Drugs 42 (Suppl. 4): 25-29, 1991 0012-6667/91/0400-0025/$2.50/0 © Adis International Limited. All rights reserved, DRSUP3254
Cefixime vs Amoxicillin in the Treatment of Acute Otitis Media in Infants and Children Nicola Principi and Paola Marchisio Pediatric Department, University of Milan, Milan, Italy
Summary
Cefixime is a new oral cephamycin antibiotic with a broad spectrum of antibacterial activity
in vitro. It is resistant to hydrolysis by most {1-lactamases and has pharmacokinetic characteristics which allow administration in a single daily dose for the treatment of some bacterial infections. The aim of this study was to compare the clinical efficacy of cefixime with that of amoxicillin in the treatment of acute otitis media in 40 children. Cefixime 8 mg/kg was given once daily at bedtime, whereas amoxicillin 50 rug/kg/day was administered in 3 divided doses; both drugs were given for 10 days. IS days after starting the trial, a favourable clinical response was demonstrated in 18 of 20 children in both treatment groups. Cure rates, recurrences and persistent middle ear effusions were not significantly different in the 2 study groups during a 3-month follow-up. It was concluded that cefixime is clinically effective and well tolerated in the treatment of children with acute otitis media.
Acute otitis media (AOM) is one of the commonest diseases of infants and children. A study by Teele and associates (1989) is the most representative of several different epidemiological studies demonstrating that only about 20%of the paediatric population do not experience an episode of AOM in the first 3 years of life, while almost 50% experience 3 or more episodes. Although it is recognised that 20% of episodes of AOM are caused by viruses, nearly all children with AOM are treated with an antibiotic. Reasons for this decision include both the difficulty of identifying the aetiology of the single episode at the time of diagnosis (Bluestone 1989) and the possibility that viral AOM can be complicated by superimposed bacterial infections (Chonmaitree et al. 1990). The choice of the best antibacterial drug for treating AOM depends on several factors, the most important being knowledge of the bacterial species
commonly responsible for the disease and their susceptibility to commonly used antibiotics. Studies performed in both the USA and Europe have demonstrated that Streptococcus pneumoniae, Haemophilus injluenzae and Branhamella (Moraxella) catarrhalis account for over two-thirds of the bacteria recovered from middle ear fluid during AOM (Bluestone 1989;Francois et al. 1988; Karma et a1. 1987). As a consequence, amoxicillin has been considered the drug of choice, while cefaclor and cotrimoxazole have been proposed in cases in which amoxicillin cannot be used. However, recent microbiological research, particularly that conducted in the USA, has demonstrated an increasing prevalence of isolates of {1-lactamaseproducing strains of H. injluenzae and B. catarrhalis from children with AOM. In the Scottsdale region, for example, in the period 1981 to 1990, the percentages of {1-lactamase-producing strains
26
Drugs 42 (Suppl. 4) 1991
of H. influenzae and B. catarrhalis have increased from 17 to 40% and from 67 to 95%, respectively (McLinn 1990). In Italy, the incidence of i3-lactarnase-producing strains of bacteria responsible for AOM varies considerably between different geographical areas where middle ear fluids were obtained and cultured. In our experience of children living in Milan, the problem still seems to be of limited importance. However, the availability of drugs active against i3-lactamase-producing bacteria may be very important. Cefixime, an orally absorbed broad spectrum bactericidal o-lactam antibiotic, is a compound exhibiting both a pharmacokinetic profile and microbiologicalactivity that are of great interest for AOM therapy. This agent can be administered once daily and is resistant to hydrolysis by a wide range of 13lactamases, For these reasons, it has the potential to become a first-line treatment for AOM. This paper reports the results of an open label randomised prospective trial comparing cefixime with amoxicillin in Italian children with AOM.
