Submitted in Fulfilment for the Doctor of Philosophy Degree in Pharmaceutical Science (Pharmaceutics) Thesis Presented By

Transcription

1 PHARMACOECONOMIC STUDY TO DETERMINE THE CLINICAL EFFECT OF DEFFERENT ANTIBIOTICS INCLUDED IN THERAPUTIC REGIMENS USED IN THE TREATMENT OF PATIENTS SUFFERING OTITIS MEDIA, THEIR COST, AND THEIR RELATION WITH THE PATIENTS RESPONSE Submitted in Fulfilment for the Doctor of Philosophy Degree in Pharmaceutical Science (Pharmaceutics) Thesis Presented By Noha Mohamed Fathy Abd El Fattah El Adawy Under The Supervision of Prof. Dr. Saadia A. Tayel Prof. of Pharmaceutics and Industrial Pharmacy Faculty of Pharmacy Cairo University Prof. Dr. Mohamed A. El-Nabarawi Prof. of Pharmaceutics and Industrial Pharmacy Faculty of Pharmacy Cairo University Dr. Nirmeen A. Sabry Assistant Prof. of Clinical Pharmacy Faculty of Pharmacy Cairo University Dr. Ahmed Shawki Mohamed Assistant Prof. of E.N.T Faculty of Medicine Cairo University Cairo University Faculty of Pharmacy Department of Pharmaceutics (2012)

2 ACKNOWLEDGMENT I would like to express my deepest gratitude to Professor Dr. Saadia Ahmed Tayel, Professor of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, who enriched this work by her knowledge and offered me much of her time, effort and help. I would also like to express my greatest appreciation to Professor Dr. Mohamed Ahmed El Nabarawi, Professor of Pharmaceutics and Industrial Pharmacy, Cairo Universityfor his continuous guidance, gracious supervision and support throughout the execution of this work. I feel greatly indebted to Dr. Nirmeen Ahmed Sabry, Assistant Professor of Clinical Pharmacy, Faculty of Pharmacy, Cairo University, for her tremendous help, time and effort. I would also like to express my heartily thankfulness for Dr. Ahmed Shawki Mohamed, Assistant Professor of E.N.T, Faculty of Medicine, Cairo University, for his generous help and invaluable advice all through the way. i

3 Table of Contents List of Tables...iii List of Figures......vii List of Abbreviations...ix Abstract...xi General Introduction CHAPTER I: Determination of Cost Effective Antibiotic Therapy for Patients Suffering Acute Otitis Media... Introduction.31 Experimental 33 Results Economic Study...69 Discussion...78 CHAPTER II: Determination of the Cost Effective Drug Therapy for Patients suffering Otitis Media with Effusion... Introduction...95 Experimental..96 Results Economic Study Discussion Conclusion and Recommendations References Arabic Summary ii

4 List of Tables Table# Title Table I : Table II : Table III : Table IV : Table V: Table VI: Table VII: Table 1: Table 2: Table 3: Table 4: Table 5: Table 6: Table 7: Table 8: Table 9: Table 10: Diagnostic feature of OME and AOM Relationship between the age of the child and the possibilities of using antibiotics. Microbiology of AOM Suggested antimicrobial therapy for AOM The process used to identify situations when a pharmacoeconomic analysis is needed. Examples of direct and direct non-medical costs Some major examples of indirect costs The demographic data of the patients recruited in this study Average Pain Score during the First Visit Parameter Average Hear Loss Score during the First Visit Average Body Temperature C (SD) during the First Visit Tympanic Membrane Examination during the First Visit Nasal Examination during the First Visit The Percentage of the Patients who Reported Pain Improvement during the Second Visit Pain Improvement using VAS for Patients Older than 3 Years Old During the Second Visit The Improvement in the Hear Loss during the Second visit Compared with the First Visit. The average Body Temperature during the First and the second Visits iii

