The Journal of International Medical Research 1990; 18: 235 - 239
Comparative Study of Cefuroxime Axetil Suspension and Amoxycillin Syrup in the Treatment of Acute Otitis Media in General Practice D.P. Brodie', J.V. Griggs 2 and K. Cunningham" 'The Phygtle Surgery, Chalfont St Peter, UK; 2Glaxo Research Ltd, Greenford, UK In a multicentre general practice study, 660 children aged between 3 months and 12 years with otitis media were randomized to receive a 10day course of cefuroxime axetil suspension or amoxycillin syrup. Children under 2 years of age were given 125 mg cefuroxime axetil twice daily after food or 125 mg amoxycillin three times daily; older children received 250 mg cefuroxime axetil twice daily or 250 mg . amoxycillin three times daily. The overall cure or improvement rate was 94.3 % for those treated with cefuroxime axetil and 94.5% for those receiving amoxycillin. Both treatments were well tolerated, with no differences in the number of patients who experienced at least one adverse event or who were withdrawn from treatment. Haemophilus influenzae was isolated in 29 % of specimens obtained, Streptococcus pneumoniae in 22% and Moraxella cata"halis in 6%. Some Strep. pneumonia and M. catarrhalis infections were resistant to amoxycillin. It is concluded that cefuroxime axetil suspension given twice daily has comparable efficacy to amoxycillin syrup given three times daily in the treatment of children with otitis media. KEY WORDS: Cefuroxime axetil; amoxycillin; otitis media.
INTRODUCTION
O
titis media is a distressing and disabling infection that commonly afflicts young children; most children will have had one episode by the age of 3 years
Received for publication 2 April 1990; accepted 5 April 1990. Address for correspondence: Dr D.P. Brodie, The Phygtle Surgery, Rickmansworth Lane, Chalfont St Peter, Buckinghamshire SL9 OND, UK. © Copyright 1990 by Cambridge Medical Publications Ltd
and 30% or more will have suffered from at least three attacks by this age.' Fortunately, very few children now develop serious complications from otitis media, such as mastoiditis or chronic otitis media; however, a significant number suffer from recurrent otitis media and have persistent middle ear effusion. Many have impaired hearing, which may interfere with language development and progress at school.' Furthermore, children with persistent middle ear effusions frequently require myringotomy or inser235
D.P. Brodie, J.V. Griggs, K. Cunningham tion of tympanostomy tubes. Cefuroxime is a broad-spectrum parenteral cephalosporin that is well established in the treatment of a wide range of infections caused by Gram-positive and Gramnegative organisms, including J3-lactamaseproducing strains.' Cefuroximeaxetil, which is an ester pro-drug of cefuroxime, is deesterified during absorption across the intestinal wall, releasing the active compound cefuroxime into the systemic circulation. The tablet formulation of cefuroxime axetil has now been extensively studied and has proven efficacy in a variety of infections, including otitis media;" - 7 however, crushed cefuroxime axetil tablets have a bitter taste and are therefore inappropriate for use in young children. Consequently, a suspension of cefuroxime axetil granules has been developed for the treatment of bacterial infections in children who are unable to swallow the tablets. The granules for the suspension contain cefuroxime axetil coated in stearic acid to the mask the taste. The present study was set up to compare the efficacy and tolerance ~f cefuroxime axetil suspension with those of amoxycillin syrup in the treatment of otitis media in children. PATIENTS AND METHODS
Patients Children suffering from otitis media and aged between 3 months and 12 years were included in a multicentre study. Parental consent was obtained for all patients before treatment commenced. Children with penicillin or cephalosporin allergy, with serious infections, who had previously entered a study or who had received antibiotic therapy within 3 days of starting treatment were excluded from the trial. Treatment An open study was performed in which
children were place in one of two dosage groups according to their age and were then 236
