| | Etiology of acute otitis media in childhood and evaluation of two different protocols of antibiotic therapy: 10 days cefaclor vs. 3 days azitromycinReceived 1 May 2002; received in revised form 19 September 2002; accepted 20 September 2002. Abstract Backgrounds: Acute otitis media (AOM) is a common childhood infection that is frequently treated by antibiotics. There are no prospective and comprehensive trials evaluating childhood AOM for etiologic pathogens and resistance pattern in Turkey. The aims of the study were to determine the bacterial etiologies and resistance patterns, and identify the efficacy and the relapse rates of 3 days of azitromycin and 10 days of cefaclor therapy in AOM. Methods: This prospective, randomized, single-blind, open study was carried out in 78 cases of AOM. Mean age was 30.7±27 months. Tympanocentesis and aspiration of middle ear fluid (MEF) were used to obtain purulent material from the middle ear. Group 1 consisted of the cases (n=41) on azitromycin therapy and Group 2 (n=37) on cefaclor. Dosage of azitromycin was 10 mg/kg per day for 3 days and cefaclor 40 mg/kg per day for 10 days. The patients were evaluated on days 3–5 (second visit), day 10 (third visit), and day 30 (fourth visit) during follow-up. Results: A total of 50 species were isolated from 44 of 78 cases from which materials were obtained (44/78; 56.4%). Most frequently isolated microorganism was Streptococcus pneumoniae (n=18; 36%), followed by Haemophilus influenzae (n=11; 22%), S. aureus (n=9; 18%), Moraxella catarrhalis (n=4; 8%), and group A beta-hemolytic streptococcus (GAS, n=4; 8%). Enterococcus faecalis was isolated from three cases and H. parainfluenzae from one. Penicillin and amoxicillin resistances of bacteria were found to be 40 and 36%, respectively. The frequency of penicillin and amoxicillin resistance in ≤24-month age group was 59 and 66.6%, respectively. The patients did not demonstrate significant differences in terms of cure rate on the third to fifth day (Group 1: 32.5%; Group 2: 36.4%), 10th day (Group 1: 76.9%; Group 2: 84.8%), and on 30th day (Group 1: 91.3%; Group 2: 81.8%). There were no significant differences with respect to side effects, relapse, and re-infection rate between the two groups. Conclusion: In more than half of the AOM cases, bacteria were isolated from MEF and most frequently isolated organisms were S. pneumoniae, H. influenzae, and S. aureus. Three-day azitromycin therapy was as effective as 10-day cefaclor therapy.
1. Introduction  Acute otitis media (AOM) is a common childhood infection that is frequently treated by antibiotics [1], [2]; if it is relapsed or frequent re-infection with persistent middle ear fluid (MEF) occurred, it may lead to difficulties in learning and verbal communication [3], [4]. In many countries, etiologic pathogens and resistance patterns have been identified; however, there are no prospective and comprehensive trials evaluating childhood AOM from this standpoint in Turkey. On the other hand, for an effective empirical therapy, knowledge of local resistance patterns and prevailing pathogens is essential. Current research focuses on the treatment of etiologic pathogens like penicillin-resistant Streptococcus pneumoniae (S. pneumoniae) or beta-lactamase-producing Haemophilus influenzae (H. influenzae) [5], [6], [7], [8], [9]. Beta-lactam antimicrobials including amoxicillin, amoxicillin/clavulanic acid, and second-generation oral cephalosporins and macrolides are the main antibiotic choices for AOM [10], [11]. In this trial, middle ear effusions were collected by tympanocentesis, etiologic pathogens and resistance patterns were determined, and the efficacy of 10 days of cefaclor therapy and 3 days of azitromycin therapy was evaluated. 2. Methods This prospective, single-blind, randomized case research was conducted in the Ambulatory Clinic of the Department of Pediatrics, Faculty of Medicine, Istanbul University, between January 1998 and May 2000. A total of 330 AOM cases were examined in Pediatric Ambulatory Clinic in study period. Among 330 AOM cases, only 78 children fulfilled all inclusion criteria and they participated in the study. These cases covered all inclusion criteria and were admitted to hospital during the day (between 08:00 a.m. and 17:00 p.m.). Children with clinical findings suggestive of AOM (fever, irritability, and ear ache) were first examined by a pediatrician, then referred to ENT specialist for microscopic otoscopy. Finally, ENT specialist confirmed AOM diagnosis. The ENT specialist had no information about the study arms and what kind of antibiotic they were taking on follow-up period. So, he or she was blinded to treatment on follow-up period. 