Antibiotic Prescribing Patterns and Outcomes. Caroline Quach-Thanh, MD. Department of Epidemiology and Biostatistics,. McGill University, Montréal. Submitted ...
Acute Otitis Media in Quebec's Children: Antibiotic Prescribing Patterns and Outcomes
Caroline Quach-Thanh, MD Department of Epidemiology and Biostatistics, McGill University, Montréal
Submitted in April 2003
A thesis submitted to the Faculty of Graduate Studies and Research, McGill University in partial fulfilment of the requirements of the degree of Master of Science
© Caroline Quach-Thanh, 2003.
ABSTRACT
Acute otitis média ( AOM) is one of the most common indications for antibiotic use in children. We used the Régie de l'assurance maladie du Québec databases to better understand the prescribing patterns of physicians and to assess the effectiveness of différent antibiotics in the treatment of AOM. We selected a cohort of 60,513 children aged < 6 years with a first épisode of AOM between June 1999 and June 2002. Failure was defined as either a new dispensation of antibiotic or a hospitalization or outpatient visit for complications related to AOM in the following 30 days. The antibiotic most widely used was amoxicillin (42.8%). Failure occurred in 12,693 (21%) children. Overall, azithromycin was the only antibiotic that was less associated with failure when compared to amoxicillin (odds ratio 0.88; 95% confidence interval 0.82, 0.94). In the first 3 days of treatment, a 50% increased risk of failure was seen when macrolides were initially given. However, azithromycin was associated with a 20% decrease in the risk of failure occurring > 14 days after the beginning of treatment. Other risk factors associated with treatment failure were âge < 24 months, antibiotics or hospitalization in the preceding month, and otitis-prone conditions. Considering the results of the effectiveness study, the importance of macrolides résistance among pneumococci, and because there is no single factor or combination of factors that predict with certainty which child will develop early or late failure, amoxicillin should remain the first-lme drug of choice.
RESUME
L'otite moyenne aiguë (OMA) est un des principaux diagnostics menant à une prescription d'antibiotiques en pédiatrie. Nous avons utilisé les bases de données de la Régie de l'assurance maladie du Québec afin de décrire l'utilisation des antibiotiques, tout en déterminant l'efficacité pragmatique de divers antibiotiques dans le traitement de l'OMA. Nous avons sélectionné une cohorte de 60 513 enfants âgés de < 6 ans avec un 1er épisode d'OMA entre juin 1999 et juin 2002. Était défini comme échec, toute nouvelle prescription d'antibiotique ou toute hospitalisation ou visite en externe pour une complication reliée à l'OMA dans les 30 jours suivant la prescription initiale. L'antibiotique le plus utilisé était l'arnoxicilline (42,8 %). Un total de 12 693 enfants (21%) ont eu un échec de traitement. Seule l'azithromycine était moins associée avec un risque d'échec comparativement à l'arnoxicilline (odds ratio 0,88; intervalle de confiance à 95 % 0,82, 0,94). Durant les 3 premiers jours de traitement, l'administration initiale de macrolides était associée avec une augmentation de 50 % du risque d'échec. Par ailleurs, l'azithromycine était associée avec une diminution de 20 % du risque d'échec survenant > 14 jours après le début du traitement. Les autres facteurs associés à un échec étaient l'âge < 24 mois, antibiotiques ou hospitalisation dans le mois précédent et les conditions prédisposant à l'OMA. Étant donné les résultats de l'étude d'efficacité pragmatique, du taux de résistance aux macrolides parmi les pneumocoques et compte tenu qu'on ne puisse identifier avec certitude quel enfant développera un échec précoce ou tardif, l'arnoxicilline devrait demeurer l'antibiotique de première ligne dans le traitement des OMA.
To Stéphan, and
m
Nicolas
Elizabeth
TABLE OF CONTENTS
Abstract Résumé Table of contents List of tables and figures List of abbreviations Acknowledgements Préface Contribution ofAuthors
i ii iv vii viii ix xi xiii
CHAPTER1:
1
Introduction
1.1 Acute otitis média 1.1.1 Diagnostic criteria 1.1.2 Physiopathology 1.1.3 Burden of disease 1.1.4 Causative agents of AOM 1.1.5 Clinical course of AOM 1.1.6 Risk factors for developing AOM 1.1.7 Prévention of AOM
2 2 3 3 5 6 8 9
1.2 Management of AOM 1.2.1 Antibiotic treatment 1.2.2 Surgical treatment
11 11 14
1.3 Treatment failure 1.3.1 Penicillin-resistant Streptococcus pneumoniae
16 17
1.3.2
Risk factors for treatment failure
19
1.4 Clinical efficacy studies
21
1.5 Study objectives and présentation of articles
23
1.6 Références
31
IV
CHAPTER 2:
Acute Otitis Media in Children: A Review of Antibiotic 39 prescribing Patterns
2.1 Préface
39
2.2Abstract
41
2.3 Introduction
42
2.4 Methods 2.4.1 Data source 2.4.2 Study population 2.4.3 Amoxicillin daily dosage calculation 2.4.4 Conformity of prescribed and dispensed antibiotics with the published consensus 2.4.5 Statistical analysis
44 44 45 46 46 47
2.5 Results 2.5.1 Study population 2.5.2 Antibiotic utilization review 2.5.3 Conformity of antibiotic prescription
47 47 48 49
2.6 Discussion
50
2.7 Références
57
CHAPTER 3:
Effectiveness of Amoxicillin, Azithromycin, Cefprozil, 60 and Clarithromycin in the Treatment of Acute Otitis Media in Children: A Population-based Study
3.1 Préface
60
3.2 Abstract
62
3.3 Introduction
63
3.4 Methods 3.4.1 Data source 3.4.2 Study population 3.4.3 Outcomes 3.4.4 Exposure to antibiotics 3.4.5 Covariates 3.4.6 Statistical analysis
64 64 65 66 67 67 68
3.5 Results 3.5.1 Treatment failure 3.5.2 Effectiveness of antibiotics
69 69 70
3.6 Discussion
71
3.7 Références
80
CHAPTER 4:
Summary and Conclusion
84
4.1 Summary and conclusion
84
4.2 Références
89
APPENDICES: 1. Antibiotics approved for the treatment of acute otitis média 2. ICD-9 codes for AOM complications and procédures codes 3. Ethics certificate from McGill University
VI
91 92 94
LIST OF TABLES AND FIGURES
Chapter 1 Table 1.1
Complications associated with acute otitis média (AOM)
24
Table 1.2
Consensus on treatment of AOM (The Drug-resistant Streptococcus pneumoniae Therapeutic Working Group)
25
Table 1.3
Consensus on treatment of AOM (European panel)
26
Table 1.4
Clinical efficacy/effectiveness studies
27
Table 2.1
Description of antibiotics prescribed for first épisodes of AOM
53
Table 2.2
Predictors associated with the prescription of various antibiotics in the treatment of AOM in children
54
Table 2.3
Conformity with the consensus of antibiotics prescribed for first 55 épisodes of AOM
Figure 2.1
Distribution of conformity scores among physicians with 5 patients or more
56
Table 3.1
Characteristics of children with and without treatment failure
76
Table 3.2
Predictors associated with overall treatment failure
78
Table 3.3
Predictors associated with treatment failure at différent times
79
Figure 3.1
Time to failure by antibiotics
77
Appendix 1
Antibiotics approved for the treatment of AOM
91
Appendix 2
ICD-9 codes for AOM complications and procédure codes
92
Chapter 2
Chapter 3
Appendix
vu
LIST OF ABBREVIATIONS
95%CI
95% confidence interval
AOM
Acute otitis média
ENT
Ear, nose and throat
FDA
Food and Drug Administration
HIV
Human immunodeficiency virus
ICD-9
International Classification of Diseases - Ninth Revision
MIC
Minimum inhibitory concentration
NR-AOM
Non-responsive acute otitis média
OR
Odds ratio
PNSP
Penicillin non-susceptible Streptococcus pneumoniae
PRSP
Penicillin-resistant Streptococcus pneumoniae
RAMQ
Régie de l'assurance maladie du Québec
RR
Rate ratio
T&A
Tonsillectomy and adenoidectomy
TMS
Trimethoprim-sulfamethoxazole
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ACKNOWLEDGEMENTS
J'aimerais tout d'abord remercier mon directeur de thèse, Dr Jacques LeLorier, pour son support et sa disponibilité, ainsi que pour l'autonomie qu'il m'a laissée dans la poursuite de ce projet. Grâce à son expertise et son enthousiasme, j'ai eu la chance d'approfondir mes connaissances tout en élargissant mes horizons.
De plus, j'aimerais remercier Dr Jean-Paul Collet, mon co-directeur, pour son support et ses encouragements, ainsi que pour ses revues critiques des manuscrits soumis. Ses conseils ont été judicieux.
J'aimerais remercier le Collège des médecins du Québec qui m'a alloué du financement pour une année supplémentaire de formation en pharmacologie clinique, me permettant ainsi de compléter ma maîtrise.
L'équipe au sein de laquelle j'ai travaillé me fut d'un support inestimable. Je tiens à remercier Marc Dorais pour ses conseils en SAS et pour les fous rires qui ont détendu l'atmosphère. Je remercie également Amir Tahami d'avoir été mon ultime ressource dans les moments désespérés et Odile Sheehy pour son support tant technique que moral au cours de ce projet. Merci également à M. Ovid Da Silva, grâce à qui l'anglais de cette thèse est conforme aux meilleures règles de syntaxe et d'orthographe. Et bien sûr, merci Anita Massicotte, pour tout!
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J'envoie une pensée toute spéciale de l'autre côté de l'Atlantique, à Laetitia Huiart, maintenant à Marseille avec qui j'ai passé des moments inoubliables. Merci d'avoir pris le temps de relire les premiers jets de ma thèse. Tu es une éditrice sévère mais ça en valait la peine. J'ai beaucoup appris en travaillant avec toi mais je me suis aussi bien amusée. Merci également à Marie-Pierre et Bernard(s), complices de tous les cours.
Finalement, le plus gros des merci à ma maman et à ma sœur, parce qu'elles ont toujours été là, pour moi et pour les enfants. Sans leur soutien continuel, je n'en serais pas là. Merci à Stéphan, mon mari, qui m'a toujours appuyée dans la poursuite sans fin de mes multiples spécialités et diplômes. Merci pour tous ces quarts de travail supplémentaires à l'urgence qui m'ont permis de me consacrer pleinement à mes études, sans autre souci. Et bien sûr, merci les enfants, Elizabeth et Nicolas. Vous êtes le soleil de ma vie. Grâce à vous, j'ai redéfini mes priorités puisque rien ne vaut des enfants heureux et en santé.
PREFACE
This thesis consists of four chapters: the introduction, two manuscripts intended for journal publication, and an overall summary and conclusion. Chapter 1 gives an overview of the literature on acute otitis média (AOM) and summarizes the study objectives. Chapter 2 reports the results of the antibiotics utilization review in the treatment of AOM in the province of Québec. Chapter 3 compares the effectiveness, in a population-based study, of four commonly-used antimicrobial agents in the treatment of AOM: amoxicillin (usual and high-dose), azithromycin, cefprozil, and clarithromycin. Chapter 4 provides an overall summary of the findings reported in the two manuscripts. Tables, figures and références are provided at the end of each chapter. Because the chapter manuscripts were submitted for publication to différent journals, there is some répétition of material in the literature review and in the methods section. The Faculty of Graduate Studies and Research, McGill University approves the format of this thesis. The following statements from the 'Guidelines Concerning Thesis Préparation' must be included in the Préface. " As an alternative to the traditional thesis format, the dissertation can consist of a collection of papers of which the student is an author or co-author. Thèse papers must hâve a cohesive, unitary character making them a report of a single program of research. The structure for the manuscript-based thesis must conform to the following:
XI
1. Candidates hâve the option of including, as part of the thesis, the text of one or more papers submitted, or to be submitted, for publication, or the clearlyduplicated text of one or more published papers. Thèse texts must conform to the 'Guidelines for Thesis Préparation' with respect to font size, line spacing, and margin sizes and must be bound together as an intégral part of the thesis. 2. The thesis must be more than a collection of manuscripts. Ail components must be integrated into a cohesive unit with a logical progression from one chapter to the next. In order to ensure that the thesis has continuity, Connecting texts that provide logical bridges between each manuscript are mandatory. 3. The thesis must conform to ail other requirements of the 'Guidelines for Thesis Préparation' in addition to the manuscripts. The thesis must include the following: (a) a table of contents; (b) a brief abstract in both English and French; (c) an introduction which clearly states the rationale and objectives of the research; (d) a comprehensive review of the literature; (5) a final conclusion and summary; (6) a thorough bibliography; (7) appendix containing an ethics certificate. 4. As manuscripts for publication are frequently very concise documents, where appropriate, additional material must be provided in sufficient détail to allow a clear and précise judgement to be made of the importance and originality of the research reported in the thesis.
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5. In gênerai, when co-authored papers are included in a thesis, the candidate must hâve made a substantial contribution to ail papers included in the thesis. In addition, the candidate is required to make an explicit statement in the thesis as to who contributed to such work and to what extent. This statement should appear in a single section entitled 'Contributions of Authors' as a préface to the thesis. 6. When previously published copyright material is presented in a thesis, the candidate must include signed waivers from the publishers and submit thèse tôt the Graduate and Postdoctoral Studies Office with the final déposition, if not submitted previously. The candidate must also include signed waivers from any co-authors of unpublished manuscripts. 7. In no case can a co-author of any component of such a thesis serve as an external examiner for that thesis."
Contribution of Authors This manuscript-based thesis includes two co-authored papers. In ail cases, I formulated the principal research questions independently and was responsible for the study design, data management, statistical analysis, and manuscript préparation. The co-authors of the two manuscripts were ail members of my Thesis Supervisory Committee. They provided methodological and editorial advice through the entire process.
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Chapter 1 Introduction
Modem medicine has various milestones, but one of the most important is, without doubt, the discovery of effective agents to prevent and treat infections caused by bacteria and other microorganisms. Antibiotics were first used clinically in 1936, starting with sulfonamides and followed in the 1940s by penicillin and streptomycin (1). Thereafter, new molécules were discovered on a regular basis and the golden âge of antimicrobial chemotherapy was under way. Unfortunately, along with the introduction of new molécules, a foreseeable problem emerged: résistance of microorganisms to available antibiotics. Antimicrobial résistance is currently increasing Worldwide, leading to a reduced therapeutic arsenal against common infections such as respiratory tract infections, as well as more invasive infections. The situation is worrisome and judicious administration of antibiotics is warranted to stabilize and hopefully reverse this trend. Previous studies hâve shown a corrélation between the total use of antibiotics at the municipal level and the prevalence of résistance in respiratory tract pathogens (2-4). To reduce inappropriate antibiotic prescription, Sweden initiated, in 1994, a national project which focused on inappropriate prescribing of antibiotics to children with respiratory tract infections and surveillance of antimicrobial résistance (5). This initiative stopped the progression of résistance among Streptococcus pneumoniae, the leading cause of pneumonia, bacteremia, meningitis and acute otitis média (AOM) in children (6).
