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Are Cephalosporins Appropriate for the Treatment of Acute Otitis Media in This Era of Increasing Antimicrobial Resistance Among Common Respiratory Tract Pathogens?

Posted on: Friday, 18 March 2005, 03:00 CST

Introduction

Acute otitis media (AOM) is the most common reason that antimicrobials are prescribed for children in the United States, accounting for more than 20 million prescriptions per year. ' Many of these prescriptions are made over the telephone without the physician having examined the patient. Children 2 years of age and younger spend nearly 50 days per year on antimicrobial therapy, with more than 90% of these agents prescribed for the treatment of AOM.2 The number of physician office visits for AOM increased from 9.9 million visits in 1975 to 24.5 million visits in 1990.3,4 The economic burden imposed by AOM is enormous. The annual cost (in 1998 dollars) for office visits and treatment (antimicrobials and surgery) in the United States is estimated at $5.3 billion.5 Indirect costs for lost work productivity and special childcare arrangements increase this amount substantially.

The dramatic increase in antimicrobial resistance among common respiratory pathogens in recent years has complicated treatment of AOM. In the mid-1990s, Streptococcus pneumoniae was the most common bacterial pathogen isolated from children with AOM (40-50%), followed by Haemophilus influenzae (20-30%) and Moraxella catarrhalis (10-15%).6 However, recent data suggest that H. influenzae is becoming as important, if not more important, than S. pneumoniae as a leading cause of AOM, and a considerable percentage of cases (17%) are caused by infection with both pathogens.7,8 Data obtained between 1998 and 2000 in the Alexander project, a worldwide surveillance study of antimicrobial susceptibility, demonstrated that among 8882 isolates of S. pneumoniae, 13.5% were penicillin- intermediate (penicillin minimum inhibitory concentration [MIC] 0.12- 1.0 g/mL) and 18.2% were penicillin-resistant (penicillin MIC ≥2.0 g/mL).9 β-Lactamase production was documented in 16.9% of 8523 worldwide H. injluenzae isolates, and 29.6% of 2073 US isolates. Among US isolates, there was a significant increase in pneumococcal penicillin resistance between 1998 (22.2%) and 1999 (31.0%) (p<.001). Furthermore, penicillin resistance among S. pneumoniae often occurs together with resistance to other drug classes, such as macrolides, tetracyclines, chloramphenicol, and trimethoprim-sulfamethoxazole. For example, among US isolates obtained during this surveillance study, 25.8% were resistant to 3 drug classes and 15.5% were resistant to 4 drug classes. Data obtained in children 12 years of age and younger in 2001-2002 show much higher rates of antimicrobial nonsusceptibility in this population (Figure I).10 Such rapid and extensive proliferation of resistance complicates selection of an appropriate antimicrobial.

It is tempting to approach the challenge of AOM treatment by selecting an agent with a broad spectrum of activity in the hope that it will provide coverage against resistant bacterial strains. Cephalosporins are often prescribed for AOM because of the perception that their spectrum of activity covers a broad range of pathogens. Of cephalosporins approved for use in children with AOM, older cephalosporins, such as cephalexin and cephradine, have excellent activity against most gram-positive cocci but limited activity against gram-negative pathogens; these agents are not the drugs of choice for any pediatric infections.11 Cefuroxime axetil, cefaclor, and ccfprozil have greater activity against some gram- negative pathogens; however, cefaclor and cefprozil have inferior activity against H. influenzae, including β-lactamase-negative strains. These agents have been considered effective in empiric treatment of community-acquired respiratory tract infections, including AOM, but are not initial (empiric) drugs of choice. Newer cephalosporins (cefdinir, ceftriaxone, cefpodoxime, ceftibuten) have a broader in vitro spectrum of activity, are more active against gram-negative pathogens, and are more stable against β- lactamase enzymes. Although these agents generally have greater activity against penicillin-susceptible strains of S. pneumoniae than older agents, their poor activity against penicillin- nonsusceptible strains limits their clinical utility in the treatment of AOM caused by this pathogen. Of these approved agents, ceftriaxone is the only agent that is not available in an oral formulation. Cephradine and cefuroxime axetil are available in both oral and injectable formulations. Thus, treatment decisions must involve consideration of a number of factors beyond in vitro spectrum of activity. The purpose of this article is to review and evaluate current knowledge regarding the use of cephalosporins in the treatment of AOM during this era of increasing antimicrobial resistance in an effort to elucidate rational treatment decisions.

