Scandinavian Journal of Infectious Diseases
ISSN: 0036-5548 (Print) 1651-1980 (Online) Journal homepage: http://www.tandfonline.com/loi/infd19
Double-blind comparison of cefixime and cefaclor in the treatment of acute otitis media in children Toivo Piippo, Sigurdur Stefansson, Timo Pitkäjärvi & Christer Lundberg To cite this article: Toivo Piippo, Sigurdur Stefansson, Timo Pitkäjärvi & Christer Lundberg (1991) Double-blind comparison of cefixime and cefaclor in the treatment of acute otitis media in children, Scandinavian Journal of Infectious Diseases, 23:4, 459-465 To link to this article: http://dx.doi.org/10.3109/00365549109075094
Published online: 08 Jul 2009.
Submit your article to this journal
Article views: 13
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Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=infd19 Download by: [ECU Libraries]
Date: 29 September 2015, At: 00:34
Scand J Infect Dis 23: 459465. 1991
Double-Blind Comparison of Cefixime and Cefaclor in the Treatment of Acute Otitis Media in Children T O I V O PIIPPO',SIGURDUR STEFANSSON',TIMO PITKAJARVI' and CHRISTER LUNDBERG'
Downloaded by [ECU Libraries] at 00:34 29 September 2015
From the 'Community Health Cmtre oj the City of Tumpere, Tampere, Finland, the EN7 Departments of 'Reykjavik City Hospital, Reykjavik, Iceland and iSahlgren's Hospital. Gutdwrg. Fweden
In a double-blind study cefixime, an oral cephalosporin of the third generation, was compared to cefaclor in the treatment of acute otitis media in 397 children aged 6 months to 12 years. Clinical evaluation was carried out at the beginning, at day 10-12 and day 28-35 after the start of the treatment. Specimens for bacterial culture and sensitivity testings were taken from the nasopharynx at the initial visit. Patients were randomized either to cefixime in a dose of 8 mg/kg/day or cefaclor in a dose 40 mg/kg/day in the proportion of 2 cefixime patients to 1 cefaclor patient. Two daily doses were administered for 7 days. At day 10-12, 93.5% in the cefixime group and 90.5% in the cefaclor group @=0.08) were clinically cured or improved. At day 28-35 the rate of cured or improved patients had decreased, mostly due to reinfections, to 90.1% in the cefixime group and to 86.6% in the cefaclor group @=0.12), respectively. 375 patients (69.9%)had positive bacterial culture in the nasopharynx of at least one strain of Haemophilus intluenzae, Streptococcus pneumoniae, Branhamella (Moraxella) catarrhalis or combinations of these 3. 73.6% of the B. catarrhalis strains were beta-lactamase producing and 11.4% of the H. influenzae strains, respectively. All isolated bacteria were sensitive to cefixime. Adverse events were reported in 17.9% in the cefixime and 10.6% in the cefaclor group. Most reactions were of moderate or mild nature and mostly affected skin or the gastrointestinal region. No serious adverse experiences occurred. In view of the good clinical results obtained cefixime seems to he at least as effective as cefaclor in the treatment of acute otitis media in children. T . Pitkayarvi, M D , Community Health Centre, Hatanpiiii, SF-33100 Tampere, Finland
INTRODUCTION Acute otitis media (AOM) is a frequently occurring disease. More than 50% of all children are reported to have suffered from at least one episode of A O M before the age of 4 (1, 2). The highest incidence occurs between the ages of 6 months and 2 years (2, 3). The most frequently occurring pathogen in AOM, Streptococcus pneumoniae, is isolated in 3&.50% of middle ear effusions, and Haemophilus influenzae in 15-20% (4). Branhamella (Moraxella) catarrhalis is found in about 10% (3, 4). During recent years betalactamase producing H. influenzae and B. catarrhalis have increased in Scandinavia and are at present reported in approximately &10% and 4&60%, respectively (4). In treatment failures with phenoxymethylpenicillin the importance of such strains is documented ( 5 ) . but based o n some studies these beta-lactamase producing strains have n o significant effect on treatment results (6, 7). Cefixime is the first third generation oral cephalosporin (8). It has a broader spectrum of activity against Gram-negative bacteria as compared to other oral cephalosporins. Furthermore, it is stable to hydrolysis by most beta-lactamases and is often active against bacteria resistant to other oral cephalosporins and aminopenicillins. The MIC,, value of cefixime against H. influenzae and B. catarrhalis is 5 0.25 mgil.
