of the sulfonamide treatment, it had been continued, and 91 episodes of URI that satisfied the protocol for prophylactic treatment had occurred in the 2'/2-year period among these 115 patients. Five cases of recurrent otitis did occur despite treatment. This 5.5% recurrence rate correlates well with the 5.6% of the initial study period. During the total study period and subsequent review period involving
chemotherapeutic exposures, only one possible drug reac¬ tion, a dermatitis thought to be due to a trisulfapyrimidines preparation. 194
there
was
The dermatitis failed to recur on later challenge with the medicine. Another concern was the possibility of masking subacute infection and
providing inadequate treatment with subsequent problems with hearing. At no time on subsequent examination of these children during the 2V2-year period of observation or since has
there been clinical or audiometrie evidence of hearing loss. Children who have recently recov¬ ered from an episode of acute otitis media have an increased risk of recur¬ rence if they develop a new URI. Intervention with sulfonamides in full treatment dosage at the time of onset of the URI reduced the incidence of recurrent otitis by 71% when com¬ pared with a control group using only decongestants—a significant differ¬ ence. This appears to provide a meth¬ od of treatment, suitable for use in a primary care practice, that decreases the recurrence of a painful, potential¬ ly harmful otitis, yet limits the expo¬ sure of the patient to the risks of continuous prophylactic medication.
Pat Wahl, PhD, Department of Biostatistics, of Washington School of Public Health and Community Medicine, performed the statistical analysis.
University
References 1. Davis SD, Wedgwood RJ: Antibiotic prophylaxis in acute viral respiratory diseases. Am J Dis Child 109:544-553, 1965. 2. Mortimer EA Jr: Rational use of prophylactic antibiotics in children. Pediatr Clin North Am 15:261-273, 1968. 3. Gardner P: Antimicrobial drug therapy in pediatric practice. Pediatr Clin North Am 21:617\x=req-\ 648, 1974. 4. Carvajal HF, Daeschner CW: Urinary tract infection, in Gellis SS, Kagan BM (eds): Current
Pediatric
Therapy. Philadelphia,
Co, 1976, vol 7,
WB Saunders
pp 389-392.
5. Bluestone CD, Shurin PA: Middle ear disease in children: Pathogenesis, diagnosis, and management. Pediatr Clin North Am 21:379-400, 1974. 6. Shurin PA: Antibacterial therapy and middle ear effusions. Ann Otol Rhinol Laryngol 85(suppl 25):250-253, 1976. 7. Ensign PR, Urbanich EM, Moran M: Prophylaxis for otitis media in an Indian popula-
Downloaded From: http://archpedi.jamanetwork.com/ by a Michigan State University User on 06/17/2015
tion. Am J Public Health 50:195-199, 1960. 8. Maynard JE, Fleshman JK, Tschopp CF: Otitis media in Alaskan Eskimo children. JAMA 219:597-599, 1972. 9. Perrin JM, Charney E, MacWhinney JB Jr, et al: Sulfisoxazole as chemoprophylaxis for recurrent otitis media: A double-blind crossover study in pediatric practice. N Engl J Med 291:664\x=req-\ 667, 1974.
\s=b\Alternating cases of upper respiratory infection (URI) occurring within two months of an episode of otitis media were treated with either sulfonamides or decongestants. One hundred three cases of uncomplicated URI were treated with sulfonamide and 98 with decongestant. When adjusted for possible recrudescence rather than recurrence the rate was 4/71 (5.6%) and 15/76 (20%) in the treated and control groups, respectively. This difference is significant (P < .001) and suggests that intermittent prophylactic treatment can modify the recurrence rate of otitis media in children. (Am J Dis Child 132:681-683, 1978) acute otitis media is a and frequently recurring illness that may endanger hearing. In the patient who has recently recov¬ ered from an episode of otitis media a new upper respiratory infection (URI) often results in recurrent otitis. With the advent of the chemotherapeutic agents and antibiotics, hope of effective prophylaxis of the bacterial complications of viral illnesses flared, sputtered, and died. Multiple studies1-1
In childhood, common
From the
Department of Pediatrics,
Universi-
ty of Washington School of Medicine, Seattle. Reprint requests to 245 Fourth St Bldg, Bremerton, WA 98310 (Dr Biedel).
