© Borgis - New Medicine 2/2001, s. 14-19
Henryk Kawalski, Ewa Blacha, Marek Kopacz, Mariusz Moś, Elżbieta Cierpioł-Tracz, Marek Wełniak, Beata Dudziak, Sonia Bojda, Bożena Kossowska, Ewa Gatniejewska, Michał Ligacz
Azithromycin vs. Clarithromycin and Co-amoxiclav: clinical and economic comparison in the treatment of acute otitis media in children
Scientific and Didactic Base of the Silesian Academy of Medicine. Department of Children´s Otorhinolaryngology, Chorzów
Head: Henryk Kawalski, MD. PhD.
Summary
170 children with acute otitis media were treated from 1999 to 2000. The patients were randomly divided into 3 groups. In particular groups therapy was performed with Azithromycin for 3 days, or with Co – amoxiclav and Clarithromycin for 10 days.
In the course of therapy bacteriological, biochemical, morphological and clinical parameters were examined. The results were analysed statistically and economically. A high efficiency was found for all antibiotics used. The best results were achieved with Azithromycin.
INTRODUCTION
Acute otitis media (AOM) is a frequent disease in children and the cause of visits to a children˘s otolaryngologist (4).
About 25% of children up to 2 years of age suffer from acute otitis media (7). Oral application of antibiotic drugs is common in the therapy of AOM. Some researchers believe that antibiotics should be reserved for patients with a more complicated form of AOM (1). They prefer not to reduce natural immunity (11).
However, it is difficult to tell which child with AOM has its life threatened or will suffer hearing loss. This is why antibiotic therapy is commonly regarded as a normal method of treatment (5, 6). Although there are a lot of effective antibiotics it is difficult to find the best for initial use (10). The selected antibiotic should be effective against these bacterial strains responsible for AOM (9). The treatment is effected by the experience and knowledge of the children´s otorhinolaryngologist (3).
Azithromycin is an azalide antimicrobial agent structurally related to the macrolide antibiotic erythromycin. Its mechanism of action is by interference with bacterial protein synthesis. The Azithromycin extended spectrum of activity includes gram – positive microorganisms: Streptococcus pyogenes, S. pneumoniae, Staphylococcus aureus, St. epidermidis, gram negative organisms: Haemophilus influenzae, H. parainfluenzae, Moraxella catarrhalis, Legionella pneumophila, Bordetella pertussis, B. parapertussis, Campylobacter spp, Neisseria gonorrhoeae, Gardnerella vaginalis, most of the anaerobes except Bacteroides fragilis, spirochetes Borrelia burgdorferi, and Treponema pallidum, as well as Mycoplasma spp. and Chlamydia spp.
Absorption is approximately 37% after a 500 mg oral dose. Drug elimination is polyphasic, with a terminal half – life of up to 68 hours. The results of numerous clinical trials prove that a 3 – day or 5 – day course of Azithromycin administered once daily (in a total dose of 30 mg/kg, maximum 1.5 g) is as effective as other commonly – used oral antimicrobials in the treatment of acute otitis media.
Clarithromycin is a new generation macrolide antibiotic. It is effective against strains such as Haemophilus influenzae, Moraxella catarrhalis, Legionella pneumophila, Chlamydia, Mycobacterium avium, and Toxoplazma qondi.
It shows cross – resistance with other macrolide antibiotics, and is quickly absorbed from the digestive tract. It reaches a maximum concentration after 2 hours.
Clarithromycin is metabolised in the liver and is removed with the urine and faeces as 20 to 30% in its primary form.
Co-amoxiclav is a beta – lactamase antibiotic consisting of Amoxicilline and potassium clavulanic. It is effective against such strains as Haemophilus influenzae,
Moraxella catarrhalis, Staphylococcus aureus, Escherichia coli, and Bacterioides fragili.
Co-amoxiclav is well absorbed from the digestive tract and passed well on to the middle ear. The half – life in the blood is from 0.9-1.3 h. About 50% of the drug is removed with the urine.
AIM OF STUDY
The aim of the study is to compare the clinical and economic efficacy of Azithromycin (A), Claritromycin (B) and Co-amoxiclav (C) in the treatment of AOM in children, and consequently an assessment of which antibiotic shows the best therapeutic efficacy at the lowest cost.
ETHICAL ASPECTS
The study was conducted according to the principles of good clinical practice and the Declaration of Helsinki as modified by the 41st World Medical Assembly, Hong Kong.
Prior to starting the study this protocol was approved by the Bioethical Committee of the Silesian Academy of Medicine in Katowice (No. 243/99 – 28/4/1999).
