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 I: General Principles, the Antibiotic Armamentarium, and Special Therapeutic Considerations
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.
Outcome-effective management of patients with acute otitis media (AOM) remains one of the most debated, investigated, and controversial areas in outpatient medicine. A number of factors account for the wide spectrum of recommendations and approaches used in this patient population. Among the most important issues is the emergence of resistant organisms causing AOM, a trend that has complicated its treatment, and more specifically, identification of first-line antimicrobials for initial management of children with AOM.
The clinical burden of AOM in pediatric and emergency practice has been well-documented. It is estimated that the number of physician visits for AOM has increased from 9 million in 1975 to more than 25 million by the 1990s.1 In one large study, investigators identified and retrospectively followed 22,000 children younger than 10 years of age who had one or more episodes of AOM.2 Study subjects averaged 2.9 physician office visits for management of otitis media; among children younger than 2 years of age, one-fourth had six or more such visits. Amoxicillin was prescribed as initial therapy in more than one-half (56.6%) of all episodes of acute otitis media, followed by cephalosporins (18.3%), trimethoprim-sulfamethoxazole (12.3%), macrolides (6.4%), and amoxicillin-clavulanate (6.0%). Over multiple episodes, however, use of amoxicillin declined by about 50%.2
Organisms commonly responsible for causing AOM include Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. The evolution of pneumococcal resistance to penicillins, trimethoprim-sulfamethoxazole, and oral cephalosporins may require use of other agents as initial therapy. Moreover, beta-lactamase-producing H. influenzae and M. catarrhalis are becoming increasingly resistant to penicillins, trimethoprim-sulfamethoxazole, oral cephalosporins, and erythromycin.
Mechanisms of resistance include changes in penicillin-binding proteins, production of beta-lactamase, alterations in target enzymes, and inhibition of drug access to the site of action. Regional variations also are present. One study reported that the prevalence of penicillin-nonsusceptible (intermediate and resistant) pneumococci was highest in the South Atlantic (44%) and East South Central (43%) regions and lowest in the Mid-Atlantic (28%) and New England (28%) regions.3 Because of changing resistance patterns and the increasingly limited spectra of activity of many currently available antimicrobials, new agents have been developed in the hope of improving therapeutic outcomes.
Selecting an antibiotic for initial treatment of AOM—as well as for treatment failures—has become the subject of intensive analysis by pediatricians, emergency physicians, and infectious disease specialists. While amoxicillin and trimethoprim-sulfamethoxazole are still considered appropriate first-line agents by some experts and panels, children at risk for resistant infections—as well as those risk-stratified into a more serious subgroup—may be treated initially with cefuroxime axetil, azithromycin, or amoxicillin-clavulanate.
Additional debate has focused on the necessity—or lack thereof—of treating mild or initial cases of AOM. Although some experts point out antibiotics may not be routinely indicated in all cases—especially mild or first episodes—of AOM, it remains the position of the CDC and most U.S. experts that antibiotics should be used to treat documented cases of AOM. Certainly, this is the accepted standard for children with risk factors for poor outcome. Finally, there has been substantial investigation into the value, effectiveness, and potential compliance-enhancement associated with short-course (5 days or less) therapy for AOM.
With these issues in clear focus, the purpose of this review is to present a rational and evidence-based approach to and analysis of current treatment strategies, published recommendations, and clinical support tools designed to maximize clinical outcomes in children with AOM.
— The Editor
Etiology
The primary reason for colonization of the middle ear with pathogenic bacteria is eustachian tube dysfunction. It occurs in infants and children mainly because of the abnormal tubal compliance, leading to collapse of the eustachian tube and delayed innervation of the tensor veli palatini muscle, which serves to open the tube. The three most common bacteria involved in AOM are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Anaerobic organisms, as well as viruses, can also contribute to the infection. One study recently determined the prevalence of various respiratory viruses in the middle ear fluid of children (age 2 months to 7 years) with AOM.4 In 168 of 456 children, the etiology for their respiratory tract infection was viral. Respiratory syncitial virus was the most common virus found in middle ear fluid during AOM, followed by parainfluenza virus, influenza A or B virus, enteroviruses, and adenoviruses. The risk factors that lead to AOM are shown in Table 1.5 The factors that most increase the occurrence of AOM are child care outside the home and parental smoking.6
| Table 1. Risk Factors for Otitis Media |
| • Day care attendance |
| • Siblings at home |
| • Second-hand cigarette smoke |
| • Lack of exclusive breast feeding for the first four months |
| • Male sex |
| • White race |
| • Native American race |
| • Craniofacial abnormalities, including cleft palate |
| • Family history of otitis media |
| • Family history of atopy |
| • History of otitis media |
Clinical Features
Most commonly, a viral upper respiratory infection precedes AOM. Sudden development of ear pain and fever in one-third to one-half of patients can signal the onset of AOM. In infants, the symptoms can be less localized and can include irritability, vomiting, diarrhea, and fever.