460
T. Piippo et al.
S c a d J Infect Dis 23
Table I . Distribution of sex and age of all randomized patients Cefixime (n=264)
Cefaclor
No. of pat. %
NO. of pat.
(n=133) Yo
Total
(n=397)
No. ofpat. Yo
Sex
Downloaded by [ECU Libraries] at 00:34 29 September 2015
Male Female Age 5 2 years 2 4 years >h years
143 121
54.2 45.8
65 68
48.9 51.1
208 189
52.4 47.6
95 107 62
36.0 40.5 23.5
53 60 20
39.8 45.1 15.0
148 167 82
37.3 42.1 20.7
Due to its high antibacterial activity against pathogens known t o cause A O M , cefixime should be a suitable second choice alternative to other cephalosporins or aminopenicillins. Cefixime has been given to more than 2 500 adult patients and 1300 children for treatment of urinary tract infections as well as lower and upper respiratory tract infections including otitis media. The incidence of adverse experiences has been reported to be from 1-5% skin reactions to 10-15% gastrointestinal reactions (8, 9). The present study was conducted to document the therapeutic effect as well as the safety in a sufficiently great number of children with AOM. Cefaclor has been chosen as the reference drug in this study since it belongs to the same class of antibiotics and has good efficacy and tolerance in A O M infections (10, 11). PATIENTS A N D METHODS The study was carried out as a controlled, randomized, double-blind trial with parallel group design from March 1987 to January 1988 with the participation of 2 clinics: a general practitioner unit in the Community Health Centre of the City of Tampere, Finland, and an otologic specialist unit in Reykjavik, Iceland. The study was approved by the Ethical Committee of the City of Tampere and University of Reykjavik. Informed consent of the parents was obtained. A total of 450 patients, were planned to be enrolled in the study. Of these at least 345 were assumed to be evaluable for last valid visit efficacy. This number was based o n demonstrating equivalence between treatments with a cure rate of 90% and a difference between treatments with at most 10%units (12). 397 children of both sexes aged 6 months to 12 years were included in the study, 173 from Finland and 224 from Iceland. The distribution of sex and age of all randomized patients is seen in Table 1. The
children were all outpatients with a diagnosis of AOM based on an otoscopic examination of the eardrum with signs of the disease including thick, red, bulging eardrum with decreased mobility or spontaneous perforation. At least one of the following additional symptoms had to be present: earache, irritability or fever. Exclusion criteria were: hypersensitivity to cephalosporins andlor penicillins, insertion of tympanostomy tubes, antibiotic therapy within the preceding 4 days, concomitant infections apart from upper respiratory tract infections, severe underlying disease including immunological deficiences, previous inclusion in the study or paracentesis performed at the first visit and chronic ear disease (chronic perforation). Four patients, all in the cefixime group, had long-term medication, for epilepsy ( 1 patient) or bronchial asthma (3 patients). Each patient was randomized to either cefixime or cefaclor suspension in the proportion of 2 cefixime patients to 1 cefaclor patient, thus yielding twice as many patients on cefixime treatment. The randomizations were carried out in blocks of 6 and stratified by a computer. The doses were: cefixime suspension 20 mg/ml in a dose of 8 mg/kg/day or cefaclor suspension 50 mg/ml in a dose of 40 mg/kg/day. Both drugs were divided in 2 daily doses for 7 days. Specimens for bacteriological culture and sensitivity testing were taken from nasopharynx at the initial visit. Normal routines were used for the handling and transport of the samples. Isolated
Cefixime and cefaclor in acute otitis media 461
Scand J Infect DI\ 23
Table 11. Cure rates at day 10-12 and 28-35 ~
Curc rate
Downloaded by [ECU Libraries] at 00:34 29 September 2015
At day 1&12 Cured Improved Failure
Cefixime
Cefaclor
N o . o f pat.
Yo
150~ 85 16
59 x 33 9 6.4
Total
25 1
At day 28-35 Cured Improvcd Failure
18hh 41 25
Total
252
No. of pat.