2.1. Inclusion criteria All the patients had clinical signs suggesting AOM like fever, irritability, crying, vomiting, etc. Then, AOM was confirmed by discoloration (hyperemia or opacity), bulging or retraction, and signs of MEF [1]. All the cases were in one of the three different stages of AOM (hyperemic, exudative, or suppurative). The inclusion criteria were as follows: (1) age between 6 months and 12 years; (2) no antibiotic treatment during the last 2 weeks and no treatment with depot-penicillin during the last 6 weeks; (3) no diagnosis of chronic otitis media and no acute perforation on tympanic membrane; (4) absence of allergy to study drugs; (5) absence of chronic, progressive diseases that may hinder the process of treatment and follow-up; and (6) obtainment of written consent from the parents. 2.2. Exclusion criteria (1) Age under 6 months at the enrollment period of the study; (2) patients taking an antibiotic 6 weeks before the admission to the study; (3) patients who had a chronic disorder, cyctic fibrosis, chronic renal failure, an immunodeficiency syndrome, etc. during the study; (4) inappropriate usage of an antibiotic which was used in the study or (5) lost on follow-up period; and (6) a patient whose parents did not sign the written consent. 2.3. Study design We used the antibiotics, which could be indicated for the AOM treatment. Patients were randomized to one of the following treatment arms with the assistance of a computerized randomization list—Group 1: 10 mg/kg per day azitromycin p.o., daily once for 3 days; Group 2: 40 mg/kg per day cefaclor p.o., in three divided doses for 10 days. Consumption of antibiotics used in therapy was checked by controlling the drug level at the bottle and the medicine control form filled by the parents of patients. The patients were evaluated on days 3–5 (second visit), day 10 (third visit), and day 30 (fourth visit). All the patients were evaluated between 08:00 a.m. and 17:00 p.m. The follow-up period could be extended for patients in whom persistence of MEF was observed. The local ethics committee approved the study protocol. 2.4. Collection of middle ear specimens After otoscopic examination, the cerumen in the external ear canal was cleaned mechanically without application of antiseptic solutions. Tympanocentesis was performed with a sterile paracentesis knife, and John Tymp-Top MEF aspirator (Xamed Surgical Products, Jacksonville) was used to obtain purulent material from the middle ear. The collected specimen was placed into the transport medium and sent to the microbiology laboratory. 2.5. Microbiology The specimens were cultured on 5% sheep blood agar, chocolate agar, Mac Conkey agar, Saboraud Dextrose agar, and thioglyconate liquid agar (OXOID) in aerobic conditions. All were incubated at 35–37 °C for 24–48 h. Preparations from specimens were directly examined by gram staining. S. pneumoniae was identified on the basis of sensitivity to optichin and alpha-hemolysis in blood agars. Penicillin resistance was evaluated by oxacilline disks and disk diffusion method. Group A beta-hemolytic streptococci were defined on the basis of bacitricine sensitivity, PYR positivity, and beta-hemolysis on blood agar and were grouped by latex agglutination test (Streptex-OXOID). Haemophilus species were identified on the basis of growth in chocolate agar, requirement for factors X and V, and observation of gram-negative coccobacilli in gram stain. Oxidase-positive, DNAase-positive, and gram-negative cocci were identified as Moraxella catarrhalis (M. catarrhalis). Other organisms were classified according to classical methods and the diagnoses were confirmed by API, STREP, API STAPH, API NH (Bio Merieux) kits. Beta-lactamase production in H. influenzae and M. catarrhalis strains was investigated by nitroceftin (OXOID). Serotypes of H. influenzae were defined by H. influenzae type b antibody (Difco) test. The penicillin resistance in S. pneumoniae and staphylococci were determined by the use of oxacilline tests (NCCLS method) and disk diffusion method. Also, the level of resistance of other isolated strains to antimicrobials (including azitromycin and cefaclor) was determined by disk diffusion method as defined by NCCLS. Haemophilus strains with a zone diameter of <16 and <19 mm for cefaclor and azitromycin, respectively, were considered resistant; if the zone diameter was >20 and 19 mm for cefaclor and azitromycin, respectively, the strains were considered sensitive. Other strains with a zone diameter of <14 and <13 mm for cefaclor and azitromycin, respectively, were considered resistant, and organisms with a zone diameter of >18 and >18 mm, respectively, were considered sensitive. Antimicrobial sensitivity of S. pneumoniae, group A beta-hemolytic streptococci, and enterococci was evaluated in 5% sheep blood Müller-Hindon agar; antimicrobial sensitivity of staphylococci, Haemophilus strains, and M. catarrhalis strains was evaluated in Müller-Hindon agar, respectively [12]. 2.6. Follow-up criteria The criteria for success/failure were as follows: (1) cure—complete resolution of all clinical and otoscopic findings (hyperemia, bulging, MEF, etc.); (2) failure—persistence of clinical and otoscopic findings at third to fifth day of evaluation visit of serous material during otoscopic examination; (3) improvement—resolution of clinical findings but persistence of serous material in middle ear; (4) relapse—recurrence of clinical and otoscopic findings at day 10, after an initial period of improvement; and (5) re-infection—recurrence of clinical and otoscopic findings in a patient during the 30-day follow-up period for whom cure or improvement had been detected on day 10. MEF on follow-up period was detected by otoscopic examination. 2.7. Statistical methods Quantitative parameters were compared using Student's t-test, non-parametric t-test, and χ2-test on SPSS software media (ver. 9.0). The statistical significance was set at P<0.05. 3. Results There were 41 cases (52.6%) in azitromycin group and 37 cases (47.4%) in cefaclor group; 45 patients (58%) were male and 33 (42%) were female; mean age was 30.7±27 months (6.0–118.0 months). Right ear was infected in 39.7% of the cases (n=31) and left ear was infected in 29.5% of the cases (n=23); 24 cases (30.8%) had bilateral AOM. There were no significant differences with regard to age, gender, duration of infection, and time to resolution of symptoms between the study group and group in which no etiologic pathogens were identified (P>0.05). At the time of first clinical presentation fever, ear ache, and irritability were present in 89.7% (n=70), 35.9% (n=28), and 62.8% (n=49), respectively, of all patients. As indicated by patient's history, 67.9% of the patients had their first AOM episode of their lives and 21.8% had the second episode. On average, there was a delay of 3.3 days from the onset of infection and clinical presentation (range: 1–7 days); mean leukocyte count at the time of first clinical presentation was 8300 (range: 4600–11 800 mm−3). There were no significant differences between azitromycin (Group 1) and cefaclor (Group 2) groups concerning the age, weight, height, duration of infection, frequency of ear ache, irritability, presence of upper respiratory tract infection, and bacteria isolation rates (P>0.05; Table 1). | | |  | | Group 1 (azitromycin group) (n=41) | Group 2 (cefaclor group) (n=37) | Total (n=78) | |
|---|
| Gender (F/M) | 21/20 | 12/25 | 33/45 | |
| Age (months, mean±S.D.) | 30.1±27.5 | 27.8±26.6 | 30.7±27 | |
| Weight (kg, mean±S.D.) | 12.8±5.7 | 13.0±6.5 | 13.2±6.5 | |
| Height (cm, mean±S.D.) | 85.8±19.7 | 84.5±17.5 | 85.8±19.3 | |
| Culture-positive cases, n (%) | 23 (56) | 21 (56.7) | 44 (56.4) | |
| Duration of infection (days, mean) | 3.6 | 3.0 | 3.3 | |
| Bilateral middle ear infection, n (%) | 10 (24.3) | 14 (37.8) | 24 (30.8) | |
| Excluded casesa, n (%) | 6 (14.6) | 4 (10.8) | 10 (12.8) | |
| | | | | |
| Complaints | | |
| Fever, n (%) | 36 (87.8) | 34 (91.9) | 70 (89.7) | |
| Ear ache, n (%) | 15 (36.5) | 13 (35.1) | 28 (35.9) | |
| Irritability, n (%) | 24 (58.5) | 25 (67.6) | 49 (62.8) | | | | |
|
a
Total number of cases lost on follow-up (P>0.05). |
