Abstract
Empiric antibiotic treatment of acute otitis media (AOM) must take into account risk factors for infection due to the rapidly rising number of resistant pathogens such as penicillin resistant S. pneumoniae and beta lactamase producing Haemophilus influenzae. Recommendations have been offered by the Centers for Disease Control for management of antibiotic resistant Streptococcus pneumoniae AOM episodes. Amoxicillin remains the antibiotic treatment of first choice, although a double dose (80-100 mg/kg//day to a maximum of 3 grams/day) may improve the likelihood of eradication of resistant S. pneumoniae. Cefuroxime axetil, Amoxicillin-clavulanate combined with amoxicillin and injections of Ceftriaxone are suggested second line choices. These recommendations should be considered in the context of varying anticipated efficacy, safety, and compliance potential among these and other drugs approved for use in AOM. Withholding antibiotics as treatment for AOM has been proposed as an option, particularly in children beyond 3 years of age. Shortening the standard duration of antibiotics to 5 days results in similar outcomes as 10 days therapy, in most patients, with less side effects and cost. Selective use of tympanocentesis is now being advocated to allow pathogen-specific antibiotic selection after treatment failures.

Physicians often feel overwhelmed when it comes to understanding the variable spectrum of activity of the many antibiotics with an AOM indication (Table 1). The situation is getting more complex due to changing and escalating resistance patterns among the AOM pathogens (1-5). An evaluation of reported pathogens and rates of resistance in AOM based on data obtained prior to 1993 (6) almost certainly would not be reflective of the current situation. Resistance rates vary geographically and among patient groups. The primary explanation for the increasing rates of antibiotic resistance is antibiotic selective pressure followed by geographic migration of strains (7).

Reduced penicillin (and amoxicillin) susceptibility among strains of S. pneumoniae now ranges between 30% and 60% in the United States (2, 4, 5); trimethoprim-sulfamethoxazole resistance generally exceeds 50% (5). Quinolone resistance among S. pneumoniae strains is rising (8).
The proportion of beta lactamase-producing H. influenzae and M. catarrhalis strains has nearly tripled from rates of 15-20% in the 1980s to currently reported rates of up to 55% for H. influenzae (1-3, 9); virtually 100% of M. catarrhalis strains from AOM infected patients in the US produce beta lactamase (1-3, 9). Resistance of H. influenzae to trimethoprim-sulfamethoxazole is increasing (10, 11).

Antibiotic resistance occurs most frequently in a recently treated AOM patient. Our group reported a 46% rate of penicillin-resistant S. pneumoniae from patients recently treated (9); 33% of 93 S. pneumoniae strains were highly penicillin-resistant (9). The incidence of resistant pathogens is higher in children in day care, especially the winter time (12) and in children below 4 years of age (13) (Table 2).
Much mis-information has been generated regarding the role of Mycoplasma pneumoniae and Chlamydia pneumoniae in AOM. Klein et al (14) noted in the 1970s that M. pneumoniae was recovered from only one of 771 tympanocentesis samples. Block et al (15) isolated
C. pneumoniae from 8 of 101 children with AOM; however it was the sole microbe isolated in only two children. Viruses cause AOM as the sole pathogen in < 10% of cases; viral upper respiratory infections frequently precede AOM and viruses are not uncommonly isolated along with the typical AOM bacterial pathogens from middle ear effusions (16). Anaerobes may play a role in chronic otitis media but not AOM.

Antibiotic Impact on Outcomes from AOM
In the past, physicians have been accustomed to optimistic reports of high cure rates for most antibiotics used to treat AOM. Then again, ten years ago, S. pneumoniae were almost universally susceptible to amoxicillin and 20 years ago, H. influenzae infrequently produced the beta lactamase enzyme and M. catarrhalis was not pathogenic. Particularly, non-tympanocentesis clinical trials almost always revealed successful clinical outcomes. Explanations for such positive results included: 1) over-diagnosis at study entry (patient never had AOM in the first place), 2) the lack of validated otoscopists as investigators conducting the evaluations, 3) inclusion of only mild to moderate AOM cases, 4) exclusion of difficult to treat patients, and 5) use of overly broad criteria for satisfactory outcome assessments (symptom resolution only).