64' 50 12
"/o
50.8 39.7 9.5
126
73.x 16.3 9.9
84h 26 17
66. I 20.5 13.4
127
= 0.081, confidence interval - 9.1%, 2.8% " p = 0.12, confidence interval - 10.4%, 3.5%
organisms were identified and sensitivity testing was performed against cefixime, ccfaclor and cephalexin using the disk diffusion method. In sensitivity testing the zone limits for cefixime were 2 26 (sensitive) and 5 20 mm (resistant) and for cefaclor 2 23 (sensitive) and I16 mm (resistant) with disc contents of 30 pg cefixime or cefdch/disc. Beta-lactamase production was checked by the nitroccfin method (13). The clinical evaluation of the treatment was carried out at 2 follow-up visits, scheduled 10-12 days and 28-35 days after start of treatment. The clinical efficacy was classified as cured (a normal and mobile eardrum and absence of symptoms), improved (thin eardrum with sign of middle-ear effusion) or failure (remaining signs or symptoms of AOM). Nonspecific questions were asked to establish a baseline of medical condition and all reported experiences over and above those reported at the initial visit were recorded and evaluated with regard to the possibility of side effects. The patients were considered valid for efficacy if they had data from at least 1 follow-up visit, had taken the study drug for at least 5 days (10 consecutive doses) and had had no concomitant antibiotic medication before the follow-up visit. All patients for whom data were available and who had received at least 1 dose were included in the analysis of safety.
Statistits Thc short term cure rate (day 1 C 1 2 ) and the last valid visit cure rate (day 2&35) were compared for the two drugs by chi-square tests and 2-sided 95% confidence intervals. The same methods were used for adverse events. In addition, Mantel-Haenzel tests were used to compare the cure rates adjusted for the prognostic factors, centre, sex. recurrence and initial bacteriological finding of established pathogens. Possible differences in cure rates for the prognostic factors were investigated by the Breslow-Day test for homogeneity of odd ratios. Wilcoxon's 2-sample tests for the graded clinical responses (cured vs improved vs failure) were used for the short-term and last valid visit cure rates.
RESULTS Out of the patients in both treatment groups 95.5% (n=379) were valid for efficacy. Cure rates in the cefixime and cefaclor groups at day 10-12 and the last visit are presented in Table 11. 39 patients (23 in the cefixime treated group and 16 in the cefaclor treated group) initiated other antibacterial treatment between control visits, mainly because of an AOM requiring further antibiotic treatment. From the 379 patients valid for efficacy evaluation, a total of 618 bacterial strains were isolated from nasopharynx at the initial visit. Samples from 17 patients were classified either as no growth or no sample taken. 231 patients (60.9%) had an initial positive culture of at
462
T. Piippo et al.
Scand J Infect Dis 23
Table 111. Bacterial strains isolated from nasopharynx at entry from patients valid for efficacy
Downloaded by [ECU Libraries] at 00:34 29 September 2015
Initial hacteria
Cefixime
Cefaclor
No. of strains
No. of strains
Total %
Haemophilus influenzae Streptococcus pneumoniae Branhamella catarrhalis Other species Ordinary flora
90 77 68 125 48
42 46 23 75 24
21.4 19.9 14.7 32.4 11.6
Total
408
210
100.0
least one strain of H. influenzae, S. pneumoniae or B. catarrhalis or different combinations of these 3 bacteria. As seen in Table 111, these 3 bacterial species constituted 56.0% of all bacteria isolated and they were relatively evenly distributed in the two treatment groups. Sensitivity testing showed that the strains of H. influenzae, S. pneumoniae and B. catarrhalis were all sensitive to cefixime but showed intermediate sensitivity to cefaclor in the case of H. influenzae (26/132 strains) and B. catarrhalis (16/91 strains). In addition, 5 strains of H. influenzae were judged to be resistant to cefaclor (one of these strains was a beta-lactamase producer). 91 patients had a positive culture of B. catarrhalis at the initial visit. Out of these, 67 children (73.6%) had beta-lactamase producing strains. The short-term cure rate at day 1&12 for these children was 46.0% in the cefixime group and 23.5% in the cefaclor group. The number of patients in each group is too low to allow statistical analyses. 132 patients had a positive culture of H . influenzae at the initial visit and out of these 15 (11.4%) had beta-lactamase producing strains. Here the same tendency is apparent with short-term rate of 45.5% in the cefixime group compared to 25.0% in the cefaclor group, but again not possible to analyse stastistically. Of the 397 patients included, 394 were valid for safety analysis. As seen in Table IV, there was no statistical difference (p = 0.06) in adverse experiences, reported by the patients in the cefixime and cefaclor groups. 18 children discontinued treatment prematurely for the reason given in Table V. Seven patients (2.7%) in the cefixime group discontinued treatment prematurely due to adverse events. Five of these patients had diarrhoea (3 of moderate intensity and 2 severe) and the other 2 mild disturbances in breathing and moderate vomiting, respectively. The symptoms ceased spontaneously after 3-5 days. Three patients (2.3%) in the cefaclor group discontinued treatment due to adverse events. Two patients had diarrhoea of moderate intensity that
Table IV. Adverse reactions according to intensity (patients valid for safety) Maximum intensity of adverse reactions
Cefixime
No. of pat.