Middle ear effusion (MEE) is the hallmark of otitis media. If MEE is associated with symptoms such as pain or fever, the condition is called AOM. When MEE is asymptomatic, the condition is called otitis media with effusion (OME). Erythema of the tympanic membrane without associated MEE is myringitis or tympanitis.7
Examination of the tympanic membrane is best accomplished with pneumatic otoscopy to determine movement. A normal tympanic membrane is flaccid, and lack of motion when the ear is insufflated implies middle ear fluid. Tympanometry can also be used to assess MEE. Table 2 lists the signs and symptoms seen most commonly when there is inflammation and fluid in the middle ear.5
| Table 2. Common Signs and Symptoms of Inflammation and Fluid in the Middle Ear5 |
| • Otalgia |
| • Ear pulling |
| • Diminished hearing |
| • Fever |
| • Loss of appetite |
| • Irritability |
| • Vomiting |
| • Vertigo |
| • Tinnitus |
| • Otorrhea |
Differential Diagnosis
Although otalgia is the number one symptom of patients presenting with AOM, a substantial number of patients presenting with this symptom will have normal-appearing ear canals and tympanic membranes.8 When the ear appears normal, the physician must consider the possibility of referred pain to the ear.
The sensory innervation is supplied through a combination of cranial nerves five, seven, nine, 10, and a number of cervical nerves. The convergence of these cranial and upper cervical somatic afferents into a common synaptic region can explain the occurrence of referred pain in the head and neck region. Common sources of referred otalgia include abscessed teeth, malocclusion, temporomandibular joint disorders, myofascial pain syndromes (especially in the masseter muscles), nasopharyngeal carcinoma, infections in the paranasal sinuses, pharynx and salivary glands, carotodynia, temporal arteritis, cervical arteritis, and neuralgias.9 The age of the patient can allow exclusion of many of the above possible causes.
In most developed countries (except the Netherlands), the standard treatment for AOM is antibiotic therapy. However, in 1992, the U.S. Institute of Medicine warned of the growing threat posed by resistant bacteria, and in 1996, the Centers for Disease Control and Prevention convened the Drug-resistant Streptococcus Pneumoniae Therapeutic Working Group made up of pediatricians, family physicians, internists, and public health practitioners to determine how best to use antimicrobial resistance data to make informed decisions for treatment of AOM.10 Penicillin resistance has been found everywhere that surveillance data are available. The proportion of invasive disease caused by penicillin nonsusceptible S. pneumoniae (minimum inhibitory concentration [MIC] 0.1 mcg/mL) ranges from 8% to 34%, with the higher rates in children rather than adults, especially if the children are in day care or have received antibiotic therapy within the preceding three months.11 One study found the rate of ampicillin resistance of bacteria in effusions to be three times higher during recurrent AOM as compared to an initial untreated episode of AOM.12
General Principles, Issues, and Controversies
From a practical, clinical perspective, it is well accepted that antibiotic prescribing for AOM is almost always empiric in nature and rarely benefits from microbiological identification or susceptibility results. Some clinicians note that mild cases—especially those with low-grade fever and no risk factors for poor outcomes—may either have viral etiologies and/or not benefit greatly from antibiotic therapy. However, experts point out that distinguishing among patients who, on the basis of clinical grounds alone, do and do not require antimicrobial intervention can be a formidable challenge for the front-line practitioner.
In addition, there are other "real world" issues that enter the equation, even after antibiotic therapy is chosen. Even if an antibiotic with an appropriate spectrum of coverage is identified, there is always the "give" and "take" issue associated with antibiotic administration (i.e., parents have to "give" the antibiotic, and in turn, children must be willing to "take" the drug). This give-and-take interaction is fundamental to maximizing cure rates in the real-world environment.