1. Materials and Methods Children with clinical signs and symptoms of AOM were enrolled in the study. The diagnosis of AOM was based on clinical data (fever or otalgia or both), pneumatic otoscopy (hyperaemia or opacity, accompanied by fullness or bulging of the tympanic membrane, immobility) and tympanometric findings (a flat, type B curve and absent stapedial reflex). Children with otorrhoea were included only if the ear had been draining for no longer than 12 hours. Patients were assigned in an open label fashion to receive treatment with either cefixime or amoxicillin according to a table of random numbers. Cefixime dosage was 8 mg/kg administered once daily at bedtime and amoxicillin 50 rug/kg/day was given in 3 divided doses for to days. No other medication was administered except for antipyretics if needed. Laboratory evaluations were performed at the time of enrolment and at the end of treatment. Blood tests consisted of a complete blood count
with differential and platelet evaluation and a biochemistry profile including urea nitrogen, serum creatinine, and aspartate aminotransferase. Patients with apparently clinically significant results were repeatedly retested until either normal laboratory values were noted or it was concluded that treatment was unsuccessful, Tympanocentesis was not performed because it was considered not justifiable on ethical grounds except for specific clinical situations in selected patients. Early therapeutic efficacy was evaluated from clinical, otoscopic and tympanometric findings midtreatment and 5 days after the completion of therapy. Particular attention was also given to the evaluation of adverse reactions strictly related to antibiotic administration, such as nausea, vomiting, diarrhoea and skin rashes. Early outcome was defined as follows: • Cure: normalisation of clinical, otoscopic and tympanometric findings. • Improvement: relief of acute signs and symptoms of AOM with persistent unilateral or bilateral middle ear effusion demonstrated by otoscopy (abnormalities of the tympanic membrane, i.e. diffusely opaque or presence of air-fluid level) and tympanometric findings (flat, type B curve and absent stapedial reflex). • Failure: persistence of signs and symptoms of AOM midtreatment and/or need for discontinuation of treatment because of adverse effects. Children in whom treatment was considered to be a failure were discharged from the study and treated with other antibiotics. The other children were scheduled to be re-examined 30, 60 and 90 days after entering the study and at any time during the study period if symptoms of disease recurred. Each visit included an interval history and physical examination with pneumatic otoscopy and tympanometry. On the basis of the data collected during these visits, late outcome was defined as follows: • Cure: resolution of otitis media with effusion demonstrated by normalisation of otoscopic tympanometric findings. • Recurrence: a new episode of AOM. • Persistence of effusion: either unilateral or bilateral middle ear effusion.
27
Cefixime and Acute Otitis Media in Children
Table I. Demographic details of infants and children with acute otitis media enrolled in a randomised comparison of cefixime and amoxicillin Cefixime (n = 20)
%
n Age (years) 0.5 0.5-1.9 2.0-6.0 6.0-12.0
Amoxicillin (n = 20)
40 300/mm 3, SD ± 6400) in the amoxicillin group. Pretreatment mean CRP serum level was 43.3 mg/ L (range 5 to 159 mg/L, SD ± 41.8) in the cefixime group and 43.6 mg/L (range 6 to 189 mg/L, SD ± 42.0) in the amoxicillin group. The differences were not statistically significant.
%
n
2.2 Early Outcome 1 6
9 4
5 30 45 20
1
Sex Male Female
11 9
55 45
Prior otitis media None Prior episodes
8
40
7
12
60
13
35 65
Laterality of disease Unilateral Bilateral
10 10
50 50
10 10
50 50
8 8 3
13
7
5 40 40 15
65 35
The results were statistically analysed using the Student's paired t-test and x 2 analysis with Yates correction unless the sample size was too small, in which case Fisher's exact test was used. All reported p values were 2-sided. The level of significance selected was p < 0.05.
2. Results 2.1 Group Comparability and Laboratory Values A total of 40 patients entered the study, 20 for each treatment group. Children treated with cefixime and amoxicillin were similar with respect to age, sex, prior history of AOM and laterality of disease (table I). Moreover, most patients in each group had high white blood cell (WBC) counts and C-reactive protein (CRP) serum levels, possibly indicative of a bacterial aetiology of the episode. Pretreatment mean WBC count was 12600/mm 3 (range 7700 to 19900/mm 3, SD ± 3800) in the cefixime group and 12 500/mm 3 (range 5700 to
Two of20 (10%) children treated with cefixime were considered cured compared with 4 (20%) of those given amoxicillin (table II). Improvement was noted in 16 (80%) of the children treated with cefixime, compared with 14 (70%) of those in the amoxicillin group. Two patients in each treatment group (10%) were considered treatment failures. Of those treated with cefixime, 1 had a suppurative complication (mastoiditis), caused by Pseudomonas aeruginosa resistant to cefixime, while treatment was discontinued in the other because of vomiting. Both children who failed amoxicillin therapy had persistent signs and symptoms of AOM after 5 days of therapy. Laboratory investigations performed 5 days after the end of treatment showed that all the patients, excluding failures, had WBC counts and CRP serum levels within the normal range. 2.3 Late Outcome Cure rates and frequency of persistence of effusion at 30, 60 and 90 days after the acute episode were similar in both groups (table II), showing an upward trend in cure rate and a concomitant downward trend in persistence of effusion. Adverse reactions were infrequent with only one cefixime-treated child requiring withdrawal of the drug because of vomiting, and 3 patients in each group experiencing mild diarrhoea, which did not require withdrawal of therapy.