confirmed that complications follow¬ ing viral respiratory disease were not prevented and antibiotic toxicity and superinfection with resistant bacteria were
constant
phylactic
dangers. However, pro¬ directed against
measures
certain bacteria are successful. Two examples are the control of recurrent streptococcal infections in patients with acute rheumatic fever and con¬ trol of gonococcal ophthalmia. Long-term prophylactic therapy in recurrent or chronic urinary tract infection also has become a recom¬ mended pattern of treatment.' Since the pathogenesis of recurrent otitis media is believed to be related to defects in Eustachian tube function3 involving either obstruction of venti¬ lation and drainage or excessive reflux of nasopharyngeal contents, the parallel with urinary tract disease is apparent. In addition, the common bacteria of otitis media (Pneumococ-
Haemophilus influenzae, Streptococcus:'K) are relatively susceptible to cus,
antibiotic
measures.
et alv treated Eskimo children with sulfamethoxypyridazine for a period of nine months, with a 56% reduction in the incidence of draining ears. Maynard et al" conducted a double-blind study
In
Alaska, Ensign
Downloaded From: http://archpedi.jamanetwork.com/ by a Michigan State University User on 06/17/2015
using continuous ampicillin prophy¬ laxis for a period of one year in Eski¬ mo children, with an overall 47% reduction in episodes of otorrhea and a 67% reduction where medication compliance was good. Perrin et al" used sulfisoxazole over a period of six winter months in a double-blind study of 54 children who previously had experienced an increased incidence of otitis media. There were four cases of otitis in the treatment period com¬ pared to 21 in the control period, a reduction of 81%. Many pediatricians have attempted to modify the recurrences of otitis with their own empiric routines. This study is a test of one such program in
primary care pediatrie practice. Using a low-cost sulfonamide rather than a broad-spectrum antibiotic, and limiting medication to short periods on a specific basis, we hoped to lessen a
the amount of medication used and thus lessen reactions and the oppor¬ tunity for the development of resist¬ ant organisms. We theorized that the residual edema of the mucosa or lymphoid tissue obstructing the Eustachian tube would subside if reinfec¬ tion could be prevented for a period of six to eight weeks following an episode of otitis. This should allow a
Table 1—Sex and Age Distribution of Study Groups No. (%) of Patients
Boys
Girls
Age
0-6
mo
6-12 mo 1-2 yr 3-4 yr 5-9 yr
>10yr
Chemo-
Decon-
therapy (N = 103) 48 (47) 55 (53)
gestant (N = 98) 44 (45) 54 (55)
4
(4) 14(14) 36(35) 23(22) 24 (23) 2(2)
Table 2.—Recurrences of Otitis With New URI Sulfonamide Group Cases of Otitis
(6) (16) 26(27) 18(18) 25 (26) 7(7) 6 16
Weeks After Initial Otitis 2-8 Total
return to normal function and lessen the likelihood of recurrent episodes.
PATIENTS AND METHODS The patients were all from the author's pediatrie practice and had just recovered from an episode of acute otitis media. The diagnosis of acute otitis, both initially and made on the basis of in the drum asso¬ ciated with distortion of normal landmarks and evidence of fluid on pneumatic otoscopy. (Without tympanocentesis and culture, clinical diagnosis is only about 70% accu¬ rate.) Those patients who were diagnosed as having serous otitis were not included in the study. Since all examinations were done by the same physician, the criteria were constant for all patients so that any diagnostic errors would apply equally to treatment and control patients. Recovery was considered to be complete when eardrum landmarks had returned to normal on physical examination, and there was normal mobility of the tympanic membrane on pneumatic otoscopy and/or a normal screening audiogram with the tritone audiometer. As each patient recovered from the attack of otitis, the pattern of the clinical investigation was explained to the parent and consent for participation obtained. Each parent was instructed to call the office promptly in the event of any sign of a new URI during the two months follow¬ ing recovery from the otitis so that appro¬ priate treatment could be prescribed. When parents reported symptoms typical of the "common cold" no further criteria were required. If unusual symptoms were reported or the patient had a history of allergic disease, decision to treat was made on the basis of additional telephone histo¬ ry, actual examination, or even nasal smears for eosinophilia. The precise cause of the respiratory symptoms was not always possible to determine, but the same
on
recurrence,
Decongestant Group
was
inflammatory changes
-
Episodes of URI 32
Episodes
No.