Making matters worse is the difficulty of identifying an appropriate, cost-effective antibiotic that is "smart" enough to provide coverage against the most likely offending organisms in any individual patient. For example, in children with otitis media, a so-called "high-performing" or "correct spectrum" antibiotic must have a sufficiently targeted spectrum to cover appropriate—and increasingly, penicillin-resistant—species of Streptococcus pneumoniae (PRSP), Haemophilus influenzae, and Moraxella catarrhalis.
Moreover, because time-honored agents such as amoxicillin, especially at previously recommended, so-called low doses of 40 mg/kg/d, have demonstrated inconsistent in vitro activity against beta-lactamase-producing bacterial isolates as well as against PRSP species, many experts have recommended alternative agents or new dosing protocols for established agents, among them, ceftriaxone, cefuroxime, amoxicillin-clavulanate, advanced macrolides (azithromycin) and amoxicillin (80-90 mg/kg).2,13-20
Finally, the road from the prescription pad to clinical cure depends on many factors beyond spectrum of coverage, including prescription, parent, patient, and drug resistance (PPPD factors). The PPPD approach to antimicrobial selection in otitis media attempts to account for all the factors and potential "barriers" that go into the equation for clinical cure, such as cost of the medication, compliance profile, palatability issues, duration of therapy, gastrointestinal side-effect profile, convenience of dosing, spectrum of coverage, resistance patterns, and day care administration concerns. Overcoming all these barriers to clinical cure is essential for enhancing clinical outcomes and reducing the costs of therapy and complications of the disease.
Antibiotic Selection in Acute Otitis Media: The Case for and Against Routine Antibiotic Therapy
Who should be treated? When are antibiotics indicated, and when is watchful waiting with close follow-up the most appropriate course? The majority of pediatricians, family practitioners, and emergency physicians—and, in fact, many parents of children with otitis media—are aware that the necessity to routinely treat otitis media with antibiotics has been the subject of heated debate over the past decade.
In this regard, a number of factors are widely cited as evidence that current indications for antibiotic treatment should be re-evaluated. Four placebo-controlled trials examining the effect of withholding antibiotic therapy in acute otitis media found that 76% of untreated children demonstrated "spontaneous cure" or significant improvement without treatment.21 A recent meta-analysis of 30 studies evaluating 5400 cases of acute otitis media found an 81% rate of spontaneous symptom resolution and improvement in the appearance of the tympanic membrane.22 While some of these spontaneously resolving cases may represent patients with ear infections of viral etiology, the high percentage of recovery without treatment suggests that a significant percentage of bacterial infections will also clear without antibiotic therapy.
These data have led some practitioners to view AOM as a self-limited disease that does not generally require medical (i.e., antimicrobial) intervention. In Europe, particularly in Scandinavia and the Netherlands, watchful waiting is an accepted standard of care for AOM. Most physicians in these countries will initiate antibiotic therapy only when fever and symptoms persist for more than 24-72 hours or when complications develop.22-24 By withholding antibiotics for the majority of patients, it has been argued, unnecessary antibiotic treatment with its attendant costs and side effects is minimized, and the rise of multidrug-resistant bacterial organisms may be curtailed.
These studies, however, should be interpreted with great caution, since the majority of the trials included in the meta-analysis did not follow children over the long term and, therefore, could not evaluate the risk of recurrent infections, hearing loss, development of otitis media with effusion, and other complications. Moreover, the rate of spontaneous recovery appears to be bacterial species-specific, with some organisms associated with better non-treatment recovery rates than others. In this regard, one study reported that in about 50% of patients with H. influenzae, 80% of those with M. catarrhalis, and in only 20% of those with S. pneumoniae, was there a spontaneous recovery.25 Unfortunately, because confirmation of a specific etiologic diagnosis is the exception rather than the rule in AOM, it is almost impossible to predict which patients will and will not benefit from antibiotic therapy. Accordingly, most experts in the United States do not favor withholding antibiotic therapy in AOM.
