Acute Otitis Media (AOM) Year 2000 Update: A Rational and Evidence-Based Analysis of Current Controversies in Antibiotic Therapy and Drug Selection for AOM
Acute Otitis Media (AOM) Year 2000 Update: A Rational and Evidence-Based Analysis of Current Controversies in Antibiotic Therapy and Drug Selection for AOM
Part II: Evidence-Based Trials, CDC Recommendations, Divergent Opinion, and the PPPD Approach to Antimicrobial Drug Selection
Author: Gideon Bosker, MD, FACEP, Assistant Clinical Professor, Yale University School of Medicine; Associate Clinical Professor, Oregon Health Sciences University, Portland, OR.
Peer Reviewer: Steven M. Winograd, MD, FACEP, Attending Physician, Department of Emergency Medicine, Sturgis Hospital, Sturgis, MI, Allegan General Hospital, Allegan, MI; Southwestern Michigan Emergency Services, PC.
Acute otitis media: common, unpredictable, challenging, and now more than ever, fiercely debated at the front lines of clinical practice and in the ivory towers of medicine. In fact, the continuing controversy surrounding outcome-effective treatment strategies has attracted the interest of nationally recognized clinicians, epidemiologists, and clinical scholars from the disciplines of emergency medicine, pediatrics, and infectious diseases. As might be expected, each expert or consensus panel brings their own set of biases to the challenge of establishing critical pathways for this common condition. One group may emphasize Streptococcus pneumoniae resistance patterns (PRSP), while another will put a priority on dosing schedule, side effects, and compliance-enhancement.
In response to PRSP species and emerging resistance among some antibiotics, the Centers for Disease Control and Prevention (CDC) was prompted to convene experts in the management of otitis media to form the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group. The objective was to provide consensus recommendations for the management of acute otitis media (AOM) and strategies for surveillance of drug-resistant Streptococcus pneumoniae.
In this concluding part of our two-part series, we closely examine the CDC recommendations. They are carefully evaluated against the backdrop of evidence-based trials, practical considerations, resistance surveillance studies, and national expert opinion that may offer other treatment strategies and that diverge in some aspects from these published pathways. Moreover, this review discusses, in detail, the prescription, parent, patient, and drug resistance (PPPD) approach to antibiotic selection for AOM—a drug selection framework that includes a number of disease management factors, including cost, compliance, patient toleration, taste, side effects, dosing schedules, and convenience factors, all of which can affect the journey from prescription pad to clinical cure.
Finally, this review of AOM will also examine the implications of recent evidence-based trials that have investigated the role of bacteriologic eradication in producing clinical cure in patients with AOM and effective approaches to AOM treatment failures.
— The Editor
Predictors of Patient Outcomes
Regardless of the specific antibiotic selected for AOM, there appears to be a relationship between early bacterial eradication of the organism from the middle ear and cure rates in children with AOM.1 To determine the relation between early bacteriologic eradication and clinical outcome of AOM in infants and young children treated with various antibiotics, an Israeli group studied patients ages 3 to 24 months seen in a pediatric emergency department.
Patients enrolled in this trial presented with symptoms and physical findings consistent with AOM of 7 days or less duration. Moreover, the following criteria were met: 1) there was no spontaneous perforation or tympanostomy tubes; 2) there was a positive initial middle ear fluid culture; and 3) a follow-up culture on at least Day 10 ± of the study, with a second culture performed 72-96 h after initiation of antibiotic treatment. Any patient with a positive middle ear fluid culture 72-96 h after initiation of antibiotic treatment was considered to have bacteriologic failure.1
Otologic evaluation was done by an otolaryngologist unaware of the culture results and of the study drug allocation. A clinical score based on body temperature, report of irritability and ear tugging observed by the parents, and the appearance and redness of the ear drum as observed by the otolaryngologist was also used for clinical evaluation.
Of the 123 patients evaluated in the study, 57 (46%) had positive middle ear fluid 72-96 h after initiation of antibiotic treatment. Clinical failure was observed in 21 of 57 (37%) patients in whom bacteriologic eradication did not occur vs. only two of 66 (3%) patients with bacteriologic eradication after 3-4 days of treatment (P < 0.001). Clinical score for both moderate and severe disease decreased significantly faster in those with bacteriologic eradication than in those in whom middle ear fluid was still culture-positive 72-96 h after initiation of treatment.1
The investigators concluded that clinical failures in their population were associated with inability to eradicate the causative organisms of AOM from the middle ear fluid within 3-4 days after initiation of antibiotic therapy. Most patients (including those without bacteriologic eradication) improved after 3-4 days of treatment, but patients with sterile middle ear fluid felt better after 3-4 days of treatment than patients in whom middle ear fluid was still culture-positive.1
Short Course Therapies for AOM. One of the important, practical questions when selecting an antibiotic for AOM is how long a course of therapy should be in order to maximize clinical outcomes. Some practitioners have advocated 7- to 10-day treatment courses, even though studies show that medication noncompliance rates with 10-day regimens can be as high as 92% by the last day of drug therapy.2-6
Unfortunately, a recent working group statement from the CDC did not address the issue of short courses for AOM in a systematic manner.7 Evaluating the efficacy of short duration therapy for AOM, however, must be addressed in a drug-specific manner, inasmuch as all short courses do not have the same pharmacokinetic properties. For example, some short half-life antibiotics are given for a short duration and, as predicted, provide only short duration "bug-drug" contact at the locus of infection (i.e., the middle ear). In contrast, other agents such as azithromycin, offer the potential convenience and compliance advantages of a short five-day course, while maintaining longer duration, MIC-effective bug-drug contact at the tissue level for an additional 5-7 days after the last dose.8
To shed light on this aspect of the AOM treatment controversy, one group of investigators conducted a meta-analysis of randomized, controlled trials of antibiotic treatment of AOM in children to determine whether outcomes were comparable in children treated with antibiotics for less than seven days or at least seven days or more.8 Current Contents and Science Citation Index searches were conducted to identify randomized controlled trials of the treatment of AOM in children with antibiotics of different durations. Studies were included if they met the following criteria: subjects were between the ages of 4 weeks and 18 years; they had a clinical diagnosis of AOM; there was no antimicrobial therapy at time of diagnosis; and patients were randomized to less than seven days of antibiotic treatment vs. seven days or more of antibiotic treatment.8
Trial methodological quality was assessed independently by seven reviewers; outcomes were extracted as the number of treatment failures, relapses, or reinfections. Trials evaluated in this meta-analysis were grouped by antibiotic used in the short course. There were: 1) 15 short-acting oral antibiotic trials (penicillin V potassium, amoxicillin, amoxicillin/clavulanate, cefaclor, cefixime, cefuroxime, cefpodoxime proxetil, and cefprozil); 2) four intramuscular ceftriaxone sodium trials; and 3) 11 oral azithromycin trials.