The investigator informed the patient˘s parent or legal guardian about the nature and purpose of the study, methods, anticipated benefits and potential hazards.
PATIENTS
170 patients were included in the study.
INCLUSION CRITERIA
The patients were qualified for clinical studies from among those coming to get advice from one of the three laryngological clinics in Chorzów. The patients were selected randomly and divided into three groups. The following patients were included in the study:
1. Children of both sexes, aged 6 months to 12 years, whose parents/legal guardians gave informed consent on their behalf;
2. The presence of middle ear effusions (MEE) shown by pneumatic otoscopy;
3. The presence of at least one of the following symptoms: ear pain, ear drainage, fever (=38°C axillary or=38.5°C rectally), irritability, vomiting or diarrhoea.
EXCLUSION CRITERIA
1. History of allergy macrolides and/or beta- -lactamase antibiotics and/or clavularic acid.
2. Marked renal or hepatic impairment (creatinine clearance <40 ml/min. or elevation of liver aminotransferases twice above the upper reference limit);
3. Evidence of chronic diarrheal disease or other gastrointestinal disorder which might affect absorption;
4. Chronic otitis media
5. Antimicrobial treatment (more than 1 daily dose) within 7 days before study enrolment or treatment with any long – acting penicillin injection within 4 weeks before study enrolment;
STUDY METHODS
Randomization
The study was a multi – centre,”blind investigators” type. The patients were randomized to receive Azithromycin, Clarithromycin or Co – amoxiclav in accordance with a randomization schedule (Microsoft comp. No 00 – 065 – 0400 – 26162962). Three antibiotics were randomly allocated to sequential numbers, strictly in order of presentation. Three groups of children with OME were created:
Group A – treated with Azithromycin, n=58
Group B – treated with Clarithromycin, n=53
Group C – treated with Co – amoxiclav, n=59
Dosage regimen
Group A – Azithromycin
Azithromycin was taken as SUMAMED suspension 100 mg/5ml, or SUMAMED forte 30ml, 200mg/5ml. SUMAMED was given orally, once daily for 3 days, the average daily dose being 10 mg/kg. Azithromycin was given at least 1 hour before or 2 hours after a meal.
Group B – Clarithromycin
Clarithromycin was taken as Klacid suspension, 60 or 100 ml bottles. The concentration of Clarithromycin was 125 mg per 5 ml, given orally every 12 hours for 10 days, the average daily dose being 15 mg/kg.
Group C – Co-amoxiclav
Co-amoxiclav was taken as Augmentin suspension 156 mg or 312 mg/5 ml. Co – amoxiclav was given orally every eight hours for 10 days. The average daily dose was 50 mg/kg.
Concomitant medication
During the study the patients did not receive any other antimicrobial drugs. The researcher could recommend only antipyretic drugs such as Paracetamol, Pyralgin, or Polopirin, and intestinal flora renovation drugs such as Trilac or Lakcid.
Drug compliance
No valid proof of compliance could be obtained for outpatients. However, the parent was asked about regular administration of medicine.
Study drug discontinuation
The study drug could be discontinued at any time when the researcher thought its further application harmful:
Clinical examination
Clinical signs and symptoms of disease were assessed:
– within 24 hours before the start of treatment (pretreatment visit),
– 72 hours after the start of treatment (early control visit),
– 10-12 days after the start of treatment (end of therapy visit),
– 4 weeks (26-30 days) after the start of treatment (follow-up visit),
– 6 weeks after the start of treatment (optional visit for patients with MEE at follow-up).
The presence and severity of signs and symptoms was scored in the following way:
| Symptom or sign | Score |
| | 0 | 1 |
| Fever: if measured axillary | =38,0°C | >38,0°C |
| if measured rectally | =38,5°C | >38,5°C |
| Ear pain | absent | present |
| Purulent otorrhoea | absent | present |
| rritability or lethargy | absent | present |
| Vomiting or diarrhoea | absent | present |
| Tympanic membrane: |
| Erythema | absent | present |
| Bulging | absent | present |
| Perforation | absent | present |
| Hypomobility | absent | present |
The sum of all scores was the total clinical score (TCS).
Bacteriology
Bacteriological confirmation was obligatory. Specimens for bacteriological studies were taken from the middle ear and the area of the auditory tube.
Bacteriological studies were performed when the tympanic membrane was spontaneously perforated, or when in the opinion of the investigator diagnostic or therapeutic tympanocentesis was indicated. Susceptibility to Azithromycin, Clarithromycin and Co – amoxiclav was determined for all pathogens, cultured by the disc diffusion method.
