J Int Med Res (1979) 7, 546
Recurrence of Otitis Media after Antibiotic Therapy: Comparison of Cephradine and Amoxycillin Samuel E McLinn, MD, Uptown Professional Building, 2645 North Third Street, Suite 150, Harrisburg, Pennsylvania 17110, USA
The long-term effectiveness of cephradine and amoxycillin in the treatment of otitis media was evaluated in one hundred children ranging in age from 4 months to 14 years. The immediate clinical response was comparable in both treatment groups, but the recurrence rate during a 12-monthfollow-up period was considerably lower in the patients treated with cephradine. The incidence ofside-effects was similar in the two groups.
Introduction Acute otitis media is one of the most frequent and perplexing infectious diseases of infants and children. Studies of various populations have shown that 76% to 90% of all children have at least one episode of otitis media by the age of 6 years (Bluestone & Shurin 1974, Howie 1975). About half of the infants who develop middle-ear infections at less than 1 year of age become otitis-prone (Howie, Ploussard & Sloyer 1975). Permanent structural changes have been reported in as many as 32% of these chronically infected children (Howie 1975). Recent literature has reported more insidious complications such as learning disabilities, lowering of intelligence, and social and language difficulties (Kaplan et al 1973, Holm & Kunze 1969). Antibiotics, principally penicillin and penicillin analogs such as ampicillin, have contributed to the reduction of these problems. However, there appears to be an increasing number of reports of ampicillin-resistant strains (typable and 0300-0605/79/060546-05 $02·00
non-typable) of Haemophilus influenzae, which is a major cause of otitis media in young children. This would suggest the need for additional antibiotic agents (Crosson et al 1976, Nelson 1974, Kahn, Rodrequez & Ross 1976). The present study was conducted to compare the effectiveness of cephradine and amoxycillin in the treatment of otitis media, and to try to demonstrate the possible effect of drug therapy on recurrence patterns in children with that disease. Patients and Methods One hundred children with otitis media due to Streptococcus pneumoniae, Haemophilus infl uen z ae , Streptococcus pyogenes (beta-haemolytic), or Staphylococcus aureus were enrolled in this study, which was conducted in a private paediatric practice. Individuals with a history of sensitivity to penicillins or cephalosporins, or who had received another antibiotic for the present episode, were not included. Informed consent was obtained from
©Cambridge Medical Publications Limited
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S EMcLinn
547
each child's parent or legally constituted representative after the nature of the study had been fully explained. Patients were randomly assigned to one of two treatment groups of fifty children each. One group received cephradine oral suspension (100 mg/kg/day, in four equally divided doses), and the other group received amoxycillin oral suspension (40 mg/kg/day, in three equally divided doses). The specified treatment period for both groups was 10 days. There were fifty-four males and forty-six females, and nearly all (95%) were Caucasian. The age range was somewhat narrower in the cephradine group: 4 months to 9 years (average, 1·9 years) as compared to 4 months to 14 years (average, 2·4 years) in the amoxycillin group. To identify the infecting organism, specimens for cultures were obtained from the middle ear by tympanocentesis with a Sentura aspirator prior to starting treatment. The organisms cultured were tested for sensitivity to cephalosporins and ampicillin according to the Kirby-Bauer method (Bauer et at 1966). Culturing and sensitivity testing were repeated approximately 48 hours after initiating therapy and again, if middle-ear fluid was still present, after 7 days of treatment, at the conclusion of treatment, and at 4 and 20 days posttreatment. Serum IgM levels were determined on treatment days 1 and 10 and again at 4 days post-treatment to detect any elevation in antibody titre. Tympanometry was performed before and at the conclusion of treatment, as well as 1,3,6, and 12 months after the course of therapy. Each child was examined at intervals deemed clinically appropriate, usually on therapy days 2, 7, and 10. These observations were made to determine the time when clinical improvement first became apparent and when it reached its greatest degree. The results of tympanometry and changes in signs and symptoms such as fever, pain, and discharge were all considered in making the evaluation of clinical improvement. An overall evaluation of response was made at the conclusion of therapy, taking into account the initial severity of the infection and the time required for initial clinical improvement and subsequent cure. The children also were observed throughout the study for evidence of any adverse reactions. Each child had a complete clinical
evaluation and, if necessary, a bacteriologic examination at 1, 3, 6, and 12 months after initiation of treatment to detect any recurrence of the infection.