5 Table 11: Table12: Table 13: Table 14: Table 15: Table 16: Table 17: Table 18: Table 19: Table 20: Table 21: Table 22: The Percentage of Patients Showing Improvement in the Clinical Picture of the Tympanic Membrane during the Second Visit The Percentage of the Patients showing Improvement in the Ear Discharge during the Second Visit The Number of patients still suffering from nasal discharge during the second visit. The Overall Number and Percentage of Completely Cured Patients in each Drug Group. Post-hooked Chi-Square Test to Show the Difference between the Number of Patients Cured in the Azithromycine and other Patients Belonging to the Other Study Groups. Post-hooked Chi-square Test Showing the Difference between the Number of Patients Cured between the Ampicillin/Clavulanic Acid Group and Study Groups except the Azithromycine Group. Post-hooked Chi-square Test Showing the Difference between the Number of Patients Cured between the Ampicillin group and both of Cephradine and Cefprozil groups. Post-hooked Chi-square Test Showing the Difference between the Number of Patients Cured between the Cephradine and Cefprozil Groups. The Pain Control Pattern among the Five Drug Groups. Post-hooked Chi-square Test for the Pain Control. Cost calculation including volume per unit, recommended dose, price per unit and price for ten days treatment Calculation of the therapeutic failure cost including the calculation of the extra physician visit and the extra cost of the new drug prescribed iv

6 Table 23: Table 24: Table 25: Table 26: Table 27: Table 28: Table 29: Calculation of net cost- effectiveness Calculation of savings gained by using the medication. Cost effectiveness of antibiotic regimens used in the treatment of AOM. The Demographic Data of the Recruited Patients. Average Hear Loss Score During the First Visit. Average Body Temperature C (SD) During the First Visit. Ear Drum Examination During the First Visit. Table 30: Table 31: Table 32: Table 33: Table 34: Table 35: Table 36: Table 37: Table 38: Table 39: Table 40: Table 41: Table 42: Table 43: Table 44: Middle Ear effusionexamination During the First Visit. Tympanometric Examination During the first Visit. Average Hear Loss Score During the Second Visit. The Average Body Temperature during the First and the Second Visits. Ear Drum Examination During the Second Visit Middle Ear Effusion Examination During the Second Visit Tympanometric Examination During the Second Visit Average Hear Loss Score During the Third Visit Ear Drum Examination During the Third Visit Middle Ear EffusionExamination During the Third Visit Tympanometric Examination During the Third Visit Average Hear Loss Score During the Fourth Visit Ear Drum Examination During the Fourth Visit Middle Ear EffusionExamination During the Fourth Visit Post hock Test for the Assessment of Middle Ear Effusion in the Three Drug v

7 Groups During the Fourth Visit Table 45: Table 46: Table 47: Table 48: Table 49: Table 50: Table 51: Table 52: Table 53: Tympanometric Examination During the Fourth Visit Adverse Drug Reactions Reported by the Patients in the Three Drug Groups The Post Hocked Chi-square Test for the Adverse Drug Reactions Affected Patients in the Three Drugs Under Study The Surgical Score in the Three Drug Groups Cost Calculation Including Volume/unit, Recommended dose, Price/unit and Price for 2 Weeks Treatment Calculation of the Cost of the Side Effects Calculation of the Net Costs Calculation of Savings Gained by Using the Studied Medication Regimens The Cost Effectiveness Results of the Drug Regimens Used to Treat OME vi

8 List of Figures Figure No. Figure I Figure II Figure III Figure IV Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15 Figure 16 Title The Eustachian Tube in both Adults and Infants Standard Gamble for a Chronic Health State Algorithm for the Choice of the Pharmacoeconomic Methodology Process for Incorporating Pharmacoeconomic Evaluation in Formulary Decision. The Percentage of Patients Showed Pain Improvement in each Drug Group The Total Percentage of the Patients who Showed Pain Improvement Among the Whole Studied Sample The Percentage of Patients Showed Improvement in their Hear Loss in each Antibiotic Group The Total Percentage of the Patients who Showed Hear Loss Improvement among the Whole Studied Sample Percentage of Patients with Red Tympanic Membrane before and after Initiation of the therapy Percentage of Patients with Bulging Tympanic Membrane before and after Initiation of the Therapy The Percentage of Patients Showed Improvement in the Tympanic Membrane in each Group Separately The Total Percentage of Patients who Showed Improvement in their Tympanic Membrane Percentage of the Patients with no Ear Discharge before and after Initiation of the Therapy Percentage of Patients Showed an Improvement in the Ear Discharge in Each group. The Percentage of the Patients with Nasal Discharge before and after Initiation of the Therapy The Percentage of Patients Showed Improvement in the Nasal Discharge in Each Group The Percentage of Patients Showed improvement in the Nasal Discharge The Percentage of Patients Reporting Pain Control after Day One The Percentage of Patients Reporting Pain Control after Day Two The Percentage of Patients Reporting Pain Control after Day Three vii