Laboratory tests
Laboratory tests were performed before treatment and 10-12 days after.
Haematology
Erythrocyte sedimentation rate, white blood cell count with differential and platelet counts were performed.
Blood biochemistry
Total bilirubin, AST, ALT. Any significant abnormalities occurring during the trial were followed up until the cause of abnormality was established or the results returned to normal.
Additional tests
USG sinuses and ultrasonoscopy of the tympanic cavity were performed.
The most important part of these non – invasive tests was the assessment of the contents of the tympanic cavity and sinuses and confirmation or not of presence of liquid.
Adverse events
All observed or volunteered adverse events were recorded in CRF.
Even if the adverse event was unlikely to be causally related to treatment it was documented. The severity of an adverse event was evaluated according to the following definitions:
MILD: awareness of symptoms but no interference with daily activities;
MODERATE: symptoms cause discomfort with some interference with daily activities;
SEVERE: disabling the patient, who is unable to conduct daily activities;
Abnormalities in test results were regarded as adverse events.
Evaluation of efficacy
Clinical efficacy
Clinical efficacy was evaluated in patients who finished their treatment with no major protocol violations. It was evaluated at the end of therapy (day 10-12) and at the follow-up visit (day 26-32). Clinical outcome was defined as:
1. Cure
Complete disappearance of signs and symptoms of infection (TCS = 1), excluding middle ear effusions;
2. Improvement
Partial disappearance of signs and symptoms of infection without a need for additional antibiotic treatment;
3. Failure
Persistence or progression of signs and symptoms of infection after at least 72 hours of treatment, requiring substitution with other antimicrobial agent;
4. RECURRENCE
Reappearance of signs and symptoms of infection within 4 weeks after the start of treatment.
Bacteriological efficacy
Bacteriological outcome was evaluated only in patients with positive pretreatment culture.
1. Eradication
The causative pathogen couldn´t be isolated in cultures of middle ear aspirate obtained at any time after at least 72 hours of treatment.
2. Presumed eradication
Pretreatment culture of the middle ear aspirate was positive and a post – treatment culture wasn´t performed due to the complete disappearance of clinical signs and symptoms.
3. Persistence
Positive culture of an adequate specimen obtained after at least 72 hours of treatment.
4. Relapse
Causative pathogen isolated in culture of an adequate specimen obtained at any time after one negative culture.
RESULTS
The results that were achieved during the study were analyzed clinically and financially. The results of the observations were analyzed statistically and were concerned with two features: quality (for example, sex and the kind of antibiotic used) and quantity. The quantity feature was represented by a continuous variable (for example, age, weight, leucocytes) and also by a periodic variable (for example, clinical evaluation). Statistical conclusions concerning the data in the form of the two series of results for the same patients were based on tests for dependent variables. Thus, in each group, for a continuous variable a hypothesis of the average difference between the pre – therapy and the post – therapy visits was verified.
For the jumping feature (difference between the second and the post – therapy visit) the non – parametric sequence par Wilcox test was used. Then comparisons of the three unrelated trials (including independent groups of patients) were made using a single factor variance analysis (ANOVA) or its non – parametric equivalent, the Kruskal – Wallis test. The assumptions allowing performing the above–mentioned parametric tests were checked when it was necessary to verify the hypothesis of the distribution compatibility of the trial with the normal distribution – a Chi squared compatibility test was used, but a level test was used in the case of homogeneity variance. The relation between the quality features and the unrelated trials was analyzed using the independent Chi squared test, and the Mc Nemary test was used for related trials. When the full data were not available for the last test, fraction comparison was made by means of the Fisher test.
The hypotheses were verified at a significance level of p = 0.05.
The calculations were made using the PL v 5.1 statistical program.
The results of the study point to a lack of important differences between the arithmetic means of the examined groups of the patients in groups A, B and C, if we take into account the patients´ ages (6.5 – 6.8 years old), their weight (25.4 – 26.1 kg) and their sex (ANOVA). The results of the bacteriological tests were analysed statistically (KRUSKALA – WALLIS test) and they did not show any important bacteriological differences in patients (tables 1, 2).