Results
All patients in both treatment groups received the prescribed 10 days of therapy. The organism isolated from the pre-treatment cultures most frequently was S. pneumoniae, which was present in 68% of the cephradinetreated patients and 62% of the patients treated with amoxycillin. The second most prevalent organism was H. influenzae, which was present in 24% of the patients in both treatment groups. The pathogen isolated in the remaining patients was S. aureus or S. pyogenes (beta-haemolytic), with the latter accounting for only 2% of the isolates in both patient groups. In most patients, the pathogen was eradicated within 2 days after initiating treatment (Table 1). It is interesting to note that H. influenzae was eradicated within 2 days in eleven of the twelve patients harbouring this organism in both the cephradine and amoxycillin treatment groups. Clinical improvement of signs and symptoms was noted after 1 day of treatment in most patients in both treatment groups, and a majority also were asymptomatic at that time (Table 2). The overall evaluation of response (Table 3) was Excellent in thirty-two (64%) of the patients given cephradine and in thirty (60%) of those given amoxycillin. An evaluation of Excellent required initial improvement in less than 3 days and a cure within 3 to 4 days in mild infections, 5 to 6 days in infections of moderate severity, and 7 to 8 days in severe infections. Serum IgM levels were obtained from about half of the patients in each treatment group. There was only one abnormal IgM level in the cephradine group and two in the amoxycillin group. The elevation or lack of elevation of specific IgM was measured in an attempt to ascertain if this factor would help determine which patients would have a recurrence of otitis media because of a lack of specific IgM to their infecting organism. No such correlation could be found, however. The findings of the follow-up physical and bacteriologic examinations showed that
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The Journal ofInternational Medical Research
548 thirteen patients (26%) in the cephradine group and twenty-six patients (52%) in the amoxycillin group had recurrences within the 12-month period after therapy. In the cephradine group, the majority occurred during the first and second months after therapy; however, during the 3- to 12-month
follow-up period, fourteen patients in the amoxycillin group had a recurrence, as compared to only three in the cephradine group (Table 4). In most instances the organism isolated at the time of recurrence (Table 5) was the same as that in the initial culture.
Table 1
Table 3
Time required for eradication of pathogens
Overall evaluation of therapeutic response
Number ofpatients
Number ofpatients
No.of days
Cephradine group
Amoxycillin group
Overall response
Cephradine group
Amoxycillin group
1
2
-
Excellent
32 (64%)
30 (60%)
2
43
44
Good
13 (26%)
17 (34%)
3
4
4
4
1
Not reported
-
Total
50
-
Fair
2 (4%)
Poor
3 (6%)
Total
50
-
3 (6%) 50
2 50
Table 2 Time to initial improvement of signs and symptoms
Patients with recurrence post-treatment
Number ofpatients Time (days)
Cephradine group
3
1*
-
No improvement
2
-
49t
50
Total patients
Table 4
A moxycillin group
*Did not improve until tenth day of therapy tOne patient was initially asymptomatic
Time 0/ occurrence (months)
Cephradine group
Amoxycillin group
1
6
8
2
4
4
3
1
2
4
0
4
5
0
1
6
1
2
9
0
2
12
1
3
Total
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13 (26%)
26 (52%)
S E McLinn
549
Table 5 Identity of organisms among patients with recurrent episodes of otitis media
Recurrence
S. pneumoniae H. irfluenzae S. aureus
Total
S.pyogenes
Unidentified
Unknown
Original pathogen
C
A
C
A
C
A
C
A
C
A
C
A
C
A
S. pneumoniae
IO
16
9
IO
0
1
0
0
0
1
0
1
1
3
H. influenzae
1
7
0
1
1
5
0
0
0
0
0
0
0
1
S. aureus
2
3
0
0
0
0
2
0
0
0
0
1
0
2
13
26
9
11
1
6
2
0
0
1
0
2
1
6
Total
C = cephradine A = amoxycillin