To evaluate the appropriateness of antibiotic prescription in the province of Québec, AOM was chosen as the index disease because it is the most common reason for consulting a physician as well as the most common indication for antibiotics in children (7,8). Moreover, treatment recommendations for AOM were issued in 1999 and thus, enabled us to use them for référence (9,10). We compared the risk of treatment failure among patients managed with différent antibiotics, to see if recommended treatments were, in fact, associated with a decreased risk of failure. The province's administrative database where over 60,000 children had experienced a first épisode of AOM allowed us to assess the clinical effectiveness of various antimicrobial treatments in the management of AOM in a real-life setting.
1.1 Acute otitis média 1.1.1
Diagnostic criteria AOM has been defined by an expert panel to be "the présence of middle ear
effusion in conjunction with the rapid onset (< 48 hours) of > 1 signs or symptoms of inflammation of the middle ear (defined as otalgia, ear tugging or otorrhea and irritability or fever ± anorexia, nausea and vomiting)" (11). Although définitions of AOM exist, its diagnosis is not easy in young children since thèse criteria are often not strictly followed. For example, a survey of 165 pediatricians working in the U.S.A. revealed 147 différent sets of diagnostic criteria, making comparison between studies very difficult (12). Also, it is likely that many physicians, who find ambiguous signs of AOM on examination, still choose to treat the patient with antibiotics(13).
1.1.2 Physiopathology In most circumstances, AOM is preceded by an upper respiratory viral infection. This usually benign infection causes congestion of the respiratory tract, including the nose and eustachian tube, resulting in its obstruction. Mucosal sécrétions from the middle ear, which normally drain through the eustachian tube, are blocked and accumulate in the middle ear. The effusion may be asymptomatic, but if bacteria colonizing the nasopharynx are also présent in the middle ear before eustachian tube obstruction and are now trapped, they will multiply and cause an infection resulting in symptoms of AOM (14).
1.1.3
Burden of disease AOM is one of the most common infectious diseases of childhood. By âge 1
year, 62.4% of children expérience at least one épisode of AOM, compared with 75% by âge 3 years and 90% by âge 7 years (15-17). Studies following cohorts of newborns (18,19) up to the âge of 7 years (15) hâve revealed that 41.8%» expérience at least one AOM épisode by âge 2 years with a peak incidence during the second half of the first year of life (15,18). Up to 91.1% expérience at least one épisode of middle ear effusion and spend a médian of 28 days on antibiotics for the treatment of AOM (19). Récurrent AOM, defined as > 4 épisodes in 12 months, were recorded in 5.4% of thèse children. In a single year, 46.8% of children aged 13 to 24 months will be diagnosed as having AOM compared with 35.4% of those aged 25 to 36 months and 9.6% of 7- to 13-years-old (20). Higher incidence of AOM was noted among White children,
especially in rural areas, with rates of 34.5% (21) particularly during the fall and winter (16). Overall, approximately 30% of children less than âge 3 years in the U.K. visit their physician each year for AOM, and of thèse, 97% receive antibiotics (22). On average, 1.6 antibiotic courses are given per child with AOM in a given year (20). In the U.S., AOM represents more than 20 million visits to physicians per year, with an average of 2.9 physician office visits per child. One-fourth of children aged less than 2 years make 6 visits or more to their physician for AOM per year (23-25). The Food and Drug Administration (FDA) has estimated that 45 million courses of antibiotics were prescribed in 1986 for children less than 10 years of âge, of which 42% were for AOM. Between 1980 and 1992, an increase was noted in the use of broad spectrum and more expensive antimicrobial agents (26). The American National Center for Health Statistics reported that the diagnosis of AOM climbed from approximately 10 million visits per year in 1975 to approximately 25 million in 1990, which represents an incrément of 224% in the annual visit rate for children less than 2 years of âge (26). An increase in prevalence was also noted in another study where the proportion of children less than âge 10 years suffering from AOM rose from 14% in 1978 to 21% in 1994, with a doubling in the proportion of récurrences (6% to 12%). Paradoxically, this was accompanied by an overall milder clinical picture of AOM, likely because of consulting at an earlier time (27). In the province of Québec (1980), diseases of the sensory organs ranked third as the leading cause of ambulatory care, and seventh for the number of hospital-days among children aged 1 to 14 years, with AOM accounting for 61.4% of ambulatory care use and 57% of hospital-days (28,29). In 1988, acute and chronic suppurative otitis
média had a yearly incidence of 633/1000 3-year-old boys and 602/1000 3-year-old girls (28). The costs imposed on health Systems hâve been estimated to be between US$ 3 and 4 billion (16,30). Nearly half of the expenditures associated with AOM treatment were incurred before the âge of 3 years. The per capita cost of AOM treatment in children aged between 1 and 3 years has been estimated to be 453 in 1002-USS due mainly to physician visits since only 54.3 surgical procédures are performed per 1000 children with AOM (21).
1.1.4
Causative agents of AOM Many studies hâve attempted to détermine the etiologic agents of AOM via
tympanocentesis performed before treatment. Under normal conditions, the middle ear space is stérile and, therefore, organisms isolated from middle ear fluid are perceived to be the cause. Although the contribution of various pathogens may hâve changed over time, the principal infectious agents of AOM hâve remained the same. In gênerai, approximately 30% of spécimens are stérile for bacteria. This may reflect, in part, the limitations of bacterial culture methods because antigen détection tests often indicate the présence of pneumococcal capsular polysaccharide in stérile middle ear fluid (31). Twenty-five to 40% of cases are caused by Streptococcus pneumoniae, 20 to 35% by Haemophilus influenzae (non-typeable strains), 5 to 20% by Moraxella catarrhalis and a smaller proportion by Streptococcus pyogenes (Group A Streptococcus) (24,32-36). In most cases, only one pathogen is found for a given infection (76%). However, in 17%> of cases, 2 microorganisms are isolated, and in 7%, 3 pathogens hâve been recovered (32). The proportion of antibiotic résistance has been shown to be as high as
67% in pneumococcus (36). More than 90% of M. catarrhalis and 20% of H. influenzae hâve been found to be P-lactamase producers, enabling them to destroy penicillin and other related antibiotics (35). Interestingly, H. influenzae and M catarrhalis are likely to be co-pathogens with S. pneumoniae when the latter is résistant to penicillin (25% vs. 10% when sensitive to penicillin) (34). As mentioned previously, viral infections frequently precipitate AOM, but were reported as the sole pathogen in only 6% of cases (34). The viruses associated with AOM are mainly respiratory syncytial virus, parainfluenza virus, influenza virus and adenovirus. When thèse co-exist with bacteria as causative agents of AOM, the bacteria tend to persist longer in the middle ear fluid (37).
1.1.5
Clinical course of AOM Although it is a very fréquent illness, AOM usually has a benign course. A very
high proportion résolves spontaneously (38). This proportion has been said to be between 60 and 90%, depending on the study and the organism involved. AOM infections caused by viruses, for example, will résolve on their own, if not superinfected by bacteria. In a 1950s study, placebo-controlled, AOM épisodes that were not treated tended to hâve a longer duration when compared to those treated with penicillin. However, ail épisodes that failed to heal responded to a course of penicillin without significant morbidity (39). AOM caused by S. pneumoniae usually resolved spontaneously in 20% of cases compared with 50% spontaneous recovery if//. influenzae was the etiologic agent and an even higher proportion for M. catarrhalis: « 80%o. Spontaneous resolution is seen with most AOM in children older than 2 years of
âge (40). Récurrence and âge between 6 months and 2 years hâve been shown to be prédictive of a complicated course. However, no relation has been found between the severity of tympanic membrane inflammation and the clinical course over a 3-day period, even when adjusted for âge, initial température, and antibiotic use (41). Considering this favourable clinical course, some authors hâve compared AOM outcome when treated with an antibiotic or placebo. An open, randomized trial in the U.K. reported that delaying treatment for 72 hours with observation did not hâve any impact on mean pain scores, épisodes of distress or absence from school when compared with children who had received antibiotics. The benefits of antibiotics occurred after the first 24 hours of treatment and coincided with an improvement of symptoms in the observed patients as well. This strategy resulted in a 76% decrease in antibiotic use (42). Thèse finding were supported by a Cochrane systematic review which revealed that by 24 hours, 2/3 of children recovered - whether or not they had received antibiotics, with a spontaneous recovery rate of 80% in 2 to 7 days. Adding antibiotics to the management of AOM achieved a further 28% relative réduction in the risk of pain (95% confidence interval (CI) 15 - 38%) with a number needed to treat of 17. There was no différence between the two groups in terms of hearing impairment but antibiotics were associated with an increase in adverse events (33). Thèse untoward reactions hâve been estimated to occur in 5 to 29% of children treated for AOM with commonly used antibiotics (43). When taking an early endpoint for comparison, e.g. after 4 days of treatment, not receiving antibiotics seemed to be associated with a greater risk of persistent symptoms (adjusted odds ratio (OR) for persistent symptoms 1.79; 95%>CI 1.03-3.13).
However, at day 11 after the beginning of treatment, the différence became nonsignificant, both in terms of symptoms and otoscopic findings (44). After an AOM épisode, middle ear fluid usually persists in 41 to 85% of cases for 14 days, and in 5 to 25% of cases for up to 12 weeks without altération by antibiotics (15). Mastoiditis is another classical complication associated with AOM with an estimated incidence ranging from 1/1,000 to 1/2,000 children with AOM not treated with antibiotics (30,33). An open, randomized clinical trial in 1954 comparing penicillin to sulfonamides and placebo reported a mastoiditis rate of 17% in the untreated group vs. 1.5% in the sulfonamide group and 0% in the penicillin group (39). This study, however, was not properly randomized since some patients who requested to be entered in the penicillin group were included in it. Other complications of AOM are summarized in Table 1.12 (45).
1.1.6 Risk factors for developing AOM Young âge is associated with an increased risk of developing AOM, reflecting the size of young children's eustachian tube as it is shorter, wider, straighter and more horizontal, allowing organisms from the nasopharynx to easily reach the middle ear (14). Anatomy plays a rôle in AOM proneness in children with trisomy 21, cleft palate and other abnormalities of the ear, nose and throat area (34,37). Studies hâve shown an increased prevalence of AOM in Alaskan Eskimo and Native Americans (34) as well as in African Americans but mainly during their first year of life (19). A higher prevalence in maies compared with females and in non-breastfed infants has been reported (15,19). Genetic prédisposition is demonstrated by a higher prevalence of AOM in children with a familial history of récurrent AOM (34). Yamanaka and Faden hâve suggested that
otitis-prone children are unable to mount an adéquate anamnestic antibody response to non-typeable H. influenzae (46). Socioeconomic factors hâve been associated with an increased risk of AOM. For example, passive smoking (47), low socioeconomic status and high exposure to other children such as by daycare attendance (48) hâve been identified as risk factors (19). Some factors are however difficult to separate from low socioeconomic status. Thèse include low birth weight and young maternai âge. Age at first AOM plays a rôle in otitis-proneness. Looking at children who were followed for > 24 months after their initial AOM, Teele and collaborators (15) estimated that 62% of children having an épisode of AOM before the âge of 6 months will hâve at least 2 more épisodes in the next 2 years. In comparison, only 26% of children who had their first AOM after the âge of 1 year developed > 2 other épisodes in the subséquent 2 years (15). Kvaerner and collaborators showed that children with at least one épisode of AOM occurring before 9 months of âge had more than a 2-fold increase in risk of becoming otitis-prone (rate ratio (RR) 2.3; 95%CI 1.5-3.5) compared with children whose first épisode occurred between the âge of 10 and 12 months (18).
1.1.7
Prévention of AOM To prevent AOM, modification of environmental risk factors may be useful, but
if available vaccines could reduce its incidence, such a strategy would be interesting. Respiratory viruses, mainly influenza virus, play a crucial rôle in the development of AOM (49). An inactivated influenza vaccine that is safe and immunogenic in children aged 6 months or more exists and is effective in preventing AOM (50). Cléments et al.
reported a protective outcome of vaccination (OR 0.69; 95%CI 0.49-0.98) against AOM during the influenza season in children aged 6 to 30 months attending daycare (51). Heikkinen et al. found a 36% réduction of AOM after vaccination during an influenza épidémie (49). S. pneumoniae, the most fréquent bacterial pathogen involved in AOM, is associated with increasing antimicrobial résistance. Vaccines against pneumococcus are also available. A polysaccharide vaccine, including 23 pneumococcal serotypes, was however, not immunogenic in children less than 2 years of âge. It had no effect on AOM prévention in children aged less than 24 months and was minimally efficacious in those aged 24 months and older (RR 0.864; 95%CI 0.68-0.98) (52). To overcome this low immunogenicity, a new vaccine was developed where the antigens were conjugated to a carrier protein (conjugated vaccine), making it immunogenic even in young children, but this vaccine could only include 7 serotypes. Two large, randomized, controlled trials assessed its efficacy in terms of preventing AOM. They showed a 9% réduction in the risk of récurrent disease (53;54). When accounting for the number of AOM épisodes due to pneumococcal serotypes included in the vaccine, a protective effect was demonstrated (RR 0.43; 95%CI 0.34-0.54), but the results also indicated that AOM épisodes due to non-vaccine serotypes were increased in children who received the conjugated vaccine (RR 1.3; 95%CI 1.01-1.72) (54). A Cochrane systematic review concluded that overall, the effect of both pneumococcal vaccines in preventing AOM was "minimal", giving numbers needed to treat of 57 for the polysaccharidic vaccine and of 39 for the conjugated vaccine (52). The use of prophylactic antibiotics to prevent récurrent AOM is discouraged since it is associated with the émergence of résistance (50). 10
1.2.