Figure 1. Surveillance data obtained from children 12 years of age and younger in the United States between January 2001 and September 2002 (reproduced from reference 10, with permission). * West includes isolates from Alaska and Hawaii. MIC = minimum inhibitory concentration.

Table 1

NATIONAL COMMITTEE FOR CLINICAL LABORATORY STANDARDS SUSCEPTIBILITY BREAKPOINTS FOR SELECT PENICILLINS AND CEPHALOSPORINS AGAINST BACTERIAL PATHOGENS RESPONSIBLE FOR ACUTE OTITIS MEDIA*

Antimicrobial Resistance Among Common Acute Otitis Media Pathogens

Resistance among the 3 most common bacterial pathogens in AOM has increased in recent years. Streptococcus pneumoniae exhibits resistance to penicillins and cephalosporins through alterations in penicillin-binding proteins (PBPs), reducing susceptibility to virtually all β-lactams in a stepwise fashion as the number of PBP alterations increases.12 Resistance among H. influenza? and Moraxella catarrhalis usually occurs as the result of β- lactamase production. In the United States, penicillin nonsusceptibility among S. pneumoniae was documented in 37% of isolates (12.0% intermediate and 25.0% resistant), and β- lactamase production was documented in 30% of H. influenzae and 92% of M. calarrhalis between 1998 and 2000.9 Current susceptibility breakpoints for these pathogens are shown in Table 1.13

Table 2

IN VITRO ACTIVITY OF AMOXICILLIN AND CEPHALOSPORINS AGAINST STREPTOCOCCUS PNEUMONIAE ACCORDING TO PENICILLIN SUSCEPTIBILITY

Clinical Implications of Antimicrobial Resistance

Susceptibility of respiratory tract pathogens to penicillin has important implications for treatment with cephalosporins. Although penicillin-susceptible strains of S. pneumoniae are susceptible to the cephalosporins, MIC^sub 90^ values (MIC necessary to inhibit 90% of isolates) for these antimicrobials increase dramatically against both penicillin-intermediate and resistant strains (Table 2).6 For example, the MIC^sup 90^ values of cefprozil, cefaclor, ceftibuten, and cefixime against penicillin-intermediate and -resistant S. pneumoniae preclude their use as empiric therapy for AOM, especially in areas with a high prevalence of penicillin-nonsusceptible pneumococci.

Several investigators have demonstrated a convincing relationship between increasing resistance among S. pneumoniae and poor bacteriologic response. For example, a comparative study of cefaclor (40 mg/kg/day) and cefuroxime axetil (30 mg/kg/day) found that overall bacteriologic eradication after 4-5 days of treatment occurred in 94% of patients when pretreatment isolates were penicillin-susceptible (penicillin MIC <0.1 g/mL).14 Bacteriologic eradication rates decreased with increasing penicillin MICs, such that 79% of isolates were eradicated when pretreatment MICs were 0.125-0.25 g/mL, but only 36% were eradicated when pretreatment MICs were 0.38-1.0 g/mL (p<.001 compared with penicillin-susceptible group). Similar results were observed in a larger study of 248 children with AOM treated with a β-lactam antimicrobial.15 Overall bacteriologic eradication was 92% among penicillin- susceptible S. pneumoniae 72% among nonsusceptible strains. In this study, cefaclor and single-dose intramuscular ceftriaxone were not significantly more effective than placebo against nonsusceptible strains (Figure 2, Panel A).