3.1. Microbiological results Microbiological sampling was performed in 78 patients, and totally 50 species from 44 of these 78 patients were isolated (44/78; 56.4%). S. pneumoniae was the most frequently isolated organism (n=18; 36%) followed by H. influenzae (n=11; 22%), S. aureus (n=9; 18%), M. catarrhalis (n=4; 8%), and group A beta-hemolytic streptococci (n=4; 8%). Other bacteria that were isolated includes Enterococcus faecalis (n=3; 6%) and H. parainfluenzae (H. parainfluenzae) (n=1; 2%) (Fig. 1). Three of 11 H. influenzae strains were ‘b type’ (27.2%). While none of the H. influenzae strains had beta-lactamase activity, all the M. catarrhalis strains were beta-lactamase-positive. Five of pneumococcal strains had penicillin resistance (5/18; 27.7%). Sixty-five percent of the cases (n=51) was in 6–24-month age group. A total of 34 bacteria were isolated from 31 of these 51 patients (31/51; 60.7%). With regard to the remaining patients (age>24 months; n=27), a total of 16 bacteria from 13 patients were isolated (13/27; 48.1%). Although the number of patients from whom a bacterial pathogen was isolated was higher in ≤24-month age group, the difference was not significant (P>0.05). Half of the patients in the 6–24-month age group were in Group 1 and half were in Group 2. Most frequently isolated organisms in this group were as follows: S. pneumoniae (n=12; 35.2%), S. aureus (n=7; 20.5%), H. influenzae (n=7; 20.5%), group A beta-hemolytic streptococcus (n=3; 8.8%), M. catarrhalis (n=2; 6%), H. parainfluenzae (n=1; 3%), and E. faecalis (n=2; 6%). 3.2. Follow-up period Throughout the follow-up period, after the administration of antibiotics following the first examination and specimen collection, three cases did not attend to the second evaluation visit (days 3–5) and two cases who used non-study antibiotics were excluded (n=73) from the analysis. After the second evaluation, one patient was lost to follow-up. Therefore, a total of 72 patients were included in the third examination and relapse was observed only in one patient. Sixty-eight patients attended the last visit (day 30). On the whole study groups, a total of 10 cases were excluded from the study according to exclusion criteria. Six of them were in azitromycin group (Group 1) and four of them were in the cefaclor group (Group 2) (P>0.05). At the second evaluation visit, the percentage of patients who were cured or had improvement was 34.2% (n=25) and 64.4% (n=47), respectively. There was one treatment failure in one patient (1.4%) in Group 1; this patient was switched to another antibiotic regimen. We used a third-generation antibiotic, ceftriaxone for this patient. At third visit (day 10), the percentage of cure and improvement was 80.6% (n=58) and 16.6% (n=12), respectively. The percentage of cure, improvement, and relapse after the completion of 30-day period was 86.7% (n=59), 5.9% (n=4), and 4.4% (n=3), respectively. 3.3. Between-group comparisons Bacteria were isolated from 23 cases in Group 1 (23/41; 56%) and from 21 cases in Group 2 (21/37; 56.7%). For patients in Group 1 who were followed under the study protocol, the percentage of patients with ‘cure’, ‘improvement’, or ‘ failure’ at second visit (days 3–5) was 32.5, 65, and 2.5%, respectively; the corresponding values for cure and improvement at third visit (n=39) were 76.9 and 20.5%, respectively. In Group 2 (n=33), the percentage of patients with cure and improvement at second visit (days 3–5) was 36.4 and 63.6%, respectively; the cure, improvement, and relapse rates at third visit (n=32) were 84.8, 12.1, and 3.1%, respectively. There were no significant differences between the two groups with regard to the cure rates during the follow-up period (Table 2, P>0.05). During the 30-day follow-up period, the percentage of patients with cure/improvement was 91.3 and 2.9% in Group 1 and 81.8 and 9% in Group 2, respectively. There were no statistically significant differences between the two groups (Table 3). | | | | Groups | Second examination (3–5th day) (total n=73; Group 1: 40; Group 2: 33) | Third examination (10th day) (total n=72; Group 1: 39; Group 2: 33) | |
|---|
| | Cure | Improvement | Failure | Cure | Improvement | Failure | Relapse | |
|---|
| Group 1, n (%) | 13 (32.5) | 26 (65) | 1 (2.5) | 30 (76.9) | 8 (20.5) | 1 (2.6) | – | |
| Group 2, n (%) | 12 (36.4) | 21 (63.6) | – | 28 (84.8) | 4 (12.1) | – | 1 (3.1) | |
| | | | | | | | | |
| Total, n (%) | 25 (34.2) | 47 (64.4) | 1 (1.4) | 58 (80.6) | 12 (16.6) | 1 (1.4) | 1 (1.4) | | | | |