The summary odds ratio for treatment outcomes at 8-19 days in children treated with short-acting antibiotics for five days vs. 8-10 days was 1.52 (95% confidence interval [CI], 1.17-1.98), but by 20-30 days outcomes between treatment groups were comparable (odds ratio, 1.22; 95% CI, 0.98 to 1.54). The risk difference (2.3%; 95% CI, -0.2% to 4.9%) at 20-30 days suggests that 44 children would need to be treated with the long course of short-acting antibiotics to avoid one treatment failure. This similarity in later outcomes was observed for up to three months following therapy (odds ratio, 1.16; 95% CI, 0.90-1.50). Comparable outcomes were shown between treatment with ceftriaxone or azithromycin, and at least seven days of other antibiotics. The authors of this meta-analysis concluded that five days of short-acting antibiotic use is effective treatment for uncomplicated AOM in children.8
In a European trial, a comparison was made of the clinical effectiveness of azithromycin (once daily for 3 days at a dose of 10 mg/kg in children or 500 mg/d in adults) and amoxicillin/clavulanic acid and cefaclor (standard doses for 7-14 days) in acute ear, nose, and throat infections in an open, randomized study.9 The group with azithromycin included 37 patients with otitis media, 24 with pharyngotonsillitis, and six with maxillary sinusitis (n = 67). The amoxicillin/clavulanic acid group included 22 patients with otitis media, 19 with pharyngotonsillitis, and six with maxillary sinusitis (n = 47). The cefaclor group had 15 patients with otitis media, 12 with pharyngotonsillitis, and four with maxillary sinusitis (n = 31).9
Fifteen days after beginning treatment, 97% (65 of 67) of the patients who received azithromycin had improved or cured, compared with 85% (40 of 47) of those who received amoxicillin/clavulanic acid, and 84% (26 of 31) of those treated with cefaclor (P < 0.02).9 Pathogens were not eradicated in 3% (2 of 58) of the patients who received azithromycin, compared with 13% (4 of 28) who received amoxicillin/clavulanic acid and 15% (4 of 28) who received cefaclor.9
Patients with azithromycin showed an earlier clinical improvement and more rapid normalization of the leukocyte count, erythrocyte sedimentation rate (ESR), and acute phase proteins. No patient with azithromycin had adverse effects vs. 15% (7 of 47) of patients with amoxicillin/clavulanic acid and 16% (5 of 31) with cefaclor-treated patients. Treatment compliance was 100%, 83% (39 of 47) and 84% (26 of 31), respectively (P < 0.01).9 It should be pointed out that three-day courses of azithromycin for AOM are not currently approved in the United States, nor is azithromycin indicated for maxillary sinusitis.
Another open, randomized, multicenter study compared the clinical efficacy of a short 5-day course of cefuroxime axetil (CAE) suspension with that of amoxicillin/clavulanate (A/CA) suspension for 8 or 10 days.10 Children ages 6 to 36 months with AOM with effusion, diagnosed by tympanocentesis and microbiologic culture, were randomized to receive CAE (30 mg/kg/d in two divided doses for 5 days) or A/CA 40 mg/kg/d in three divided doses for 10 days (A/CA-10). In French centers, A/CA was given at 80 mg/kg/d in three divided doses for 8 days (A/CA-8). Patients were assessed 1-4 days after completing the course (post-treatment) and followed-up 21-28 days after completing the course.10
Of the 716 patients randomized, 252 were treated with CAE, 255 with A/CA-10, and 209 with A/CA-8. In the clinically evaluable population, the proportions of patients with clinical cure at post-treatment were 175 of 203 (86%), 181 of 205 (88%), and 145 of 164 (88%) in the CAE, A/CA-10, and A/CA-8 groups, respectively, demonstrating equivalence among the three treatments. For patients older than 18 months, clinical cures occurred in 111 of 134 (83%), 116 of 131 (89%), and 83 of 99 (84%) in the CAE, A/CA-10, and A/CA-8 groups, respectively; equivalence was also demonstrated. At follow-up, 130 of 175 (74%) CAE patients, 121 of 172 (70%) A/CA-10, and 112 of 142 (79%) A/CA-8 had maintained cure.