Management of AOM
1.2.1
Antibiotic treatment Despite the usually favourable course of AOM, potentially serious
complications may arise so that the Centers for Disease Control and the American Academy of Pediatrics still support the need for antibiotic treatment (40). Antibiotics are used for treating AOM in 97.7% of cases in the U.S. A. but in only 31% of cases in the Netherlands (7). Based on usually encountered pathogens and their antimicrobial résistance patterns, a consensus on treatment of AOM was published by Dowell and collaborators in 1999 (10). Table 1.2 summarizes their recommendations. Briefly, amoxicillin should remain the first-line drug, ideally at a high dose of 90 mg/kg/day. In case of failure, amoxicillin-clavulanic acid, ceftriaxone, or cefuroxime axetil with or without tympanocentesis should be used. Another European expert panel also recommended amoxicillin as the first-line drug with cefuroxime axetil, cefpodoxime and ceftriaxone as alternatives (see Table 1.3) (55). This same group reported that in Spain, inadéquate antibiotic choices were made in 23.5% of AOM. An antibiotic utilization review in the early 1990's, using a Medicaid database, revealed that amoxicillin was the most frequently prescribed drug for AOM but that its prescription decreased with subséquent visits for récurrent AOM whereas cefaclor and trimethoprim-sulfamethoxazole (TMS) showed the greatest increase. Office-based physicians prescribed more cephalosporins than hospital personnel who tended to prescribe more TMS. General practioners prescribed more cephalosporins than pediatricians (56). Thompson and collaborators conducted a similar study using claims data from a large New England health insurer in 1996 (n = 22,004 children aged < 10 years) (25). For first épisodes of AOM, il
amoxicillin was prescribed in 65% of cases, followed by cephalosporins in 14.8%, and TMS in 10.2%). With multiple épisodes, amoxicillin prescription declined by almost 50%, while that of cephalosporins, macrolides and amoxicillin-clavulanic acid doubled. Treatment recommendations reflect the higher proportion of AOM caused by S. pneumoniae, which are not only more résistant to antibiotics but also the pathogen with the lowest rate of spontaneous resolution. Pharmacokinetics and pharmacodynamics data support the use of high-dose amoxicillin for treating S. pneumoniae, even if résistance to penicillin is présent. In AOM, antibiotics penetrate into the middle ear fluid by diffusion from the surrounding mucosa and concentrate in the interstitial fluid with levels very similar, although lower, than in sérum concentration. Antibiotic concentrations in the middle ear fluid show a slower response to changes, giving a lower peak and a higher trough level. Marked variations in concentration occur among différent patients (57). For P-lactams, a highly significant corrélation exists between the time when the antibiotic concentration in the biological fluid is above the minimum inhibitory concentration (MIC)1 of a given bacteria and its bacteriological efficacy. To attain a cure rate of 80 to 85%, the time above the MIC should be at least 40 to 50% of the dosing interval (57). Seikel et al reported that an amoxicillin dosage of 45 mg/kg/day (regular dosage) is be effective against 2/3 of intermediate-resistant pneumococcal strains and approximately 1/3 of résistant strains causing AOM (58). Currently, the expected clinical failure rate of amoxicillin treatment has been estimated to be equal to or less than 6%, when considering the expected pathogens and their rate of résistance to penicillin (40).
MIC: the minimum concentration that inhibits growth of 90% of a given strain of bacteria
12
Second-line agents are targeted towards either a pneumococcus that is highly résistant to penicillin and did not respond to high-dose amoxicillin or towards other [3lactamase-producing bacteria. Agents that should not be used as second-line drugs because of high résistance levels are TMS (25% of bacteria causing AOM are résistant) and macrolides (almost 30% of strains are résistant to azithromycin and erythromycin) (59). Cefaclor and cefixime are not préférable because of their low pneumococcal activity (10). Although cefuroxime axetil had been recommended by Dowell et al. (10) as a second-line agent with good activity against penicillin-resistant S. pneumoniae (PRSP), récent guidelines based on surveillance data suggest that this efficacy is no longer achievable (60). The duration of therapy is variable. A survey in 1990 revealed that physicians in the U.S.A. tended to treat AOM for 8 to 10 days, whereas those in the U.K. treated for 5 days and physicians in the Netherlands treated for 6 to 7 days. Age seems to be a significant déterminant correlated inversely with the duration of treatment (7). Recommendations in the U.S. A from 1999 now propose a duration of 10 days if the patient is less than 2 years of âge and 5 to 7 days if the patient is older than 2 years with uncomplicated AOM (40). Dutch guidelines, on the other hand, suggested that children 2 years and older be treated only symptomatically for the first 3 days of illness with réévaluation if the symptoms persist beyond 3 days, at which time either continued observation or antibiotic treatment for 7 days may be prescribed. In case of tympanic membrane perforation, antibiotic treatment is recommended only if symptoms persist for 14 days or more. In children between 6 months and 2 years, the same guidelines apply except
13
for mandatory contact with physician after 24 hours. If symptoms hâve not abated, antibiotics may be started with or without referral to an ear-nose and throat (ENT) specialist (22).
1.2.2 Surgical treatment In some circumstances, antibiotics alone are not sufficient and drainage of the infected middle ear fluid is necessary. The technique comprises a myringotomy with or without placement of tympanostomy tubes. The usual indications for such a surgical procédure are AOM in patients with severe otalgia who are seriously ill or toxic, patients with unsatisfactory response to antibiotics, AOM onset in a patient already on antibiotics, AOM associated with confirmed or potential suppurative complication, and AOM in a newborn, a sick neonate or an immunodeficient patient (26). Such a procédure, however, was not found to improve AOM outcome compared with antibiotics alone in uncomplicated AOM, and should not be used routinely but retained for the indications mentioned above (61). Adenoidectomy was shown to be effective for a duration of 2 years in reducing the occurrence of AOM in children who had developed AOM after tympanostomy tube extrusion (62). Adding tonsillectomy to adenoidectomy (T&A) gave divergent results. Paradise and collaborators undertook a randomized, controlled trial, with a complex structure, on the efficacy of adenoidectomy and T&A in the prévention of récurrent AOM (63). Randomization was stratified by âge (3 âge groups) and nasal obstruction (n = 461 children). Patients were then assigned to 2 différent trials based on the présence or absence of a médical indication for tonsillectomy. Children not requiring tonsillectomy were randomized to adenoidectomy alone, T&A, or control, whereas 14
children requiring a tonsillectomy were randomized to T&A or control. Forty-seven subjects assigned to surgery withdrew from the study because their parents were unable to afford the cost of surgery, which could hâve led to a sélection bias. The results of this study are difficult to interpret because multiple comparisons were made using various référence catégories. The authors used Poisson régression to analyze the rate of AOM occurrence in the following years but did not give RRs for each intervention adjusted for other covariates. Considering the study design (stratified randomization), their sample size was small. The only resuit that was significant was the différence in the rate of AOM between children assigned to T&A and the control group (3-way trial), and only during the first year of follow-up (1.4 vs. 2.1 p < 0.001). The authors, therefore, concluded that surgical procédures should not be used routinely if the only indication is récurrent AOM. Coyte and collaborators (64) used the Ontario hospital discharge records from 1992 to 1997 to assess the usefulness of adjuvant surgery in preventing tympanostomy tube reinsertion, selecting only AOM with a complicated course. They identified patients aged < 19 years who underwent myringotomy ± insertion of tympanostomy tubes, tonsillectomy, adenoidectomy or T&A, and selected only patients whose first surgery for AOM was tympanostomy tube insertion (n = 37,316). They found that adjuvant adenoidectomy ± tonsillectomy was associated with a decreased risk of tympanostomy tube reinsertion (RR 0.4; 95%CI 0.4-0.5). The study was well designed, but the results cannot be generalized to ail children with uncomplicated AOM.
15
1.3 Treatment failure Treatment failure is defined as the lack of improvement in signs and symptoms of acute infection as well as in otoscopic findings. When this occurs 48 to 72 hours after the start of antibiotic therapy, it is said to be an early treatment failure (65). Thèse same signs and symptoms may also persist or recur at the end of therapy or within 14 days after a 10-day course of antibiotics, after an initial period of improvement (early récurrence) (37). Treatment failure was observed in approximately 19% of AOM (95%CI 10-28%) (30;37), occurring more frequently in children < 12 months of âge (56). Administrative database analysis revealed that a second course of antibiotics was necessary in almost 12% of treated AOM épisodes. This was found in 11.6% of cases after a treatment with amoxicillin, TMS or Pediazole, and in 13.2% after treatment with cefaclor, amoxicillin-clavulanic acid and cefixime (56). When looking at thèse numbers, one has to wonder if patients with more severe disease received proportionally more second-line drugs, explaining the higher proportion needing a second course of antibiotics and experiencing treatment failure (confounding by indication) (66). Résistance to antibiotics predicts bacteriological failure. S. pneumoniae are more prévalent in non-responsive AOM (NR-AOM). Furthermore, inability to eradicate the pneumococci from the nasopharynx may represent an important cause of therapeutic failure (67;68).
16
1.3.1 Penicillin-resistant Streptococcus pneumoniae Résistance to penicillin in S. pneumoniae (PRSP) has been defined by the National Committee for Clinical Laboratory Standards (69). A penicillin nonsusceptible strain of S. pneumoniae (PNSP) is defined as having MIC between 0.12 and 1 mg/L whereas a résistant strain (PRSP) has a MIC to penicillin greater or equal to 2 mg/L. Before 1990, most S. pneumoniae strains were sensitive to penicillin. In 1997 the province of Québec initiated a surveillance program for invasive infections caused by S. pneumoniae. From thèse reports, it was shown that in 1997, 13.6% of isolated S. pneumoniae were non-susceptible to penicillin with 6.9% being PRSP. Comparing thèse figures with the data collected in 2001, a slight increase was seen in the proportion of non-susceptible strains. This proportion has risen to 16.9% of ail isolated S. pneumoniae being PNSP with 8% of strains being PRSP (70;71). Thèse numbers are représentative of what is found elsewhere. A review reported that invasive disease caused by PNSP ranged between 8 and 34% with the highest prevalence found in children (10). Thèse data, however, are not directly transposable to AOM strains since it was shown that invasive isolâtes hâve the lowest proportion of résistant strains, middle ear isolâtes hâve intermediate rates, and nasopharyngeal strains hâve the highest proportion (72). Moreover, when comparing an entire population, children exhibited the highest proportion of résistant strains, particularly those with AOM (35). For example, of ail PRSP isolated in France in 1994, 55% were recovered from children with AOM, 23% from patients with community-acquired pneumonia, and 27% from patients with meningitis (73). The proportion of résistant isolâtes found also varied with geography. It was shown that pneumococcus isolâtes from the respiratory tract
17
expressed a résistant phenotype in 7.8% of cases in Germany compared to 66.5% in France (74). Risk factors associated with PRSP infections and colonization hâve been studied extensively. The most important factor remains the use of antibiotics in the previous month - short course or low-dose prolonged course - with aminopenicillins and TMS being implicated most of the time, likely because they were the most prescribed (24;26;34;75-78). Approximately 79% of pneumococci isolated in patients who had recently been treated with antibiotics were found to be résistant to the previous antibiotic given. Paradoxically, 77% of H. influenzae isolated were still susceptible to the antibiotic (76). Young âge (< 24 months), daycare attendance, and exposure to other children in the household hâve also been reported as risk factors (17;26;34;77). As well, having an otitis-prone condition and NR-AOM were also associated with PRSP as up to 44% of S. pneumoniae isolated in those conditions were PRSP (34;76). Nosocomial acquisition and récent hospitalization hâve also been linked with PRSP infection (24;34). Using logistic régression, it was shown that having more than 2 risk factors for PRSP was associated with treatment failure on days 12 to 15 and on days 25 to 28 after the start of antibiotic therapy (17). Infection with a PRSP will lead to treatment failure in a proportion as high as 60% (34). Moreover, PRSP nasopharyngeal carnage has been found to be highly prédictive of bacteriological failure in a proportion of 66% (79). S. pneumoniae hâve been isolated significantly less frequently from patients currently receiving amoxicillin or amoxicillin-clavulanic acid, whereas a high failure rate has been associated with the use of erythromycin-sulfisoxazole (Pediazole) (35;77). It is interesting to see that after only 3 or 4 days of antibiotic treatment, more 18
than 50% of penicillin-susceptible S. pneumoniae colonizing the nasopharynx are eradicated compared with almost none of the PRSP strains leading to a sélection towards résistant strains. When comparing nasopharyngeal carnage before and after 4 days of antibiotic treatment, Dagan and collaborators showed a significant increase in résistant strains, from 47% to 74%, to at least one antibiotic tested. They also reported that modification in the nasopharyngeal flora occurred quite early after the initiation of antibiotics (80).
1.3.2 Risk factors for treatment failure Predictors of treatment failure include factors already described as risk factors for infection caused by a PRSP. In a double-blinded, randomized clinical trial comparing 5 vs. 10 days of cefpodoxime axetil (n = 450), Cohen and collaborators reported that a 5-day regimen was associated with failure at 12-14 days (15.9% vs. 7.6%), mainly in children with risk factors for PRSP, such as daycare attendance (81). On the other hand, using a prospective observational study where physicians were allowed the choice of the antibiotic to be given, Pichichero and collaborators found that for most children, a 5-day antibiotic course was sufficient (82). Thèse authors reported 18.4%, 18.2%, and 17.1% failure for antibiotic treatment durations of 5, 7 and 10 days respectively. AOM in the preceding month as well as an AOM épisode in the previous 12 months or more than 3 épisodes were ail associated with poor outcome (82-84). First-line or second-line antibiotics had no impact on treatment failure (82). Patel et al established that in compliant patients only those patients with a concomitant viral infection were found to be at increased risk for bacteriological failure (83), which could explain why an AOM occurring during the winter season is at greater 19
risk of failure (84). It was also shown that, the nasopharyngeal carriage rate of S. pneumoniae increases during acute viral infection. Rapid sterilization of the middle ear fluid with antibiotics may promote the growth of preexisting, non-susceptible organisms that will easily invade the middle ear because the initial offending event - in this case, a viral respiratory infection - is still présent (79). A cohort of 131 children with AOM revealed that âge < 2 years (OR 28.6; 95%CI 3.5-210.6), a history of skin allergy or respiratory symptoms (OR 4.4; 95%CI 1.2-16.4), and earache lasting > 6 hours before treatment (OR 2.4; 95%CI 1.2-4.9) were risk factors for treatment failure, in a logistic régression model. The duration of earache before antibiotic administration as a risk factor for failure seems to go against other reports where waiting 24 to 48 hours before treatment did not alter the prognosis (33,42). Patients enrolled in Jero's study (85) were seen by an ENT specialist and, therefore, may hâve had a more severe AOM that would hâve needed antibiotic treatment in the end, explaining why a delay in treatment may hâve worsened the prognosis, compared to children in other studies. Adenoidectomy seemed to protect against failure since none occurred in children with adenoidectomy (85). Most failures hâve been described not during but after the end of antibiotic treatment (81). Early récurrences were mainly caused by a new organism rather than by bacteria that had evoked the initial infection (86). Jero and collaborators showed that having > 3 factors among potential factors analyzed (âge < 2 years, maie gender, no adenoidectomy, AOM-proneness, allergy, bilatéral AOM, severe infection, earache > 6 hours, pathogens isolated in middle ear fluid) was associated with a 60% risk of failure (85). However, this study, as described earlier, was small (n = 131 children) with an
20
heterogeneous population and a limited number of events (15 failures), limiting the power to identify risk factors.