randomized to receive either amoxycilin syrup or cefuroxime axetil suspension. Patients under 2 years of age received either 125 mg cefuroxime axetil suspension twice daily after food or 125 mg amoxycillin syrup three times daily for 10 days. Older children were given 250 mg cefuroxime axetil suspension twice daily or 250 mg amoxycillin syrup three times daily for 10 days. Clinical assessment The patients were assessed before treatment started: otoscopic examination was performed and the presence of a middle ear infection was confirmed. In some patients, bacteriological samples were obtained by tympanocentesis, but most of the specimens were swabs taken from children with discharging ears. The patients were also examined 1 - 4 days after fmishing the 10day course of treatment and the clinical response was assessed as cure, improvement or failure. At 12 - 16 days after the end of treatment, further enquiry was made into the resolution or development of any adverse events and relapse of the infection. RESULTS
A total of 660 patients entered the study, of whom 658 receivedeitheramoxycillin syrup or cefuroxime axetil suspension (Table 1). The proportion of evaluable patients who were cured or improved when assessed 1 4 days after completing treatment was comparable in both groups (Table 2). The percentage of evaluable patients whose infections had recurred by 12 - 16 days after completing treatment was 5% in the cefuroxime axetil-treated group and 8% in the amoxycillin-treated group. Cefuroxime axetil was administered to 332 patients, of whom 69 (20.8%) were not evaluable, compared with 34/328 (10.4%) patients who received amoxycillin. Of the patients who were not evaluable and had received cefuroxime axetil, 35 failed to attend the first follow-up visit, 17 did not
Cefuroxime axetil vs amoxycillin in otitis media
Table 1 Demographic details of patients with otitis media treated with 125 or 250 mg cefuroxime axetil suspension twice daily or 125 or 250 mg amoxycillin syrup for 10 days Measure
No. of patients Female Male Median age (years) Mean weight (kg)
Cefuroxime axetil
Amoxycillin
125mg
250mg
125 mg
250mg
144 74 70 1.3 10.8
188 93 95 5.0 21.4
140 69 71 1.2 10.7
188 92 96 5.0 22.2
comply with the dosage regimen, including some patients who were unable to tolerate the taste of the suspension, 15 stopped treatment due to an adverse event and two patients did not receive any medication. The patients who were not evaluable and had received amoxycillin included 27 patients who failed to attend the first followup visit, four who did not comply with the dosage regimen and three who stopped due
to an adverse event. Of the 332 patients who were treated with cefuroxime axetil, 68 (20.5%) experienced at least one adverse event compared with 51/328 (15.5%) patients treated with amoxycillin; this difference was not statistically significant (P = 0.69). There were 35/332 (10.5%) of the cefuroxime axetiltreated group of patients who experienced gastro-intestinal adverse events compared
Table 2 Clinical outcome of evaluable patients treated with 125 or 250 mg cefuroxime axetil suspension twice daily or 125 or 250mg amoxycillin syrup three times daily for 10 days Clinical outcome
125 mg cefuroxime axetil
125 mg amoxycillin
Patients aged 3 months - 2 years Evaluable Cured or improved Failure Unevaluab1e
114 108 (94.7%) 6 (5.3%) 30
123 116 (94.3%) 7 (5.7%) 17
Patients aged 2 - 12 years Evaluable Cured or improved Failure Unevaluable
149 140 (94.0%) 9 (6.0%) 39
171 162 (94.7%) 9 (5.3%) 17
237
D.P. Brodie, J.V. Griggs, K. Cunningham with 14/328 (4.3%) of the equivalent amoxycillin-treated group (P = 0.002). Despite this difference, only a few patients from either treatment group were withdrawn due to adverse event: 17/332 (5.1%) of those receiving cefuroxime axetil compared with 11/328 (3.4%) of those treated with amoxycillin. A total of 96 bacterial isolates were obtained from the ear swabs, with Haemophi/us influenzae being the most common isolate (29%), followed by Streptococcus pneumoniae (22%) and Moraxella catarrhalis accounting for six isolates (6%). All the isolates were sensitive to cefuroxime axetil with the exception of four pseudomonal isolates, three Pseudomonas aeruginosa infections and one Pseudomonas species. The organisms were tested for amoxycillin susceptibility and the following isolates were found to be resistant: H. influenzae 2/28 (7.1%); Staphylococcus aureus 12/16 (75%), five ofwhich produced ~-lactamase; M. catarrhalis 3/6 (50%), two of which produced ~-Iactamase. All were cleared, however, after treatment with the exception of one H. influenzae and one Strep. pneumoniae isolate from each treatment group.