71 103
criteria were applied to both patient groups. Patients were placed alternately in the treatment and control groups as the reports of symptoms were received. The only exception to strict alternation of treatment groups occurred when siblings were involved in a single telephone call, at which time the same medication was prescribed for each sibling involved. Those patients in the treatment group were given sulfisoxazole or trisulfapyrimidines in a dosage of 100 to 130 mg/kg/24 hr or sulfamethoxazole in a dosage of 55 mg/kg/24 hr. Sulfisoxazole was used for 90% of the patients. Since we recognized that most parents on their own initiative will treat a URI in their child with some type of decongestant, we gave the control patients a proprietary decongestant in recommended dosage. In all cases, treat¬ ment was prescribed for a minimum of six days and for the total duration of more extended respiratory symptoms. In the event of any earache or suspected loss of hearing during the course of the respiratory infection, the child was always examined. A clinical otitis occurring during treatment for a URI with either sulfona¬ mide or decongestant or within six days of the conclusion of treatment was defined as an episode of recurrent otitis. When bacte¬ rial complications other than otitis oc¬ curred during the URI and were verified by examination, culture, and/or roentgenography, the patient was treated with appropriate antibiotics and excluded from the study group for that episode. This pattern of short-term treatment was continued for each episode of URI that occurred during the eight-week period of this study. Some children were therefore treated more than once, but not necessarily in the same treatment group. Strong emphasis on completing the prescribed course of treatment has always been part of the education of patients in this practice, and the actual amount of
Downloaded From: http://archpedi.jamanetwork.com/ by a Michigan State University User on 06/17/2015
12
5.6 7.8
of URI 22 76 98
15 22
32 20 22
medication taken is always verified when a is reexamined at the end of a treated illness. No attempt was made, however, to determine actual compliance in completing the prophylactic medication. Some obvious episodes of noncompliance became apparent and will be discussed later. As Maynard et als demonstrated, poor compliance tends to decrease the effectiveness of prophylaxis and would lessen the difference between the treat¬ ment and control groups.
patient
RESULTS
One hundred twenty-nine children involved in 233 episodes of URI that fulfilled the protocol criteria. were
Thirty-two patients had acute bacteri¬ al complications requiring antibiotics.
One hundred three trials with sulfon¬ amide prophylaxis (the treatment group) and 98 trials with decongestants (the control group) were carried out in uncomplicated URL Analysis of the two groups (Table 1) showed no significant difference in the age and sex distribution. There were eight cases of recurrent otitis in the total treatment group (7.8%) (Table 2) and 22 cases in the control group (22%). In reviewing the results, it was suggested that those cases of otitis occurring in the first week after conclusion of treatment of the original otitis media might be a recrudescence of an incompletely treated infection and should not be included. Accordingly, only those re¬ currences beginning after the first week of observation were considered in the final statistical analysis. Those cases occurring in the second to eighth week of observation consti¬ tute the adjusted group. Of the 76
episodes of URI that were treated with decongestant, there were 15
of recurrent otitis media (20%), whereas the 71 cases of URI treated with sulfonamides were followed by only four episodes of otitis (5.6%). This 71% reduction in incidence is highly
cases
significant (P < .001).