9 Figure 17 Figure 18 Figure 19 Figure 20 Figure 21 Figure 22 Figure 23 Figure 24 Figure 25 Figure 26 Figure 27 Figure 28 Figure 29 The frequency of the Possible Answer to the Question Discovering the Regular Use of the Medication The Frequency of the Possible Answer to the Question Discovering the Patients/Caregivers Beliefs Regarding the Efficacy of the Medication The Patients/Caregivers Opinion Regarding the Suitability of the Price of the Medication Patients Cured after Two-Week Therapy Percentage of Patients Recovered after Four Weeks Therapy Percentage of Patients Recovered after Six Weeks Therapy Total Number of Patients Completely Cured After Six Weeks in each Drug Group Percentage of the Total Number of Patients Reported No Adverse Drug Reactions The Number of Patients Suffered Adverse Drug Reaction in Each Drug Group Percentage of Patients Underwent Surgical Procedure The Frequency of the Different Answers of the Second Question: do you believe that the medication is really helping the patients? The Frequency of the Different Answers of the Third Question: do you believe the price of medication is suitable? The Percentage of the Patients who Believed that the Price of the Medication was Suitable viii

10 List of Abbreviations 1 (X 2 ) Pearson s Chi-squared Test 2 AAFP American Academy of Family Physicians 3 AAP American Academy of Pediatrics 4 ABCS Active Bacterial Core Surveillance 5 AHCPR Agency for Health Care Policy and Research 6 ANOVA Analysis of Variance test 7 AOM Acute Otitis Media 8 C Degree Celsius 9 C/E Cost Effectiveness ratio 10 CBA Cost-Benefit Analysis 11 CCA Cost-Consequence Analysis 12 CDCP Centre of Disease Control and Prevention 13 CEA Cost-Effectiveness Analysis 14 CMA Cost-Minimization Analysis 15 COI Cost of Illness 16 CSOM Chronic Suppurative Otitis Media 17 CSS Cigarette Smoke Solution 18 CUA Cost-Utility Analysis 19 DALYs Disability Adjusted Life Years 20 E.N.T Ear, Nose and Throat 21 ECHO Economic Clinical Humanistic Outcomes 22 EGFR Epidermal Growth Factor Receptor 23 H. influenzae Haemophilus influenzae 24 HMEECs Human Middle Ear Epithelial Cells 25 HMO Health Maintenance Organization 26 HRQoL Health Related Quality of Life 27 HYEs Healthy Year Equivalents 28 ICA Incremental Cost Analysis 29 ICER Incremental Cost Effectiveness Ratio 30 Ig Serum immunoglobulin 31 L.E Egyptian pound 32 M. catarrhalis. Moraxella catarrhalis ix

11 33 MCOs Managed Care Organizations 34 MEE Middle ear effusion 35 mrna Messenger RNA 36 MUC5AC Human mucin gene 37 NSAIDs Non-Steroidal Anti-Inflammatory Drugs 38 OM Otitis Media 39 OME Otitis Media with Effusion 40 PAS Paediatric academic society 41 PE Pharmacoeconomics 42 PNSP Penicillin non-susceptible Pneumococcal 43 QALY Quality Adjusted Life Year 44 QHIDB Quebec Health Insurance Database 45 RCTs Randomized Clinical Trials 46 S. pneumoniae Streptococcus pneumonia 47 SD Standard deviation 48 SPSS Statistical Package for Social Science 49 TM Tympanic Membrane 50 TNF-α Tumor necrosis factor-alpha 51 U Mann Whitney test 52 UK United Kingdom 53 URI Upper Respiratory Infection 54 URTI Upper Respiratory Tract Infection 55 V.T Ventilation Tube 56 VAS Visual Analogue Score x