Cefaclor
Total
%
No. of pat.
%
118
89.4 6.8 3.8
333 31 21 3
84.5 9.4 5.3 0.8
100.0
394
100.0
None Mild Moderate Severe
215 28 16 3
82.1 10.7 6.1 1.1
5 None
Total
262
100.0
132
9
No. of pat.
/'o
C‘efixime and cefaclor in acute otitis media 463
S c d I Infcct DIS23
TMe V. Reasons for premature di.scontinuation of treatment of all randomized putienfs Reason
Cefixime ( n
=
264)
No. of pat.
Deteriorated or not improved Adverse cvcnts Patients refusal
Downloaded by [ECU Libraries] at 00:34 29 September 2015
Total
Cefaclor ( n = 133) No. of pat.
?,:
%
I.5
3 2
I .5 2.3 1 .s
4.2
7
5.3
-
2
7 4
2.7
11
lasted for 3 and 5 days respectively. The third patient developed - during medication - a pneumonia that was considered cured at follow-up visit day 12. No serious adverse events were reported. The numbers of patients reporting adverse experiences spontaneously or after a nonleading question are presented in Table VI. Diarrhoea and loose stools were more often reported from Iceland than Finland, occurring in 19% of the patients in Iceland compared to 6.1% in Finland. Diarrhoea and loose stools occurred most frequently in children
ISSN: 0036-5548 (Print) 1651-1980 (Online) Journal homepage: http://www.tandfonline.com/loi/infd19
Double-blind comparison of cefixime and cefaclor in the treatment of acute otitis media in children Toivo Piippo, Sigurdur Stefansson, Timo Pitkäjärvi & Christer Lundberg To cite this article: Toivo Piippo, Sigurdur Stefansson, Timo Pitkäjärvi & Christer Lundberg (1991) Double-blind comparison of cefixime and cefaclor in the treatment of acute otitis media in children, Scandinavian Journal of Infectious Diseases, 23:4, 459-465 To link to this article: http://dx.doi.org/10.3109/00365549109075094
Published online: 08 Jul 2009.
Submit your article to this journal
Article views: 13
View related articles
Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=infd19 Download by: [ECU Libraries]
Date: 29 September 2015, At: 00:34
Scand J Infect Dis 23: 459465. 1991
Double-Blind Comparison of Cefixime and Cefaclor in the Treatment of Acute Otitis Media in Children T O I V O PIIPPO',SIGURDUR STEFANSSON',TIMO PITKAJARVI' and CHRISTER LUNDBERG'
Downloaded by [ECU Libraries] at 00:34 29 September 2015
From the 'Community Health Cmtre oj the City of Tumpere, Tampere, Finland, the EN7 Departments of 'Reykjavik City Hospital, Reykjavik, Iceland and iSahlgren's Hospital. Gutdwrg. Fweden
In a double-blind study cefixime, an oral cephalosporin of the third generation, was compared to cefaclor in the treatment of acute otitis media in 397 children aged 6 months to 12 years. Clinical evaluation was carried out at the beginning, at day 10-12 and day 28-35 after the start of the treatment. Specimens for bacterial culture and sensitivity testings were taken from the nasopharynx at the initial visit. Patients were randomized either to cefixime in a dose of 8 mg/kg/day or cefaclor in a dose 40 mg/kg/day in the proportion of 2 cefixime patients to 1 cefaclor patient. Two daily doses were administered for 7 days. At day 10-12, 93.5% in the cefixime group and 90.5% in the cefaclor group @=0.08) were clinically cured or improved. At day 28-35 the rate of cured or improved patients had decreased, mostly due to reinfections, to 90.1% in the cefixime group and to 86.6% in the cefaclor group @=0.12), respectively. 375 patients (69.9%)had positive bacterial culture in the nasopharynx of at least one strain of Haemophilus intluenzae, Streptococcus pneumoniae, Branhamella (Moraxella) catarrhalis or combinations of these 3. 73.6% of the B. catarrhalis strains were beta-lactamase producing and 11.4% of the H. influenzae strains, respectively. All isolated bacteria were sensitive to cefixime. Adverse events were reported in 17.9% in the cefixime and 10.6% in the cefaclor group. Most reactions were of moderate or mild nature and mostly affected skin or the gastrointestinal region. No serious adverse experiences occurred. In view of the good clinical results obtained cefixime seems to he at least as effective as cefaclor in the treatment of acute otitis media in children. T . Pitkayarvi, M D , Community Health Centre, Hatanpiiii, SF-33100 Tampere, Finland