3.4. Serous material after otitis (persistence of MEF) At the third visit (day 10), persistence of MEF was detected in 12 cases (eight cases in Group 1 and four cases in Group 2; between-group comparison: P>0.05; 12/72; 16.7%); at day 30, this was reduced to four (three cases in Group 1 and one case in Group 2; 4/68; 5.8%). There were no significant differences between the two groups concerning the persistence of MEF after the episode of otitis media (P>0.05). Tympanometry could be applied in four cases out of 12 cases with MEF at day 30. In all four cases, tympanometry results correlated with microscopic otoscopy findings. Extended follow-up (up to 2 months) demonstrated that in two of these four cases, serous effusion resolved. Other two patients were lost to follow-up. In nine of these 12 cases, 11 bacteria were isolated. Bacteria were as follows: H. influenzae (n=4), S. pneumoniae (n=3), S. aureus (n=3), and E. faecalis (n=1). Among H. influenzae isolates, no ‘type b’ strains were identified; one of the S. pneumoniae strains was penicillin-resistant. Eight of these 12 patients (66.6%) were <24 months of age. In the cases with serous otitis persisting beyond 30 days of follow-up, two strains of S. aureus and one strain of H. influenzae were isolated. 3.5. Antibiotic resistance All M. catarrhalis strains were beta-lactamase-positive; in contrast, none of the H. influenzae and H. parainfluenzae strains had beta-lactamase activity. Penicillin resistance was noted in all S. aureus strains, in 27.7% of S. pneumoniae strains (5/18), and in all H. influenzae and M. catarrhalis strains (Table 4). Overall, 40% of the strains was penicillin-resistant and 36% was amoxicillin-resistant. Four (80%) of the pneumococcal strains and seven (77.7%) of the staphylococcal strains with penicillin resistance were isolated from children ≤24 months of age. Of the 14 cases from which penicillin-resistant pneumococci and staphylococci were isolated, 11 were ≤24 months of age (P>0.05). One of the M. catarrhalis strains with beta-lactamase activity was detected in this group. Frequency of penicillin-resistant bacteria was 40% in the whole group and 59% in the ≤24 months of age group (P>0.05). Ratio of amoxicillin-resistant strains in the ≤24 months of age group was 66.6%. All bacterial pathogens were sensitive to amoxicillin–clavulanate. 9, 4, and 4% of all strains were resistant to cefaclor, azitromycin, and cefuroxime, respectively. All bacteria were sensitive to ceftriaxone. 3.6. Side effects For the duration of antibiotic therapy, one patient in each group experienced gastrointestinal side effects (vomiting and diarrhea) that did not necessitate discontinuation of the study drug (2/78; 2.6%). 4. Discussion It has been reported that bacteria, viruses plus bacteria, or viruses are present in 62, 45, and 75% of the AOM cases, respectively [2], [13]. The most likely pathogens show some degree of geographical variation and as antibiotics are used more and more frequently, resistance patterns change every year in a dynamic manner [14], [15]. However, most frequently reported etiologic pathogens in AOM in decreasing order are S. pneumoniae, H. influenzae (no typing), and M. catarrhalis [16], [17], [18], [19]. On the other hand, Dagan et al. [20] reported H. influenzae as the most common organism. In our study, the incidence of bacteria, namely S. pneumoniae and H. influenzae was different when compared to senses reported in literature. In the literature, M. catarrhalis is the third most common organism and group A beta-hemolytic streptococcus is a rare organism. In this study, M. catarrhalis and group A beta-hemolytic streptococcus organisms were in the fourth place and S. aureus, which is usually considered ‘rare’ in the literature was the third most common organism. In developed countries, the reported incidence for S. aureus (1–2%) is somewhat lower than the incidence in developing countries (4%) [14], [15]. But in our study, this incidence was even higher. Almost 38% (37.5%) of H. influenzae strains were of ‘b type’ and none of the H. influenzae strains had beta-lactamase activity; these findings also represent a divergence from reported data. Similar to other studies, all M. catarrhalis strains were beta-lactamase-positive [4], [14]. S. pneumoniae is the leading pathogen in AOM and although there are some geographical differences, the reported penicillin resistance is about 40% [21]. In this study, 27.7% of pneumococci were penicillin-resistant. But it should be remembered that the resistance was evaluated by oxacilline disc. In view of that, more detailed information could be obtained if E-test and