3. Discussion This study confirms data reported by Howie and Owen (1987), Kenna et al. (1987) and McLinn (1987), who demonstrated that cefixime is at least
Drugs 42 (Suppl. 4) /99/
28
Table II. Clinical outcome (no. of patients) at different time intervals after beginning treatment with cefixime (C) or amoxicillin (A) in 40 infants and children with acute otitis media
Clinical outcome
Time after start of treatment 15 days
Cure Improvement Persistent effusion Failure Recurrence Lost to follow-up
C
A
2 16
4 14
2
2
C
A
C
3
5
5
14
13
8
0
3 2
as effective as, or superior to, the antibiotics traditionally employed in the treatment of AOM in infants and children. In particular, our data demonstrate that cefixime 8 mg/kg given once daily is as effective as amoxicillin 50 rug/kg/day in 3 divided doses. The normalisation of the clinical picture and of acute phase reactants in most patients after 10 days' treatment with either antibiotic demonstrates the efficacy of both cefixime and amoxicillin in the treatment of AOM. However, in contrast to other bacterial paediatric infectious illnesses, in which the therapeutic goal is to resolve the acute phase of the disease, children with ADM require long term monitoring of middle ear condition. In fact, it has been demonstrated that the persistence of effusion in the middle ear cavity for a long period of time (more than 3 to 6 months) causes a conductive hearing loss and may result in language, behavioural and learning defects (Marchant et al. 1984; Teele et al. 1984). Rates of persistence of middle ear effusion were similar in both treatment groups, although somewhat higher than in other reports. The difference may be related to the time of year in which the study was conducted (winter) and to the high proportion of children who had experienced previous episodes of ADM. We conclude that cefixime is effective and well tolerated when used in the treatment of ADM both in infants and children. An antibiotic requiring only once daily administration and with activity against
90 days
60 days
30 days
A
C
A
7
7
9
10
5
7
4
2
[1-lactamase-producing strains of common pathogens is undoubtedly a suitable alternative to traditional therapy.
References Bluestone CD. Modern management of otitis media. Pediatric Clinics of North America 36: 1371-1387,1989 Chonmaitree T, Owen MJ, Howie VM. Respiratory viruses interfere with bacteriologic response to antibiotic in children with otitis media. Journal of Infectious Diseases 162: 546-549, 1990 Francois M, Bingen E, Margo JN, et al. Etude bacteriologique de l'otite moyenne aigue en pratique hospitaliere et en pratique liberale. Archives Francaises de Pediatrie 45: 471-476, 1988 Howie VA, Owen MJ. Bacteriologic and clinical efficacy of cefixime compared with amoxicillin in acute otitis media. Pediatric Infectious Disease Journal 6: 989-991, 1987 Karma PH, Pukander JS, Sipila MM, et al. Middle ear fluid bacteriology of acute otitis media in neonates and very young infants. International Journal of Pediatric Otorhinolaryngology 14: 141-150, 1987 Kenna MA, Bluestone CD, Fall P, et al. Cefixime vs cefaclor in the treatment of acute otitis media in infants and children. Pediatric Infectious Disease Journal 6: 992-996, 1987 Marchant CD, Shurin PA, Turczyk VA, et al. Course and outcome of otitis media in early infancy: a prospective study. Journal of Pediatrics 104: 826-831,1984 McLinn SE. Randomized, open-label, multicenter trial of cefixime compared with amoxicillin for treatment of acute otitis media with effusion. Pediatric Infectious Disease Journal 6: 997-1001, 1987 McLinn SE. Microbiology of acute otitis media in the Scottsdale Pediatric Center, 1981-1990. Lederle Laboratories reports, 1990
Cefixime and Acute Otitis Media in Children
Teele DW, Klein JO, Rosner B, et al. Otitis media with effusion during the first three years of life and development of speech and language. Pediatrics 74: 282-287, 1984 Teele DW, Klein JO, Rosner B, et al. Epidemiology of otitis media during the first seven years oflife in child-
29
ren in Greater Boston: a prospective, cohort study. Journal of Infectious Diseases 160: 83-94, 1989 Correspondence and reprints: Prof. Nicola Principi, Pediatric Department IV, University of Milan, via GBGrassi 74,20157 Milan, Italy.