A total of 837 pretreatment pathogens were isolated from middle ear fluid in 73% (522 of 716) of patients, the majority of isolates were S. pneumoniae (30%) and H. influenzae (27%). The most common adverse events were gastrointestinal, the incidence of drug-related diarrhea being higher in the A/CA-10 group (18%) than in either the CAE or A/CA-8 groups (10%). The investigators concluded that a 5-day course of CAE, given twice daily, was shown to be equivalent to the two regimens of A/CA for treatment of AOM with effusion in children.10
Treatment Failures. The value of intramuscular ceftriaxone for use in those children who have failed initial oral therapy for AOM deserves careful consideration by pediatricians, emergency physicians, and pediatric emergency medicine specialists. The most compelling data, perhaps, has been generated by a multicenter, noncomparative, nonrandomized study evaluating the clinical efficacy and safety of ceftriaxone for treating AOM in children following clinical failure of oral antibiotic therapy. Middle-ear fluid samples were collected on day 0 and on day 3, 4, or 5 (day 3 to 5) and were used to test whether ceftriaxone therapy can eradicate Streptococcus pneumoniae isolates with increased resistance to penicillin (MIC ³ 1 mg/L). At the first visit, on day 0, middle-ear fluid was sampled for bacteriological testing by tympanocentesis or otorrhea pus suction.11
Patients were administered 50 mg of ceftriaxone/kg of body weight/day, injected intramuscularly once daily, for 3 days. A second sample was collected by tympanocentesis if a pneumococcus isolate for which the MIC of penicillin was 1 mg/L or greater was detected in the day-0 sample and if the middle-ear effusion persisted on days 3 to 5. This second sample was tested for bacterial eradication. One hundred eighty-six children ages 5 months to 5 years, 10 months, with AOM clinical failure were enrolled and treated in this trial. On day 10-12, 145 (83.8%) of the 173 patients evaluable for clinical efficacy were clinically cured. Of the 59 patients infected by pneumococci, 36 had isolates for which the MICs of penicillin were 1 mg/L or higher. Of those patients, on day 10-12, 32 (88.9%) were clinically cured.11
Middle-ear fluid samples collected by day 3-5 following the onset of treatment with ceftriaxone were sterile for 24 of the 27 (88.9%) patients who were infected as of day 0 by pneumococci for which the MICs of penicillin were 1 mg/L or higher and who were evaluable for bacteriological eradication. On day 10-12, 81.4% of S. pneumoniae-infected children and 87.5% of Haemophilus influenzae-infected children were clinically cured. No discontinuation of treatment due to adverse events, particularly due to local reactions at the injection site, were reported.11
Only 11 adverse events which had doubtful, probable, or possible links with the study treatment were recorded. Both the bacteriologically assessed eradication of pneumococci for which the MICs of penicillin were 1 mg/L or higher and the clinical cure rates demonstrate that ceftriaxone is of value in the management of AOM unresponsive to previous oral antibiotic therapy. The role of ceftriaxone as an initial agent for treatment of AOM is potentially compromised by the "semi-invasive" nature of an intramuscular injection, cost, parental and patient acceptance, necessity for a brief observation period, and necessity for three injections in the outpatient office setting.11
Centers for Disease Control and Prevention Guidelines: Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group
The concern about evolving resistance to S. pneumoniae prompted the CDC to convene experts in the management of otitis media to form the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group. The objective was to provide consensus recommendations for the management of AOM and strategies for surveillance of drug-resistant Streptococcus pneumoniae (DRSP).
The Group addressed five principal questions: 1) Can amoxicillin remain the best initial antimicrobial agent for treating AOM, especially in the current period of increasing prevalence of DRSP? 2) What are suitable alternative agents for use if amoxicillin fails? 3) Should empiric treatment of AOM vary by geographic region? 4) Where can clinicians learn about resistance patterns in their patient populations? And, 5) What modifications to laboratory surveillance would improve the utility of the information for clinicians treating AOM?
The recommendations were made on the basis of both published and unpublished data summarized from the scientific literature and experience from the experts present. After group presentations and review of background materials, subgroup chairs prepared draft responses to the five questions, discussed the responses as a group, and edited those responses.7
Although the precise universe of studies included or excluded and the process by which data were used for making specific antibiotic recommendations was not discussed in detail, the Group did issue recommendations. And even though the consensus group was limited to a relatively small number of experts, they issued rather rigid recommendations limited to four agents, among them, that oral amoxicillin should remain the first line antimicrobial agent for treating AOM. They proposed that in view of the increasing prevalence of DRSP, the safety of amoxicillin at higher than standard dosages, and evidence that higher dosages of amoxicillin can achieve effective middle ear fluid concentrations, an increase in the dosage used for empiric treatment from 40 to 45 mg/kg/d to 80 to 90 mg/kg/d was recommended.7
For patients with clinically defined treatment failure after three days of therapy, the group presented a limited number of useful alternative agents that included oral amoxicillin/clavulanate, cefuroxime axetil, and intramuscular ceftriaxone. They noted that many of the 13 other FDA-approved otitis media drugs lack good evidence for efficacy against DRSP, but did not specify which drugs did and which ones did not.
They also concluded that, currently, local surveillance data for pneumococcal resistance that are relevant for the clinical management of AOM are not available for most areas in the United States. Their recommendations to improve surveillance include establishing criteria for setting susceptibility breakpoints for clinically appropriate antimicrobials to ensure relevance for treating AOM, testing middle ear fluid or nasal swab isolates in addition to sterile site isolates, and the testing of drugs that are useful in treating AOM.
Challenging the Guidelines, Resistance Surveys, and Implications For Clinical Practice. For a number of reasons, the Working Group recommendations have fueled controversy and well-reasoned, evidence-based counter-responses from a number of experts and investigative groups. For example, one Cleveland Clinic group conducted an exhaustive study of the susceptibilities of Streptococcus pneumoniae (1476 strains) and untypeable Haemophilus influenzae (1676 strains) to various oral beta-lactam, macrolide-azalide, and fluoroquinolone antimicrobial agents. Resistance patterns were determined by broth microdilution. Organisms were isolated from specimens obtained from outpatients in six geographic regions of the United States. MIC data were interpreted according to pharmacodynamically derived breakpoints applicable to the oral agents tested.12
Overall, 94% of S. pneumoniae isolates were susceptible to amoxicillin and amoxicillin/clavulanate, 69% were susceptible to azithromycin and clarithromycin, 63% were susceptible to cefprozil and cefuroxime, 52% were susceptible to cefixime, 22% were susceptible to cefaclor, and 11% were susceptible to loracarbef. Based on these susceptibility data, it may be difficult to decipher why the CDC recommended cefuroxime as a second line alternative to amoxicillin but did not not include a short-course macrolide option such as azithromycin, even though in this surveillance study, as well as others cited below, it had marginally superior activity against S. pneumoniae as compared to the cephaloporin.12-15
In this regard, the activity of macrolides against S. pneumoniae and other etiologic agents has been confirmed in other surveillance data as well.13 For example, the susceptibility of Canadian isolates of three respiratory tract pathogens (Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae) to several antimicrobial agents were tested by two different methods. Beta-lactamase was produced by 68 of 211 (32.2%) H. influenzae isolates and 64 of 75 (85.3%) M. catarrhalis isolates. For S. pneumoniae, 19 of 156 (12.2%) isolates were resistant to penicillin (MIC ³ 0.12 mg/L) and two isolates had MICs of 1.5 mg/L. For some combinations of agents and organisms, different methods gave different values for the proportion of isolates susceptible.13
Regardless of methodology, for H. influenzae the most active antimicrobials based on proportion of strains susceptible were ciprofloxacin (100%) and cefpodoxime (98.5-100%). For M. catarrhalis, the most active agents were azithromycin, cefaclor, cefixime, cefpodoxime, cefuroxime, ciprofloxacin, clarithromycin, and loracarbef (100% each); the least active was ampicillin.