bactericidal MIC concentrations were used. Previously, moderate and high resistance to penicillin have been reported in 31.8 and 3.5% of S. pneumoniae strains, respectively, in Turkey [22], [23], [24]. From this data and response to azitromycin and cefaclor of our five penicillin-resistant pneumococci, we thought that this resistance might be moderate. As a result of increasing levels of resistance in bacterial AOM pathogens, the recommended dose for amoxicillin is 80–90 mg/kg per day [8], [25], [26]. The reported incidence for amoxicillin resistance is between 62 and 89% and patients younger than 12 months of age account for the majority of the penicillin-resistant cases [21], [25], [26]. A previous survey in Turkey demonstrated that majority of the S. pneumoniae strains with high resistance to penicillin was obtained from children [24]. Children younger than 24 months have high levels of resistance so that this age group represents an important therapeutic target [10]. Similarly, in this study, majorities of resistant pneumococci were detected in children ≤24 months of age. Overall, the rate of amoxicillin resistance was 36.4%. However, high levels of resistance in children ≤24 months of age suggest that amoxicillin/clavulanate, second-generation oral cephalosporins, or azitromycin rather than amoxicillin should be the first antibiotic choice in this age group. Regarding to the beta-lactams with short half-lives, 10 days of standard therapy vs. short-course therapy (5 days) were evaluated in some studies; although some meta-analyses suggest that these approaches have equal efficacy, important methodological differences that exist between these studies should not be ignored [11], [26]. Azitromycin has some unique pharmacological features and while the serum levels are not bactericidal, the concentrations in middle ear tissues and leukocytes provide efficacy; so this macrolide agent is one of the antibiotic choices in AOM [7]. It has a half-life of 40 h, achieves much higher concentrations in middle ear than in serum, and offers a bacteriostatic effect. Azitromycin is used for 3 or 5 days and equal efficacy has been reported for these two different forms of therapy [11]. In many case-controlled studies, azitromycin and some beta-lactams have proven to be efficacious in the treatment of AOM [27], [28], [29], [30], [31]. In this study, 3 days of azitromycin therapy (10 mg/kg per day) was shown to be as effective as 10 days of cefaclor therapy. Rodriguez [32] found that cefaclor and azitromycin have similar efficacy in the treatment of AOM. It is obvious that compliance to therapy will be enhanced with shorter therapies. In a multi-center study, Dagan et al. reported that 5 days of azitromycin therapy was significantly less effective than amoxicillin/clavulanate therapy and with azitromycin, bactericidal concentrations for H. influenzae was not reached in the middle ear tissue. In contrast, very stringent inclusion criteria were used in our study and no difference between azitromycin and cefaclor was noted. Inclusion criteria in the study by Dagan et al. were different from our criteria. Penicillin-resistant pneumococci also have azitromycin resistance as well; in this study, one relapse case was seen in cefaclor group but we did not see any patient with relapse in Group 1. Difference between groups for relapse rate is not statistically significant. This may be explained by intermediate level of resistance or discordance between in vitro tests and clinical efficacy. In conclusion, more than half of AOM cases in this population had bacteriologic etiology and most frequently isolated organisms were S. pneumoniae, H. influenzae, and S. aureus, respectively. Of all H. influenzae strains, 37% were ‘type b’. Overall, resistance to penicillin and amoxicillin was noted in 54.5 and 37.5% of the pathogens, respectively. Penicillin resistance was more frequent in patients with ≤24 months of age (60%). These data suggest that amoxicillin/clavulanate, second-generation cephalosporins, or azitromycin should be preferred in the treatment of patients suffering from AOM, particularly for children ≤24 months of age. Notably, short-course azitromycine and cefaclor therapies had comparable in vivo efficacy; this finding may be important concerning compliance to therapy. Three days of azitromycin therapy and 10 days of cefaclor therapy were equally effective. References [1].