Figure 2. Bacteriologic response to β-lactam antimicrobials based on penicillin susceptibility in children with acute otitis media caused by Streptococcus pneumoniae (Panel A) or Haemophilus influenzas (Panel B). Cefaclor = 40 mg/kg/day; cefuroxime axetil = 30 mg/kg/day; amoxicillin* = 40 mg/kg/day amoxicillin or 45 mg/kg/ day amoxicillin/clavulanate; amoxicillin[dagger] = 40 mg/kg/day amoxicillin in β-lactamase-negative H. influenzae; amoxicillin[double dagger] = 40 mg/kg/day amoxicillin in β- lactamase-positive H. influenzae; amoxicillin/clavulanate = 40/8 mg/ kg/day; ceftriaxone 1 = 50 mg/kg 1 dose; ceftriaxone 3 = 50 mg/ kg/day 3 days (adapted from reference 15, with permission).

A compilation of data from several studies including 392 children with AOM caused by H. influenzae demonstrated that β-lactamase production also is an important consideration when selecting antimicrobial therapy.15 As previously mentioned, cefaclor has inferior activity against H. influenzae an\d is not much more effective than placebo at eradicating this pathogen from middle-ear fluid (MEF) (Figure 2, Panel B). Against β-lactamase-positive strains, bacteriologic failure with amoxicillin was comparable to that seen with placebo; however, the addition of clavulanate drastically improved bacteriologic response. The increasing prevalence of AOM caused by both S. pneumoniae and H. influenzae, and the increasing prevalence of penicillin nonsusceptibility among these pathogens, necessitate treatment with an antimicrobial that possesses good in vitro activity against penicillinnonsusceptible strains of both pathogens.

Some clinicians may question whether bacteriologic failure translates into clinical failure in patients with AOM because AOM is a condition that exhibits a high rate of spontaneous clinical recovery, even in the absence of antimicrobial therapy. In a study of 123 infants and children with AOM, bacteriologic failure after 3- 4 days of antimicrobial therapy was noted in 57 patients.16 Clinical failure occurred in 37% of these children, compared with only 3% of those who were cured bacteriologically (p<.001) (Figure 3). The clinical implication of a seemingly small difference in clinical outcome between 2 antimicrobials could translate into a significant number of clinical failures each year. For example, in the United States, there are an estimated 20 million cases of AOM per year; if 2 antimicrobials produce a 1% difference in clinical cure, this would translate into 200,000 clinical failures on an annual basis.15

Figure 3. Clinical outcome after 3 to 4 days of antimicrobial therapy in 57 patients with acute otitis media based on bacteriologic outcome (adapted from reference 16, with permission). *p<.001.

Treatment Guidelines for Acute Otitis Media

Treatment guidelines for AOM have been developed by the Drug- Resistant S. pneumoniae Therapeutic Working Group of the Centers for Disease Control and Prevention (CDC),6 as well as a panel of experts on AOM.17,18 Treatment guidelines are continually updated to reflect changes in the etiology of AOM and antimicrobial resistance patterns among common respiratory pathogens. Because penicillin- nonsusceptible S. pneumoniae and β-lactamase-producing H. influenzae are the most important pathogens in AOM, clinicians should not use their usual mode of selecting therapy based on dosing convenience, palatability, patient convenience, or other considerations. Rather, selection should be made based on coverage of S. pneumoniae and H. influenzae, with less consideration given to M. calarrhatis. High-dose amoxicillin (80-90 mg/kg/day) is widely considered to be first-line therapy for treatment of patients at risk for infection with penicillin-nonsusceptible S. pneumoniae (e.g., antimicrobial use within the previous 3 months, daycare attendance, and age younger than 2 years); however, this treatment provides little to no coverage of β-lactamase-producing H. influenzae. The use of highdose amoxicillin/clavulanate (80-90 mg/ kg/day of the amoxicillin component) is recommended as first-line therapy in patients who have received antimicrobial therapy within the previous month, and is appropriate in patients at risk for infection with β-lactamase-producing pathogens.