Moreover, European studies, it has been noted, do not have sufficient power to detect low complication rates and represent only children not prone to recurrent infections.21,26 It is argued that complications such as intratemporal or intracranial infections, which are now rare, occurred in up to 20% of patients with AOM in the pre-antibiotic era.21 In particular, antimicrobial therapy was largely responsible for reducing the incidence of mastoiditis as a sequela of otitis media from 17% to less than 1%.27 Furthermore, a recent rise in the number of cases of acute mastoiditis in German infants and children has been attributed to inadequate or absent antibiotic treatment of AOM.28
In addition to the limitations of the aforementioned studies, recent investigations and meta-analyses demonstrate antibiotic therapy to be significantly more effective than a strategy of watchful waiting.22,29 Despite the high spontaneous cure rate, treatment with antimicrobial agents improves the incidence of symptom resolution in AOM by about 15% and reduces treatment failure eightfold compared to observation alone.22,30 In light of these studies, and given the dramatic reduction in complications since the introduction of antibiotics, most pediatric and emergency medicine authorities—as well as the CDC—in the United States recommend routine antibiotic treatment for acute otitis media suspected to be of bacterial origin.1,31
The Pediatric Antimicrobial Armamentarium: The Challenge of Making Sound Therapeutic Choices
Although one of the principal concerns when choosing antibiotic therapy is the drug’s in vitro efficacy against the most likely infective organisms—including potentially resistant species—many studies have found that a number of available antimicrobial agents are virtually equally effective in treating otitis media.32 In this regard, it also should be noted that a drug’s efficacy in a clinical trial setting and its therapeutic worthiness in the "real-world environment"—which is characterized by well-recognized impediments to clinical cure such as day care-mediated administration of the drug, palatability of the medication, cost considerations, and discontinuation due to side effects—often diverge depending on the clinical environment and patient population. Development of agents permitting more convenient administration but which also maintain in vitro coverage against the appropriate bacterial species represents an attempt to mitigate these potential barriers.
The most commonly isolated bacterial pathogens in both acute and recurrent otitis media are Streptococcus pneumoniae, Haemophilus influenzae (nontypable), and Moraxella catarrhalis.33,34 Consequently, first-line agents should demonstrate adequate in vitro coverage against this spectrum of organisms. In children between 1 month and 10 years of age, S. pneumoniae and H. influenzae each account for about 40% of infections; M. catarrhalis accounts for about 20%.35 It should be stressed that neonates may also develop infections with gram-negative enteric bacilli and Staphylococcus aureus, together accounting for 15-20% of otitis media cases in this age group.26 Other pathogenic bacteria include Streptococcus pyogenes and anaerobic organisms.36 Children younger than 6 years of age with patent tympanostomy tubes and acute symptoms have pathogens similar to other children, while Pseudomonas aeruginosa and Staphylococcus aureus are occasionally isolated from older children with tubes.37
Drug resistance among bacteria involved in otitis media is rapidly emerging.13,34 In this regard, beta-lactamase production is common among isolates of H. influenzae and M. catarrhalis, rendering about 30-50% of H. influenzae and up to 80% of M. catarrhalis isolates resistant to ampicillin.38 The emergence of PRSP has dominated current concerns about antimicrobial therapy.19,20 Although variable from patient to patient and region to region, these emerging resistance patterns may explain the failure rates associated with such traditional therapeutic approaches—and older dosing recommendations—as amoxicillin.13,34
Accordingly, the evolution of antibiotic-resistant bacterial strains implicated in otitis media has fueled interest in alternatives and back-up therapy to amoxicillin, which, primarily because of its cost, has been the traditional first-line agent for this infection, despite showing increasing resistance. This problem can be circumvented by adding a beta-lactamase inhibitor such as clavulanic acid to amoxicillin (i.e., amoxicillin-clavulanate), increasing the dose of amoxicillin, or by choosing alternative antibiotics, among them, azithromycin, cefuroxime, or ceftriaxone.
A far more disturbing trend is the emergence of penicillin-resistant S. pneumoniae. Although the incidence of resistant strains demonstrates regional variations, the continued prevalence of S. pneumoniae as the principal etiologic agent in otitis media has important therapeutic implications. In addition to the older, so-called "standard antibiotics," most notable among them the penicillins such as amoxicillin and TMP/SMX, there are many newer oral agents, particularly cephalosporins and macrolides, that play an important role in treating bacterial infections commonly encountered in children.
Typically, antibiotics have been evaluated by comparing spectrum of activity, clinical efficacy, toxicity (adverse drug reactions and interactions), pharmacokinetics, convenience, compliance with dosing, and cost. When antibiotics are indicated, however, the choice is often more complicated than it may seem to be on the surface. Addressing resistance issues is important, but other aspects of the treatment plan also require evaluation.