Against penicillin-sensitive and -resistant pneumococci, the activity was not significantly different for azithromycin and clarithromycin (93.4-100%) and ciprofloxacin (MIC90 2.0 and 1.5 mg/L, respectively), but was different for cefuroxime (99.3% and 31.6%, respectively), cefaclor (MIC90 0.75 and ³ 256 mg/L, respectively), cefpodoxime (MIC90 0.047 and 1.5 mg/L, respectively), and loracarbef (MIC90 0.75 and ³ 256 mg/L, respectively). This study indicates the increasing incidence, in Canada, of beta-lactamase resistance in H. influenzae and M. catarrhalis and penicillin resistance in S. pneumoniae. The authors concluded that macrolides provide excellent in vitro activity against the three most common bacterial offenders—H. influenzae, M. catarrhalis, and S. pneumoniae—encountered in AOM.13
As part of the ongoing multinational SENTRY antimicrobial resistance surveillance program, a total of 1047 respiratory tract isolates of Streptococcus pneumoniae, 845 from 27 United States medical centers and 202 from seven Canadian institutions, were collected between February and June 1997 and characterized in a central laboratory. In the United States, the overall percentages of penicillin-intermediate strains and strains with high-level resistance to penicillin were 27.8% and 16.0%, respectively. In Canada, these values were 21.8% and 8.4%, respectively. Among the 31 centers in the United States and Canada that contributed at least 19 isolates, the combined rate of intermediate plus resistant strains varied between 24.0% and 67.8%.14
The in vitro activity of 19 other antimicrobials was assessed against all study isolates. Overall rates of resistance among selected agents in the United States and Canada, respectively, were as follows: amoxicillin, 18.1% and 10.5%; cefaclor, 38.3% and 26.2%; cefuroxime, 19.5% and 12.9%; cefpodoxime, 18.6% and 11.4%; cefepime, 8.2% and 4.5%; cefotaxime, 4.0% and 3.0%; macrolides (i.e., erythromycin, azithromycin, and clarithromycin), 11.7-14.3% and 5.0-7.4%; clindamycin, 3.5% and 3.5%; chloramphenicol, 3.9% and 4.0%; tetracycline, 10.2% and 10.9%; and trimethoprim-sulfamethoxazole, 19.8% and 15.8%.14
Divergence in Expert Opinion. Because of the ample body of literature supporting macrolide activity against common etiologic agents in AOM, and the growing number of published studies demonstrating effectiveness of short-course therapy with azithromycin and some cephalosporins, pediatric, emergency medicine, and infectious disease experts have expressed well-reasoned reservations about strict adherence to a dogmatic, guidelines-directed treatment strategy in AOM.16
Some experts prefer to consider a more multi-factorial view of organisms implicated in AOM, middle ear drug levels, and the possible emergence of atypical organisms as causes of infection.17 The Kentucky Research Group notes that S. pneumoniae, H. influenzae, and M. catarrhalis are the most frequently isolated pathogens in patients with AOM. Other potential causative pathogens include Streptococcus pyogenes in older children and Chlamydia pneumoniae in younger children. The recent emergence of penicillin-resistant S. pneumoniae and the increasing frequency of beta-lactamase-producing strains of M. catarrhalis and H. influenzae are creating concerns regarding the use of amoxicillin as traditional first-line empiric therapy for AOM in younger children.17
The omission of specific antibiotics has elicited counterpoint positions by a significant number of pediatric experts, pharmacologists, and clinical scholars. Both the in vitro antibiotic activity against these more resistant causative pathogens and the antibiotic concentrations achieved in middle ear fluid must be considered when selecting antibiotics for treatment of refractory AOM. The newer macrolides, azithromycin and clarithromycin, provide reasonable in vitro coverage against penicillin-resistant S. pneumoniae and beta-lactamase-producing H. influenzae, although azithromycin is more active against the latter. Both drugs also achieve notably higher, sustained concentrations in middle ear fluid than do beta-lactam antibiotics. Thus, according to this evaluation based on in vitro data and epidemiological trends, the newer macrolides represent important new, rational alternatives for the management of AOM.17
In a roundtable session discussing the potential pitfalls in the CDC working group recommendations, several key points were emphasized.16 At least two members felt the guidelines were limiting. Dr. Jeffrey Blumer, Chief of Pediatric Pharmacology at the University Hospitals of Cleveland, suggested that the antibiotic choices in the published guidelines "are, in some ways, problematic." Specifically, he expresses concern that the guidelines may have "left out a number of useful agents that may perform as well as other agents," adding that he is not sure he is in "full concurrence [with the CDC guidelines]." Appropriately, Blumer emphasizes that there are about "17 agents [labeled by the FDA] for use in acute otitis media," and "none of them is labeled as second-line agents." He summarizes his position this way: " I think the consensus statement and guidelines fall short by not encompassing anything that really points out the similarities and differences [among available antibiotics]."16
The fact is, studies and surveillance data are inconsistent in identifying specific outcome data confirming the efficacy of one antibiotic vs. another in AOM.10,12-16,18 Although Dr. Scott F. Dowell, medical epidemiologist at the CDC, stressed that the working group recommendations focused specifically on antibiotic issues as they relate to S. pneumoniae resistance, other roundtable participants concurred with Dr. Blumer and emphasized the shortcomings of the published guidelines. Dr. Itzhak Brook, Professor of Pediatrics at Georgetown University, expressed concern "that the guidelines are limiting us to only three options, and each of the three options have their own problems." Potential limitations cited by the pediatrician included the diarrhea associated with amoxicillin/clavulanate, the poor taste toleration of cefuroxime in liquid form, and the potential discomfort of three intramuscular injections of ceftriaxone. Brook concluded with an opinion that clinicians "should also consider other agents that would be able to achieve similar goals," and then added that it might be difficult "following these less-than-practical guidelines, which will only result in frustration."