12 ABSTRACT Introduction and Objectives Otitis media (OM) is a common illness affecting both infants and children, often multiple times during the first few years of life. The aim of this study is to determine the most cost effective drug for treatment of otitis media. Chapter One: Determination of Cost Effective Antibiotic Therapy for Patients Suffering Acute Otitis Media In Abouelreesh children hospital, 150 child aged 2-6 with ear pain were randomly divided into 5 groups A, B, C, D and E to be given amoxicillin/clavulanic acid, ampicillin, cephradine, cefprozil and azithromycin respectively for 10 days.amoxicillin/clavulanic acid represents the highest percentage of patients improved in the degree of pain (31%), hearing loss (32%), tympanic membrane (31%), and running nose (31%) among the whole sample under study. Although amoxicillin/clavulanic acid showed the highest percentage of cured patients (70%), yet there was no significant difference with ampicillin or Cephradine. Showing the lowest number of cured patients, azithromycin (15.4%) showed no significant difference with cefprozil (32%). There was no significant difference. Using cost effectiveness analysis model, amoxicillin/clavulanic acid showed the highest effectiveness value (0.7) although ampicillin provided the maximum savings. Chapter Two: Determination of the cost effective drug therapy for patients suffering otitis media with effusion Forty five child aged 2-6 suffering hearing loss were randomly divided into 3 groups X, Y and Z to be given phenadone syrup, cephradine/phenadone and amoxicillin/clavulanic acid/phenadone respectively. Patients were re-assessed every 2 weeks for 6 weeks. Uncured patients were subjected to myringotomy. There was no significant difference between the 3 groups in the post assessment of hear loss, ear-drum examination or tympanograph during either the second, third or fourth visits. No significant difference was detected in the middle ear effusion during the second or third visits. xi

13 The percentage of patients cured in the phenadone group was (31%), cephradine/phenadone (35%) and 34% in the amoxicillin/clavulanic acid/phenadone.28% of the total patients who experienced side effects were belonging to the phenadone group,33% in the phenadone/amoxicillin/clavulanic acid group and 39% in the phendone/cephradine group. Un cured patients (20%) were subjected to myringotomy with no significant difference between the 3 groups. Phenadone showed the highest cost saving (4, L.E/patient), with cost effectiveness/patient of 40.54L.E. Conclusion Amoxicillin/clavulanic acid is the recommended most cost effective drug therapy for treatment of patients suffering Acute Otitis Media while phenadone (without the addition of antibiotics) is the most cost effective choice for treatment of patients suffering Otitis Media with Effusion. xii

14 GENERAL INTRODUCTION Anatomically, an ear is a vertebrate organ of hearing responsible for sensing and collecting sounds as well as maintaining equilibrium. The human ear is divided into three anatomical divisions (1-2) 1. Outer ear 2. Middle ear 3. Inner ear Ear infection Ear infections can affect anyone, but mostly affect children. (1-2) The most common type of ear infection affects the middle ear. The medical term for a middle ear infection is Otitis Media (OM). (3) The middle ear infection can affect one or both ears. (3) The main types of infection are listed below. (4) 1. Acute otitis media (AOM) AOM is defined as the recent, abrupt onset of middle ear effusion accompanied by signs or symptoms of inflammation of the middle ear. (5) 2. Otitis media with effusion (OME) or (Glue Ear) It is also called secretory otitis media. It is defined as inflammation of the middle ear, accompanied by the accumulation of fluid in the middle ear cleft without the symptoms and signs of acute inflammation. OME is often asymptomatic and earache is relatively uncommon. (6) OME usually follows an episode of acute AOM. (6) 3. Chronic suppurative otitis media (CSOM) CSOM is assumed to be a complication of AOM. (7) Frequent upper respiratory tract infections and poor socioeconomic conditions (overcrowded housing, and poor hygiene and nutrition) (7) may be related to the development of CSOM. (8-9) CSOM represents the most frequent cause of moderate hearing loss (40 60 db). (10) Persistent hearing loss during the first two years may increase learning disabilities and poor scholastic performance. (11) Progressive hearing loss may occur among those in whom infection persists. Less frequently, spread of infection may lead to life threatening complications such as intracranial infections and acute mastoiditis. (12) 1

15 Mechanism of ear infection The small space behind the eardrum in the middle ear is normally filled with air. It is connected to the back of the throat by a tiny channel called the Eustachian tube. (13) Figure I The Eustachian tube in both adults and infants The tissues surrounding the Eustachian tube swell due to an upper respiratory infection, allergies, or dysfunction of the tubes. (14) The Eustachian tube remains blocked most of the time. The air present in the middle ear is slowly absorbed into the surrounding tissues. A strong negative pressure creates a vacuum in the middle ear. The vacuum reaches a point where fluid from the surrounding tissues accumulates in the middle ear. (14) The accumulated fluid may become infected. It has been found that dormant bacteria behind the Tympanum (eardrum) multiply when the conditions are ideal infecting the middle ear fluid. (14) When the middle ear becomes acutely infected (AOM), pressure builds up behind the ear drum. In severe cases, the tympanic membrane may rupture. Once perforated, the pus drains out into the ear canal. In most cases, a burst eardrum heals by itself. (14) Risk Factors for OM in children 1. Anatomically: Acute middle ear infections are most common in children. (15) Children below the age of seven years are much more prone to OM since the Eustachian tube is shorter and at more of a horizontal angle than in the adult ear (figure 1). Children aged less than 10 accounts for three quarters of those affected. (6) 2. Immunologically: They also have not developed the same resistance to viruses and bacteria as adults. (1) 2