In the cephradine group, three children had diarrhoea and two vomited during the course of treatment. One child developed urticaria on the third day of cephradine treatment, and one developed a rash on the chest and trunk, similar in appearance to roseola. In the amoxycillin group, three children had diarrhoea during treatment, and one had concurrent episodes of vomiting and rash. Another child developed a generalized roseola-type rash. Discussion and Conclusion The most significant advance in the identification of middle-ear disease is the use of a new instrument, the electro-acoustic impedance bridge, with which a tympanogram can be obtained (Jerger 1970). This instrument was used in this study as a diagnostic aid and to follow resolution of middle-ear effusion and pressure. Although 90% of the patients studied had improved clinically and bacteriologically after 10 days of treatment, 69% still had abnormal tympanograms as evidenced by high negative pressure (- 150 mm H 2 0 ) and presence of effusion. After 30 days, 39% were abnormal; at 60 days, 20%; and at 90 days, 12% were still abnormal. There were no essential differences between treatment groups. It is difficult to determine the meaning of persistent high negative pressure in the middle-
ear and what, if anything, should be done. It has been suggested that pressures of - 100 to - 150 mm H 2 0 may predispose the patient to accumulation of middle-ear effusions (Bluestone 1976). In this study of patients with otitis media, cephradine and amoxycillin were both highly effective in eradicating the infecting organism, including Haemophilus influenzae, which was initially isolated from an equal number of patients in both treatment groups. The incidence of recurrence with this pathogen, however, was considerably lower in the cephradine-treated patients (2%) than in the amoxycillin-treated patients (10%). The overall incidence of homologous, post-treatment recurrence was 24% in the cephradine group and 30% in the amoxycillin group, although the latter figure may likely be higher since reaspiration was not performed or the organism isolated was not identified in eight (31 %) of the patients experiencing recurrence after amoxycillin treatment. The overall incidence of recurrent infection (homologous and non-homologous) in the cephradine group was only half that in the amoxycillin group. Although these differences were not statistically significant due to the small study population, there is sufficient clinical evidence to consider the use of cephradine when treating children with recurrent otitis media.
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550
The Journal ofInternational Medical Research
Acknowledgements Editorial advice and technical assistance was provided by Mr Gerald Bernfeld, Dr Dionisio Caloza, and Mr Richard Semar.
Crosson F J, Watson W C, Baily D W & MacLowry J D (1976) Acute otitis media caused by ampicillin-resistant Haemophilus injluenzae type b. Journal ofthe American Medical Association 236, 2778 Holm V A & Kunze L H (1969) Effect of chronic otitis media on language and speech development. Pediatrics 43, 833 HowieVM (1975) Natural history of otitis media. Annals ofOtology, Rhinology and Laryngology 84, (SuppI19), 67 Howie V M, Ploussard J H & Sloyer J (1975) The otitis-prone condition. American Journal of Diseases ofChildren 129,676 Jerger J (1970) Clinical experience with impedance audiometry. Archives ofOtolaryngology 92, 311 Kahn W N, Rodrequez W J & Ross S (1976) Incidence of ampicillin-resistant strains of Haemophilus species in the Greater Washington area. Abstract presented at The Society for Pediatric Research Conference. April 1976 Kaplan G J, Fleshman K J, Bender T R, Baum C & Clark P S (1973) Long-term effects of otitis media. Pediatrics 52, 577 NelsonJD (1974) Editorial: Should ampicillin be abandoned for the treatment of Haemophilus injluenzae disease? Journal of the A merican Medical Association 229, 322
Non-proprietary Names and Trademarks of Drugs Cephradine - A nspor, Velosej. Amoxycillin - Amoxil, Larotid, Polymox.