Also, AOM has a favorable natural history. By the fifth day after symptom onset, about 89% of M. catarrhalis infections, 50% of H. influenzae infections and 20% S. pneumoniae infections have been eradicated by the body's natural host defenses (17). A meta-analysis of studies conducted from 1966 to 1992 (18) concluded that the overall spontaneous resolution rate of AOM was 81% (95% confidence interval 69% to 94%). The benefit of antibiotics on AOM was 13.7% (95% confidence interval, 8.2% to 19.2%) over placebo. Examined another way, antibiotics were assessed to offer approximately 2 days of faster resolution of pain compared to non-treatment or treatment with analgesics (19). These "marginal" benefits has led to a proposed non-treatment paradigm (20) or a delay in treatment of about 2 days to see if symptoms resolve on their own. In my view, these recommendations are flawed because the data upon which they are based come from a different era of bacterial resistance.

Bacterial Resistance After Antibiotic Therapy Failures
During the 1980s, H. influenzae accounted for the majority (46%-62%) of pathogens recovered from bacteriologic failures in AOM (21). Currently, it appears that S. pneumoniae, and in particular resistant strains, may account for the majority of pathogens recovered from antibiotic
failures (9, 22, 23). The highest risk for penicillin-resistant S. pneumoniae occurs in those who have been recently treated (particularly within the preceding month) or are failing antibiotics (9, 22 23).

When treating persistent and recurrent AOM, practitioners should expect success rates in the range of 60%-70% even when the most efficacious broad spectrum oral antibiotics are chosen (1, 22). Currently, minimal data are available regarding the treatment of AOM caused by fully penicillin-resistant S. pneumoniae. Thus far only five antibiotics (amoxicillin, amoxicillin-clavulanate, cefuroxime, cefprozil, ceftriaxone) have demonstrated (9, 23-25). Studies with other broad spectrum agents are currently underway.

CDC Recommendations for AOM Management
The CDC report from the drug-resistant S. pneumoniae therapeutic working group, which included representatives of the American Academy of Family Physicians, gave specific recommendations for treatment of AOM (Table 3) (26). The CDC working group distinguished initial treatment options based on recent antibiotic exposure because recent exposure clearly increases the risk of resistant pathogens, as previously discussed. A switch in empiric therapy was recommended on day 3 of therapy and/or 10-28 days after initial diagnosis in cases of clinically defined treatment failure. Agents selected for alternative therapy met two criteria according to the report. The antibiotics were effective against (1) S. pneumoniae, including most drug-resistant strains, and (2) H. influenzae and M. catarrhalis, including beta lactamase resistant strains. For empiric therapy after amoxicillin treatment failure three agents were selected: high dose amoxicillin-clavulanate (AMX-CLV), cefuoxime axetil and intramuscular ceftriaxone. With currently available U.S. formulations, the AMX-CLV regimen would require two prescriptions: amoxicillin (dosed at 40 mg/kg/day) and for AMX-CLV (also dosed at 40 mg/kg/day of amoxicillin). Different from the approved use of ceftriaxone in uncomplicated AOM where a single injection is acceptable, treatment with ceftriaxone when resistant bacteria are suspected was said to require three injections over three days. Two other antibiotics were strongly considered as empiric candidates-cefprozil and cefpodoxime-but were not included among the preferred choices because more data were needed. Cefdinir, the newest approved antibiotic for AOM was not licensed at the time of the CDC review. Tympanocentesis was recommended as an option at both time points of clinically defined treatment failure (day three on treatment and day 10-28 after completion of treatment). Tympanocentesis was viewed as "particularly important if a child has recently received several courses of antimicrobial therapy and if therefore more likely to harbor a multiply resistant strain" (26). In this context, the working group stated, "In an era of increasing antimicrobial resistance, clinicians treating children with AOM should consider developing the capacity to perform tympanocentesis themselves or establish ready referral mechanisms to a clinician with this capacity" (26). If tympanocentesis is performed and S. pneumoniae are isolated then clindamycin becomes a treatment option (Table 3).