INTRODUCTION Acute otitis media (AOM) is a frequently occurring disease. More than 50% of all children are reported to have suffered from at least one episode of A O M before the age of 4 (1, 2). The highest incidence occurs between the ages of 6 months and 2 years (2, 3). The most frequently occurring pathogen in AOM, Streptococcus pneumoniae, is isolated in 3&.50% of middle ear effusions, and Haemophilus influenzae in 15-20% (4). Branhamella (Moraxella) catarrhalis is found in about 10% (3, 4). During recent years betalactamase producing H. influenzae and B. catarrhalis have increased in Scandinavia and are at present reported in approximately &10% and 4&60%, respectively (4). In treatment failures with phenoxymethylpenicillin the importance of such strains is documented ( 5 ) . but based o n some studies these beta-lactamase producing strains have n o significant effect on treatment results (6, 7). Cefixime is the first third generation oral cephalosporin (8). It has a broader spectrum of activity against Gram-negative bacteria as compared to other oral cephalosporins. Furthermore, it is stable to hydrolysis by most beta-lactamases and is often active against bacteria resistant to other oral cephalosporins and aminopenicillins. The MIC,, value of cefixime against H. influenzae and B. catarrhalis is 5 0.25 mgil.
460
T. Piippo et al.
S c a d J Infect Dis 23
Table I . Distribution of sex and age of all randomized patients Cefixime (n=264)
Cefaclor
No. of pat. %
NO. of pat.
(n=133) Yo
Total
(n=397)
No. ofpat. Yo
Sex
Downloaded by [ECU Libraries] at 00:34 29 September 2015
Male Female Age 5 2 years 2 4 years >h years
143 121
54.2 45.8
65 68
48.9 51.1
208 189
52.4 47.6
95 107 62
36.0 40.5 23.5
53 60 20
39.8 45.1 15.0
148 167 82
37.3 42.1 20.7
Due to its high antibacterial activity against pathogens known t o cause A O M , cefixime should be a suitable second choice alternative to other cephalosporins or aminopenicillins. Cefixime has been given to more than 2 500 adult patients and 1300 children for treatment of urinary tract infections as well as lower and upper respiratory tract infections including otitis media. The incidence of adverse experiences has been reported to be from 1-5% skin reactions to 10-15% gastrointestinal reactions (8, 9). The present study was conducted to document the therapeutic effect as well as the safety in a sufficiently great number of children with AOM. Cefaclor has been chosen as the reference drug in this study since it belongs to the same class of antibiotics and has good efficacy and tolerance in A O M infections (10, 11). PATIENTS A N D METHODS The study was carried out as a controlled, randomized, double-blind trial with parallel group design from March 1987 to January 1988 with the participation of 2 clinics: a general practitioner unit in the Community Health Centre of the City of Tampere, Finland, and an otologic specialist unit in Reykjavik, Iceland. The study was approved by the Ethical Committee of the City of Tampere and University of Reykjavik. Informed consent of the parents was obtained. A total of 450 patients, were planned to be enrolled in the study. Of these at least 345 were assumed to be evaluable for last valid visit efficacy. This number was based o n demonstrating equivalence between treatments with a cure rate of 90% and a difference between treatments with at most 10%units (12). 397 children of both sexes aged 6 months to 12 years were included in the study, 173 from Finland and 224 from Iceland. The distribution of sex and age of all randomized patients is seen in Table 1. The