DISCUSSION The results of the present study indicate comparable efficacy for amoxycillin and cefuroxime axetil, with a similar percentage of patients cured or improved in both treatment groups. Although there was no significant difference in the overall incidence of adverse events between the two treatments, there was a higher incidence of drug-related gastro-intestinal events in the cefuroxime axetil-treated group of patients. Both tympanocentesis and ear swabs were used to obtain bacteriological specimens; the pathogens isolated in the present study corresponded to the bacteriology from other trials," Strep. pneumoniae and H. influenzae are the two main pathogens found in otitis media, with 20 - 30% of
238
H. influenzae producing ~-lactamase.8 - 10 M. catarrhalis has been increasingly recognized as a pathogen in otitis media, with studies demonstrating a prevalence of 19% or more; this is particularly important as many are ampicillin-resistant.w-" Some of the organisms isolated in the study were resistant to amoxycillin, including Staph. aureus, M. catarrhalis and H. influenzae. This contrasts with the absence of significant resistance to cefuroxime, apart from four pseudomonal isolates, which were resistant to both cefuroxime and amoxycillin. The present study has demonstrated that for the treatment of otitis media in children cefuroxime axetil suspension given twice daily was as effective and well tolerated as amoxycillin syrup given three times daily. REFERENCES 1. Teele OW, Klein JO, Rosner BA: Epidemiology of otitis in children. Ann Otol Rhinol Laryngol 1980; 89 (suppI68): 5 - 6. 2. Bishop DVM, Edmundson A: Is otitis media a major cause of specific developmental language disorder? Br J Disord Commun 1986; 21: 321 338. 3. Smith BR, LeFrock JL: Cefuroxime: antimicrobial activity, pharmacology and clinical efficacy. Ther Drug Monit 1983; 5: 149 - 160. 4. Emmerson AM: Cefuroxime axetil (leading article). J Antimicrob Chemother 1988; 22: 101 103. 5. Aronovitz GH: Treatment of otitis media with cefuroxime axetil. South MedJ 1988; 81: 978 -980. 6. McLinn SE, Werner K, Cocchetto OM: Clinical trial of cefuroxime axetil versus cefaclor for acute otitis media with effusion. Curr Ther Res 1988; 43: I-II. 7. Finn AL, Sherrill JM, Debussey SS: A comparative study of cefuroxime axetil and cefaclor in the treatment of otitis media with effusion (Abstract). Program and Abstracts ofthe Twenty-fifth Interscience Conference on Antimicrobial Agents and Chemotherapy, Minneapolis, 29 September - 2 October 1985. Washington: American Society for Microbiology, 1985; p. 202. 8. Giebink GS: The microbiology of otitis media. PediatrInfect Dis J 1989; 8: SI8 - S20. 9. Nelson JD: Changing trends in the microbiology and management of acute otitis media and sinusitis. Pediatr Infect Dis J 1986; 5: 749 - 753. 10. Bluestone CD: Otitis media and sinusitis: man-
Cefuroxime axetil vs amoxycillin in otitis media agement and when to refer to the otolaryngolist. Pediatr Infect Dis] 1987; 6: 100 - 106. 11. Shurin PA, Marchant CD, Kim CH, et al: Emergence of beta-lactamase-producing strains of
Branhamella catarrhalis as important agents of acute otitis media. Pediatr Infect Dis] 1983; 2: 34 -38.