The PPPD Approach to Selecting Antimicrobial Suspensions in Children
Given the diversity of opinion, variability in study designs for AOM, and conflicting results of surveillance trials, as well as the continuing controversies surrounding antibiotic selection in AOM, another approach to antibiotic may be considered. Specifically, this framework for antibiotic selection attempts to account not only for S. pneumoniae resistance, but also such other factors as: pharmacokinetic parameters, beta-lactamase producing species of H. influenzae and M. catarrhalis, regional variations, and real world barriers (cost, compliance, patient toleration, taste, side effects, dosing schedules, convenience factors, etc.) that can affect the journey form prescription pad to clinical cure. It can be argued that this is a more comprehensive, outcomes-oriented approach—one that is also evidence-based—because it attempts to account for all potential barriers that may obstruct or compromise optimal clinical outcomes in the real world.1,4-6,10,15,17,19,30-33,35-37,51
PPPD Resistance Barriers for Oral Antibiotic Therapy. In the best and most cost-effective of all worlds, the antibiotic selection process for AOM would be based on an outcome-oriented assessment of the total cost of cure for this common, and sometimes recurrent and distressing, infection in the pediatric age group. (See Tables 1 and 2.) Close examination of Table 2 underscores the importance of identifying therapeutic agents that, because of favorable cost, compliance, and coverage features, are able to reduce barriers to achieving clinical cure.
| Table 1. Organisms Isolated by Tympanocentesis in Acute Otitis Media |
| Common |
| Streptococcus pneumoniae |
| Haemophilus influenzae |
| Moraxella catarrhalis |
| Less common |
| Streptococcus pyogenes |
| Staphylococcus aureus* |
| Gram-negative enteric bacteria* |
| Anaerobic bacteria |
| Viral pathogens: |
| • respiratory syncytial virus |
| • rhinovirus |
| • adenovirus |
| • influenza |
| • parainfluenza |
| * relatively common in neonates (< 1 month of age) |
| Table 2. Factors Considered in Determining Total Outcome Costs for Otitis Media in Children |
| • Cost of initial physician (or extended provider) visit |
| • Cost of the first antibiotic prescription |
| • Cost of subsequent human resource time (telephone consultations, re-evaluations, etc.) expended by nurses, physicians, and other providers to service queries about the drug, its side effects, dosing schedule, and other questions |
| • Cost of practitioner re-evaluation time to assess cause of treatment failures |
| • Cost of subsequent antibiotic prescriptions (i.e., additional courses of therapy) in response to treatment failures |
| • Economic opportunity costs sustained by parents or guardians because of time lost from work to care for child or in order to administer medication |
| • Cost of medications or other measures (diapers) to service gastrointestinal side effects (diarrhea) of antibiotics |
| • Cost of managing sequelae related to treatment failure: recurrent infections, tympanostomy, mastoiditis, hearing loss, learning disability, otitis media with effusion, etc. |
Antimicrobial agents that satisfy these criteria (acceptable spectrum of coverage, reasonable cost, excellent toleration, acceptable taste, and streamlined dosing schedule) will likely improve "first time around" cure rates and thereby reduce overall outcome costs. Among the factors that would be included in such an outcome analysis (i.e., the total costs associated with diagnosis, management, and cure of otitis media) are the following: cost of the medication used for the initial course of therapy, cost of the initial physician visit, human resource time (telephone time, revisits, etc.) required to service queries regarding the drug and/or its side effects, the cost of practitioner re-evaluations for treatment failures, the cost of additional courses of therapy for therapeutic failures, the economic opportunity cost sustained by parents because of time lost from work to care for their child, the cost of medications or other devices (diapers, etc.) to service the gastrointestinal side effects (diarrhea) of the medication, and the short- and long-term sequelae of treatment failure or repeated episodes of infection (hearing loss, linguistic difficulties, tympanostomy tubes, mastoiditis, otitis media with effusion, etc.).
Although comprehensive, outcome-directed studies addressing all of these variables for AOM are not currently available, other outcome-sensitive drug therapy assessment tools can be pressed into service for the purpose of drug selection. In this regard, the prescription, parent, patient, and drug resistance (PPPD) approach to drug selection permits pediatricians, family practitioners, and pediatric emergency physicians to evaluate and compare the clinical success profiles (CSPs) of one antibiotic vs. another. (See Table 3.) These comparisons are based on a synthetic approach constructed according to established specifications and parameters such as price, daily dosing frequency, duration of therapy, in vitro resistance data from numerous studies, palatability, side-effect profile, and spectrum of coverage.1,2,10,15,17,20,21,26-29,31-39,51
| Table 3. PPPD Factors Influencing Antibiotic Selection for Acute Otitis Media in Children |
| Prescription and Pharmacy Resistance Barriers |
| Cost of course of therapy |
| Prescription coverage by health plan |
| Formulary status/availability |
| Previous experience with medication |
| Physician and pharmacist-based patient education |
| Written instructions for parent/guardian regarding medication intake |
| Emphasizing importance of medication compliance |
| Parent Resistance Barriers |
| Number of days required to complete a course of therapy |
| Daily dose frequency of the medication (once-daily dosing is optimal) |
| Day care considerations: Can all doses of the antibiotic be given by the parent without reliance on day care personnel or other caretakers to ensure administration? |
| Can medication be taken with or without food, or are special timing considerations required? |
| Do side effects (diarrhea, GI discomfort, etc.) deter parents from completing a full course of therapy? |
| Does the drug require refrigeration? |
| Patient Resistance Barriers |
| Taste of medication: Does the suspension have a pleasant and appealing flavor, and a palatable consistency? |
| Or, is the taste excessively bitter and the consistency granular and unappealing for the child? |
| Gastrointestinal tolerance profile: GI distress? Diarrhea? Nausea? Rash? |
| Discontinuation rate of antibiotic |
| Does child feel "forced" to take antibiotic? |
| Drug Resistance Barriers |
| What are clinical cure rates in well-designed clinical trials? |
| Does antibiotic show increasing in vitro resistance to S. pneumoniae species? |
| Does antibiotic show increasing in vitro resistance to beta-lactamase-positive middle ear pathogens, H. influenzae, and M. catarrhalis? |
| What are the regional or local antibiotic resistance patterns? |
From the perspective of prescribing antibiotics in the outpatient setting, it must be emphasized that each of these four resistance barriers is important, and that if one or more of these barriers (cost, side-effect profile, lack of convenience, inadequate coverage) is of sufficient magnitude, it may influence the overall real-world cure rate.2,15,21,28
Optimal PPPD Profiles.6 Optimal PPPD profiles are characterized by antibiotics with low prescription, parent, patient, and drug resistance barriers. In this regard, the most desirable agent—in other words, the antibiotic producing the greatest likelihood of clinical success in the real-world patient encounter—will satisfy the following criteria: 1) It will be priced attractively enough to encourage prescription filling and/or its cost is sufficiently competitive to ensure formulary acceptance at cost-sensitive, managed care health plans and HMOs; 2) it is easy enough to store, prepare, and give to encourage parental administration; 3) it is sufficiently well-tolerated by the patient to promote ingestion of the drug without undue patient resistance; and 4) the agent demonstrates in vitro activity against all the anticipated bacterial pathogens in AOM (S. pneumoniae, H. influenzae [including beta-lactamase producing species], and M. catarrhalis) so that its empiric use will provide appropriate coverage with initial therapy, thereby reducing the necessity for pharmacologic reservicing due to treatment failures. A drug with an acceptable drug resistance profile will also have demonstrated in clinical studies that it is effective in treating AOM.