Table 1. Kinds of micro-organisms isolated during the pre therapy and post therapy visit.
| Kind of antybiotic |
| | A - SUMAMED | B - KLACID | C - AUGMENTIN |
| | Number of cases Pre therapy visit | Number of cases Post therapy visit | Number of cases Pre therapy visit | Number of cases Post therapy visit | Number of cases Pre therapy visit | Number of cases Post therapy visit |
| 1. Streptococcus pneumoniae | 1 | 0 | 2 | 0 | 1 | 0 |
| 2. Haemophilus influenzae | 1 | 0 | 1 | 0 | 0 | 0 |
| 3. Moraxella catarrhalis | 2 | 0 | 1 | 0 | 1 | 0 |
| 4. Staphylococcus aureus | 19 | 2 | 16 | 3 | 18 | 2 |
| 5. Streptococcus pyogenes | 2 | 0 | 2 | 0 | 1 | 0 |
| 6. Other | 9 | 2 | 10 | 1 | 12 | 2 |
| 7. None | 24 | - | 21 | - | 26 | - |
Sources – own calculations.
Table 2. Evaluation of bacterial sensitivity of antibiotics used. Statistical analysis (KRUSKAL – WALLIS´ test) did not reveal any differences between the three groups of antibiotics.
| Kind of sensitivity | GROUP A | GROUP B | GROUP C |
| | SUMAMED | KLACID | AUGMENTIN |
| Resistant | 3 | 2 | 1 |
| Not examined | 24 | 21 | 26 |
| Sensitive to A | 24 | 14 | 22 |
| Sensitive to B | 19 | 17 | 19 |
| Sensitive to C | 25 | 16 | 27 |
Sources – own calculations
Table 3. Evaluation of bacteriological efficiency did not reveal any differences between the used antibiotics. All the antibiotics were highly effective.
| Bacteriological efficacy | Antibiotic |
| | A | B | C |
| 0. Not evaluable | 17 | 18 | 20 |
| 1. Eradication | 23 | 14 | 16 |
| 2. Presumed eradication | 14 | 18 | 12 |
| 3. Persistence | 3 | 2 | 1 |
| 4. Relapse | - | 1 | - |
| 5. Superinfection | 1 | - | 0 |
| 6. Other | - | - | 1 |
Sources – own calculations
The children were examined clinically four times. The results of visits (after 4 and 7 days) and post – therapy between the 10th and the 14th days of treatment were carefully analysed.
In group A the highest percentage of the patients described as cured was already achieved at visit II (66.5 %).
In group B, 22% of the patients were cured just as in group C (22%).
Using the Wilcox test, quite a considerable difference (p=0.0000) between the clinical examinations during visit II and post – therapy in group B was observed, as well as quite a marked difference (p=0.0001) in group C. In group A only a marked difference (p=0.0076) was observed. These results point to a high percentage of the children in group A being already cured at visit II.
Some selected haematologic and biochemical parameters using the ANOVA test were also analysed. In each group of children treated with antibiotics A, B, and C, the sedimentation test and leucocytes revealed quite a marked difference between the pre – therapy visit and post – therapy. A fall in the sedimentation test and leucocytes did not depend on the antibiotic used. The results of AST and ALT do not confirm any statistically important differences between pre – therapy and post – therapy visits, and they are also independent of the kind of antibiotic used. USG examination of the sinuses did not reveal any important differences between pre – therapy and post – therapy visits.
The receding changes occurred systematically in each group. Ultrasonoscopy examination of the tympanic cavity revealed a highly marked difference in group A during visit II (p=0.0001).
The antibiotic used in this group had a very good effect on causing liquid to recede from the area of the middle ear, and a similar result in group B and C was recorded only after 10 days of therapy. No adverse effects were observed in the studies. A few cases of food intolerance of drugs A, B and C did not reveal any basic differences. In group A two cases of intolerance were recorded, in group B two, and in group C three. In one case in group C it was necessary to perform a single hydration parenterally. The information obtained from parents or guardians concerning compliance clearly points to a very significant difference (p=0.001) being favourable for drug A and significant for drug B (p=0.0063). The children much preferred taking SUMAMED once daily for an average period of 3.7 days to taking Klacid twice daily for 9.3 days and Augmentin in 3 daily doses administered for an average period of 9.3 days. For parents/guardians a 3-5 day therapy was much easier to carry out than a therapy consisting of 20 or 30 doses taken for 10 days. An organoleptic evaluation did not reveal any significant differences.