The newer antibiotic suspensions, although possessing variable increases in the spectrum of activity and convenience factors over older agents, have uniformly been shown in clinical trials to be equally, but rarely more, efficacious than standard therapy. It should be stressed, however, that within the context of clinical trials, patients are frequently counseled and followed with pill counts to ensure compliance with their regimens. As a result, outcomes in these studies may deviate (i.e., they may be better than) from those observed in the "real world," where noncompliance with antibiotics is a major barrier impeding the pathway from the prescription pad to clinical cure.39-42 Consequently, it may be difficult to extrapolate from cure rates published in idealized clinical trials to observed results at the front lines of clinical practice.
Special Therapeutic Considerations in AOM: Evidence-Based Analysis of Treatment Options
The clinical debate surrounding outcome-effective therapy for AOM has been fueled by the need to consider a multiplicity of issues that go into the equation for drug selection. For example, while adequate in vitro activity against increasingly resistant S. pneumoniae may be the focus of one panel evaluating therapeutic options, another group may focus its attention on b-lactamase-producing organisms, i.e., H. influenzae or M. catarrhalis species. And while in vitro activity against organisms implicated in AOM is certainly an important parameter to follow, other experts have generated their recommendations based on the antibiotic levels achieved in the middle ear, as well as intracellular drug concentrations and the effect on bacterial infection.
Although identification of emerging resistance patterns is an essential component of developing treatment pathways (see Figure), it is acknowledged that the precise relationship between antimicrobial resistance (as measured by in vitro studies) and real-world clinical results in children with AOM is far from conclusive. Some observers have challenged surveillance studies reporting resistance to certain antibiotics, pointing out the "disconnect" between in vitro results, tissue levels of the antibiotic, and clinical outcomes.1,18,43-46 These experts also emphasize the inconsistency in findings reported by such surveys, which are conducted according to different study designs. Still other trials have focused on the efficacy of short treatment courses, and stress that many consensus panels have failed to account for the usefulness of this approach in AOM treatment protocols.1-3,25,47-49 Finally, there is the issue of treatment failures and identifying second-line agents that predictably produce acceptable cure rates in patients who have failed their first course of therapy.
What is clear is that any treatment recommendation for AOM must account for as many of the potential variables, resistance patterns, pharmacokinetic parameters, regional variations, and real world barriers—cost, compliance, patient toleration, taste, side effects, dosing schedules, and convenience factors—that can affect the journey from prescription pad to clinical cure. The PPPD approach to antibiotic selection for AOM (see next section) attempts to account for all these factors, including the CDC working group recommendations. In the sections that follow, an evidence-based approach to evaluating critical issues in AOM management is presented.
Antibiotics For Beta-Lactamase-Producing Organisms: Treatment Implications. From Nov. 1, 1997, to April 30, 1998, 726 Moraxella catarrhalis isolates and 1529 Haemophilus influenzae isolates were obtained from 34 medical centers throughout the United States. Rates of beta-lactamase production were 94.6% among M. catarrhalis and 31.1% among H. influenzae strains. Susceptibility rates of M. catarrhalis isolates to selected antimicrobial agents were greater than 99% for amoxicillin-clavulanate, cefixime, cefpodoxime, cefuroxime, cefaclor, loracarbef, clarithromycin, azithromycin, chloramphenicol, and tetracycline, 97.8% for cefprozil, 50.4% for trimethoprim-sulphamethoxazole, and 28.1% for ampicillin.50
Of the antimicrobials tested against H. influenzae, the only agents with susceptibility rates below 96% were loracarbef (87.6%), cefprozil (83.4%), cefaclor (82.7%), trimethoprim-
sulphamethoxazole (67.3%) and ampicillin (64.7%). The clarithromycin susceptibility rate was 67.4% but this agent was not tested in the presence of its 14-OH metabolite. This survey supports the susceptibility of beta-lactamase-producing strains of both H. influenzae and M. catarrhalis to such agents as azithromycin, amoxicillin-clavulanate, and cefpodoxime. Conversely, its suggests potentially less-than-optimal susceptibility rates to these species for such agents as ampicillin and trimethoprim-sulfamethoxazole. The precise implications on clinical cure and failure rates cannot be assessed from the study.50
Pneumococcal Macrolide Resistance: Drug Selection Implications. At least one consensus panel report has attempted to justify downgrading the use of macrolides for treatment for AOM on the basis of in vitro resistance patterns reported with Streptococcus pneumoniae. This has created a formidable debate about which agents—amoxicillin, amoxicillin-clavulanate, azithromycin, or the cephalosporins—represent the best initial choice for AOM.