239
Comparative Study of Cefuroxime Axetil Suspension and Amoxycillin Syrup in the Treatment of Acute Otitis Media in General Practice D.P. Brodie', J.V. Griggs 2 and K. Cunningham" 'The Phygtle Surgery, Chalfont St Peter, UK; 2Glaxo Research Ltd, Greenford, UK In a multicentre general practice study, 660 children aged between 3 months and 12 years with otitis media were randomized to receive a 10day course of cefuroxime axetil suspension or amoxycillin syrup. Children under 2 years of age were given 125 mg cefuroxime axetil twice daily after food or 125 mg amoxycillin three times daily; older children received 250 mg cefuroxime axetil twice daily or 250 mg . amoxycillin three times daily. The overall cure or improvement rate was 94.3 % for those treated with cefuroxime axetil and 94.5% for those receiving amoxycillin. Both treatments were well tolerated, with no differences in the number of patients who experienced at least one adverse event or who were withdrawn from treatment. Haemophilus influenzae was isolated in 29 % of specimens obtained, Streptococcus pneumoniae in 22% and Moraxella cata"halis in 6%. Some Strep. pneumonia and M. catarrhalis infections were resistant to amoxycillin. It is concluded that cefuroxime axetil suspension given twice daily has comparable efficacy to amoxycillin syrup given three times daily in the treatment of children with otitis media. KEY WORDS: Cefuroxime axetil; amoxycillin; otitis media.
INTRODUCTION
O
titis media is a distressing and disabling infection that commonly afflicts young children; most children will have had one episode by the age of 3 years
Received for publication 2 April 1990; accepted 5 April 1990. Address for correspondence: Dr D.P. Brodie, The Phygtle Surgery, Rickmansworth Lane, Chalfont St Peter, Buckinghamshire SL9 OND, UK. © Copyright 1990 by Cambridge Medical Publications Ltd
and 30% or more will have suffered from at least three attacks by this age.' Fortunately, very few children now develop serious complications from otitis media, such as mastoiditis or chronic otitis media; however, a significant number suffer from recurrent otitis media and have persistent middle ear effusion. Many have impaired hearing, which may interfere with language development and progress at school.' Furthermore, children with persistent middle ear effusions frequently require myringotomy or inser235
D.P. Brodie, J.V. Griggs, K. Cunningham tion of tympanostomy tubes. Cefuroxime is a broad-spectrum parenteral cephalosporin that is well established in the treatment of a wide range of infections caused by Gram-positive and Gramnegative organisms, including J3-lactamaseproducing strains.' Cefuroximeaxetil, which is an ester pro-drug of cefuroxime, is deesterified during absorption across the intestinal wall, releasing the active compound cefuroxime into the systemic circulation. The tablet formulation of cefuroxime axetil has now been extensively studied and has proven efficacy in a variety of infections, including otitis media;" - 7 however, crushed cefuroxime axetil tablets have a bitter taste and are therefore inappropriate for use in young children. Consequently, a suspension of cefuroxime axetil granules has been developed for the treatment of bacterial infections in children who are unable to swallow the tablets. The granules for the suspension contain cefuroxime axetil coated in stearic acid to the mask the taste. The present study was set up to compare the efficacy and tolerance ~f cefuroxime axetil suspension with those of amoxycillin syrup in the treatment of otitis media in children. PATIENTS AND METHODS
Patients Children suffering from otitis media and aged between 3 months and 12 years were included in a multicentre study. Parental consent was obtained for all patients before treatment commenced. Children with penicillin or cephalosporin allergy, with serious infections, who had previously entered a study or who had received antibiotic therapy within 3 days of starting treatment were excluded from the trial. Treatment An open study was performed in which
children were place in one of two dosage groups according to their age and were then 236