Cefixime vs Amoxicillin in the Treatment of Acute Otitis Media in Infants and Children Nicola Principi and Paola Marchisio Pediatric Department, University of Milan, Milan, Italy
Summary
Cefixime is a new oral cephamycin antibiotic with a broad spectrum of antibacterial activity
in vitro. It is resistant to hydrolysis by most {1-lactamases and has pharmacokinetic characteristics which allow administration in a single daily dose for the treatment of some bacterial infections. The aim of this study was to compare the clinical efficacy of cefixime with that of amoxicillin in the treatment of acute otitis media in 40 children. Cefixime 8 mg/kg was given once daily at bedtime, whereas amoxicillin 50 rug/kg/day was administered in 3 divided doses; both drugs were given for 10 days. IS days after starting the trial, a favourable clinical response was demonstrated in 18 of 20 children in both treatment groups. Cure rates, recurrences and persistent middle ear effusions were not significantly different in the 2 study groups during a 3-month follow-up. It was concluded that cefixime is clinically effective and well tolerated in the treatment of children with acute otitis media.
Acute otitis media (AOM) is one of the commonest diseases of infants and children. A study by Teele and associates (1989) is the most representative of several different epidemiological studies demonstrating that only about 20%of the paediatric population do not experience an episode of AOM in the first 3 years of life, while almost 50% experience 3 or more episodes. Although it is recognised that 20% of episodes of AOM are caused by viruses, nearly all children with AOM are treated with an antibiotic. Reasons for this decision include both the difficulty of identifying the aetiology of the single episode at the time of diagnosis (Bluestone 1989) and the possibility that viral AOM can be complicated by superimposed bacterial infections (Chonmaitree et al. 1990). The choice of the best antibacterial drug for treating AOM depends on several factors, the most important being knowledge of the bacterial species
commonly responsible for the disease and their susceptibility to commonly used antibiotics. Studies performed in both the USA and Europe have demonstrated that Streptococcus pneumoniae, Haemophilus injluenzae and Branhamella (Moraxella) catarrhalis account for over two-thirds of the bacteria recovered from middle ear fluid during AOM (Bluestone 1989;Francois et al. 1988; Karma et a1. 1987). As a consequence, amoxicillin has been considered the drug of choice, while cefaclor and cotrimoxazole have been proposed in cases in which amoxicillin cannot be used. However, recent microbiological research, particularly that conducted in the USA, has demonstrated an increasing prevalence of isolates of {1-lactamaseproducing strains of H. injluenzae and B. catarrhalis from children with AOM. In the Scottsdale region, for example, in the period 1981 to 1990, the percentages of {1-lactamase-producing strains
26
Drugs 42 (Suppl. 4) 1991
of H. influenzae and B. catarrhalis have increased from 17 to 40% and from 67 to 95%, respectively (McLinn 1990). In Italy, the incidence of i3-lactarnase-producing strains of bacteria responsible for AOM varies considerably between different geographical areas where middle ear fluids were obtained and cultured. In our experience of children living in Milan, the problem still seems to be of limited importance. However, the availability of drugs active against i3-lactamase-producing bacteria may be very important. Cefixime, an orally absorbed broad spectrum bactericidal o-lactam antibiotic, is a compound exhibiting both a pharmacokinetic profile and microbiologicalactivity that are of great interest for AOM therapy. This agent can be administered once daily and is resistant to hydrolysis by a wide range of 13lactamases, For these reasons, it has the potential to become a first-line treatment for AOM. This paper reports the results of an open label randomised prospective trial comparing cefixime with amoxicillin in Italian children with AOM.