Based on the parameters outlined above, it is possible to categorize and compare antibiotic suspensions according to whether and how consistently they satisfy specific PPPD criteria. The antibiotic with the most favorable overall PPPD profiles is azithromycin, followed by amoxicillin/clavulanate and ceftriaxone. (See Table 4.)
| Table 4. PPPD Approach to Selection of Oral Antibiotic Suspensions for Treatment of Acute Otitis Media in Children4-6,10,19-25,31,32,34,50 | ||||
| Oral Antibiotic Suspension | Prescription Resistance | Parental Resistance | Patient Resistance | Drug Resistance |
| (Generic name) | (Cost for course of therapy < $40) | (Once-daily dosing) | (Palatability and GI effect profile considered extremely favorable) | (Less than 30% of S. pneumoniae isolates from middle ear show in vitro resistance and drug shows adequate coverage of beta-lactamase-producing H. influenzae and M. catarrhalis) |
| Amoxicillin | ++ ($7.49) | ± (BID) | + | - |
| Amoxicillin-clavulanate | + ($39.40) | ± (BID) | - (diarrhea) | + |
| Azithromycin | +($30.35) | +(QD) | + | + |
| Cefaclor | + ($39.40) | - (BID/TID) | + | ± |
| Cefixime | - ($47.20) | + (QD) | + | ± |
| Cefpodoxime | - ($56.00) | + (QD) | - (poor taste) | + |
| Cefprozil | - ($47.35) | ± (BID) | - (poor taste) | + |
| Cefuroxime | - ($64.84) | ± (BID) | + | + |
| Clarithromycin | - ($44.60) | ± (BID) | - (poor taste) | + |
| Erythromycin-sulfisoxazole | + ($23.60) | - (TID or QID) | - (poor taste, GI intolerance) | ± |
Antibiotics of Choice
The outcome-sensitive, cost-effective oriented criteria considered in the PPPD system can be used to guide initial selection of antibiotics for otitis media. (See Table 4.) Because price is an important issue, especially in managed care environments, Table 4 presents therapeutic recommendations that have been broken down according to price categories (i.e., suspensions costing < $40 for an entire course vs those costing > $40). As discussed, many authorities still consider amoxicillin to be the drug of first choice for AOM because of its efficacy, low cost, and tolerability.38 A more critical look at changing resistance patterns to PRSP species has induced the CDC group to recommend a dosing schedule of amoxicillin 80-90 mg/kg/d.
Introduction of new antimicrobial options with shorter courses and more convenient dosing schedules has forced a re-evaluation of this agent’s time-honored position among many pediatric and infectious disease experts.15-17,29,34-37,39 Nevertheless, because amoxicillin has been an "institution" in the therapeutic arsenal for otitis media, it justifies inclusion among first-line options costing less than $10 per course of therapy, albeit with some reservations. In this regard, amoxicillin may be a less-than-optimal initial agent in patient subgroups at higher risk for treatment failure due to poor medication compliance and in communities where a high percentage of penicillin-resistant S. pneumoniae isolates and beta-lactamase producing species have been documented.3,5,29,40
Among agents that cost more than $20 but less than $40, three agents with acceptable PPPD profiles merit inclusion in the first-tier group: azithromycin, amoxicillin/clavulanate, and ceftriaxone (when administered as a single dose). Based on azithromycin’s PPPD profile, which reflects a reasonable acquisition cost ($29.40-$31.60 per course of therapy), its once-daily, five-day therapeutic course, low discontinuation rate (< 1% due to side effects) efficacy studies confirming cure rates comparable to amoxicillin/clavulanate, and acceptable in vitro activity against implicated bacterial species, azithromycin justifiably can be positioned as a first-line-or alternate to amoxicillin-agent for AOM in children.19,41-45 Amoxicillin/clavulanate, which also merits inclusion in this "first-line" group, has the advantages of appropriate spectrum of coverage and evidence-based trial support for its efficacy. Ceftriaxone, another first-line PPPD recommendation, has the advantage of established efficacy in treatment failures, and an acceptable level of activity against the three most common organisms implicated in AOM, including PRSP species. It must be administered by the intramuscular route, and in one study three days of once-daily IM injections were required, which may adversely affect patient and parental acceptance. (See Table 5.)