According to some experts—as well as clinicians who have had excellent clinical results using macrolides for AOM in their own practice—justification for this cautious assessment of some macrolides is questionable, especially in light of rigorous clinical studies that have compared the safety and efficacy of azithromycin to amoxicillin-clavulanate for the treatment of acute otitis media in children.13,15,20,51,52 In these large trials, clinical cure rates of up to 87.5% were reported, and the authors concluded that azithromycin was as effective as, but better tolerated than, amoxicillin-clavulanate for the treatment of AOM in the pediatric age group.14-16,18,51
How, then, does one reconcile expert recommendations with antimicrobial sensitivity data, practitioner experience, and in vivo clinical trial results? The simple answer: only with difficulty. The controversy over antibiotic selection for AOM has been fueled by the observation that use of macrolides and amoxicillin over the past several years has been accompanied by increases in resistance. Despite this trend—which, to some degree or another applies to all antibiotics including cephalosporin—some investigators propose that use of macrolides, in particular, for such conditions as AOM be evaluated according to parameters other than in vitro results exclusively.
To provide a balanced approach to this dilemma, it has been proposed by one author from the Clinical Pharmacology Research Center in Cooperstown, NY, that microbiology laboratories should return to the habit of providing the clinician with MIC values for pathogenic isolates rather than generic susceptibility reports ([S]usceptible, [I]ntermediate, [R]esistant) that are based on standard disc diffusion testing. Although agar dilution MIC testing is a bulky and labor-intensive practice, it provides the best data when conducted in the appropriate environment.
Secondly, and more importantly, these MIC values need to be compared with in vivo antibiotic pharmacokinetics and pharmacodynamics. Although it is possible to compare MIC values directly with serum concentrations of beta-lactams and aminoglycosides, this is not a valid practice, it has been suggested by Amsden, for azithromycin or the macrolides. Rather, MICs of azithromycin and the macrolides must be compared with the infection site and phagocytic cell concentrations to determine the utility, or lack thereof, of one of these agents.18
In this regard, the author appropriately emphasizes that there are differences among the macrolides. For example, whereas azithromycin cellular penetration potentially allows maximal pharmacodynamics, perhaps even against moderately or highly resistant pneumococci, other macrolides may do so less optimally. Although there are no reports of widespread clinical failures resulting from macrolide/azalide resistance in pneumococci, it is expected that such reports will appear if and when these isolates become consistently highly resistant. This is likely to affect the macrolides, erythromycin and clarithromycin, before the azalide, azithromycin owing to the differences in pharmacokinetics of these drugs.18
Until then, it will be important to determine the MICs of not just one macrolide, but of all the specific macrolides and azalides for the isolates evaluated. This approach will permit clinicians to make pharmacokinetically and pharmacodynamically sound choices and distinctions. The author of this analysis proposes that by choosing clinical MIC breakpoints of 4-8 mg/L for oral macrolides and 32 mg/L or less for oral azithromycin, rather than the present standard breakpoints, the clinician can make a macrolide/azalide choice that will optimize the pharmacodynamics of the drug against the isolated pathogen and result in the best possible clinical outcome.18
The aforementioned theoretical advantages of azithromycin have been supported by other in vitro investigations as well as clinical trials.18,46,52 As emphasized, the prevalence of PRSP and beta-lactamase-producing Haemophilus influenzae in otitis media infections is increasing; emergence of these pathogens has complicated treatment. This study attempted to evaluate the incidence of penicillin resistance and the in vitro activity of amoxicillin/clavulanate, cefaclor, loracarbef, cefixime, trimethoprim-sulfamethoxazole, azithromycin, and clarithromycin in S. pneumoniae isolates.47
The in vitro activity of azithromycin, clarithromycin and cefaclor was also evaluated in beta-lactamase-positive and -negative isolates of H. influenzae. Bacterial isolates of S. pneumoniae and H. influenzae were obtained by tympanocentesis and subsequent culture of middle ear effusion from children with acute otitis media enrolled in a multicenter trial. Susceptibility to test agents was assessed by disk diffusion and broth dilution techniques with criteria established by the National Committee for Clinical Laboratory Standards.