1.4 Clinical efficacy studies Multiple studies hâve looked at the clinical efficacy of various antibiotic regimens for AOM treatment. Table 1.4 détails the findings of some studies as well as their définitions of clinical success and failure when available. Thèse studies are, however, difficult to summarize since différent définitions of disease as well as failure hâve been used. Moreover, outcomes hâve been assessed at différent time points, making the conclusions even more difficult to compare. Clinical failure rates are very différent when assessed at 4 to 7 days vs. 28 to 42 days. In 1985, Howie and collaborators (87) suggested the use of "in vivo sensitivity test" to assess clinical effectiveness. The method consisted of performing tympanocentesis upon entry in the trial to identify the causative pathogen(s) followed by a repeat tympanocentesis 3 to 6 days later - regardless of clinical status - to establish the bacteriological efficacy of the antibiotic studied (87). Most trials thereafter hâve used this method but some still relied on clinical status to judge efficacy. High rates of discrepancies may occur between clinical and bacteriological outcomes. Marchant and collaborators (88) hâve shown that a drug with bactericidal activity, which éliminâtes bacteria from the middle ear fluid in 100% of cases will not hâve a 100% clinical response because of other factors, such as concurrent viral infection. On the other hand, a drug with minimal antibacterial activity will appear to be almost as effective as a highly efficacious drug because of the high proportion of spontaneous resolutions. This effect will predominate until 21
bacteriological efficacy reaches 85 to 90% and has been named the "Pollyanna phenomenon" or tendency towards false optimism in honour of the blindly optimistic heroine of the novel Pollyanna (89). Moreover, the studies done were not contemporary and were performed in différent géographie locations which will be associated with heterogeneous rates of PRSP, as shown earlier and, thus, will lead to différent proportions of clinical failure. The methods used to culture pathogens isolated from the middle ear fluid were also différent, varying from immédiate inoculation in broth médium with incubation in proper atmosphère (17;38;67;68;76) to collecting spécimens on swabs and inoculating them within 16 hours (90). Thèse variations in methodology will hâve an impact on the number of S. pneumoniae isolated, as it is a very labile organism. Therefore, the currently available literature makes it very difficult to compare the effectiveness of multiple agents in a similar population and during a defined time period. Since résistance to antibiotics predicts bacteriological failure, comparing the effectiveness of various antibiotics would be préférable if done on a single population over a defined time-span to minimize variations in résistance rates. Moreover, a population-based study that may be more représentative of real-life than randomized clinical trials may bring new information on the effectiveness of antibiotics in AOM. Data are currently lacking on the prescribing patterns of physicians for AOM treatment in Canada. In Spain, in a prospective study of antibiotic appropriateness, 23% of prescriptions for AOM were found to be inappropriate (55), which makes us believe that such a situation is likely to be présent in the province of Québec. By using inappropriate, and therefore, ineffective antibiotics, treatment failures may ensue, and with them, potential complications. 22
1.5 Study objectives and présentation of articles The principal objectives of the studies presented as part of this thesis were to describe the patterns of antibiotic utilization among Québec physicians in children treated as having AOM and to assess the conformity of antibiotics dispensed with the previously-published consensus (see Table 1.2) (10). The secondary objective were to assess the clinical effectiveness of the 4 most commonly-used antibiotics in Québec in the treatment of first AOM épisodes, and to identify risk factors associated with treatment failure. A cohort of children aged < 6 years with a first épisode of clinically diagnosed AOM was selected from the Québec health insurance databases (Régie de l'assurance maladie du Québec). Amoxicillin, azithromycin, cefprozil, and clarithromycin were the antibiotics studied in the effectiveness analysis. Chapter 2 présents the results of the drug utilization review and the Chapter 3 reports on the effectiveness analysis as well as the identified risk factors associated with treatment failure.
23
Table 1.1: Complications associated with acute otitis média (AOM) (45)
Complications Classical complications
Meningitis Mastoiditis Intracranial abscess Latéral sinus thrombosis Chronic suppurative otomastoiditis Tympanic membrane perforation Persistent effusion with hearing loss Speech and language delay Cholesteatoma
Related to antibiotic
Persistent purulent disease
résistance
Increased costs of antibiotics Increased referrals for uncontrolled disease Increased number of surgeries
24
Table 1.2:
Consensus on treatment of AOM (The Drug-resistant Streptococcus pneumoniae Therapeutic Working Group) (10)
Antibiotics received in previous month
No
Yes
Treatment
If failure by day 3
If failure by day 10-28
Amoxicillin usual dose or high dose (90 mg/kg)
Amoxicillinclavulanic acid (90 mg/kg) Cefuroxime axetil IM Ceftriaxone
Same as on day 3
Amoxicillin high dose (90 mg/kg) Amoxicillinclavulanic acid high dose Cefuroxime axetil
IM Ceftriaxone Clindamycin Tympanocentesis
Amoxicillinclavulanic acid (90 mg/kg) Cefuroxime axetil IM Ceftriaxone Tympanocentesis
25
Table 1.3:
Consensus on treatment of AOM (55)
Présence of risk factors for treatment failure ]\0
Yes
First choice
Alternatives
Amoxicillin Cefuroxime axetil Amoxicillin-clavulanic acid Cefpodoxime No treatment if > 18 months If allergy: macrolides Amoxicillin-clavulanic acid Amoxicillin (high dose) Cefuroxime axetil Cefpodoxime Ceftriaxone
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1.6 Références (1) Moellering RC. Principles of anti-infective therapy. In: Mandell GL, Bennett JE, Dolin R, editors. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. United States: Churchill Livingstone, 2000: 223-235. (2) Arason VA, Kristinsson KG, Sigurdsson JA, Stefansdottir G, Molstad S, Gudmundsson S. Do antimicrobials increase the carnage rate of penicillin résistant pneumococci in children? Cross sectional prevalence study. BMJ 1996; 313(7054):387-391. (3) Melander E, Ekdahl K, Jonsson G, Molstad S. Frequency of penicillin-resistant pneumococci in children is correlated to community utilization of antibiotics. Pediatr Infect Dis J 2000; 19(12): 1172-1177. (4) Bronzwaer SL, Cars O, Buchholz U, Molstad S, Goettsch W, Veldhuijzen IK et al. A European study on the relationship between antimicrobial use and antimicrobial résistance. Emerg Infect Dis 2002; 8(3):278-282. (5) Molstad S, Cars O. Major change in the use of antibiotics following a national programme: Swedish Stratégie Programme for the Rational Use of Antimicrobial Agents and Surveillance of Résistance (STRAMA). Scand J Infect Dis 1999; 31(2):191-195. (6) Musher DM. Streptococcus pneumoniae. In: Mandell GL, Bennett JE, Dolin R, editors. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. USA: Churchill Livingstone, 2000: 2128-2147. (7) Froom J, Culpepper L, Grob P, Bartelds A, Bowers P, Bridges-Webb C et al. Diagnosis and antibiotic treatment of acute otitis média: report from International Primary Care Network. BMJ 1990; 300(6724):582-586. (8) Bergus GR, Levy BT, Levy SM, Slager SL, Kiritsy MC. Antibiotic use during the first 200 days of life. Arch Fam Med 1996; 5(9):523-526. (9) McCracken GH, Jr. Treatment of acute otitis média in an era of increasing microbial résistance. Pediatr Infect Dis J 1998; 17(6):576-579. (10) Dowell SF, Butler JC, Giebink GS, Jacobs MR, Jernigan D, Musher DM et al. Acute otitis média: management and surveillance in an era of pneumococcal résistance - a report from the Drug-resistant Streptococcus pneumoniae Therapeutic Working Group. Pediatr Infect Dis J 1999; 18(l):l-9. (11) Chan LS, Takata GS, Shekelle P, Morton SC, Mason W, Marcy SM. Evidence assessment of management of acute otitis média: IL Research gaps and priorities for future research. Pediatrics 2001; 108(2):248-254.
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(12) Hayden GF. Acute suppurative otitis média in children. Diversity of clinical diagnostic criteria. Clin Pediatr (Phila) 1981; 20(2):99-104. (13) Dowell SF, Marcy SM, Phillips WR, Gerber MA, Schwartz B. Otitis média: Principles of judicious use of antimicrobial agents. Pediatrics 1998; 101(Suppl Pt2):165-171. (14) Klein JO, Bluestone CD. Otitis média. In: Feigin RD, Cherry JD, editors. Textbook of Pédiatrie Infectious Diseases. Philadelphia: Saunders, 1998: 195211. ( 15) Teele DW, Klein JO, Rosner B. Epidemiology of otitis média during the first seven years of life in children in greater Boston: a prospective, cohort study. J Infect Dis 1989; 160(l):83-94. (16) Hoppe HL, Johnson CE. Focus on antimicrobial résistance and new treatment options. Am J Health Syst Pharm 1998; 55:1881-1897. (17) Dagan R, Hoberman A, Johnson C, Leibovitz EL, Arguedas A, Rose FV et al. Bactériologie and clinical efficacy of high dose amoxicillin/clavulanate in children with acute otitis média. Pediatr Infect Dis J 2001; 20(9):829-837. (18) Kvaerner KJ, Nafstad P, Hagen JA, Mair IW, Jaakkola JJ. Récurrent acute otitis média: the significance of âge at onset. Acta Otolaryngol 1997; 117(4):578-584. (19) Paradise JL, Rockette HE, Colborn DK, Bernard BS, Smith CG, Kurs-Lasky M et al. Otitis média in 2253 Pittsburgh-area infants: prevalence and risk factors during the first two years of life. Pediatrics 1997; 99(3):318-333. (20) Byrns PJ, Bondy J, Glazner JE, Berman S. Utilization of services for otitis média by children enrolled in Medicaid. Arch Pediatr Adolesc Med 1997; 151(4):407-413. (21) Bondy J, Berman S, Glazner J, Lezotte D. Direct expenditures related to otitis média diagnoses: extrapolations from a pédiatrie medicaid cohort. Pediatrics 2000; 105(6):E72. (22) Froom J, Culpepper L, Jacobs M, DeMelker RA, Green LA, van Buchem L et al. Antimicrobials for acute otitis média? A review from the International Primary Care Network. BMJ 1997; 315(7100):98-102. (23) Jacobs J, Springer DA, Crothers D. Homéopathie treatment of acute otitis média in children: a preliminary randomized placebo-controlled trial. Pediatr Infect Dis J 2001; 20(2): 177-183. (24) Dagan R. Clinical significance of résistant organisms in otitis média. Pediatr Infect Dis J 2000; 19(4):378-382.
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(25) Thompson D, Oster G, McGarry LJ, Klein JO. Management of otitis média among children in a large health insurance plan. Pediatr Infect Dis J 1999; 18(3):239-244. (26) Bluestone CD. Rôle of surgery for otitis média in the era of résistant bacteria. Pediatr Infect Dis J 1998; 17(11):1090-1098. (27) Joki-Erkkila VP, Pukander J, Laippala P. Altération of clinical picture and treatment of pédiatrie acute otitis média over the past two décades. Int J Pediatr Otorhinolaryngol 2000; 55(3): 197-201. (28) Croteau N, Hai V, Pless IB, Infante-Rivard C. Trends in médical visits and surgery for otitis média among children. Am J Dis Child 1990; 144(5):535-538. (29) Levasseur M. Des problèmes prioritaires: la maladie selon les âges de la vie. Québec, Canada: Conseil des affaires sociales et de la famille, 1983. (30) Takata GS, Chan LS, Shekelle P, Morton SC, Mason W, Marcy SM. Evidence assessment of management of acute otitis média: I. The rôle of antibiotics in treatment of uncomplicated acute otitis média. Pediatrics 2001; 108(2):239-247. (31 ) Leinonen MK. Détection of pneumococcal capsular polysaccharide antigens by latex agglutination, counterimmunoelectrophoresis, and radioimmunoassay in middle ear exudates in acute otitis média. J Clin Microbiol 1980; 11(2): 135140. (32) Gehanno P, Panajotopoulos A, Barry B, Nguyen L, Levy D, Bingen E et al. Microbiology of otitis média in the Paris, France, area from 1987 to 1997. Pediatr Infect Dis J 2001; 20(6):570-573. (33) Glasziou PP, Del Mar CB, Sanders SL, Hayem M. Antibiotics for acute otitis média in children (Cochrane Review). Cochrane Database Syst Rev 2002;(2). (34) Block SL. Stratégies for dealing with amoxicillin failure in acute otitis média. Arch Fam Med 1999; 8(l):68-78. (35) Cohen R. The antibiotic treatment of acute otitis média and sinusitis in children. Diagn Microbiol Infect Dis 1997; 27(l-2):35-39. (36) Brook I, Gober AE. Résistance to antimicrobials used for therapy of otitis média and sinusitis: effect of previous antimicrobial therapy and smoking. Ann Otol Rhinol Laryngol 1999; 108(7 Pt l):645-647. (37) Harrison CJ, Belhorn TH. Antibiotic treatment failures in acute otitis média. Pediatr Ann 1991; 20(ll):600-608.