children were all outpatients with a diagnosis of AOM based on an otoscopic examination of the eardrum with signs of the disease including thick, red, bulging eardrum with decreased mobility or spontaneous perforation. At least one of the following additional symptoms had to be present: earache, irritability or fever. Exclusion criteria were: hypersensitivity to cephalosporins andlor penicillins, insertion of tympanostomy tubes, antibiotic therapy within the preceding 4 days, concomitant infections apart from upper respiratory tract infections, severe underlying disease including immunological deficiences, previous inclusion in the study or paracentesis performed at the first visit and chronic ear disease (chronic perforation). Four patients, all in the cefixime group, had long-term medication, for epilepsy ( 1 patient) or bronchial asthma (3 patients). Each patient was randomized to either cefixime or cefaclor suspension in the proportion of 2 cefixime patients to 1 cefaclor patient, thus yielding twice as many patients on cefixime treatment. The randomizations were carried out in blocks of 6 and stratified by a computer. The doses were: cefixime suspension 20 mg/ml in a dose of 8 mg/kg/day or cefaclor suspension 50 mg/ml in a dose of 40 mg/kg/day. Both drugs were divided in 2 daily doses for 7 days. Specimens for bacteriological culture and sensitivity testing were taken from nasopharynx at the initial visit. Normal routines were used for the handling and transport of the samples. Isolated
Cefixime and cefaclor in acute otitis media 461
Scand J Infect DI\ 23
Table 11. Cure rates at day 10-12 and 28-35 ~
Curc rate
Downloaded by [ECU Libraries] at 00:34 29 September 2015
At day 1&12 Cured Improved Failure
Cefixime
Cefaclor
N o . o f pat.
Yo
150~ 85 16
59 x 33 9 6.4
Total
25 1
At day 28-35 Cured Improvcd Failure
18hh 41 25
Total
252
No. of pat.
64' 50 12
"/o
50.8 39.7 9.5
126
73.x 16.3 9.9
84h 26 17
66. I 20.5 13.4
127
= 0.081, confidence interval - 9.1%, 2.8% " p = 0.12, confidence interval - 10.4%, 3.5%
organisms were identified and sensitivity testing was performed against cefixime, ccfaclor and cephalexin using the disk diffusion method. In sensitivity testing the zone limits for cefixime were 2 26 (sensitive) and 5 20 mm (resistant) and for cefaclor 2 23 (sensitive) and I16 mm (resistant) with disc contents of 30 pg cefixime or cefdch/disc. Beta-lactamase production was checked by the nitroccfin method (13). The clinical evaluation of the treatment was carried out at 2 follow-up visits, scheduled 10-12 days and 28-35 days after start of treatment. The clinical efficacy was classified as cured (a normal and mobile eardrum and absence of symptoms), improved (thin eardrum with sign of middle-ear effusion) or failure (remaining signs or symptoms of AOM). Nonspecific questions were asked to establish a baseline of medical condition and all reported experiences over and above those reported at the initial visit were recorded and evaluated with regard to the possibility of side effects. The patients were considered valid for efficacy if they had data from at least 1 follow-up visit, had taken the study drug for at least 5 days (10 consecutive doses) and had had no concomitant antibiotic medication before the follow-up visit. All patients for whom data were available and who had received at least 1 dose were included in the analysis of safety.
Statistits Thc short term cure rate (day 1 C 1 2 ) and the last valid visit cure rate (day 2&35) were compared for the two drugs by chi-square tests and 2-sided 95% confidence intervals. The same methods were used for adverse events. In addition, Mantel-Haenzel tests were used to compare the cure rates adjusted for the prognostic factors, centre, sex. recurrence and initial bacteriological finding of established pathogens. Possible differences in cure rates for the prognostic factors were investigated by the Breslow-Day test for homogeneity of odd ratios. Wilcoxon's 2-sample tests for the graded clinical responses (cured vs improved vs failure) were used for the short-term and last valid visit cure rates.