Interpreting Empiric Antibiotic Selection Recommendations
of the CDC Working Group
Higher doses of amoxicillin were recommended by the CDC as one strategy to address the issue of penicillin resistant pneumococci (26). By increasing the dose, higher levels of antibiotic have been demonstrated in middle ear fluid (27). Beta lactam antibiotics follow first order kinetics. Thus, the strategy favored by the CDC to achieve a longer time above the MIC was to give a higher dose; the decline in drug concentration according to half-life should result in a longer time above the MIC. Regardless of the dose, amoxicillin will not eradicate beta lactamase producing H. influenzae or M. catarrhalis. For this reason, alternatives to amoxicillin should have stability against beta lactamases.

The pharmacodynamics model (28, 29)-whereby achievable antibiotic levels at the site of infection and the MIC of pathogens for particular drugs are used as predictors of successful bacteriologic killing-heavily influenced the CDC recommendations. It seems reasonable to presume that an effective antibiotic must have in vitro killing activity against a specific pathogen in order to offer benefit to the patient. In turn, the minimum concentration of antibiotic to kill the bacteria must be achievable in vivo (in the patient) at the specific site of infection (middle ear mucosa and effusion space). Nevertheless, this model has shortcomings: 1) Bacteriologic eradication is correlated with a successful clinical outcome in > 90% of cases. However, even when bacteriologic eradication is not achieved, clinical success occurs in > 90% of patients. Much of this depends on the endpoint one considers most important. Eventually almost everyone gets better. Is the endpoint faster resolution of pain and fever, or prevention of suppurative extension of infection, e.g., mastoiditis, or faster resolution of middle ear effusion, as a cause of temporary hearing loss or prevention of permanent deafness? 2) Validation of the pharmacodynamic model relies on double tap studies (wherein tympanocentesis cultures allow identification of the causative bacteria and then a second ear tap is done about 5 days later to determine if the antibiotic given has killed the bacteria) and measurements of antibiotic levels in the middle ear fluid (from acute and chronically infected AOM patients). Some antibiotics such as azithromycin and clarithromycin concentrate intracellularly and/or are bacteriostatic for some AOM pathogens. The model may not accurately assess the likelihood of bacteriologic or clinical success for these agents 3) The MIC breakpoints used by the CDC were based on NCCLS standards and these changed six months after the CDC publication.

The CDC recommendations put a strong emphasis on tympanocentesis. Yet very few family physicians have ever performed the procedure or they performed it several decades ago. Otolaryngologists infrequently are available to accommodate a same day referral for the procedure and fewer still have done it without the benefit of general anesthesia. Until 1999, only about 100 pediatricians had performed an office-based tympanocentesis and fewer than 30 did so regularly. While family physicians and pediatricians are now receiving CME-accredited training (Outcomes Management Educational Workshops: 1-877-EAR-OMEW or www.omew.com) it will take years before this skill becomes generally acquired. Thus, while it appears that an ear tap will increasingly come back into the purview of the family physician (as bacterial resistance rises), for now it is somewhat impractical in most cases.

Empiric Antibiotic Selection Without Tympanocentesis
In the absence of bacteriologic data provided by tympanocentesis, empiric selection of antibiotics is guided by each drug's spectrum of activity (1, 17, 23, 26). The major considerations in empiric antibiotic selection for AOM include comparative drug efficacy, safety, compliance potential and cost (1, 17). Sources of antibiotic information are often confusing and conflicting. Pharmaceutical representatives produce brochures touting their drug as effective, at least as good in clinical outcome as their main competitor and perhaps better in some other way (diarrhea rate, taste, dosing frequency, need for refrigeration of suspension, or a few dollars lower in cost that day at the local pharmacy). In my opinion, comparative efficacy assessments must take into account the intrinsic antibacterial activity of the antibiotic (in vitro susceptibility), clinical outcomes from patient trials, the resistance patterns of bacterial pathogens present in a particular community, and the pharmacologic properties of drugs under consideration.