| Table 5. Antibiotics of Choice for Pediatric Otitis Media4-6,10,19-25,31,32,34,50 | |||||
| First-Line Antibiotic Suspensions for Acute Otitis Media in Children (cost for course of therapy usually less than $10) | |||||
| Generic name | Trade Name | Dosage | Duration | Cost | Comments |
| Amoxicillin | Amoxil | 80-90 mg/kg/d in two or three divided doses | 10 days | $6.02-$8.13 | Significant resistance to beta-lactamase-producing H. influenzae and M. catarrhalis. Up to 25% of S. pneumoniae resistant at lower doses. Widely used as first-line agent. |
| Second-line Antibiotic Suspension for AOM (cost < $10) | |||||
| Generic name | Trade Name | Dosage | Duration | Cost | Comments |
| Trimethoprim-Sulfamethoxazole | Septra or Bactrim | 8/40 mg/kg/d | 10 days | $5.36-$7.70 | Increasing resistance (up to 30%) to S. pneumoniae species. Allergic reactions: Stevens-Johnson (rare) |
| First-Line Antibiotic Suspensions for Acute Otitis Media in Children (cost for course of therapy usually less than $45) | |||||
| Generic name | Trade Name | Dosage | Duration | Cost | Comments |
| Amoxicillin-clavulanate | Augmentin | 80/20 mg/kg/d | 10 days | $38.10-$44.30 | Diarrhea common (16% of patients) |
| Azithromycin | Zithromax | 10 mg/kg day 1, 5 mg/kg days 2-5 | 5 days | $28.40-$32.20 | Compliance-enhancing. Good in vitro coverage of beta-lactamase-producing H. influenzae and M. catarrhalis. Clinical cure rates in pediatric otitis media comparable to those seen with oxicillin/clavulanate. |
| First-Line Antibiotic Suspensions for Acute Otitis Media in Children (cost for course of therapy usually more than $40) | |||||
| Generic name | Trade Name | Dosage | Duration | Cost | Comments |
| Cefuroxime | Ceftin | 30 mg/kg/d | 10 days | $62.84 | |
| Ceftriaxone | Rocephin | 50 mg/kg/d IM | 1-3 days | $24-$72 | Intramuscular dosing may be inconvenient |
| Second-Line Antibiotic Suspensions for Acute Otitis Media in Children (cost for course of therapy usually more than $40) | |||||
| Generic name | Trade Name | Dosage | Duration | Cost | Comments |
| Clarithromycin | Biaxin | 15 mg/kg/d | 10 days | $42.40-$44.10 | Palatability may be a consideration |
| Cefpodoxime | Vantin | 10 mg/kg/d | 10 days | $54.00-$57.20 | Palatability may be a consideration |
Antibiotics such as trimethoprim-sulfamethoxazole can be very useful when cost issues predominate in drug selection and in patients with penicillin allergies.46 However, evolving S. pneumoniae resistance makes trimethoprim-sulfamethoxazole a less-than-ideal choice as compared to high dose amoxicillin (90 mg/kg), which also has cost advantages. Among medications usually costing in excess of $40 for a course of therapy, first-line agents would include cefuroxime, a CDC working group alternative to amoxicillin. Second-line agents in this category would include clarithromycin and cefpodoxime, both of which may pose palatability problems. Cefpodoxime has the advantage of once-daily dosing and a short course of therapy.
Disposition and Follow-up
The majority of children with AOM can be treated successfully as outpatients. Indications for hospitalization include toxic appearance, refractory vomiting, severe volume depletion, and intracranial or intratemporal extension, including acute mastoiditis and meningitis. Febrile neonates in the first month of life with otitis media should be managed as inpatients because of their relatively immunocompromised state and because of the risk of sepsis from gram-negative organisms and S. aureus.
Afebrile neonates younger than 1 month of age with otitis media can be treated as outpatients if they are well-appearing and have close follow-up.47 Selected febrile infants between 4 and 12 weeks of age can be treated for AOM as outpatients, provided they are non-toxic in appearance, have a white blood cell count of less than 15,000 cells/mm3, and have been carefully evaluated to exclude other sources of infection (including examination of cerebrospinal fluid, if indicated).48 It is imperative that discharged neonates have a reliable caretaker with a telephone and that prompt follow-up is assured.
Older infants and children with AOM who are well-appearing, have no underlying disease, and an otherwise normal examination do not require further laboratory evaluation in the ED. Well-appearing febrile children with otitis media have the same rate of occult bacteremia as well-appearing febrile children with no obvious source for their infection. Complete blood counts, which generally show a mild leukocytosis, and blood cultures are not routinely indicated, and results do not correlate with severity of illness or risk of complications.
Follow-Up. Upon discharge, parents and caretakers of children treated for AOM should receive careful discharge instructions highlighting potential problems related to treatment failure. In order to identify patients with infections refractory to initial antibiotic therapy, parents should be instructed to return for re-evaluation if fever, ear pain, or other signs and symptoms of acute infection are persisting 48 hours after initiation of antibiotic therapy.
Parents should also be instructed to return for re-evaluation immediately if the child exhibits evidence of worsening illness, including rising temperature, increasing irritability, anorexia, vomiting, or the development of lethargy. Signs and symptoms of infection will resolve within two days in most children treated for AOM. Assuming that the child recovers as expected, a follow-up examination in 2-3 weeks is generally recommended. The purpose of the re-evaluation is to document resolution of infection and to detect chronic effusion or other sequelae of AOM.
The necessity for routine follow-up in all cases of AOM has recently been questioned. In healthy children older than 15 months of age, parental impression of infection resolution and absence of symptoms appear to be accurate predictors of otitis resolution. Therefore, routine follow-up visits at 2-3 weeks may only be required of children 15 months of age or younger, those who have persistent symptoms of otitis media, or whose parents believe that the infection has not resolved.49 Children not meeting these high-risk criteria would still require follow-up at a later date to assess for persistent effusion, but this visit can be delayed for up to three months.
References
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8. Kozyrskyj AL, Hildes-Ripstein GE, Longstaffe SE, et al. Treatment of acute otitis media with a shortened course of antibiotics: A meta-analysis. JAMA 1998;279:1736-1742
9. Garcia Callejo FJ, Velert Vila MM, Orts Alborch MH, et al. Comparison of azithromycin, amoxicillin/clavulanic acid and cefaclor in the treatment of acute ENT infections. Acta Otorrinolaringol Esp 1998;49:306-312.