16 3. Smoke: Several studies have shown a strong correlation between parental smoking and OME. (16-17) A large cohort study showed a marked dose-dependent effect. (16) In 1999, Glasziou et al. (18) reported in a study conducted over two years and tested approximately 3,000 children from birth to age two that about 33% of the children exposed to higher than average levels of vehicle emissions developed ear infections sometime during the study. (18) 4. The use of formula milk (rather than breast milk) (19) and feeding in a flat, supine position. (19) 5. Children who suffer from frequent coughs and colds. (19) 6. Boys are more susceptible to OME than girls, as are children in day care and those with older siblings. (19) 7. Children with certain genetic conditions, such as Down's syndrome. (20-21) Children with an anatomical abnormality affecting the face, such as a cleft palate are highly susceptible to OME. (20-21) Clinical Assessment and Diagnosis 1. AOM Ear related symptoms may include earache, tugging or rubbing of the ear, (3) irritability with loss of appetite, (3, 22) restless sleep and fever. (22) Children may also have a history of cough and rhinorhea symptoms which are reported to increase the risk of AOM. Earache, however, is the single most important symptom. (23) Otoscopic typical appearances of AOM include bulging tympanic membrane with loss of the normal landmarks, change in colour (typically red or yellow), and poor mobility. (24) Additionally, AOM may leave a middle ear effusion for a variable period of time following resolution of the acute symptoms - the two forms of OM (AOM and OME) should be considered part of a disease continuum. (25-26) 2. OME Most children have middle ear effusions and are often asymptomatic. (27) There is a minority in whom effusions persist over months or years causing hearing loss which in turn potentially impairs speech development and educational performance. (28-29) 3

17 Deafness, in small children, is often mistaken for lack of attention or even behavior problems. (3) Rates of bilateral OME are twice as high during winter than summer. (30) Common cold and OME are the most frequent diseases of infancy, characterized by a multifactorial pathogenesis. (31) There is also an association between OME and respiratory infections. (32) Newborns in neonatal intensive care units have a high incidence of OME, which is also more prevalent in the first than second year of life. (33) OME is diagnosed if there is middle ear effusion on pneumatic otoscopy with no signs of acute inflammation. (27) Evidence of middle ear effusion consists of the presence of either: At least two tympanic membrane abnormalities (abnormal colour such as yellow, amber, or blue; opacification other than due to scarring; and decreased or absent mobility) (27) otoscopy typically showing a retracted/concave tympanic membrane with a colour change (typically yellow or amber). (34) Air bubbles or an air/fluid level may be present and, while not typical, fullness or bulging may be visualized. Pneumo-otoscopy will demonstrate reduced or absent mobility. (34) Table I: Diagnostic feature of OME and AOM Earache, Fever, Irritability Middle ear effusion Opaque drum Bulging drum Impaired drum mobility Hearing loss OME Usually absent Present may be absent Usually absent present Usually present AOM Present Present Present May be present present present Technical diagnostic aids In addition to clinical signs and symptoms, certain technical aids can assist in the diagnosis of OM. (35) 4

18 1. Tympanography: is quite valuable in defining the presence of middle ear effusion. However, tympanography can be difficult to perform because obtaining a seal is often quite difficult, especially in children younger than 6 months of age. (35) 2. Pneumatic Otoscopy: is the most practical diagnostic modality for AOM. (35) The pneumatic otoscope should be checked to assure that the bulb is current and the light is bright and white in color. If a yellow or orange bulb is used, the tympanic membrane will appear inflamed. (35) Medical treatment 1. Pharmacological Therapy 1.1. Treatment of AOM AOM has received much attention in recent years. (36) Studies have shown that this condition to be over diagnosed and, hence, over treated as much 50% of the time by clinicians caring for children (37, 38) and there is a great dilemma concerning the different treatment strategies Antibiotic treatment There is wide variation in the use of antibiotics between doctors in different countries, from as low as 31% of cases with AOM in the Netherlands to as high as 98% in Australia and the United States. (39) Antibiotics were previously routinely immediately started, this practice is diminishing. Antibiotics do shorten the illness by around 1/3 compared to the illness's natural history, but this is a small gain for most children. (40) However, very young children, those with bilateral OM, and those with a high fever are likely to have a more severe course and hence benefit more from antibiotics. (41, 42) Many guidelines now suggest deferring the start of antibiotics for 24 to 72 hours. (43) This results in 2 out of 3 children avoiding the need to start antibiotics,(44) and no adverse effect on long-term outcomes for those whose treatment is deferred.(45) A meta-analysis of antibiotic versus placebo trials showed that antibiotics do not influence resolution of pain within 24 hours of presentation. At two to seven days after presentation, only 14% of children in control groups still had pain, although early use of antibiotics reduced the risk of pain by about 40%. (46) Children with AOM would need to be treated with a broad spectrum antibiotic rather than no antibiotic treatment to avoid a clinical failure. (46) Antibiotics in comparison to placebo and observational 5