REFERENCES Bauer A W, Kirby M M, Sherris J C & Turck M (1966) Antibiotic susceptibility testing by a standardized single disc method. American Journal of Clinical Pathology 45, 493 Bluestone C D & Shurin P A (1974) Middle-ear disease in children. Pediatric Clinics of North America 21, 379 Bluestone C D (1976) Third International Symposium on Impedance Audiometry. New York, Sept 29th-Oct 3rd
Downloaded from imr.sagepub.com by guest on September 15, 2015
Recurrence of Otitis Media after Antibiotic Therapy: Comparison of Cephradine and Amoxycillin Samuel E McLinn, MD, Uptown Professional Building, 2645 North Third Street, Suite 150, Harrisburg, Pennsylvania 17110, USA
The long-term effectiveness of cephradine and amoxycillin in the treatment of otitis media was evaluated in one hundred children ranging in age from 4 months to 14 years. The immediate clinical response was comparable in both treatment groups, but the recurrence rate during a 12-monthfollow-up period was considerably lower in the patients treated with cephradine. The incidence ofside-effects was similar in the two groups.
Introduction Acute otitis media is one of the most frequent and perplexing infectious diseases of infants and children. Studies of various populations have shown that 76% to 90% of all children have at least one episode of otitis media by the age of 6 years (Bluestone & Shurin 1974, Howie 1975). About half of the infants who develop middle-ear infections at less than 1 year of age become otitis-prone (Howie, Ploussard & Sloyer 1975). Permanent structural changes have been reported in as many as 32% of these chronically infected children (Howie 1975). Recent literature has reported more insidious complications such as learning disabilities, lowering of intelligence, and social and language difficulties (Kaplan et al 1973, Holm & Kunze 1969). Antibiotics, principally penicillin and penicillin analogs such as ampicillin, have contributed to the reduction of these problems. However, there appears to be an increasing number of reports of ampicillin-resistant strains (typable and 0300-0605/79/060546-05 $02·00
non-typable) of Haemophilus influenzae, which is a major cause of otitis media in young children. This would suggest the need for additional antibiotic agents (Crosson et al 1976, Nelson 1974, Kahn, Rodrequez & Ross 1976). The present study was conducted to compare the effectiveness of cephradine and amoxycillin in the treatment of otitis media, and to try to demonstrate the possible effect of drug therapy on recurrence patterns in children with that disease. Patients and Methods One hundred children with otitis media due to Streptococcus pneumoniae, Haemophilus infl uen z ae , Streptococcus pyogenes (beta-haemolytic), or Staphylococcus aureus were enrolled in this study, which was conducted in a private paediatric practice. Individuals with a history of sensitivity to penicillins or cephalosporins, or who had received another antibiotic for the present episode, were not included. Informed consent was obtained from
©Cambridge Medical Publications Limited
Downloaded from imr.sagepub.com by guest on September 15, 2015
S EMcLinn
547
each child's parent or legally constituted representative after the nature of the study had been fully explained. Patients were randomly assigned to one of two treatment groups of fifty children each. One group received cephradine oral suspension (100 mg/kg/day, in four equally divided doses), and the other group received amoxycillin oral suspension (40 mg/kg/day, in three equally divided doses). The specified treatment period for both groups was 10 days. There were fifty-four males and forty-six females, and nearly all (95%) were Caucasian. The age range was somewhat narrower in the cephradine group: 4 months to 9 years (average, 1·9 years) as compared to 4 months to 14 years (average, 2·4 years) in the amoxycillin group. To identify the infecting organism, specimens for cultures were obtained from the middle ear by tympanocentesis with a Sentura aspirator prior to starting treatment. The organisms cultured were tested for sensitivity to cephalosporins and ampicillin according to the Kirby-Bauer method (Bauer et at 1966). Culturing and sensitivity testing were repeated approximately 48 hours after initiating therapy and again, if middle-ear fluid was still present, after 7 days of treatment, at the conclusion of treatment, and at 4 and 20 days posttreatment. Serum IgM levels were determined on treatment days 1 and 10 and again at 4 days post-treatment to detect any elevation in antibody titre. Tympanometry was performed before and at the conclusion of treatment, as well as 1,3,6, and 12 months after the course of therapy. Each child was examined at intervals deemed clinically appropriate, usually on therapy days 2, 7, and 10. These observations were made to determine the time when clinical improvement first became apparent and when it reached its greatest degree. The results of tympanometry and changes in signs and symptoms such as fever, pain, and discharge were all considered in making the evaluation of clinical improvement. An overall evaluation of response was made at the conclusion of therapy, taking into account the initial severity of the infection and the time required for initial clinical improvement and subsequent cure. The children also were observed throughout the study for evidence of any adverse reactions. Each child had a complete clinical
evaluation and, if necessary, a bacteriologic examination at 1, 3, 6, and 12 months after initiation of treatment to detect any recurrence of the infection.