[1]
Faden H, Duffy L, Boeve M.
Otitis media: back to basics.
Pediatr. Infect. Dis. J. 1998;17:1105–1113. MEDLINE |
CrossRef
[2].
[2]
Berman S.
Otitis media in children.
N. Engl. J. Med. 1995;332:1560–1565. MEDLINE |
CrossRef
[3].
[3]
Zielhuis GA, Gerritsen AAM, Wim HM, et al.
Hearing deficits at school age: the predictive value of otitis media in infants.
Int. J. Pediatr. Otolaryngol. 1998;44:227–234. [4].
[4]
Bennet KE, Haggard MP.
Behavior and cognitive outcomes from middle ear disease.
Arch. Dis. Child. 1999;80:28–35.
CrossRef
[5].
[5]
Chartrand SA, Pong A.
Acute otitis media in the 1990s: the impact of antibiotic resistance.
Pediatr. Ann. 1998;27:86–95. MEDLINE [6].
[6]
Grant AG, Chow AW.
Otitis media and externa.
Curr. Opin. Infect. Dis. 1993;6:644–650. [7].
[7]
Block SL.
Causative pathogens, antibiotic resistance and therapeutic considerations in acute otitis media.
Pediatr. Infect. Dis. J. 1997;16:449–456. MEDLINE |
CrossRef
[8].
[8]
Klein JO.
Clinical implications of antibiotic resistance for management of acute otitis media.
Pediatr. Infect. Dis. J. 1998;17:1084–1089. MEDLINE |
CrossRef
[9].
[9]
Jacobs MR.
Antibiotic-resistant Streptococcus pneumoniae in acute otitis media: overview and update.
Pediatr. Infect. Dis. J. 1998;17:947–952. MEDLINE |
CrossRef
[10].
[10]
Klein JO.
Review of consensus reports on management of acute otitis media.
Pediatr. Infect. Dis. J. 1999;18:1152–1155. MEDLINE |
CrossRef
[11].
[11]
Kozyrskyj A, Hildes-Ripstein E, Longstaffe SEA, et al.
Treatment of acute otitis media with a shortened course of antibiotics.
J. Am. Med. Assoc. 1998;279:1736–1742. [12].
[12]
Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, Approach Standard NCCLS Publication 17, 1997, National Committee for Clinical Laboratory Standards, pp. M7–A4. [13].
[13]
Heikkinen T, Thint M, Chonmaitree T.
Prevalence of various respiratory viruses in the middle ear during acute otitis media.
N. Engl. J. Med. 1999;340:260–264. MEDLINE |
CrossRef
[14].
[14]
Dagan R.
Can the choice of antibiotics for therapy of acute otitis media be logical?.
Eur. J. Clin. Microbiol. Infect. Dis. 1998;17:1–5. MEDLINE |
CrossRef
[15].
[15]
Arguedas A, Loaiza C, Perez A, et al.
Microbiology of acute otitis media in Costa Rican children.
Pediatr. Infect. Dis. J. 1998;17:680–689. MEDLINE |
CrossRef
[16].
[16]
Majee D, Harris T.
Acute otitis media in children.
Br. Med. J. 1997;315:321–322. [17].
[17]
Pitkaranta A, Virolainen A, Jero J, Arruda E, Hayden FG.
Detection of rhinovirus, respiratory syncytial virus and coronavirus infections in acute otitis media by reverse transcriptase polymerase chain reaction.
Pediatrics. 1998;102:291–295. [18].
[18]
Eskola J, Tapani H.
Respiratory viruses in acute otitis media.
N. Engl. J. Med. 1999;340:312–313. MEDLINE |
CrossRef
[19].
[19]
Blumer JL.