19 treatment may have a modest benefit on symptom resolution and failure rates, as variously defined, in children over the age of two years with AOM. (47) Delayed antibiotic treatment In a delayed treatment trial, 315 children aged six months to 10 years were allocated to one of two treatment strategies: immediate antibiotic or delayed antibiotic. (45) The outcome measures were symptom resolution, absence from nursery or school and paracetamol consumption. The main conclusions from this trial were that immediate antibiotics provided symptomatic benefit mainly after the first 24 hours, increase the incidence of diarrhea by 10%, only 24% of the parents in the delayed prescription group used antibiotics and a wait and see approach in the management of AOM is acceptable to most parents and results in a 76% reduction in the use of antibiotic prescriptions. (45) A wait and see strategy is the observation of the patient without antibiotic therapy. It is an option clinicians may consider under certain circumstances, as outlined in Table 2. (48) This principle is based on data generated over the last decades documenting the clinical resolution of OM among children given placebo or no therapy and on studies comparing response between children receiving placebo or no therapy and children receiving antimicrobials. (48-50) Only 2 randomized trials (51), (25) have addressed the issue of school absence: One of the two trials found no significant difference between immediate versus delayed antibiotic therapy, (51) and the other reported a significant decrease of 1.5 days for children who received antibiotic versus placebo. (25) In both studies the mean duration of pain or crying was also reduced by 0.5 to 1.0 day. Table II: Relationship Between the Age of the Child and the Possibilities of Using Antibiotics. Age of child If diagnosis of AOM is certain If diagnosis of AOM is uncertain < 6 months Antibiotics Antibiotics 6 months 2 year Antibiotics Antibiotics if severe illness Observe if non-severe illness 2 years Antibiotics if severe illness Observe Observe if non-severe illness 6

20 Choice and duration of antibiotic therapy The antimicrobial therapy of AOM depends, of course, on the microbiology of the infection (Table 3). A large number of studies (38, 52-54) have established that two organisms, Streptococcus pneumoniae and Haemophilus influenzae, are the principal aetiological agents in OM bacterial infection. (52) Recently, it was reported that, 35% to 50% of cases of AOM are caused by H. influenzae, 25% to 40% by S. pneumoniae, and 5% to 10% by Moraxella catarrhalis a gram-negative, aerobic micro-organism. (38) A negligible number of cases are due to other bacteria. Viruses have been identified as the sole cause of infection in 5% to 15% of cases. (53) With S. pneumoniae and H. influenzae, broad spectrum antibiotics such as amoxicillin, or amoxicillin with clavulanic acid, are the drugs of choice if an antibiotic is to be used. (38) Cefaclor, cotrimoxazole, trimethoprim and erythromycin can be effective, but are less safe than amoxicillin. (54) Table III: Microbiology of AOM The Organism Cases in which organism is causative Haemophilus influenzae 35% 50% Streptococcus pneumoniae 25% 40% Moraxella catarrhalis 5% 10% This recommendation is based on the recognition that amoxicillin is not only effective but also has a low incidence of side effects, is cost-effective, and, by virtue of its taste, helps to assure good compliance. (55) The suggested antimicrobial therapy for AOM is outlined in Table 4. Children who have uncertain allergy to beta-lactams or non-anaphylactic allergy are advised to take an oral cephalosporin. (55) While children with a history of anaphylaxis or severe allergy to beta-lactams warrant treatment with one of the following: azithromycin, clarithromycin, trimethoprim-sulfamethoxazole, or erythromycinsulfisoxazole. (5) Viruses 5% 15% No growth of bacterial agents 1% 15% 7