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(38) Leiberman A, Leibovitz E, Piglansky L, Raiz S, Press J, Yagupsky P et al. Bactériologie and clinical efficacy of trimethoprim-sulfamethoxazole for treatment of acute otitis média. Pediatr Infect Dis J 2001; 20(3):260-264. (39) Rudberg RD. Acute otitis média: comparative therapeutic results of sulphonamide and penicillin administered in various forms. Acta Otolaryngol 1954; 113(suppl):l-79. (40) Klein JO. Review of consensus reports on management of acute otitis média. Pediatr Infect Dis J 1999; 18(12): 1152-1155. (41) Appelman CL, Claessen JQ, Touw-Otten FW, Hordijk GJ, de Melker RA. Severity of inflammation of tympanic membrane as predictor of clinical course of récurrent acute otitis média. BMJ 1993; 306(6882):895. (42) Little P, Gould C, Williamson I, Moore M, Warner G, Dunleavey J. Pragmatic randomised controlled trial of two prescribing stratégies for childhood acute otitis média. BMJ 2001; 322(7282):336-342. (43) Bass JW, Cohen SH, Corless JD, Mamunes P. Ampicillin compared to other antimicrobials in acute otitis média. JAMA 1967; 202(8):697-702. (44) Damoiseaux RA, van Balen FA, Hoes AW, Verheij TJ, de Melker RA. Primary care based randomised, double blind trial of amoxicillin versus placebo for acute otitis média in children aged under 2 years. BMJ 2000; 320(7231):350354. (45) Poole MD. Otitis média complications and treatment failures: implications of pneumococcal résistance. Pediatr Infect Dis J 1995; 14(4 Suppl):S23-S26. (46) Yamanaka N, Faden H. Antibody response to outer membrane protein of nontypeable Haemophilus influenzae in otitis-prone children. J Pediatr 1993; 122(2):212-218. (47) Collet JP, Larson CP, Boivin JF, Suissa S, Pless IB. Parental smoking and risk of otitis média in pre-school children. Can J Public Health 1995; 86(4):269-273. (48) Collet JP, Burtin P, Gillet J, Bossard N, Ducruet T, Durr F. Risk of infectious diseases in children attending différent types of day-care setting. Epicreche Research Group. Respiration 1994; 61 Suppl 1:16-19. (49) Heikkinen T, Ruuskanen O, Waris M, Ziegler T, Arola M, Halonen P. Influenza vaccination in the prévention of acute otitis média in children. Am J Dis Child 1991; 145(4):445-448. (50) Bluestone CD. Summary and Conclusions of the meeting. Pediatr Infect Dis J 17, 1099-1101.2002.
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(51) Cléments DA, Langdon L, Bland C, Walter E. Influenza A vaccine decreases the incidence of otitis média in 6- to 30-month-old children in day care. Arch Pediatr Adolesc Med 1995; 149(10):1113-1117. (52) Straetemans M, Sanders EA, Veenhoven RH, Schilder AG, Damoiseaux RA, Zielhuis GA. Pneumococcal vaccines for preventing otitis média (Cochrane Review). Cochrane Database Syst Rev 2002;(2):CD001480. (53) Black S, Shinefield H, Fireman B, Lewis E, Ray P, Hansen JR et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group. Pediatr Infect Dis J 2000; 19(3): 187-195. (54) Eskola J, Kilpi T, Palmu A, Jokinen J, Haapakoski J, Herva E et al. Efficacy of a pneumococcal conjugate vaccine against acute otitis média. N Engl J Med 2001;344(6):403-409. (55) Solis G, Ochoa C, Perez MC. The variability and appropriateness of the antibiotic prescription of acute otitis média in childhood. The Spanish Study Group for Antibiotic Treatments. Int J Pediatr Otorhinolaryngol 2000; 56(3):175-184. (56) Berman S, Byrns PJ, Bondy J, Smith PJ, Lezotte D. Otitis media-related antibiotic prescribing patterns, outcomes, and expenditures in a pédiatrie medicaid population. Pediatrics 1997; 100(4):585-592. (57) Craig WA, Andes D. Pharmacokinetics and pharmacodynamics of antibiotics in otitis média. Pediatr Infect Dis J 1996; 15(3):255-259. (58) Seikel K, Shelton S, McCracken GH, Jr. Middle ear fluid concentrations of amoxicillin after large dosages in children with acute otitis média. Pediatr Infect Dis J 1998; 17(10):969-970. (59) Thornsberry C, Sahm DF, Kelly LJ, Critchley IA, Jones ME, Evangelista AT et al. Régional trends in antimicrobial résistance among clinical isolâtes of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States: Results from the TRUST Surveillance Program, 19992000. Clin Infect Dis 2002; 34(Suppl 1):S4-S16. (60) Hoberman A, Marchant CD, Kaplan SL, Feldman S. Treatment of acute otitis média consensus recommendations. Clin Pediatr (Phila) 2002; 41(6):373-390. (61) Kaleida PH, Casselbrant ML, Rockette HE, Paradise JL, Bluestone CD, Blatter MM et al. Amoxicillin or myringotomy or both for acute otitis média: results of a randomized clinical trial. Pediatrics 1991; 87(4):466-474. (62) Paradise JL, Bluestone CD, Rogers KD, Taylor FH, Colborn DK, Bachman RZ et al. Efficacy of adenoidectomy for récurrent otitis média in children
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previously treated with tympanostomy-tube placement. Results of parallel randomized and nonrandomized trials. JAMA 1990; 263(15):2066-2073. (63) Paradise JL, Bluestone CD, Colborn DK, Bernard BS, Smith CG, Rockette HE et al. Adenoidectomy and adenotonsillectomy for récurrent acute otitis média: parallel randomized clinical trials in children not previously treated with tympanostomy tubes. JAMA 1999; 282(10):945-953. (64) Coyte PC, Croxford R, Mclsaac W, Feldman W, Friedberg J. The rôle of adjuvant adenoidectomy and tonsillectomy in the outcome of the insertion of tympanostomy tubes. N Engl J Med 2001; 344(16):1188-1195. (65) Aronovitz GH. Antimicrobial therapy of acute otitis média: review of treatment recommendations. Clin Ther 2000; 22(l):29-39. (66) Garbe E, Boivin JF, LeLorier J, Suissa S. Sélection of controls in database casecontrol studies: glucocorticoids and the risk of glaucoma. J Clin Epidemiol 1998;51(2):129-135. (67) Leibovitz E, Piglansky L, Raiz S, Greenberg D, Yagupsky P, Press J et al. Bactériologie efficacy of a three-day intramuscular ceftriaxone regimen in nonresponsive acute otitis média. Pediatr Infect Dis J 1998; 17(12):! 126-1131. (68) Leibovitz E, Piglansky L, Raiz S, Press J, Leiberman A, Dagan R. Bactériologie and clinical efficacy of one day vs. three day intramuscular ceftriaxone for treatment of nonresponsive acute otitis média in children. Pediatr Infect Dis J 2000; 19(11): 1040-1045. (69) National Committee for Clinical Laboratory Standards (NCCLS). Performance Standards for Antimicrobial Disk Susceptibility Tests: Approved Standard Seventh Edition M2-A7. Villanova, PA: Nsational Committee for Clinical Laboratory Standards, 2002. (70) Jette L. Programme de surveillance du pneumocoque - Rapport annuel 2001. Institut national de santé publique - Laboratoire de santé publique du Québec 2002. (71) Jette L. Programme de surveillance du pneumocoque - Rapport annuel 1997. Institut National de santé publique - Laboratoire de santé publique du Québec 1998. (72) Brook I, Yocum P. Bacteriology and beta-lactamase activity in ear aspirâtes of acute otitis média that failed amoxicillin therapy. Pediatr Infect Dis J 1995; 14(9):805-808. (73) Geslin P. Beta-lactamines et pneumocoques multi-résistants isolés en France. MedHyg 1995; 53:2111-2118.
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(74) Thornsberry C, Sahm DF. Antimicrobial résistance in respiratory tract pathogens: results of an international surveillance study. Chemotherapy 2000; 46(Suppll):15-23. (75) Roger G, Caries P, Pangon B, Thien HV, Polonovski JM, Bègue P et al. Management of acute otitis média caused by résistant pneumococci in infants. Pediatr Infect Dis J 1998; 17(7):631-638. (76) Leibovitz E, Raiz S, Piglansky L, Greenberg D, Yagupsky P, Fliss DM et al. Résistance pattern of middle ear fluid isolâtes in acute otitis média recently treated with antibiotics. Pediatr Infect Dis J 1998; 17(6):463-469. (77) Gehanno P, N'Guyen L, Derriennic M, Pichon F, Goehrs JM, Berche P. Pathogens isolated during treatment failures in otitis. Pediatr Infect Dis J 1998; 17(10):885-890. (78) Quach C, Weiss K, Moore D, Rubin E, McGeer A, Low DE. Clinical aspects and cost of invasive Streptococcus pneumoniae infections in children: résistant vs. susceptible strains. Int J Antimicrob Agents 2002; 20:113-118. (79) Dagan R, Leibovitz E, Cheletz G, Leiberman A, Porat N. Antibiotic treatment in acute otitis média promûtes superinfection with résistant Streptococcus pneumoniae carried before initiation of treatment. J Infect Dis 2001; 183(6):880-886. (80) Dagan R, Leibovitz E, Greenberg D, Yagupsky P, Fliss DM, Leiberman A. Dynamics of pneumococcal nasopharyngeal colonization during the first days of antibiotic treatment in pédiatrie patients. Pediatr Infect Dis J 1998; 17(10):880-885. (81) Cohen R, Levy C, Boucherat M, Langue J, Autret E, Gehanno P et al. Five vs. ten days of antibiotic therapy for acute otitis média in young children. Pediatr Infect Dis J 2000; 19(5):458-463. (82) Pichichero ME, Marsocci SM, Murphy ML, Hoeger W, Francis AB, Green JL. A prospective observational study of 5-, 7-, and 10-day antibiotic treatment for acute otitis média. Otolaryngol Head Neck Surg 2001; 124(4):381-387. (83) Patel JA, Reisner B, Vizirinia N, Owen M, Chonmaitree T, Howie V. Bactériologie failure of amoxicillin-clavulanate in treatment of acute otitis média caused by nontypeable Haemophilus influenzae. J Pediatr 1995; 126(5 Pt l):799-806. (84) Berman S, Roark R. Factors influencing outeome in children treated with antibiotics for acute otitis média. Pediatr Infect Dis J 1993; 12(l):20-24.
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(85) Jero J, Virolainen A, Virtanen M, Eskola J, Karma P. Prognosis of acute otitis média: factors associated with poor outeome. Acta Otolaryngol 1997; 117(2):278-283. (86) Carlin SA, Marchant CD, Shurin PA, Johnson CE, Murdell-Panek D, Barenkamp SJ. Early récurrences of otitis média: reinfection or relapse? J Pediatr 1987; 110(l):20-25. (87) Howie VM, Dillard R, Lawrence B. In vivo sensitivity test in otitis média: efficacy of antibiotics. Pediatrics 1985; 75(1):8-13. (88) Marchant CD, Carlin SA, Johnson CE, Shurin PA. Measuring the comparative efficacy of antibacterial agents for acute otitis média: the "Pollyanna phenomenon". J Pediatr 1992; 120(l):72-77. (89) Porter EH. Pollyanna. Boston: LC Page, 1913. (90) Dagan R, Leibovitz E, Greenberg D, Yagupsky P, Fliss DM, Leiberman A. Early eradication of pathogens from middle ear fluid during antibiotic treatment of acute otitis média is associated with improved clinical outeome. Pediatr Infect Dis J 1998; 17(9):776-782. (91) Blumer JL, Bertino JS, Jr., Husak MP. Comparison of cefaclor and trimethoprim-sulfamethoxazole in the treatment of acute otitis média. Pediatr Infect Dis 1984; 3(l):25-29. (92) Cohen R, Navel M, Grunberg J, Boucherat M, Geslin P, Derriennic M et al. One dose ceftriaxone vs. ten days of amoxicillin/clavulanate therapy for acute otitis média: clinical efficacy and change in nasopharyngeal flora. Pediatr Infect Dis J 1999; 18(5):403-409. (93) Hendrickse WA, Kusmiesz H, Shelton S, Nelson JD. Five vs. ten days of therapy for acute otitis média. Pediatr Infect Dis J 1988; 7(1): 14-23. (94) Kozyrskyj AL, Hildes-Ripstein GE, Longstaffe SE, Wincott JL, Sitar DS, Klassen TP et al. Treatment of acute otitis média with a shortened course of antibiotics: a meta-analysis. JAMA 1998; 279(21): 1736-1742. (95) Mandel EM, Bluestone CD, Rockette HE, Blatter MM, Reisinger KS, Wucher FP et al. Duration of effusion after antibiotic treatment for acute otitis média: comparison of cefaclor and amoxicillin. Pediatr Infect Dis 1982; 1(5):310-316.
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Chapter 2 Acute Otitis Media in Children: A Review of Antibiotic-Prescribing Patterns
2.1 Préface This chapter reviews the results of antibiotic utilization among Québec physicians. Although there is a consensus on the treatment of AOM, as reported in the previous Chapter, it is hard to know to what extent physicians follow it in their clinical practice. Moreover, as inappropriate use of antibiotics may lead to the development of résistance, assessment of the predictors of antibiotic prescription is important to better define the need for continuing médical éducation in différent physicians groups. The Introduction section (page 42) acknowledges the burden of AOM in terms of disease prevalence as well as the health care resources used to cope with it. The Methods section (page 445) describes the study design, including the data source, the study population, the procédures employed to estimate daily amoxicillin dosage, définition of conformity with the consensus, and data analysis. The Results section (page 47) reviews the antibiotic utilization as well as the différent predictors associated with the prescription and dispensation of the most commonly-administered antibiotics (amoxicillin, azithromycin, clarithromycin, and cefprozil). It also reports on the conformity of antibiotic prescription with the published consensus, as well as the predictors of conformity.
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This article was submitted for publication in Pediatrics in February 2003 and should be quoted as follows: Quach C, Collet JP, LeLorier J. Acute otitis média in children: A Review of antibiotic prescribing patterns. Unpublished manuscript. Montréal: Department of Epidemiology and Biostatistics, McGill University, 2003.
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2.2 Abstract AOM is one of the most common infectious diseases of childhood and the most fréquent indication for antibiotic use in children. Objective: To better understand the prescribing patterns and appropriateness of AOM therapy, we used the Régie de l'assurance maladie du Québec (RAMQ) administrative databases. Methods: We investigated on a historical cohort, including ail children aged < 6 years in the province of Québec who had a first AOM épisode between June 1999 and June 2002 and who were covered by the RAMQ drug insurance plan. Conformity of prescriptions was based on the consensus of AOM treatment from the Drug-resistant Streptococcus pneumoniae Therapeutic Working Group. The data were analyzed using descriptive statistics, Chi-square test and logistic régression. Results: During the study period, 60,513 children < 6 years of âge experienced their first AOM épisode with a mean âge of 2.6 years. They were seen by 4,708 physicians (87% gênerai practitioners, 9% pediatricians, and 3% ENT specialists). Amoxicillin was the antibiotic that was prescribed the most (43%), followed by cefprozil and azithromycin. Overall, 42% of physicians followed the consensus in their choice of antibiotic. Compared to gênerai practitioners, pediatricians were as likely to prescribe in conformity with the consensus whereas ENT specialists were 50% less likely to conform with the consensus. Conclusion: Continuing médical éducation is necessary to reinforce the antibiotics that should be used to treat AOM, along with a better understanding of the pathogens involved in AOM and the risk factors associated with drug-resistant infections.