Results
All patients in both treatment groups received the prescribed 10 days of therapy. The organism isolated from the pre-treatment cultures most frequently was S. pneumoniae, which was present in 68% of the cephradinetreated patients and 62% of the patients treated with amoxycillin. The second most prevalent organism was H. influenzae, which was present in 24% of the patients in both treatment groups. The pathogen isolated in the remaining patients was S. aureus or S. pyogenes (beta-haemolytic), with the latter accounting for only 2% of the isolates in both patient groups. In most patients, the pathogen was eradicated within 2 days after initiating treatment (Table 1). It is interesting to note that H. influenzae was eradicated within 2 days in eleven of the twelve patients harbouring this organism in both the cephradine and amoxycillin treatment groups. Clinical improvement of signs and symptoms was noted after 1 day of treatment in most patients in both treatment groups, and a majority also were asymptomatic at that time (Table 2). The overall evaluation of response (Table 3) was Excellent in thirty-two (64%) of the patients given cephradine and in thirty (60%) of those given amoxycillin. An evaluation of Excellent required initial improvement in less than 3 days and a cure within 3 to 4 days in mild infections, 5 to 6 days in infections of moderate severity, and 7 to 8 days in severe infections. Serum IgM levels were obtained from about half of the patients in each treatment group. There was only one abnormal IgM level in the cephradine group and two in the amoxycillin group. The elevation or lack of elevation of specific IgM was measured in an attempt to ascertain if this factor would help determine which patients would have a recurrence of otitis media because of a lack of specific IgM to their infecting organism. No such correlation could be found, however. The findings of the follow-up physical and bacteriologic examinations showed that
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The Journal ofInternational Medical Research
548 thirteen patients (26%) in the cephradine group and twenty-six patients (52%) in the amoxycillin group had recurrences within the 12-month period after therapy. In the cephradine group, the majority occurred during the first and second months after therapy; however, during the 3- to 12-month
follow-up period, fourteen patients in the amoxycillin group had a recurrence, as compared to only three in the cephradine group (Table 4). In most instances the organism isolated at the time of recurrence (Table 5) was the same as that in the initial culture.
Table 1
Table 3
Time required for eradication of pathogens
Overall evaluation of therapeutic response
Number ofpatients
Number ofpatients
No.of days
Cephradine group
Amoxycillin group
Overall response
Cephradine group
Amoxycillin group
1
2
-
Excellent
32 (64%)
30 (60%)
2
43
44
Good
13 (26%)
17 (34%)
3
4
4
4
1
Not reported
-
Total
50
-
Fair
2 (4%)
Poor
3 (6%)
Total
50
-
3 (6%) 50
2 50
Table 2 Time to initial improvement of signs and symptoms
Patients with recurrence post-treatment
Number ofpatients Time (days)
Cephradine group
3
1*
-
No improvement
2
-
49t
50
Total patients
Table 4
A moxycillin group
*Did not improve until tenth day of therapy tOne patient was initially asymptomatic
Time 0/ occurrence (months)
Cephradine group
Amoxycillin group
1
6
8
2
4
4
3
1
2
4
0
4
5
0
1
6
1
2
9
0
2
12
1
3
Total
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13 (26%)
26 (52%)
S E McLinn
549
Table 5 Identity of organisms among patients with recurrent episodes of otitis media
Recurrence
S. pneumoniae H. irfluenzae S. aureus
Total
S.pyogenes
Unidentified
Unknown
Original pathogen
C
A
C
A
C
A
C
A
C
A
C
A
C
A
S. pneumoniae
IO
16
9
IO
0
1
0
0
0
1
0
1
1
3
H. influenzae
1
7
0
1
1
5
0
0
0
0
0
0
0
1
S. aureus
2
3
0
0
0
0
2
0
0
0
0
1
0
2
13
26
9
11
1
6
2
0
0
1
0
2
1
6
Total
C = cephradine A = amoxycillin