10. Pessey JJ, Gehanno P, Thoroddsen E, et al. Short course therapy with cefuroxime axetil for acute otitis media: Results of a randomized multicenter comparison with amoxicillin/clavulanate. Pediatr Infect Dis J 1999;18:854-859.
11. Gehanno P, Nguyen L, Barry B, et al. Eradication by ceftriaxone of Streptococcus pneumoniae isolates with increased resistance to penicillin in cases of acute otitis media. Antimicrob Agents Chemother 1999;43:1532.
12. Jacobs MR, Bajaksouzian S, Zilles A, et al. Susceptibilities of Streptococcus pneumoniae and Haemophilus influenzae to 10 oral antimicrobial agents based on pharmacodynamic parameters: 1997 U.S. Surveillance study. Antimicrob Agents Chemother 1999;43:1901-1908.
13. Blondeau JM, Suter M, Borsos SJ. Canadian Antimicrobial Study Group. Determination of the antimicrobial susceptibilities of Canadian isolates of Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis. Antimicrob Agents Chemother 1999;43(Suppl A):25-30.
14. Doern GV, Pfaller MA, Kugler K, et al. Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program. Clin Infect Dis 1998;27:764-770.
15. McLinn S, Williams D. Incidence of antibiotic-resistant Streptococcus pneumoniae and beta-lactamase-positive Haemophilus influenzae in clinical isolates from patients with otitis media. Pediatr Infect Dis J 1996;15(9 Suppl):S3-9.
16. Dowell SF, (Moderator) Blumer JL, Brook I, Culpepper L, et al. (Panel Members). Acute Otitis Media: Challenging the Guidelines and Course of Antibiotic Therapy. Medical Crossfire. 1999;1: June 15, 1999.
17. Block SL. Causative pathogens, antibiotic resistance and therapeutic considerations in acute otitis media. Pediatr Infect Dis J 1997;4:449-456.
18. Haddad J JR, Saiman L, Chin NX, et al. Penicillin-nonsusceptible pneumococcus in acute otitis media in New York City. Otolaryngol Clin North Am 1994;27:431-441.
19. McLinn S. Double blind and open label studies of azithromycin in the management of acute otitis media in children: A clinical review. Pediatr Infect Dis J 1995;14:S62-66.
20. Demers DM, Scotik Chan D, Bass JW. Antimicrobial drug suspensions: a blinded comparison of taste of twelve pediatric drugs including cefixime, cefpodoxime, cefprozil, and loracarbef. Pediatr Infect Dis J 1994:13:87-89.
21. Chinburapa V, Larson LN. The importance of side effects and outcomes in differentiating between prescription drug products. J Clin Pharm Ther 1992;17:333-342.
22. Beardon PH, McGilchrist MM, McKendrick AD, et al. Primary noncompliance with prescribed medications in primary care. BMJ 1993;307:846-848.
23. Berg JS, Dischler J, Wagner DJ, et al. Medication compliance: A healthcare problem. Ann Pharmacother 1993;27:S1-24.
24. Litchman HM. Medication noncompliance: A significant problem and possible strategies. R I Med 1993;76:608-610.
25. McNally DL, Wertheimer D. Strategies to reduce the high cost of patient noncompliance. Md Med J 1992; 41:223-225.
26. Anonymous. Writing prescription instructions. Can Med Assoc J 1991;44:647-648.
27. Coleman TJ. Non-redemption of prescriptions. BMJ 1994;308:135.
28. Roth HP, Caron HS. Accuracy of doctor’s estimates and patient’s statements on adherence to a drug regimen. Clin Pharm Ther 1978;23:361-370.
29. Eisen SA, Miller DK, Woodward RS, et al. The effect of prescribed daily dose frequency on patient medication compliance. Arch Intern Med 1990;150:1881-1884.
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44. Khurana C, McLinn S, Block S, et al. Trial of Azithromycin (AZ) vs Augmentin (AUG) for treatment of acute otitis media (AOM) [Abstract M61-64] Presented at the 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, Orlando, FL, Oct. 4-7, 1994.
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Physician CME Questions
Achieving middle ear culture-negativity in a patient with AOM is a predictor of clinical cure.
A. True
B. False
58. In one meta-analysis study comparing antibiotic courses with 7 days of therapy or longer to 5-day or shorter courses (including such drugs as azithromycin, ceftriaxone, and others), it was found that:
A. 10-day courses were optimal.
B. 7-day courses were optimal.
C. 5 days of short-acting antibiotic use is effective treatment for uncomplicated AOM in children.
D. 1-day therapy is optimal.
59. The CDC working group on AOM recommended which of the following?
A. An increase in the dosage of amoxicillin used for empiric treatment from 40-45 mg/kg/d to 80-90 mg/kg/d.
B. An increase in the dosage of amoxicillin used for empiric treatment from 40-45 mg/kg/d to 55-60 mg/kg/d.
C. An increase in the dosage of amoxicillin used for empiric treatment from 40-45 mg/kg/d to 70-80 mg/kg/d.
D. None of the above.
60. Some experts feel that the CDC Guidelines for AOM have "left out a number of useful agents that may perform as well as other agents."
A. True
B. False
61. Among agents that cost more than $20 but less than $40, three agents with acceptable PPPD profiles for AOM include:
A. azithromycin, cefaclor, and cefprozil.
B. clarithromycin, cefaclor, and amoxicillin.
C. azithromycin, ceftriaxone (one dose), and amoxicillin-clavulanate.
D. none of the above.
62. Older infants and children with AOM who are well-appearing, have no underlying disease, and an otherwise normal examination do not require further laboratory evaluation in the ED.
A. True
B. False
63. Which of the following antibiotics is approved for a five-day course of therapy for AOM?
A. Amoxicillin
B. Trimethoprim-sulfamethoxazole
C. Azithromycin
D. Ceftriaxone
64. Optimal PPPD profiles are characterized by antibiotics with low prescription, parent, patient, and drug-resistance barriers.
A. True
B. False
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