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2.3 Introduction Antimicrobial résistance is increasing Worldwide. Previous studies hâve shown a corrélation between the total use of antibiotics at a municipal level and the prevalence of résistant respiratory tract pathogens (1-3). In Sweden, a national initiative that targeted inappropriate antibiotic prescription in children with respiratory tract infections, succeeded in stopping the progression of résistance among S. pneumoniae (4), a major cause of pneumonia, bacteremia, meningitis, and AOM in children (5). AOM, shown to be a fréquent reason for consulting a physician, is one of the most common infectious diseases of childhood (6;7). It is also the most common indication for antibiotic use in children (6;7). Studies hâve estimated that by âge 1 year, 62.4% of children expérience at least one AOM épisode compared with 75% by âge 3 years and 90% by âge 7 years (8;9). In a single year, 46.8% of children aged 13 to 24 months will be diagnosed to hâve AOM compared with 35.4% aged 25 to 36 months and 9.6% aged 7 to 13 years (10). In the U.S.A., AOM represents more than 20 million physician visits per year, with an average of 2.9 physician office visits per child (11). The U.S. FDA has estimated that 45 million courses of antibiotics were prescribed in 1986 for children less than 10 years of âge, of which 42% were for AOM. Moreover, between 1980 and 1992, an increase was noted in the use of broader spectrum and more expensive antimicrobial agents (12). Not only is AOM a fréquent problem, but the American National Center for Health Statistics reported that AOM diagnoses hâve risen from approximately 10 million visits per year in 1975 to 25 million in 1990 for children less than âge 2 years
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(12). The costs imposed on health care Systems hâve been estimated to be between US$ 3 and 4 billion (13; 14). Nearly halfof thèse expenditures are incurred before âge 3 years. The per capita cost of AOM treatment in children aged between 1 and 3 years has been estimated to be 453 in 1992 US$, due mainly to physician visits (15). Numerous antibiotics are available for AOM treatment. However, the consensus on AOM treatment issued in 1999 recommended only a few of them as appropriate choices with amoxicillin remaining the first-line drug (16; 17). By using inappropriate and, therefore, ineffective antibiotics, treatment failures as well as bacterial résistance may resuit. To better understand the prescribing patterns of physicians and the appropriateness of AOM therapy, we studied the RAMQ administrative databases. We were consequently able to ascertain the antibioticprescription patterns of physicians, the factors associated with various antibiotics prescribed, the conformity of prescribed and dispensed antibiotics with the consensus, and the factors associated with this conformity.
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2.4 Methods 2.4.1 Data source We studied a historical cohort by reviewing antibiotics used for AOM treatment in Québec children from June 1999 to June 2002. Canada has a universal public health insurance program, which is under provincial responsibility. In the province of Québec, the RAMQ is the government body that is responsible for médical insurance. It insures medically ail Québec résidents and also has a costsharing drug insurance plan that covers Québec résidents aged 65 years and over, welfare récipients along with their children, and other workers and their children who do not hâve access to private group insurance from other sources. In 2001, the RAMQ insured over 7 million persons medically while 1.7 million people (25%) were covered under the drug plan (18; 19). Of thèse, almost 400,000 children aged less than 5 years were insured medically while approximately 25% of them were also covered by the RAMQ drug plan (19). Patient records in the différent RAMQ databases were linked using the unique patient identification numbers. In this study, we examined the médical and pharmaceutical claims databases and the database on familial links. The records database contains démographie variables (patient sex, date of birth), drug plan coverage eligibility periods as well as enrolment category, and information on siblings (date of birth, sex, number). The médical claims database includes information on date and type of service, diagnosis coded using the International Classification of Diseases - Ninth Revision (ICD-9) (20), and other médical procédures. The pharmaceutical claims database includes information on the date of
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drug dispensation, the dispensed drug (form, dosage, treatment duration, quantity dispensed, and cost) as well as information on the prescribing physician (type of practice, specialty). The prescription claims database has been validated and considered to be comprehensive and accurate (21). The médical service claims database has also been validated, using a combination of diagnostic and procédure codes, and has been found to be sensitive (22).
2.4.2 Study population Inclusion criteria: Children were included in the study if they were diagnosed between June 1999 and June 2002 to hâve AOM. The index AOM was defined as a médical service claim with an AOM diagnosis (ICD-9 codes: 382.0 [acute suppurative otitis média], 382.4 [unspecifiedsuppurative otitis média], and 382.9 [unspecified otitis média]) (20), accompanied by the dispensation of an antibiotic within 72 hours after the date of the médical service claim - for a maximum duration of 14 days. Antibiotics dispensed for more than 14 days were considered as being used for prophylaxis. The antibiotics selected as approved treatment for AOM were oral formulations of amoxicillin, amoxicillin-clavulanic acid, TMS, erythromycinsulfisoxazole, cefaclor, cefuroxime axetil, cefprozil, cefixime, ceftriaxone (IV or IM), cefotaxime (IV or IM), erythromycin, clarithromycin, and azithromycin (23). Children also needed continuous enrolment in the RAMQ drug plan for a period of 6 months prior to and until 4 weeks after the index AOM. Furthermore, they had to be aged between 3 months and 6 years inclusively.
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Exclusion criteria: Children were excluded if they had a diagnosis of AOM in the past (ICD-9 382) and if they received an antibiotic in the 6-month period prior to the index AOM without an associated diagnosis in the 72 hours preceding the dispensation. Thèse criteria served to eliminate children with a possible history of previous AOM,
2.4.3 Amoxicillin daily dosage calculation Using the antibiotic reimbursement price divided by the priée per unit as provided in the Liste des médicaments (24), we calculated the amoxicillin dosage in mg that was dispensed. We then divided the total amoxicillin dosage by the prescription duration. To obtain the dosage in mg/kg/day, we divided the daily dosage by mean weight for the patient's âge and sex (25).
2.4.4 Conformity of prescribed and dispensed antibiotics with the published consensus Conformity of the dispensed antibiotic was based on the consensus for AOM treatment from the Drug-resistant S. pneumoniae Therapeutic Working Group (17). This consensus proposes first-line treatment as well as alternatives when failure occurs. If the child received no antibiotic in the previous month, amoxicillin (usual or high-dose: > 80 mg/kg) was the recommended treatment. On the other hand, if the child had received antibiotics in the previous month, recommended treatments were high-dose amoxicillin, high-dose amoxicillin-clavulanic acid, or cefuroxime axetil. A prescription was said to be in conformity if it was in agreement with the antibiotics
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proposed in the consensus. Since an important corrélation was présent between antibiotics dispensed by a single prescribing physician, we selected the physician as the unit of analysis. We selected one patient randomly per prescribing physician présent in the database (n=4,708) and used logistic régression to détermine predictors associated with conformity. We then calculated a conformity score for each physician who saw at least 5 eligible patients throughout our study period (number of prescriptions in conformity with the consensus/total number of prescriptions for a first AOM épisode).
2.4.5 Statistical analysis The data were first analyzed using descriptive statistics, the Chi-square test and Student's t test. The déterminants of amoxicillin, cefprozil, and azithromycin versus ail other antibiotics were identified by logistic régression (SAS Institute, v 8.0). Variables were kept in the final model if their coefficient was statistically significant, if they confounded variables already présent in the model or if they significantly improved the model fit as measured by log likelihood. Ail p-values were considered significant at 0.05 and were ail two-sided.
2.5 Results 2.5.1 Study population Between June 1999 and June 2002, 60,513 children aged 6 years or less experienced a first épisode of AOM. Their mean âge was 2.6 years (SD =1.6 years). Fifty-two percent of the children were maie, and the parents of 35.9% of the children
47
were welfare récipients. Thirty percent of the children had no siblings, while 38.7% had one sibling, 19.3% had 2 siblings, and 12.4% had 3 siblings or more. Twelve percent of the children had received antibiotics in the previous month for reasons other than AOM and 74% of the otitis cases occurred between October and April (7 months, 58% of the year). A total of 4,708 physicians saw thèse children. Their specialty was gênerai practitioner (87.3%), pediatrician (9.1%), and ENT specialist (2.5%). They saw an average of 12.9 patients each (SD = 19.6, range = 1-338), while half of them saw at least 7 patients. The physicians were mainly working in private offices (74.6%); the remainder worked in emergency rooms (22.4%) and outpatient clinics (2.2%).
2.5.2 Antibiotic utilization review Table 2.1 lists the antibiotics prescribed for first AOM épisodes. Among ail specialties, amoxicillin remained the antibiotic that was mostly used (42.8% of ail antibiotics prescribed), followed by cefprozil (15.3%), and azithromycin (12.8%). The majority of patients treated with amoxicillin received usual doses. Twenty-seven percent of patients receiving amoxicillin were treated with a dosage of 35-44 mg/kg/day; 28% a dosage of 45-54 mg/kg/day; 20% 55-64 mg/kg/day; and only 5% were given the high dose (80-90 mg/kg/day). The predictors associated with the prescription of différent antibiotics are detailed in Table 2.2. Age was an important predictor of prescription of a given antibiotic. Multivariate analysis revealed that children aged less than 18 months were more likely to receive amoxicillin than any other antibiotic. The specialty of the prescribing physician was another important
48
predictor. Compared to gênerai practitioners, infectious disease specialists were twice as likely to prescribe amoxicillin, while ENT specialists were twice as likely to prescribe cefprozil. General practitioners were more likely to prescribe azithromycin compared to ail other specialties. Patients whose parents were welfare récipients were more likely to receive amoxicillin than any other antibiotic. Among the 3 study years (1999-2002), there was an increase in the prescription of newer, more expensive antibiotics: cefprozil, azithromycin, and clarithromycin were ail given more often in the last year of the study in comparison to the first 2 years. Amoxicillin use throughout the study years was not significantly différent.
2.5.3 Conformity of antibiotic prescription The conformity of antibiotics dispensed was analyzed on the basis of the consensus on for AOM treatment published in 1999 (17). Overall, 42% of ail physicians followed the consensus in their choice of antibiotic. When looking only at physicians practising in emergency rooms, 53% adhered to the consensus for AOM treatment. The predictors associated with a choice of antibiotics in conformity with the consensus are shown in Table 2.3. Children aged less than 18 months saw a 25% increase in their chances of receiving a prescription that was in conformity with the consensus. Compared to gênerai practitioners, pediatricians were as likely to conform with the consensus, whereas ENT specialists were 50% less likely than gênerai practitioners to follow the consensus. The distribution of conformity scores of physicians having 5 eligible patients or more is shown in Figure 2.1. Overall, 14.3%
49
of physicians constantly used antibiotics not recommended in the consensus, while only 4.3%o of physicians constantly prescribed in conformity with the consensus.
2.6 Discussion The study's objective was to identify the pattern of antibiotic use for AOM treatment in children. Amoxicillin remained the most widely administered antibiotic, and was prescribed most often at usual doses (40 mg/kg/day). This dosage is appropriate for AOM occurring in children without other risk factors for penicillin non-susceptible Streptococcus pneumoniae (PNSP) but the high dose (90 mg/kg/day) should be given when risk factors are présent. An important risk factor for an infection caused by PNSP is the use of an antibiotic in the previous month. Interestingly, amoxicillin was less likely to be prescribed in such cases, with azithromycin, cefprozil and clarithromycin being more likely choices. Unfortunately, thèse drugs are not effective in the treatment of PNSP, and high-dose amoxicillin alone or associated with clavulanic-acid should be administered. Another reported risk factor for PNSP was young âge (< 24 months) (9), which may partially explain why children aged < 18 months were 30% more likely to receive amoxicillin. On the other hand, the ease of administration of other molécules such as azithromycin and clarithromycin could also explain the decreased likelihood of amoxicillin prescription for older children. This study shows that a significant proportion of Québec physicians ded not follow the consensus on AOM treatment in children (17). Overall, 58%> of the prescriptions dispensed for the treatment of AOM were not in conformity with the
50
consensus, compared to 47% of prescriptions by physicians working in emergency rooms. Thèse numbers are higher than those published in a Spanish study where only 23% of the prescriptions dispensed in emergency rooms were not appropriate (26). The Spanish study, however, was prospective and the physicians knew that they were being observed. Moreover, they considered fewer antibiotics as 'not appropriate' than we ded. The most important predictor of conformity with the consensus for a physician was the physician's own previous trend in conformity. This was not retained in the logistic régression model as the corrélation between the previous trend of prescription and current conformity was too high and, therefore, not independent, making ail other variables non-significant. There are a number of limitations to the présent study due to its rétrospective and administrative nature of the data obtained from the RAMQ. Although the médical services database may be used to assess gênerai health status, it is especially difficult in children to fully understand the past médical history of a given patient. In the elderly, médical conditions may be captured by a combination of diagnosis and prescriptions filled. It has been shown to be accurate and comprehensive in this population (21 ;22), but has not been validated in pédiatrie subjects where conditions may be more difficult to assess because of the low rate of drug consumption. We assumed that the majority of our population was previously healthy. In fact, only 1.6% of our population was hospitalized prior to their first AOM, only 31 patients had a diagnosis of human immunodeficiency virus (HIV) (0.05%), and only 26 patients had trisomy-21 (otitis-prone conditions). Moreover, the use of this administrative, rétrospective database did not allow us to identify patients allergie to
51
penicillin for whom the prescription of macrolides would hâve been indicated. Also, the reported incidence of penicillin allergy was usually low, between 1 and 9% (27;28). As with most rétrospective drug claims databases, records relate only to drugs dispensed and do not take into account prescriptions given to parents but not filled, and assume that the entire amount of drug dispensed was administered. In conclusion, continuing médical éducation is necessary to reinforce antibiotic use against AOM. A better understanding by prescribing physicians of the pathogens involved in AOM and of the risk factors associated with the acquisition of drug-resistant bacteria should enable them to choose the best antibiotic according to the patient characteristics.
Acknowledgements Caroline Quach was supported by a Clinical Pharmacology Fellowship from the Collège des médecins du Québec. Jean-Paul Collet was supported by a senior Research Career Award from the Fonds de recherche en santé du Québec (FRSQ). Jacques LeLorier has acted as a consultant and paid speaker for Abbott Laboratories, Bristol-Myers Squibb Canada, GlaxoSmithKline, and Pfizer Canada. The authors thank Mr. Jacques Barry from the RAMQ, for assistance with the data, and Mr. Marc Dorais for assistance in cohort sélection.