Nineteen (31%) of the 61 S. pneumoniae isolates were resistant to penicillin. A significantly lower percentage of the S. pneumoniae isolates were resistant to azithromycin (16%) and clarithromycin (11%) than to penicillin, amoxicillin-clavulanate, cefaclor, loracarbef, or cefixime (31% in all cases). Azithromycin was also more active than cefaclor and significantly more active than clarithromycin against the 55 H. influenzae isolates. The investigators concluded that the susceptibility of resistant and nonresistant strains of S. pneumoniae to azithromycin and clarithromycin and of isolates of H. influenzae to azithromycin, coupled with penetration of azithromycin into the middle ear, may provide a significant advantage in the treatment of otitis media.
Antimicrobial Resistance Patterns and Clinical Results: The Test Tube-Real World Outcomes Disconnect Syndrome. One reason that clinicians disagree about the optimal initial agent for AOM management is the diversity in trial designs evaluating antibiotic treatment for AOM, the diversity of opinion regarding MIC levels and their relationship to in vivo patient outcomes, and the variable clinical end points used to evaluate antimicrobial efficacy.
For example, one study evaluated the susceptibilities of Streptococcus pneumoniae (1,476 strains) and untypable Haemophilus influenzae (1,676 strains) to various oral beta-
lactam, macrolide-azalides, and fluoroquinolone antimicrobial agents using broth microdilution techniques. Organisms were isolated from specimens obtained from outpatients in six geographic regions of the United States. MIC data were interpreted according to pharmaco-dynamically derived breakpoints applicable to the oral agents tested.43
In this study, 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.43
However, another study looking exclusively at AOM isolates reported different (i.e., more advantageous) resistance patterns for the macrolides—patterns, in fact, suggesting the clinical usefulness of such agents as azithromycin for this condition. In light of the prevalence of penicillin-resistant Streptococcus pneumoniae and beta-lactamase-producing Haemophilus influenzae in otitis media infections, a group of investigators set out to evaluate the incidence of penicillin resistance and the in vitro activity of amoxicillin-clavulanate, cefaclor, loracarbef, cefixime, trimethoprim-sulfamethoxazole, azithromycin, and clarithromycin in S. pneumoniae isolates. The in vitro activity of azithromycin, clarithromycin, and cefaclor was also evaluated in beta-lactamase-positive and -negative isolates of H. influenzae.44
In this straightforward and well-designed study, bacterial isolates of S. pneumoniae and H. influenzae were obtained by tympanocentesis and subsequent culture of middle ear effusion from children with AOM enrolled in a multicenter trial. Susceptibility to test agents was assessed by disk diffusion and broth dilution techniques with criteria established by the National Committee for Clinical Laboratory Standards.44
These investigators found that 19 (31%) of the 61 S. pneumoniae isolates were resistant to penicillin. A significantly lower percentage of the S. pneumoniae isolates were resistant to azithromycin (16%) and clarithromycin (11%) than to penicillin, amoxicillin-clavulanate, cefaclor, loracarbef, or cefixime (31% in all cases). As might be expected, azithromycin was also more active than cefaclor and significantly more active than clarithromycin against the 55 H. influenzae isolates. Based on these results, this pediatric investigative group concluded that the susceptibility of resistant and nonresistant strains of S. pneumoniae to azithromycin and clarithromycin and of isolates of H. influenzae to azithromycin, coupled with penetration of azithromycin into the middle ear, may provide a significant advantage for this agent in the treatment of otitis media.44
Other studies have supported the activity of macrolides in penicillin-resistant S. pneumoniae. For example, in one urban study, a pediatric team tried to determine the proportion of children with AOM presenting in New York City who were infected with nonsusceptible Streptococcus pneumoniae, and to determine the susceptibility of these organisms to penicillins and other antibiotics commonly used to treat AOM.53
The children were seen in ambulatory clinics and the emergency department of a tertiary care, inner-city medical center. During a two-year period from 1993 to 1995, 115 children (ages 6 months to 12 years) with AOM underwent tympanocentesis. Patients did not receive antibiotics for at least one week before tympanocentesis.53
Investigators found that 31 children were infected with S. pneumoniae, and 83.9% of isolates were susceptible to penicillin. Of the 16.1% strains that were nonsusceptible, most (4 of 5 strains) were intermediately resistant, and only one exhibited high-level resistance to penicillin. Of all the cephalosporins tested, only cefotaxime had consistent activity against the intermediately resistant strains. Notably, all nonsusceptible pneumococci were inhibited by macrolides.53 In contrast to the conclusions of the aforementioned U.S. studies44 demonstrating clinically useful activity of advanced generation macrolides such as azithro-mycin, an Israeli group reported bacteriologic failure rates suggesting that the susceptibility breakpoints for H. influenzae should be considerably lower than the current ones for both cefaclor and azithromycin for AOM caused by H. influenzae.45
What is clear from these and other investigations, consensus reports, and reviews, is that there is a tremendous variability— and not uncommonly, contradiction and inconsistencies—in both the design of trials and in results of antibiotic efficacy and resistance patterns for organisms causing AOM.