randomized to receive either amoxycilin syrup or cefuroxime axetil suspension. Patients under 2 years of age received either 125 mg cefuroxime axetil suspension twice daily after food or 125 mg amoxycillin syrup three times daily for 10 days. Older children were given 250 mg cefuroxime axetil suspension twice daily or 250 mg amoxycillin syrup three times daily for 10 days. Clinical assessment The patients were assessed before treatment started: otoscopic examination was performed and the presence of a middle ear infection was confirmed. In some patients, bacteriological samples were obtained by tympanocentesis, but most of the specimens were swabs taken from children with discharging ears. The patients were also examined 1 - 4 days after fmishing the 10day course of treatment and the clinical response was assessed as cure, improvement or failure. At 12 - 16 days after the end of treatment, further enquiry was made into the resolution or development of any adverse events and relapse of the infection. RESULTS
A total of 660 patients entered the study, of whom 658 receivedeitheramoxycillin syrup or cefuroxime axetil suspension (Table 1). The proportion of evaluable patients who were cured or improved when assessed 1 4 days after completing treatment was comparable in both groups (Table 2). The percentage of evaluable patients whose infections had recurred by 12 - 16 days after completing treatment was 5% in the cefuroxime axetil-treated group and 8% in the amoxycillin-treated group. Cefuroxime axetil was administered to 332 patients, of whom 69 (20.8%) were not evaluable, compared with 34/328 (10.4%) patients who received amoxycillin. Of the patients who were not evaluable and had received cefuroxime axetil, 35 failed to attend the first follow-up visit, 17 did not
Cefuroxime axetil vs amoxycillin in otitis media
Table 1 Demographic details of patients with otitis media treated with 125 or 250 mg cefuroxime axetil suspension twice daily or 125 or 250 mg amoxycillin syrup for 10 days Measure
No. of patients Female Male Median age (years) Mean weight (kg)
Cefuroxime axetil
Amoxycillin
125mg
250mg
125 mg
250mg
144 74 70 1.3 10.8
188 93 95 5.0 21.4
140 69 71 1.2 10.7
188 92 96 5.0 22.2
comply with the dosage regimen, including some patients who were unable to tolerate the taste of the suspension, 15 stopped treatment due to an adverse event and two patients did not receive any medication. The patients who were not evaluable and had received amoxycillin included 27 patients who failed to attend the first followup visit, four who did not comply with the dosage regimen and three who stopped due
to an adverse event. Of the 332 patients who were treated with cefuroxime axetil, 68 (20.5%) experienced at least one adverse event compared with 51/328 (15.5%) patients treated with amoxycillin; this difference was not statistically significant (P = 0.69). There were 35/332 (10.5%) of the cefuroxime axetiltreated group of patients who experienced gastro-intestinal adverse events compared
Table 2 Clinical outcome of evaluable patients treated with 125 or 250 mg cefuroxime axetil suspension twice daily or 125 or 250mg amoxycillin syrup three times daily for 10 days Clinical outcome
125 mg cefuroxime axetil
125 mg amoxycillin
Patients aged 3 months - 2 years Evaluable Cured or improved Failure Unevaluab1e
114 108 (94.7%) 6 (5.3%) 30
123 116 (94.3%) 7 (5.7%) 17
Patients aged 2 - 12 years Evaluable Cured or improved Failure Unevaluable
149 140 (94.0%) 9 (6.0%) 39
171 162 (94.7%) 9 (5.3%) 17
237
D.P. Brodie, J.V. Griggs, K. Cunningham with 14/328 (4.3%) of the equivalent amoxycillin-treated group (P = 0.002). Despite this difference, only a few patients from either treatment group were withdrawn due to adverse event: 17/332 (5.1%) of those receiving cefuroxime axetil compared with 11/328 (3.4%) of those treated with amoxycillin. A total of 96 bacterial isolates were obtained from the ear swabs, with Haemophi/us influenzae being the most common isolate (29%), followed by Streptococcus pneumoniae (22%) and Moraxella catarrhalis accounting for six isolates (6%). All the isolates were sensitive to cefuroxime axetil with the exception of four pseudomonal isolates, three Pseudomonas aeruginosa infections and one Pseudomonas species. The organisms were tested for amoxycillin susceptibility and the following isolates were found to be resistant: H. influenzae 2/28 (7.1%); Staphylococcus aureus 12/16 (75%), five ofwhich produced ~-lactamase; M. catarrhalis 3/6 (50%), two of which produced ~-Iactamase. All were cleared, however, after treatment with the exception of one H. influenzae and one Strep. pneumoniae isolate from each treatment group.