52
Table 2.1: Description of antibiotics prescribed for first épisodes of AOM.
n
(%)
25,873 9,258 7,771 5,764 3,691 2,724 2,591 1,778 750 173 128 12
(42.8) (15.3) (12.8) (9.5) (6.1) (4.5) (4.3) (3.0) (1.2) (0.3) (0.2) (0.0)
1,734 589 575 447
(42.2) (14.3) (14.0) (10.9)
206 82 38 27
(48.2) (19.2) (8.9) (6.3)
32 27 20 19
(27.4) (23.1) (17.1) (16.2)
Ail children (n=60,513) Amoxicillin Cefprozil Azithromycin Clarithromycin Cefaclor Trimethoprim-sulfamethoxazole Amoxicillin-clavulanic acid Erythromycin ethylsuccinate-•sulfisoxazole acetyl Cefixime Erythromycin Cefuroxime axetil Others By specialty of prescribing physician (n=4,708) General practitioner: Amoxicillin Cefprozil Azithromycin Clarithromycin Pediatrician: Amoxicillin Cefprozil Amoxicillin-clavulanic acid Azithromycin ENT specialist: Amoxicillin Cefprozil Clarithromycin Amoxicillin-clavulanic acid
53
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Table 2.3: Conformity with the consensus of antibiotics prescribed for first épisodes ofAOM Factors associated with choice of antibiotics in conformity with the published consensus (n=4,708)
OR
(95%CI)
Age > 18 months
0.76
(0.67,0.86)
Speciality of prescribing physician: (référence: gênerai practitioner) - Infectious disease specialist - ENT specialist - Pediatrician
3.15 0.54 1.28
(0.58,17.26) (0.36,0.81) (1.05,1.57)
Practising in private office
0.60
(0.53,0.69)
55
Figure 2.1: Distribution of conformity scores among physicians with 5 patients or more 1fi -, S 14(0
5tu 12
f 10o
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1
1
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56
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1
2.7 Références (1) Arason VA, Kristinsson KG, Sigurdsson JA, Stefansdottir G, Molstad S, Gudmundsson S. Do antimicrobials increase the carnage rate of penicillin résistant pneumococci in children? Cross sectional prevalence study. BMJ 1996; 313(7054):387-391. (2) Melander E, Ekdahl K, Jonsson G, Molstad S. Frequency of penicillinresistant pneumococci in children is correlated to community utilization of antibiotics. Pediatr Infect Dis J 2000; 19(12): 1172-1177. (3) Bronzwaer SL, Cars O, Buchholz U, Molstad S, Goettsch W, Veldhuijzen IK et al. A European study on the relationship between antimicrobial use and antimicrobial résistance. Emerg Infect Dis 2002; 8(3):278-282. (4) Molstad S, Cars O. Major change in the use of antibiotics following a national programme: Swedish Stratégie Programme for the Rational Use of Antimicrobial Agents and Surveillance of Résistance (STRAMA). Scand J Infect Dis 1999; 31(2): 191-195. (5) Musher DM. Streptococcus pneumoniae. In: Mandell GL, Bennett JE, Dolin R, editors. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. USA: Churchill Livingstone, 2000: 2128-2147. (6) Froom J, Culpepper L, Grob P, Bartelds A, Bowers P, Bridges-Webb C et al. Diagnosis and antibiotic treatment of acute otitis média: report from the International Primary Care Network. BMJ 1990; 300(6724):582-586. (7) Bergus GR, Levy BT, Levy SM, Slager SL, Kiritsy MC. Antibiotic use during the first 200 days of life. Arch Fam Med 1996; 5(9):523-526. (8) Teele DW, Klein JO, Rosner B. Epidemiology of otitis média during the first seven years of life in children in greater Boston: a prospective, cohort study. J Infect Dis 1989; 160(l):83-94. (9) Dagan R, Hoberman A, Johnson C, Leibovitz EL, Arguedas A, Rose FV et al. Bactériologie and clinical efficacy of high dose amoxicillin/clavulanate in children with acute otitis média. Pediatr Infect Dis J 2001; 20(9):829-837. (10) Byrns PJ, Bondy J, Glazner JE, Berman S . Utilization of services for otitis média by children enrolled in Medicaid. Arch Pediatr Adolesc Med 1997; 151(4):407-413. (11) Thompson D, Oster G, McGarry LJ, Klein JO. Management of otitis média among children in a large health insurance plan. Pediatr Infect Dis J 1999; 18(3):239-244.
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(12) Bluestone CD. Rôle of surgery for otitis média in the era of résistant bacteria. Pediatr Infect Dis J 1998; 17(11): 1090-1098. (13) Hoppe HL, Johnson CE. Focus on antimicrobial résistance and new treatment options. Am J Health Syst Pharm 1998; 55:1881-1897. (14) Takata GS, Chan LS, Shekelle P, Morton SC, Mason W, Marcy SM. Evidence assessment of management of acute otitis média: I. The rôle of antibiotics in treatment of uncomplicated acute otitis média. Pediatrics 2001; 108(2):239247. (15) Bondy J, Berman S, Glazner J, Lezotte D. Direct expenditures related to otitis média diagnoses: extrapolations from a pédiatrie Medicaid cohort. Pediatrics 2000; 105(6):E72. (16) McCracken GH, Jr. Treatment of acute otitis média in an era of increasing microbial résistance. Pediatr Infect Dis J 1998; 17(6):576-579. (17) Dowell SF, Butler JC, Giebink GS, Jacobs MR, Jernigan D, Musher DM et al. Acute otitis média: management and surveillance in an era of pneumococcal résistance - a report from the Drug-resistant Streptococcus pneumoniae Therapeutic Working Group. Pediatr Infect Dis J 1999; 18(l):l-9. (18) Nombre de personnes inscrites et admissibles au régime d'assurance maladie du Québec selon le sexe, le groupe d'âge et la région sociosanitaire 2001. Régie de l'assurance maladie du Québec. 2002. 28-8-2002. Ref Type: Electronic Citation (19) Nombre d'adhérents selon le sexe, le groupe d'âge et la région sociosanitaire de la personne assurée, régime d'assurance médicaments 2001. Régie de l'assurance maladie du Québec. 2002. 28-8-2002. Ref Type: Electronic Citation (20) World Health Organization. International Classification of Diseases, Ninth Revision (ICD-9). Geneva, Switzerland: World Health Organization, 1977. (21) Tamblyn R, Lavoie G, Petrella L, Monette J. The use of prescription claims databases in pharmacoepidemiological research: the accuracy and comprehensiveness of the prescription claims database in Québec. J Clin Epidemiol 1995; 48(8):999-1009. (22) Tamblyn R, Reid T, Mayo N, McLeod P, Churchill-Smith M. Using médical services claims to assess injuries in the elderly: sensitivity of diagnostic and procédure codes for injury ascertainment. J Clin Epidemiol 2000; 53(2): 183194.
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(23) Klein JO, Bluestone CD. Otitis média. In: Feigin RD, Cherry JD, editors. Textbook of Pédiatrie Infectious Diseases. Philadelphia: Saunders, 1998: 195211. (24) Liste des médicaments. Régie de l'assurance maladie du Québec, 2002. (25) Lawson Wilkins Pédiatrie Endocrine Society. Clinical Growth Charts. http://lwpes.org/growth_curves/growth-curves.htm . 1-9-2002. 14-1-2003. Ref Type: Electronic Citation (26) Solis G, Ochoa C, Perez MC. The variability and appropriateness of the antibiotic prescription of acute otitis média in childhood. The Spanish Study Group for Antibiotic Treatments. Int J Pediatr Otorhinolaryngol 2000; 56(3):175-184. (27) Kerr JR. Penicillin allergy: a study of incidence as reported by patients. Br J ClinPract 1994; 48(l):5-7. (28) Bowrey DJ, Morris-Stiff GJ. Drug allergy: fact or fiction? Int J Clin Pract 1998; 52(1):20-21.
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Chapter 3 Effectiveness of Amoxicillin, Azithromycin, Cefprozil, and Clarithromycin in the Treatment of Acute Otitis Media in Children: A Population-based Study
3.1 Préface This Chapter compares the effectiveness of amoxicillin, azithromycin, clarithromycin, and cefprozil in the treatment of AOM in the province of Québec, in a cohort of 60,513 children described in détail in the previous chapter. In our cohort, 21% of the children experienced treatment failure defined as (a) a new dispensation of antibiotics approved for AOM in the 30 days following the initial dispensation, (b) a hospitalization for complications related to AOM, or (c) an outpatient visit for complications related to AOM. Appendix 1 détails the antibiotics approved for AOM treatment, while Appendix 2 gives more information on the diagnoses and procédure codes used to define complications related to AOM. Effectiveness was assessed by comparing the risk of each antibiotic being associated with treatment failure. The Introduction section (page 63) gives an overview of various effectiveness studies of AOM treatment. The methodology used is similar to that described in the previous Chapter in terms of cohort sélection, but also defines treatment failure, exposure to antibiotics, covariates, and data analysis. The Results section (page 69) reports on treatment failures as well as the comparative effectiveness of the différent antibiotics studied. This manuscript was submitted for publication in The Pédiatrie Infectious Disease Journal in April 2003 and should be quoted as foliows:
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Quach C, Collet JP, LeLorier J. Effectiveness of amoxicillin, azithromycin, cefprozil, and clarithromycin in the treatment of acute otitis média in children: A Populationbased study. Unpublished manuscript. Montréal: Department of Epidemiology and Biostatistics, McGill University, 2003.
61
3.2 Abstract Population-based studies of AOM treatment in children, reflecting real-life, may give results différent from randomized clinical trials assessing the efficacy of antibiotics. Objective: To détermine the effectiveness of amoxicillin, azithromycin, cefprozil, and clarithromycin in treatment AOM among children. Methods; A cohort of children aged < 6 years, with a first épisode of AOM between June 1999 and June 2002, was selected from RAMQ databases. The index AOM was defined as a médical service claim with a diagnosis of AOM, and the dispensation of an antibiotic in the following 72 hours, in a child without a previous history of AOM. Failure was defined as the new dispensation of an antibiotic or a hospitalization or outpatient visit for complications related to AOM within 30 days after the index AOM. Failures were categorized as early (14 days). Data were analyzed by logistic régression. Results: Overall, 12,693 failures occurred among 60,513 first épisodes of AOM. Azithromycin was the only antibiotic that was associated with a decreased risk of failure overall, when compared to amoxicillin (OR 0.88, 95%CI: 0.82, 0.94). Compared to amoxicillin at the usual dose, early failures (n= 680) were more likely to occur if the child had received azithromycin as the first treatment (OR 1.6, 95%CI: 1.3, 2.0) or clarithromycin (OR 1.5, 95%CI: 1.1, 1.9). Intermediate failures occurred in 2,626 cases (20.7%) and were not associated with any spécifie antibiotic. Compared to amoxicillin, late failures (n = 9,387) were more likely to occur if the child had received cefprozil (OR 1.2, 95%CI: 1.2, 1.3) but were less likely with azithromycin (OR 0.8 95%CI: 0.8, 0.9).
62
Conclusion: Macrolides are associated with early failures, but azithromycin seems to decrease the risk of failures overall.
3.3 Introduction AOM is one of the most common infectious diseases of childhood as well as the most fréquent indication for antibiotic use in children (1 ;2). Despite the usually favourable course of AOM, potential serious complications may arise and thus justify the need for antibiotic treatment (3). Multiple studies hâve examined the clinical efficacy of various antibiotic regimens against AOM (4-19). Overall, antibiotics seem équivalent in terms of clinical and microbiological efficacy and also appear superior to placebo. A récent systematic review has shown that clinical failure - using différent définitions - is decreased by 12% at 2 to 7 days with amoxicillin rather than placebo. It has also reported that clinical failure rates are similar between penicillin V and amoxicillin, between cefaclor and amoxicillin, cefaclor and TMS, cefixime and amoxicillin, and azithromycin and amoxicillin-clavulanic acid (19). However, the différent studies reviewed were performed in various locations as well as on différent populations and at différent points in time. The PNSP rates were, therefore, likely to be very différent between one study and the next. The risk factors associated with PNSP infections hâve been investigated extensively. The most fréquent factor for résistance remains antibiotic use in the previous month (14;20-25). Young âge, daycare attendance, exposure to other children in the household, récent hospitalization and otitis-prone conditions hâve also
63
been reported as risk factors for treatment failure (7;14;20-22;24). Since résistance to antibiotics predicts bacteriological failure, the efficacies of various antibiotics would be easier to compare in a single population over a defined time span. Moreover, a population-based study, which will be closer to real-life than randomized, controlled trials, may bring newer information on the effectiveness of antibiotics in AOM. Our objectives were, therefore, to conduct a population-based investigation into the clinical utility of amoxicillin at usual and high doses, azithromycin, clarithromycin and cefprozil in the treatment of first AOM épisodes among children aged 6 years and less in the province of Québec as well as to identify risk factors associated with treatment failure.
3.4 Methods 3.4.1 Data source We used RAMQ databases to sélect a cohort of patients aged 6 years and less who had a first épisode of AOM in the province of Québec between June 1999 and June 2002. Canada has a uni versai public health insurance program, which is under provincial jurisdiction. In the province of Québec, the RAMQ is the government body that is responsible for médical insurance. It insures ail Québec résidents medically and also has a cost-sharing drug insurance plan that covers Québec résidents aged 65 years and over, welfare récipients along with their children, as well as other workers and their children who do not hâve access to private group insurance from other sources. In 2001, 559,900 children aged 6 years and less were medically insured by
64
the RAMQ, while approximately 25% of them were also enrolled in the RAMQ drug plan (26;27). Patient records in the différent RAMQ databases were linked by unique patient identification numbers. In this study, we examined the médical and pharmaceutical claims databases as well as the database on familial links. The records database contains démographie variables (patient sex, date of birth), drug plan coverage eligibility periods, enrolment category, and information on siblings (date of birth, sex, number). The médical claims database includes information on date and type of service, diagnosis coded according to the ICD-9 (28), and other médical procédures. The pharmaceutical claims database includes information on the date of drug dispensation, the dispensed drug (form, dosage, treatment duration, quantity dispensed, and cost) as well as information on the prescribing physician (type of practice, specialty). The prescription claims database and the médical service claims database hâve been validated and considered to be comprehensive and accurate (29;30).