Pharmacokinetics and pharmacodynamics of new and old antimicrobial agents for acute otitis media.
Pediatr. Infect. Dis. J. 1998;17:1070–1075. MEDLINE |
CrossRef
[20].
[20]
Dagan R, Candice J, Mclinn S, et al.
Bacteriologic and clinical efficacy of amoxicillin/clavulanate vs. azitromycin in acute otitis media.
Pediatr. Infect. Dis. J. 2000;19:95–104. MEDLINE |
CrossRef
[21].
[21]
Jacobs MR, Dagan R, Appelbaum PC, Burch D.
Prevalence of antimicrobial-resistant pathogens in middle ear fluid: multinational study of 917 children with acute otitis media.
Antimicrob. Agents Chemother. 1998;42:589–595. MEDLINE [22].
[22]
Sener B, Günalp A.
Trends in antimicrobial resistance of Streptococcus pneumoniae in children in a Turkish hospital.
J. Antimicrob. Chemother. 1998;42:381–384. MEDLINE |
CrossRef
[23].
[23]
Kanra G, Erdem G, Ceyhan M, Klugman KP, Vasas A.
Serotypes and antibacterial susceptibility of pneumococci isolated from children with infections in Ankara in relation to proposed pneumococcal vaccine coverage.
Acta Paediatr. Jpn. 1998;40:437–440. MEDLINE [24].
[24]
Gur D, Tunckanat F, Sener B, Kanra G, Akalin HE.
Penicillin resistance in Streptococcus pneumoniae in Turkey.
Eur. J. Clin. Microbiol. Infect. Dis. 1994;13:440–441. MEDLINE |
CrossRef
[25].
[25]
Le Bideau M, Mouzard A, Chamoux C, Richet H, Bordure P, Maugard T.
Bacteriological study in acute otitis media.
Arch. Pediatr. 1997;4:213–218. [26].
[26]
Del Mar CB, Glasziou PP.
Should we know hold back from initially prescribing antibiotics for acute otitis media?.
J. Paediatr. Child Health. 1999;35:9–10. MEDLINE |
CrossRef
[27].
[27]
Pichichero ME.
Changing the treatment paradigm for acute otitis media in children.
J. Am. Med. Assoc. 1998;279:1748–1750. [28].
[28]
Mohs E, Rodriguez-Solares A, Rivas E, el Hoshy Z.
A comparative study of azitromycin and amoxicillin in paediatric patients with acute otitis media.
J. Antimicrob. Chemother. 1993;31(Suppl. 1):E73–E79. [29].
[29]
Daniel RR.
Comparison of azitromycin and co-amoxiclav in the treatment of otitis media in children.
J. Antimicrob. Chemother. 1993;31(Suppl. 1):E65–E71. [30].
[30]
Schaad UB.
Multicentre evaluation of azitromycin in comparison with co-amoxiclav for the treatment of acute otitis media in children.
J. Antimicrob. Chemother. 1993;31(Suppl. 1):E81–E88. [31].
[31]
Principi N.
Multicentre comparative study of the efficacy and safety of azitromycin compared with amoxicillin/clavulanic acid in the treatment of paediatric patients with otitis media.
Eur. J. Clin. Microbiol. Infect. Dis. 1995;14:669–676. MEDLINE |
CrossRef
[32].
[32]
Rodriguez AF.
An open study to compare azitromycin with cefaclor in the treatment of children with acute otitis media.
J. Antimicrob. Chemother. 1996;37(Suppl. 1):C63–C69. a Institute of Child Health, Istanbul University, Istanbul, Turkey b Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey c Department of Otorhynolaryngology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey d Pakize Tarzi Microbiology Laboratory, Turkey  Corresponding author. Present address: Göksu Evleri Çiğdem Çıkmazı sok., B-105-B Anadoluhisari-Beykoz, Istanbul, Turkey. Tel./fax: +90-212-531-0529
PII: S0165-5876(02)00360-9 © 2002 Published by Elsevier Inc. | |
|
FULL TEXT00360-9/journalimage?img=PIIS0165587602003609.gr1.lrg.gif&fig=FIG1&kwhquery=&issn=0165-5876&ishighres=false&allhighres=false&free=yes','journalimage');)