There is very little to distinguish one antibiotic from another in terms of safety profiles. All of the antibiotics used for AOM generally are quite safe. Compliance, duration of therapy and cost are important issues. The main determinants of compliance appear to be frequency of dosing, palatability of the agent, and duration of therapy. In this regard, less frequent dosing is desirable (once or twice a day) as opposed to more frequent dosing which interferes with daily routines. In many instances, palatability ultimately determines compliance in the pediatric patient because if a parent must struggle with a child to force oral ingestion then the child may prevail in the struggle and no antibiotic will be consumed. Patients prefer a shorter course of therapy (5 days or less) in contrast with traditional 10-14 day treatment courses employed in the United States. Besides, many patients and parents only continue antibiotic therapy until they become asymptomatic and then perhaps for one or two additional days (30). The remainder of the prescription is usually saved for future use when similar symptoms arise (30). Antibiotic cost is an interesting component in the treatment paradigm. Three office visits and three injections of intramuscular ceftrixone will escalate the cost of treating AOM. Most patients and health insurers look at the acquisition cost of antibiotics rather than the total direct costs of care. Failed therapies which result in loss of parent work or child attendance at school/day care and second visits for more effective therapy should also be considered important factors when a comprehensive assessment of antibiotic cost is made.

Pathogen-Directed Antibiotic Selection
The microbiologic cause of AOM can be documented on the basis of results of appropriate cultures of middle ear effusions that have been obtained by tympanocentesis. A bacterial pathogen is generally isolated from middle ear fluid of approximately two-thirds of children with acute AOM (17) and 50% of children with persistent and recurrent AOM following antibiotic treatment (22). Even though the otoscopic examination demonstrates evidence of middle ear inflammation, the AOM episode may be sterile by the time the patient seeks care. The immune response and/or prior antibiotic therapy may have eradicated the bacteria or the pathogen was a virus for which antibiotics would be of no value. Patients with no bacteria isolated require no antibiotic treatment. If a tympanocentesis is performed, management options include: (1) waiting for culture results before selecting an antibiotic, or (2) providing the patient with 2 days of samples while waiting for cultures and changing the prescription if needed or discontinuing treatment if cultures are negative.

With tympanocentesis, the physician can identify the patients for whom the infection is more likely to self-resolve by a gram stain ($3-5) and possibly culture ($15-38) of middle ear fluid. Withholding antibiotics from a child with M. catarrhalis would make more sense than a child with S. pneumoniae. S. pneumoniae isolates can be subjected to susceptibility testing (by E test or broth dilution ($ 42-60), to determine whether the strains are penicillin-susceptible, relatively or fully resistant. With that specific information in hand, one can assess the various antibiotics available with a more compelling mandate for specific selections (Figure 1) (2, 4, 5, 23, 28, 31). Gram negative organisms (H. influenzae and M. catarrhalis) can be tested to identify whether the specific strain is beta lactamase producing. For beta lactamase producing strains, the stability and corresponding activity against these gram negative bacteria differs substantially among the various agents available (Figure 2) (2, 31).

Concluding Remarks
Many children with AOM do not benefit from antimicrobial agents because the etiology is non-bacterial or the bacterial otitis media resolves without use of a drug. At present, however, we do not have clinical criteria by which to distinguish the two groups of children. We need to implement education programs for patients as well as physicians to discourage inappropriate antibiotic use and to shift the emphasis from empiric to pathogen-directed antibiotic therapy. Even with our best effort, antimicrobial resistance of AOM pathogens is likely to continue to escalate and therefore the development of effective new antibiotics will be needed. Clinical trials are now ongoing with new families of drugs for AOM to include new oral quinolones, oxazolidinones, streptogramins, and ketolides. Also, conjugate pneumococcal vaccines are in clinical trials which we hope will prove efficacious in prevention of about half the cases of AOM caused by S. pneumoniae.

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