DISCUSSION The results of the present study indicate comparable efficacy for amoxycillin and cefuroxime axetil, with a similar percentage of patients cured or improved in both treatment groups. Although there was no significant difference in the overall incidence of adverse events between the two treatments, there was a higher incidence of drug-related gastro-intestinal events in the cefuroxime axetil-treated group of patients. Both tympanocentesis and ear swabs were used to obtain bacteriological specimens; the pathogens isolated in the present study corresponded to the bacteriology from other trials," Strep. pneumoniae and H. influenzae are the two main pathogens found in otitis media, with 20 - 30% of
238
H. influenzae producing ~-lactamase.8 - 10 M. catarrhalis has been increasingly recognized as a pathogen in otitis media, with studies demonstrating a prevalence of 19% or more; this is particularly important as many are ampicillin-resistant.w-" Some of the organisms isolated in the study were resistant to amoxycillin, including Staph. aureus, M. catarrhalis and H. influenzae. This contrasts with the absence of significant resistance to cefuroxime, apart from four pseudomonal isolates, which were resistant to both cefuroxime and amoxycillin. The present study has demonstrated that for the treatment of otitis media in children cefuroxime axetil suspension given twice daily was as effective and well tolerated as amoxycillin syrup given three times daily. REFERENCES 1. Teele OW, Klein JO, Rosner BA: Epidemiology of otitis in children. Ann Otol Rhinol Laryngol 1980; 89 (suppI68): 5 - 6. 2. Bishop DVM, Edmundson A: Is otitis media a major cause of specific developmental language disorder? Br J Disord Commun 1986; 21: 321 338. 3. Smith BR, LeFrock JL: Cefuroxime: antimicrobial activity, pharmacology and clinical efficacy. Ther Drug Monit 1983; 5: 149 - 160. 4. Emmerson AM: Cefuroxime axetil (leading article). J Antimicrob Chemother 1988; 22: 101 103. 5. Aronovitz GH: Treatment of otitis media with cefuroxime axetil. South MedJ 1988; 81: 978 -980. 6. McLinn SE, Werner K, Cocchetto OM: Clinical trial of cefuroxime axetil versus cefaclor for acute otitis media with effusion. Curr Ther Res 1988; 43: I-II. 7. Finn AL, Sherrill JM, Debussey SS: A comparative study of cefuroxime axetil and cefaclor in the treatment of otitis media with effusion (Abstract). Program and Abstracts ofthe Twenty-fifth Interscience Conference on Antimicrobial Agents and Chemotherapy, Minneapolis, 29 September - 2 October 1985. Washington: American Society for Microbiology, 1985; p. 202. 8. Giebink GS: The microbiology of otitis media. PediatrInfect Dis J 1989; 8: SI8 - S20. 9. Nelson JD: Changing trends in the microbiology and management of acute otitis media and sinusitis. Pediatr Infect Dis J 1986; 5: 749 - 753. 10. Bluestone CD: Otitis media and sinusitis: man-
Cefuroxime axetil vs amoxycillin in otitis media agement and when to refer to the otolaryngolist. Pediatr Infect Dis] 1987; 6: 100 - 106. 11. Shurin PA, Marchant CD, Kim CH, et al: Emergence of beta-lactamase-producing strains of
Branhamella catarrhalis as important agents of acute otitis media. Pediatr Infect Dis] 1983; 2: 34 -38.
239