COMMENT
The incidence of otitis in the treated group, 5.6%, is very close to the figure of 7.4% reported by Perrin et al.9 The control group had an inci¬ dence of 20%, less than the 38.4% reported by Perrin et al, but each patient of their group was followed up for six months compared to our study period of two months. One of the major problems in any prophylactic program is compliance. Of the four cases of recurrent otitis in the treatment group, three are of spe¬ cial interest. One mother gave the medication in half dosage, and anoth¬ er discontinued the medication as soon as the URI symptoms had ceased and did not give all the prescribed medi¬ cine. A third mother failed to report a continuing URI; the otitis appeared
four
days after the termination of therapy that should have been contin¬
ued. These represent one of the mech¬ anisms of failure of any treatment
regimen.
The charts of the 129 children involved were reviewed 2xk years after completion of the original study. One hundred fifteen children were still under continuing care. Because of the apparent success of the sulfonamide treatment, it had been continued, and 91 episodes of URI that satisfied the protocol for prophylactic treatment had occurred in the 2'/2-year period among these 115 patients. Five cases of recurrent otitis did occur despite treatment. This 5.5% recurrence rate correlates well with the 5.6% of the initial study period. During the total study period and subsequent review period involving
chemotherapeutic exposures, only one possible drug reac¬ tion, a dermatitis thought to be due to a trisulfapyrimidines preparation. 194
there
was
The dermatitis failed to recur on later challenge with the medicine. Another concern was the possibility of masking subacute infection and
providing inadequate treatment with subsequent problems with hearing. At no time on subsequent examination of these children during the 2V2-year period of observation or since has
there been clinical or audiometrie evidence of hearing loss. Children who have recently recov¬ ered from an episode of acute otitis media have an increased risk of recur¬ rence if they develop a new URI. Intervention with sulfonamides in full treatment dosage at the time of onset of the URI reduced the incidence of recurrent otitis by 71% when com¬ pared with a control group using only decongestants—a significant differ¬ ence. This appears to provide a meth¬ od of treatment, suitable for use in a primary care practice, that decreases the recurrence of a painful, potential¬ ly harmful otitis, yet limits the expo¬ sure of the patient to the risks of continuous prophylactic medication.
Pat Wahl, PhD, Department of Biostatistics, of Washington School of Public Health and Community Medicine, performed the statistical analysis.
University
References 1. Davis SD, Wedgwood RJ: Antibiotic prophylaxis in acute viral respiratory diseases. Am J Dis Child 109:544-553, 1965. 2. Mortimer EA Jr: Rational use of prophylactic antibiotics in children. Pediatr Clin North Am 15:261-273, 1968. 3. Gardner P: Antimicrobial drug therapy in pediatric practice. Pediatr Clin North Am 21:617\x=req-\ 648, 1974. 4. Carvajal HF, Daeschner CW: Urinary tract infection, in Gellis SS, Kagan BM (eds): Current
Pediatric
Therapy. Philadelphia,
Co, 1976, vol 7,
WB Saunders
pp 389-392.
5. Bluestone CD, Shurin PA: Middle ear disease in children: Pathogenesis, diagnosis, and management. Pediatr Clin North Am 21:379-400, 1974. 6. Shurin PA: Antibacterial therapy and middle ear effusions. Ann Otol Rhinol Laryngol 85(suppl 25):250-253, 1976. 7. Ensign PR, Urbanich EM, Moran M: Prophylaxis for otitis media in an Indian popula-
Downloaded From: http://archpedi.jamanetwork.com/ by a Michigan State University User on 06/17/2015
tion. Am J Public Health 50:195-199, 1960. 8. Maynard JE, Fleshman JK, Tschopp CF: Otitis media in Alaskan Eskimo children. JAMA 219:597-599, 1972. 9. Perrin JM, Charney E, MacWhinney JB Jr, et al: Sulfisoxazole as chemoprophylaxis for recurrent otitis media: A double-blind crossover study in pediatric practice. N Engl J Med 291:664\x=req-\ 667, 1974.