In the cephradine group, three children had diarrhoea and two vomited during the course of treatment. One child developed urticaria on the third day of cephradine treatment, and one developed a rash on the chest and trunk, similar in appearance to roseola. In the amoxycillin group, three children had diarrhoea during treatment, and one had concurrent episodes of vomiting and rash. Another child developed a generalized roseola-type rash. Discussion and Conclusion The most significant advance in the identification of middle-ear disease is the use of a new instrument, the electro-acoustic impedance bridge, with which a tympanogram can be obtained (Jerger 1970). This instrument was used in this study as a diagnostic aid and to follow resolution of middle-ear effusion and pressure. Although 90% of the patients studied had improved clinically and bacteriologically after 10 days of treatment, 69% still had abnormal tympanograms as evidenced by high negative pressure (- 150 mm H 2 0 ) and presence of effusion. After 30 days, 39% were abnormal; at 60 days, 20%; and at 90 days, 12% were still abnormal. There were no essential differences between treatment groups. It is difficult to determine the meaning of persistent high negative pressure in the middle-
ear and what, if anything, should be done. It has been suggested that pressures of - 100 to - 150 mm H 2 0 may predispose the patient to accumulation of middle-ear effusions (Bluestone 1976). In this study of patients with otitis media, cephradine and amoxycillin were both highly effective in eradicating the infecting organism, including Haemophilus influenzae, which was initially isolated from an equal number of patients in both treatment groups. The incidence of recurrence with this pathogen, however, was considerably lower in the cephradine-treated patients (2%) than in the amoxycillin-treated patients (10%). The overall incidence of homologous, post-treatment recurrence was 24% in the cephradine group and 30% in the amoxycillin group, although the latter figure may likely be higher since reaspiration was not performed or the organism isolated was not identified in eight (31 %) of the patients experiencing recurrence after amoxycillin treatment. The overall incidence of recurrent infection (homologous and non-homologous) in the cephradine group was only half that in the amoxycillin group. Although these differences were not statistically significant due to the small study population, there is sufficient clinical evidence to consider the use of cephradine when treating children with recurrent otitis media.
Downloaded from imr.sagepub.com by guest on September 15, 2015
550
The Journal ofInternational Medical Research
Acknowledgements Editorial advice and technical assistance was provided by Mr Gerald Bernfeld, Dr Dionisio Caloza, and Mr Richard Semar.
Crosson F J, Watson W C, Baily D W & MacLowry J D (1976) Acute otitis media caused by ampicillin-resistant Haemophilus injluenzae type b. Journal ofthe American Medical Association 236, 2778 Holm V A & Kunze L H (1969) Effect of chronic otitis media on language and speech development. Pediatrics 43, 833 HowieVM (1975) Natural history of otitis media. Annals ofOtology, Rhinology and Laryngology 84, (SuppI19), 67 Howie V M, Ploussard J H & Sloyer J (1975) The otitis-prone condition. American Journal of Diseases ofChildren 129,676 Jerger J (1970) Clinical experience with impedance audiometry. Archives ofOtolaryngology 92, 311 Kahn W N, Rodrequez W J & Ross S (1976) Incidence of ampicillin-resistant strains of Haemophilus species in the Greater Washington area. Abstract presented at The Society for Pediatric Research Conference. April 1976 Kaplan G J, Fleshman K J, Bender T R, Baum C & Clark P S (1973) Long-term effects of otitis media. Pediatrics 52, 577 NelsonJD (1974) Editorial: Should ampicillin be abandoned for the treatment of Haemophilus injluenzae disease? Journal of the A merican Medical Association 229, 322
Non-proprietary Names and Trademarks of Drugs Cephradine - A nspor, Velosej. Amoxycillin - Amoxil, Larotid, Polymox.
REFERENCES Bauer A W, Kirby M M, Sherris J C & Turck M (1966) Antibiotic susceptibility testing by a standardized single disc method. American Journal of Clinical Pathology 45, 493 Bluestone C D & Shurin P A (1974) Middle-ear disease in children. Pediatric Clinics of North America 21, 379 Bluestone C D (1976) Third International Symposium on Impedance Audiometry. New York, Sept 29th-Oct 3rd
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