1. Materials and Methods Children with clinical signs and symptoms of AOM were enrolled in the study. The diagnosis of AOM was based on clinical data (fever or otalgia or both), pneumatic otoscopy (hyperaemia or opacity, accompanied by fullness or bulging of the tympanic membrane, immobility) and tympanometric findings (a flat, type B curve and absent stapedial reflex). Children with otorrhoea were included only if the ear had been draining for no longer than 12 hours. Patients were assigned in an open label fashion to receive treatment with either cefixime or amoxicillin according to a table of random numbers. Cefixime dosage was 8 mg/kg administered once daily at bedtime and amoxicillin 50 rug/kg/day was given in 3 divided doses for to days. No other medication was administered except for antipyretics if needed. Laboratory evaluations were performed at the time of enrolment and at the end of treatment. Blood tests consisted of a complete blood count
with differential and platelet evaluation and a biochemistry profile including urea nitrogen, serum creatinine, and aspartate aminotransferase. Patients with apparently clinically significant results were repeatedly retested until either normal laboratory values were noted or it was concluded that treatment was unsuccessful, Tympanocentesis was not performed because it was considered not justifiable on ethical grounds except for specific clinical situations in selected patients. Early therapeutic efficacy was evaluated from clinical, otoscopic and tympanometric findings midtreatment and 5 days after the completion of therapy. Particular attention was also given to the evaluation of adverse reactions strictly related to antibiotic administration, such as nausea, vomiting, diarrhoea and skin rashes. Early outcome was defined as follows: • Cure: normalisation of clinical, otoscopic and tympanometric findings. • Improvement: relief of acute signs and symptoms of AOM with persistent unilateral or bilateral middle ear effusion demonstrated by otoscopy (abnormalities of the tympanic membrane, i.e. diffusely opaque or presence of air-fluid level) and tympanometric findings (flat, type B curve and absent stapedial reflex). • Failure: persistence of signs and symptoms of AOM midtreatment and/or need for discontinuation of treatment because of adverse effects. Children in whom treatment was considered to be a failure were discharged from the study and treated with other antibiotics. The other children were scheduled to be re-examined 30, 60 and 90 days after entering the study and at any time during the study period if symptoms of disease recurred. Each visit included an interval history and physical examination with pneumatic otoscopy and tympanometry. On the basis of the data collected during these visits, late outcome was defined as follows: • Cure: resolution of otitis media with effusion demonstrated by normalisation of otoscopic tympanometric findings. • Recurrence: a new episode of AOM. • Persistence of effusion: either unilateral or bilateral middle ear effusion.
27
Cefixime and Acute Otitis Media in Children
Table I. Demographic details of infants and children with acute otitis media enrolled in a randomised comparison of cefixime and amoxicillin Cefixime (n = 20)
%
n Age (years) 0.5 0.5-1.9 2.0-6.0 6.0-12.0
Amoxicillin (n = 20)
40 300/mm 3, SD ± 6400) in the amoxicillin group. Pretreatment mean CRP serum level was 43.3 mg/ L (range 5 to 159 mg/L, SD ± 41.8) in the cefixime group and 43.6 mg/L (range 6 to 189 mg/L, SD ± 42.0) in the amoxicillin group. The differences were not statistically significant.
%
n
2.2 Early Outcome 1 6
9 4
5 30 45 20
1
Sex Male Female
11 9
55 45
Prior otitis media None Prior episodes
8
40
7
12
60
13
35 65
Laterality of disease Unilateral Bilateral
10 10
50 50
10 10
50 50
8 8 3
13
7
5 40 40 15
65 35
The results were statistically analysed using the Student's paired t-test and x 2 analysis with Yates correction unless the sample size was too small, in which case Fisher's exact test was used. All reported p values were 2-sided. The level of significance selected was p < 0.05.
2. Results 2.1 Group Comparability and Laboratory Values A total of 40 patients entered the study, 20 for each treatment group. Children treated with cefixime and amoxicillin were similar with respect to age, sex, prior history of AOM and laterality of disease (table I). Moreover, most patients in each group had high white blood cell (WBC) counts and C-reactive protein (CRP) serum levels, possibly indicative of a bacterial aetiology of the episode. Pretreatment mean WBC count was 12600/mm 3 (range 7700 to 19900/mm 3, SD ± 3800) in the cefixime group and 12 500/mm 3 (range 5700 to
Two of20 (10%) children treated with cefixime were considered cured compared with 4 (20%) of those given amoxicillin (table II). Improvement was noted in 16 (80%) of the children treated with cefixime, compared with 14 (70%) of those in the amoxicillin group. Two patients in each treatment group (10%) were considered treatment failures. Of those treated with cefixime, 1 had a suppurative complication (mastoiditis), caused by Pseudomonas aeruginosa resistant to cefixime, while treatment was discontinued in the other because of vomiting. Both children who failed amoxicillin therapy had persistent signs and symptoms of AOM after 5 days of therapy. Laboratory investigations performed 5 days after the end of treatment showed that all the patients, excluding failures, had WBC counts and CRP serum levels within the normal range. 2.3 Late Outcome Cure rates and frequency of persistence of effusion at 30, 60 and 90 days after the acute episode were similar in both groups (table II), showing an upward trend in cure rate and a concomitant downward trend in persistence of effusion. Adverse reactions were infrequent with only one cefixime-treated child requiring withdrawal of the drug because of vomiting, and 3 patients in each group experiencing mild diarrhoea, which did not require withdrawal of therapy.