PHARMACOECONOMIC ANALYSIS
The most important part of the economic analysis was an attempt to find out which of the three strategies for treatment of ear inflammation was the most economical, taking into account the same percentage of cured patients. The choice of economic analysis depended on the benefits from the application of the alternative programmes in accordance with the guidelines for „good pharmaco – economic practice”. In the presented study we used the method of cost minimization, as the benefits from application of the alternative programmes of treatment A, B and C were identical. In practice this method had a limited application, because clinically the same effects using different programmes are rarely achieved. In our study it could be used because of the achieved results. Single factor variance analysis (ANOVA, p=0.0000) revealed a very great difference between the average costs of treatment of children with antibiotics A, B and C. Close examination of the differences between average levels made with the Tukey test (for trials of different quantity) makes it clear that the difference between the average levels of the groups is important, and in the case of groups A and C it is very important. Pharmaco – economic results reveal that treatment with Azithromycin is the most effective and cheapest kind of therapy (table 4).
Table 4. Cost analysis of treatment, and number of days of sick leave for guardian. The prices of the drugs have been averaged based on 5 pharmacies in Silesian area. (1 Euro = 3,75 zł)
| Antibiotic | Real costof treatment | Cost of DDD | Cost of treatmentof 1 child | Number of daysfor guardianon sick leave | Other costs |
A n=58
SUMAMED | 1685.04 zł
455.4 Euro | 7.85 z
2.09 Euro | 26.69 zł
7.11 Euro | 185 | 10.8 zł
2.88 Euro |
B n=53
KLACID | 2343.99 zł6
25.06 Euro | 4.75 zł
1.26 Euro | 44.17 zł
11.78 Euro | 556 | 23.3 zł
6.21 Euro |
C n=59
AUGMENTIN | 3465.72 zł
924.19 Euro | 6.24 zł
1.66 Euro | 58.65 zł
15.64 zł | 528 | 23.3 zł
6.21 Euro |
Sources – own calculations.
Quality of life:
– full recovery in group A took 6 days, in group B, 9.7 days and 9.3 days in group C. Additional costs concerning sick leave for the guardian of the sick child are closely connected with the antibiotic used. The lowest additional costs were recorded in group A.
DISCUSSION
The detailed clinical analysis points to a high level of comparable efficiency of the antibiotics used.
The children liked taking SUMAMED most because of the short and least troublesome course of therapy. Similarly, their guardians spoke very favourably of treatment with drug A, and favourably of treatment with drugs B and C. The time to make a full recovery and the time taken on sick leave by the guardian were closely connected with the drug used and the times were the shortest for group A. In view of the fact that nowadays new generation antibiotics are widely available, a therapy using an effective and safe drug taken once a day for 3 – 5 days and used to treat ear chronic illnesses constitutes an alternative choice justifiable clinically and economically.
Piśmiennictwo
1.Dhooge I.J.M. et al.: Intratemporal and intracranial complications of acute suppurative otitis media in children: renewed interest. International Journal of Ped. Oto. Rhino. Laryng. 49, suppl. 1 1999, 109-114. 2.Drummond M.F., Stoddart G.L.: Methods for the economic evaluation of healthcare programmes. Oxford: Oxford Medical Publications 1987. 3.Handel E.M. et al.: Comparative efficacy of erythromycin – sulfisoxazole, cefaclor, amoxicilin or placebo for otitis media with effusion in children. Pediatr. Infect. Dis. J. 1991, 10, 899-906. 4.Hassman-Poznańska E.: Otitis media in children. Nowa Med. 1996, 7, 9-11. 5.Kawalski H., Cierpioł-Tracz E. et al.: Antibiotic therapy in the treatment of otitis media with effusion. Clinical study of Amoxicillin, Cefradine and Azithromycin. Nowa Ped. 1999, 11:40-42. 6.Kawalski H., Cierpioł-Tracz E. et al.: Combined therapy in children with otitis media secretoria. Pediatria Pol., 1988, LXXIII, 7. 7.Kawalski H.et al.: Remote results of combined therapy in children with secretory otitis media as treated with loratdine and clemastin. 7th International Congress of Ped. Otorhinolaryngology, Helsinki 1998, 549. 8.Pharmacoeconomic Research Guideline: Ziekenfondsrad Postbus 396, 1189 BD Amstelveen, April 1999. 9.Ruben R.J.: Persistency of an effect: otitis media during the first year of life with nine years follow-up. International Journal of Ped. Oto. Rhino. Laryng. 49 suppl. 1 (1999), 115-118. 10.Ślapak I.: Azithromycin vs. Clarithromycin: clinical and economic comparison in the treatment of acute otitis media in children. Pediatric Faculty Hospital Johann Gregor Mendel. Brno Medical Publication. SUM-CH-01/2-97-CZR- 1, 1997. 11.Williams R.L. et al.: Use of antibiotics in preventing recurrent acute media and in treating otitis media with effusion. JAMA 1993, 270, 1344-1351.