Middle Ear and Tissue Antibiotic Levels. Clearly, variables other than MIC tube dilutions and serum blood levels play an integral role in determining clinical outcomes. In one study designed to determine the potential influence of variables such as the cell content in the fluid and serum levels on the concentrations of ceftibuten, cefixime, and azithromycin in the middle ear fluid of patients suffering from AOM, the authors found that the penetration of antibiotics into the middle ear fluid is influenced by its serum concentrations as well as by the cell content in the fluid. In particular, while ceftibuten and cefixime concentrations are negatively influenced by the cell content in the middle ear fluid, in contrast, the concentration of azithromycin in the middle ear fluid is positively influenced by the cell content in the fluid.46
Moreover, studies suggest that among patients who failed to respond to antimicrobial therapy—and have persistent otitis media—certain microbiological characteristics are associated with specific agents used for treatment. In an attempt to identify the pathogens isolated from children with AOM who did not respond to antimicrobial drug therapy, one Georgetown group performed a retrospective analysis of cultures obtained by tympanocentesis from 46 children.54
Organisms were recovered from 34 children (74%), and 43 isolates were recovered from these individuals. The organisms included Streptococcus pneumoniae (16 isolates), Haemophilus influenzae non-type b (12 isolates), Moraxella catarrhalis (5 isolates), Streptococcus pyogenes (5 isolates), Staphylococcus aureus (3 isolates), and Peptostreptococcus species (2 isolates).54
Resistance to the antimicrobial agent used was found in 27 (63%) of 43 isolates found in 22 patients (48%). Of patients who did not respond to amoxicillin therapy, infection with H. influenzae predominated. Streptococcus pneumoniae was recovered from five (56%) of nine of those who did not respond to trimethoprim and sulfamethoxazole therapy, four (44%) of nine patients after azithromycin therapy, three (25%) of 12 patients after amoxicillin therapy, and two (40%) of five patients after cefixime therapy. Streptococcus pyogenes was recovered from two (40%) of five patients after trimethoprim and sulfamethoxazole therapy and from two (40%) of five patients after cefixime therapy. The authors emphasize the relationship between resistance to antimicrobial drug therapy and failure of patients with otitis media to improve.54
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Physician CME Questions
49. Among children younger than 2 years of age, approximately what percentage had six or more physician office visits for otitis media?
A. 10%
B. 15%
C. 25%
D. 50%
50. What antibiotic is prescribed in more than 50% of patients with
otitis media?
A. Cefaclor
B. Trimethoprim-sulfamethoxazole
C. Amoxicillin
D. Amoxicillin-clavulanate
51. The organisms most commonly isolated in cases of AOM include:
A. Streptococcus pneumoniae, Chlamydia, and Legionella.
B. Streptococcus pneumoniae, H. influenzae, and M. catarrhalis.
C. Streptococcus pneumoniae, Chlamydia, and Mycoplasma.
D. none of the above.
52. What percentage of H. influenzae species are resistant to ampicillin?
A. 10-20%
B. 20-30%
C. 30-50%
D. 60-90%
53. What percentage of M. catarrhalis species are resistant to ampicillin?
A. Up to 20%
B. Up to 40%
C. Up to 60%
D. Up to 80%
54. The concentration of azithromycin in the middle ear fluid is positively influenced by the cell content in the fluid.
A. True
B. False
55. In one study, of the antimicrobials tested against H. influenzae, the only agent(s) with susceptibility rates below 96% was(were):
A. loracarbef.
B. cefprozil and cefaclor.
C. trimethoprim-sulphamethoxazole.
D. ampicillin.
E. all of the above.
56. PPPD factors affecting antibiotic selection include:
A. patient resistance.
B. prescription resistance.
C. parent resistance.
D. drug resistance.
E. all of the above.
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