3. Discussion This study confirms data reported by Howie and Owen (1987), Kenna et al. (1987) and McLinn (1987), who demonstrated that cefixime is at least
Drugs 42 (Suppl. 4) /99/
28
Table II. Clinical outcome (no. of patients) at different time intervals after beginning treatment with cefixime (C) or amoxicillin (A) in 40 infants and children with acute otitis media
Clinical outcome
Time after start of treatment 15 days
Cure Improvement Persistent effusion Failure Recurrence Lost to follow-up
C
A
2 16
4 14
2
2
C
A
C
3
5
5
14
13
8
0
3 2
as effective as, or superior to, the antibiotics traditionally employed in the treatment of AOM in infants and children. In particular, our data demonstrate that cefixime 8 mg/kg given once daily is as effective as amoxicillin 50 rug/kg/day in 3 divided doses. The normalisation of the clinical picture and of acute phase reactants in most patients after 10 days' treatment with either antibiotic demonstrates the efficacy of both cefixime and amoxicillin in the treatment of AOM. However, in contrast to other bacterial paediatric infectious illnesses, in which the therapeutic goal is to resolve the acute phase of the disease, children with ADM require long term monitoring of middle ear condition. In fact, it has been demonstrated that the persistence of effusion in the middle ear cavity for a long period of time (more than 3 to 6 months) causes a conductive hearing loss and may result in language, behavioural and learning defects (Marchant et al. 1984; Teele et al. 1984). Rates of persistence of middle ear effusion were similar in both treatment groups, although somewhat higher than in other reports. The difference may be related to the time of year in which the study was conducted (winter) and to the high proportion of children who had experienced previous episodes of ADM. We conclude that cefixime is effective and well tolerated when used in the treatment of ADM both in infants and children. An antibiotic requiring only once daily administration and with activity against
90 days
60 days
30 days
A
C
A
7
7
9
10
5
7
4
2
[1-lactamase-producing strains of common pathogens is undoubtedly a suitable alternative to traditional therapy.
References Bluestone CD. Modern management of otitis media. Pediatric Clinics of North America 36: 1371-1387,1989 Chonmaitree T, Owen MJ, Howie VM. Respiratory viruses interfere with bacteriologic response to antibiotic in children with otitis media. Journal of Infectious Diseases 162: 546-549, 1990 Francois M, Bingen E, Margo JN, et al. Etude bacteriologique de l'otite moyenne aigue en pratique hospitaliere et en pratique liberale. Archives Francaises de Pediatrie 45: 471-476, 1988 Howie VA, Owen MJ. Bacteriologic and clinical efficacy of cefixime compared with amoxicillin in acute otitis media. Pediatric Infectious Disease Journal 6: 989-991, 1987 Karma PH, Pukander JS, Sipila MM, et al. Middle ear fluid bacteriology of acute otitis media in neonates and very young infants. International Journal of Pediatric Otorhinolaryngology 14: 141-150, 1987 Kenna MA, Bluestone CD, Fall P, et al. Cefixime vs cefaclor in the treatment of acute otitis media in infants and children. Pediatric Infectious Disease Journal 6: 992-996, 1987 Marchant CD, Shurin PA, Turczyk VA, et al. Course and outcome of otitis media in early infancy: a prospective study. Journal of Pediatrics 104: 826-831,1984 McLinn SE. Randomized, open-label, multicenter trial of cefixime compared with amoxicillin for treatment of acute otitis media with effusion. Pediatric Infectious Disease Journal 6: 997-1001, 1987 McLinn SE. Microbiology of acute otitis media in the Scottsdale Pediatric Center, 1981-1990. Lederle Laboratories reports, 1990
Cefixime and Acute Otitis Media in Children
Teele DW, Klein JO, Rosner B, et al. Otitis media with effusion during the first three years of life and development of speech and language. Pediatrics 74: 282-287, 1984 Teele DW, Klein JO, Rosner B, et al. Epidemiology of otitis media during the first seven years oflife in child-
29
ren in Greater Boston: a prospective, cohort study. Journal of Infectious Diseases 160: 83-94, 1989 Correspondence and reprints: Prof. Nicola Principi, Pediatric Department IV, University of Milan, via GBGrassi 74,20157 Milan, Italy.