RESULTS Out of the patients in both treatment groups 95.5% (n=379) were valid for efficacy. Cure rates in the cefixime and cefaclor groups at day 10-12 and the last visit are presented in Table 11. 39 patients (23 in the cefixime treated group and 16 in the cefaclor treated group) initiated other antibacterial treatment between control visits, mainly because of an AOM requiring further antibiotic treatment. From the 379 patients valid for efficacy evaluation, a total of 618 bacterial strains were isolated from nasopharynx at the initial visit. Samples from 17 patients were classified either as no growth or no sample taken. 231 patients (60.9%) had an initial positive culture of at
462
T. Piippo et al.
Scand J Infect Dis 23
Table 111. Bacterial strains isolated from nasopharynx at entry from patients valid for efficacy
Downloaded by [ECU Libraries] at 00:34 29 September 2015
Initial hacteria
Cefixime
Cefaclor
No. of strains
No. of strains
Total %
Haemophilus influenzae Streptococcus pneumoniae Branhamella catarrhalis Other species Ordinary flora
90 77 68 125 48
42 46 23 75 24
21.4 19.9 14.7 32.4 11.6
Total
408
210
100.0
least one strain of H. influenzae, S. pneumoniae or B. catarrhalis or different combinations of these 3 bacteria. As seen in Table 111, these 3 bacterial species constituted 56.0% of all bacteria isolated and they were relatively evenly distributed in the two treatment groups. Sensitivity testing showed that the strains of H. influenzae, S. pneumoniae and B. catarrhalis were all sensitive to cefixime but showed intermediate sensitivity to cefaclor in the case of H. influenzae (26/132 strains) and B. catarrhalis (16/91 strains). In addition, 5 strains of H. influenzae were judged to be resistant to cefaclor (one of these strains was a beta-lactamase producer). 91 patients had a positive culture of B. catarrhalis at the initial visit. Out of these, 67 children (73.6%) had beta-lactamase producing strains. The short-term cure rate at day 1&12 for these children was 46.0% in the cefixime group and 23.5% in the cefaclor group. The number of patients in each group is too low to allow statistical analyses. 132 patients had a positive culture of H . influenzae at the initial visit and out of these 15 (11.4%) had beta-lactamase producing strains. Here the same tendency is apparent with short-term rate of 45.5% in the cefixime group compared to 25.0% in the cefaclor group, but again not possible to analyse stastistically. Of the 397 patients included, 394 were valid for safety analysis. As seen in Table IV, there was no statistical difference (p = 0.06) in adverse experiences, reported by the patients in the cefixime and cefaclor groups. 18 children discontinued treatment prematurely for the reason given in Table V. Seven patients (2.7%) in the cefixime group discontinued treatment prematurely due to adverse events. Five of these patients had diarrhoea (3 of moderate intensity and 2 severe) and the other 2 mild disturbances in breathing and moderate vomiting, respectively. The symptoms ceased spontaneously after 3-5 days. Three patients (2.3%) in the cefaclor group discontinued treatment due to adverse events. Two patients had diarrhoea of moderate intensity that
Table IV. Adverse reactions according to intensity (patients valid for safety) Maximum intensity of adverse reactions
Cefixime
No. of pat.
Cefaclor
Total
%
No. of pat.
%
118
89.4 6.8 3.8
333 31 21 3
84.5 9.4 5.3 0.8
100.0
394
100.0
None Mild Moderate Severe
215 28 16 3
82.1 10.7 6.1 1.1
5 None
Total
262
100.0
132
9
No. of pat.
/'o
C‘efixime and cefaclor in acute otitis media 463
S c d I Infcct DIS23
TMe V. Reasons for premature di.scontinuation of treatment of all randomized putienfs Reason
Cefixime ( n
=
264)
No. of pat.
Deteriorated or not improved Adverse cvcnts Patients refusal
Downloaded by [ECU Libraries] at 00:34 29 September 2015
Total
Cefaclor ( n = 133) No. of pat.
?,:
%
I.5
3 2
I .5 2.3 1 .s
4.2
7
5.3
-
2
7 4
2.7
11
lasted for 3 and 5 days respectively. The third patient developed - during medication - a pneumonia that was considered cured at follow-up visit day 12. No serious adverse events were reported. The numbers of patients reporting adverse experiences spontaneously or after a nonleading question are presented in Table VI. Diarrhoea and loose stools were more often reported from Iceland than Finland, occurring in 19% of the patients in Iceland compared to 6.1% in Finland. Diarrhoea and loose stools occurred most frequently in children