3.4.2 Study population Inclusion criteria: Children were included in the study if they were diagnosed to hâve AOM between June 1999 and June 2002. The index AOM was defined as a médical service claim with an AOM diagnosis (ICD-9 codes: 382.0 [acute suppurative otitis média], 382.4 [unspecified suppurative otitis média], and 382.9 [unspecified otitis média]) (28), accompanied by the dispensation of an antibiotic in the following 72 hours, for a maximum duration of 14 days. Antibiotics dispensed for more than 14
65
days were considered as being used for prophylaxis. The antibiotics selected as approved treatment for AOM were oral formulations of amoxicillin, amoxicillinclavulanic acid, TMS, erythromycin-sulfisoxazole, cefaclor, cefuroxime axetil, cefprozil, cefixime, ceftriaxone (IV or IM), cefotaxime (IV or IM), erythromycin, clarithromycin, and azithromycin (31). Children also needed continuous enrolment in the RAMQ drug plan for a period of 6 months prior to and until 4 weeks after the index AOM. Furthermore, they had to be aged between 3 months and 6 years inclusively. Children entered the cohort on the day of their first antibiotic dispensation for AOM. Exclusion criteria: Children were excluded if they had a diagnosis of AOM in the past (ICD-9 382) and if they received an antibiotic in the 6-month period prior to the index AOM without an associated diagnosis in the 72 hours preceding the dispensation. Thèse criteria served to eliminate children with a possible history of previous AOM,
3.4.3 Outcomes Treatment failure is clinically defined as the lack of improvement in signs and symptoms of the acute infection as well as in otoscopic findings (32). For the purpose of our study, we defined treatment failure as either (a) a new dispensation of antibiotic approved for the treatment of AOM 2-30 days after cohort entry, (b) hospitalization for complications related to AOM in the 30 days following cohort entry, or (c) an outpatient visit for a complication related to AOM in the 30 days after cohort entry. The complications included in the définition of treatment failure were
66
meningitis, mastoiditis, intracranial abscess, latéral sinus thrombosis, tympanic membrane perforation, persistent effusion with hearing loss, and cholesteatoma. The procédures employed in the définition of treatment failure were lumbar puncture, mastoidectomy, myringotomy, tympanostomy tubes, craniotomy, abscess incision and drainage, and paracentesis. Failures were labelled as early if they occurred within 3 days of cohort entry, intermediate if they occurred between 4 and 14 days after cohort entry, and late or reinfection if they occurred more than 14 days after cohort entry.
3.4.4 Exposure to antibiotics The antibiotics studied were amoxicillin (35-75 mg/kg/day), the référence category, amoxicillin high-dose (> 75 mg/kg/day), azithromycin, cefprozil, and clarithromycin. The daily amoxicillin dosage was calculated by dividing the antibiotic reimbursement price by the price per unit as provided in the Liste des médicaments (33), which gave the amoxicillin dosage in mg dispensed. The total amoxicillin dosage was then divided by the prescription duration. To obtain the dosage in mg/kg/day, we divided the daily dosage by the mean weight for the patient's âge and sex (34).
3.4.5 Covariates Covariates included âge, sex, parents' enrolment status (welfare vs. adhèrent), number and âge of siblings, the dispensation of antibiotics in the previous month, and hospitalization in the past month, which are known risk factors for failure and PNSP
67
(7;20-22;24). Otitis-prone conditions, such as immunosuppression, HIV, and trisomy 21, were also included in the analysis (22). Adenoidectomy, T&A, and tympanostomy tubes in the past 3 months were also used as covariates, with the type of practice of the prescribing physician, the year of the study, and season of the year.
3.4.6 Statistical analysis The data were first analyzed using descriptive statistics, the Chi-square test, and Student's t test. Survival analysis determined the probability of being treatment failure-free in the 30 days following cohort entry stratified by antibiotic used. Logistic régression models (SAS Institute, v8.2) assessed the predictors associated with treatment failure. Variables were retained in the final model if their coefficient was statistically significant, if they confounded variables already présent in the model or if they significantly improved the model fit as measured by log likelihood. Ail pvalues were considered significant at 0.05 and were two-sided.
68
3.5 Results 3.5.1 Treatment failure Between June 1999 and June 2002, of the 60,513 children aged 6 years and less who experienced a first AOM épisode, 12,693 (21.0%) were treatment failures. Children with treatment failure had a mean âge of 2.27 years (SD 1.55) and were mostly maie (54.3%). Thirty-two percent did not hâve any siblings, and. 17.1% received antibiotics in the previous month. The characteristics of children with and without treatment failure are shown in Table 3.1. In total, 680 failures were early (5.4%), while 2,626 failures occurred between 4-14 days after cohort entry (20.7%), and the majority occurred late (73.9%). Chronic serous otitis média was found in 22.6% of reported médical complications, and hearing loss, in 4.7%. Mastoiditis developed in only 4 cases for an incidence of 0.06%. Thèse mastoiditis cases initially received cefprozil, azithromycin, erythromycin and high-dose amoxicillin. Meningitis and intracranial abscess were not seen in our cohort. In total, in the month preceding their cohort entry, 7,581 (12.5%) patients had received antibiotics, mainly amoxicillin (37.1%), cefprozil (13.7%), clarithromycin (12.5%), and azithromycin (10.6%). If we compare each antibiotic with ail the others pooled as a référence, the crude ORs associated with the dispensation of various antibiotics at cohort entry were as follows. Amoxicillin was associated with an OR for failure of 0.82 (95%CI: 0.79, 0.86), azithromycin with an OR of 0.77 (95%CI: 0.73, 0.82), clarithromycin with an OR of 1.00 (95%CI: 0.94, 1.07) and cefprozil with an OR of 1.14 (95%CI: 1.01, 1.21). The unadjusted times to failure by antibiotics are shown in Figure 3.1.
69
3.5.2 Effectiveness of antibiotics The risk of overall treatment failure (at 30 days) was associated with the dispensation of cefprozil (OR 1.21, 95%CI: 1.14, 1.28), clarithromycin (OR 1.09, 95%CI: 1.02, 1.17) and even amoxicillin at high-dose (OR 1.16, 95%CI: 1.04 1.30) when compared to usual-dose amoxicillin. Azithromycin was the only antibiotic with a decreased risk of failure when compared to amoxicillin (OR 0.88, 95%CI: 0.82, 0.94). Other factors associated with overall treatment failure are detailed in Table 3.2. The factors linked with early treatment failures are shown in Table 3.3. Macrolides were more likely to be associated with early failures than other antibiotics. Compared to at usual-dose amoxicillin, the risk of early failure was increased by 59% when azithromycin was given initially (OR 1.59, 95%CI: 1.27, 2.01), and by 48%> when clarithromycin was the antibiotic received upon cohort entry (OR 1.48, 95%CI: 1.14, 1.92). The factors associated with intermediate failure also are detailed in Table 3.3. Ail antibiotics seemed comparable in terms of failure occurring 4 to 14 days after the initial antibiotic dispensation. Most failures occurred late and the associated factors too are listed in Table 3.3. Azithromycin was the only antibiotic given initially that significantly decreased the risk of late treatment failure. It showed a 19% réduction in the risk of failure (OR 0.81, 95%CI: 0.75, 0.88).
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3.6 Discussion When compared to usual-dose amoxicillin, azithromycin and clarithromycin seem more likely to be associated with early failure, but in the long run (14-30 days after the beginning of treatment) and overall, azithromycin is the antibiotic with the lowest risk of treatment failure. Looking at the effectiveness of the antibiotics used for AOM treatment, our data revealed that macrolides (azithromycin and clarithromycin) were more likely to be associated with early failures than amoxicillin. This could be explained by the fact that failures occurring in the 3 days following the beginning of therapy are more likely due to résistance, mainly PNSP (35). In the U.S A., in 2000, approximately 26% of pneumococcal isolâtes were résistant to azithromycin and erythromycin (36). However, either allergies or adverse reactions could also explain the prescription of a new antibiotic early in the course of treatment, but this is unlikely since newer génération macrolides are usually well tolerated (37). Ail antibiotics seemed equally effective when looking at failures that occurred between 4 and 14 days after the beginning of therapy. Failures occurring > 14 days after the start of initial antibiotic treatment are most often caused by a new organism rather than by bacteria that had elicited the initial infection (38). Thèse reinfections were less likely to occur if azithromycin was the initial antibiotic given, in comparison to amoxicillin. Prolonged azithromycin concentration in cells may explain the decreased risk of reinfection (39). As most failures occurred late, this also explains why azithromycin was associated with a reduced risk of overall failure.
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The présent study had the advantage of being population-based. Because of RAMQ drug plan coverage, a third of our sample was comprised of children whose parents were welfare récipients, while the remaining were children of working parents who had no group insurance and who chose to adhère to the RAMQ drug plan. The risk of treatment failure and the probability of being dispensed the antibiotics studied should not differ between the population included in our study and children whose parents had group insurance. Recall bias is unlikely as administrative databases enable us to gather précise information on the initial treatment received as well as ail other médical procédures and médications before the index AOM. The définition chosen to identify treatment failures appears to be valid as the proportion of failures in the présent study falls within the range of previouslyreported data. As well, the risk factors associated with treatment failures in our study are similar to those found in the literature. Overall, 21% of the children followed in our cohort experienced treatment failure. This proportion is consistent with the literature. In a systematic review of the literature, Takata and colleagues hâve shown that failures were reported in 19% of untreated AOM (95%CI: 10-28%) by 7 days, with a 12% decrease (95%CI: 3-22%) when antibiotics were compared to placebo (19), resulting in a failure rate of approximately 17% (95%CI: 8-27%) in treated patients. Klein (3) estimated a failure rate of 6% with amoxicillin, which is also reflected in our survival analysis, where 5.5% of children experienced failure at 10 days with amoxicillin.
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The risk factors for failure were also consistent with findings in the literature. Antibiotic use in the previous month (14;20-25), hospitalization in the previous month (20;22), âge less than 24 months (24), and otitis-prone conditions (14;22) such as trisomy 21, were associated with treatment failure. Children whose parents were welfare récipients were less likely, in our study, to expérience treatment failure. We hypothesize that welfare récipient status could be a proxy for not attending daycare (40), which could explain the protective effect observed. It has been shown previously that families with low socio-economic status were less likely to consult a physician (40), which could also explain why children whose parents were welfare récipients, had a decreased risk of failure. The OR of adenoidectomy and tonsillectomy differed from those reported in the literature: adenoidectomy was associated with an increased risk of failure between 4 and 30 days after cohort entry. Paradise and colleagues hâve noted that adenoidectomy was effective for a duration of 2 years in reducing the number of AOM after tympanostomy tube extrusion (41). Coyte and colleagues similarly showed a protective effect of adenoidectomy and tonsillectomy in preventing récurrent AOM (42). On the other hand, our population was composed of children with first épisodes of AOM while cases reported in the literature were for récurrent AOM. In the présent study, 75% of the children had their surgical procédures in the 2 years preceding the index épisode. The présent study has some limitations. Because of the nature of the data, treatment failure could hâve been misclassified. Although our définition seems valid, some patients classified as failure could hâve, in fact, received a second course of
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antibiotic because of drug intolérance or for other diagnoses not recorded in the RAMQ databases. This misclassification, if présent, would likely be non-differential (as likely to occur in patients who received amoxicillin, azithromycin, cefprozil, and clarithromycin, as thèse drugs are usually well-tolerated), biasing our results towards 1. As with most rétrospective drug claims databases, records relate only to drugs dispensed and do not take into account prescriptions given to parents but not filled and assume that the entire amount of drug dispensed was administered. Considering the rétrospective and administrative nature of the data, it was impossible to get a sensé of infection severity. Some antibiotics may hâve been more likely prescribed to children with more severe infection, which could explain the higher probability of failure associated with thèse antibiotics (confounding by indication) (43). This could hâve been the case for newer génération macrolides, accounting for the increased risk of early failure. If such is the case, continuing médical éducation is needed since none of thèse antibiotics is recommended for children with risk factors for PNSP or for severe infections that could be due to S. pneumoniae in which résistance rates to macrolides are close to 30% (44). Confounding by indication could also explain the poor performance of high-dose amoxicillin, as illustrated by one patient in our cohort who developed mastoiditis after having received high-dose amoxicillin. Another potential confounder that could not be assessed from our data was familial history of AOM, also a risk factor for récurrent otitis and failure (22). In conclusion, the effectiveness of the antibiotics studied is very similar. Compared to amoxicillin, macrolides seemed to be associated with an increased risk
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of failure early in the course of treatment, likely secondary to résistance while azithromycin was associated with less reinfections. However, there was no single or combination of risk factors that predicted with certainty which child would develop early or late failure. In this context, and acknowledging the importance of macrolides résistance among pneumococci, amoxicillin should remain the first-line drug of choice for a first AOM épisode in children aged 6 years and less.
Acknowledgements Caroline Quach was supported by a Clinical Pharmacology Fellowship from the Collège des médecins du Québec. Jean-Paul Collet was supported by a senior Research Career Award from the Fonds de recherche en santé du Québec (FRSQ). Jacques LeLorier has acted as a consultant and paid speaker for Abbott Laboratories, Bristol-Myers Squibb Canada, GlaxoSmithKline, and Pfizer Canada. The authors thank Mr. Jacques Barry from the RAMQ, for assistance with the data, and Mr. Marc Dorais for assistance in cohort sélection.
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Table 2.1: Characteristics of children with and without treatment failure (n = 60,513). Characteristics Age (years), mean ± SD Sex Maie Female Enrolment status of parents Welfare récipients Adhèrent Number of siblings None 1 2 3 and more Antibiotics in past month Otitis during winter Initial antibiotic treatment Amoxicillin usual-dose Amoxicillin high-dose Azithromycin Cefprozil Clarithromycin
Children with treatment failure
Children without treatment failure
2.27 ±1.55
2.72 ±1.64
6,897 {:54.3%) 5,796 p
0.80
-5
Azithromycin Amoxicillin Clarithromycin Cefprozil Amoxicillin HD
oo 0.75 -
0.70
n
5
v
1
—i—
10
15
20
Days to failure
77
25
^s.
30
35
Table 3.2: Predictors associated with overall treatment failure Risk factors
OR
(95%CI)
Initial antibiotic received Amoxicillin (35-75 mg/kg/day) Cefprozil Azithromycin Clarithromycin Amoxicillin high-dose Age < 24 months Female gender Trisomy 21 Previous adenoidectomy Previous tonsillectomy ± adenoidectomy Antibiotics in previous month Hospitalized in previous month Welfare récipient parents At least 1 sibling
1.00 1.21 0.88 1.09 1.16 1.65 0.91 2.82 1.61 1.16 1.48 1.32 0.88 0.92
[1.14, 1.28) [0.82, 0.94) > p-, ^ - 9 «+-i - o ^3 • " - o c_ c/o C m