Many antimicrobials have been approved by the US Food and Drug Administration (FDA) for use in AOM, including several cephalosporins. However, only 2 cephalosporins were included in treatment guidelines published by the CDC in 1999, oral cefuroxime axetil and intramuscular ceftriaxone.6 Both agents were listed as alternatives to amoxicillin along with high-dose amoxicillin/ clavulanate (80-90 mg/ kg/day of the amoxicillin component) and clindamycin. These agents (with the exception of clindamycin) were recommended because they are effective against β-lactamase- producing H. influenzae and M. calarrhalis, as well as against most penicillin-nonsusceptible S. pneumoniae. However, results from recent surveillance studies suggest that cefuroxime axetil is no longer active against penicillin-resistant S. pneumoniae, although it has reasonable activity against penicillin-intermediate strains, and a consensus panel of experts suggests that it should not be considered appropriate therapy for AOM.17 The use of 3 daily doses of intramuscular ceftriaxone is preferred over single-dose administration and is an appropriate alternative in children with refractory AOM who are not allergic to p-lactams.6,19 Patients with a true allergy to penicillin may be treated with clindamycin (if the infection is caused only by S. pneumoniae) or tympanocentesis. There is a need for an effective non-β-lactam compound to treat AOM in penicillin-allergic children. Use of a quinolone may be indicated if approved by the US FDA, but care will need to be taken not to abuse the drug with resultant selection of resistant clones, which spread in the community.

The CDC gave consideration to use of 2 other oral cephalosporins when developing their guidelines.6 Cefprozil and cefpodoxime were evaluated because of their in vitro activity against the 3 primary pathogens involved in AOM. However, the CDC could not endorse these agents because of "limited evidence to date for efficacy against DRSP (drug-resistant S. pneumoniae) from clinical trials." Suspect in vitro activity and a lack of data from adequate rigorously conducted clinical trials are limitations shared by all oral cephalosporins when penicillin-nonsusceptible S. pneumoniae are involved.

Impact of Pharmacokinetics and Pharmacodynamics on Treatment of Acute Otitis Media

The importance of considering pharmacokinetics (PK) and pharmacodynamics (PD) in the treatment of AOM should not be overlooked. Pharmacokinetics describes the relationship between antimicrobial concentration and time, whereas pharmacodynamics describes the relationship between antimicrobial concentration and antimicrobial effect.20-24 By combining these parameters, clinicians can determine the time course of antimicrobial activity for a given dosing regimen.

Antimicrobials can be divided into 2 classes depending on their pattern of bactericidal activity: those that exhibit concentrationdependent killing and those that exhibit time- dependent killing, β-Lactarns fall within this latter category. With time-dependent killing, saturation of the ability of the antimicrobial to kill the bacteria occurs at low multiples of the MIC.21,23 Achieving concentrations greater than 4-5 times the MIC does not result in any faster or more complete killing of the organism. Rather, maintaining the antimicrobial concentration above the MIC for a longer duration of the dosing interval results in increased bacterial killing; thus, time-dependent killing is usually measured by percentage of time (T) during the dosing interval when the antimicrobial concentration remains above the MIC (T>MIC). Antimicrobial concentrations do not need to exceed the MIC for the entire dosing interval to exert a powerful antimicrobial effect. In fact, several PK/PD studies of β-lactams have shown a significant effect when the concentration exceeded the MIC for just 40-50% of the dosing interval and maximal bacterial killing when T>MIC approached 60-70% of the dosing interval.21,22 Because the penicillins (e.g., amoxicillin) are more rapidly bactericidal than the cephalosporins, the T>MIC required is slightly lower for the penicillins than for the cephalosporins.

More important than the MICs achieved in serum are the MICs achieved at the site of infection (ie, MEF in the case of AOM).25 However, MEF concentrations are difficult to obtain, and data are limited. Results from one study demonstrated marked differences in serum and MEF concentrations achieved with various penicillins and cephalosporins commonly used to treat AOM (Figure 4). Generally, much lower serum and MEF concentrations were achieved with the cephalosporins than with amoxicillin. When PK/PD parameters are used to compare antimicrobials, significant differences between agents become apparent. These differences are demonstrated in Table 3, which shows the T>MIC for the 3 main pathogens found in AOM, including strains of S. pneumoniae with reduced susceptibility to penicillin.23 All of the antimicrobials achieved the T>MIC goal (40- 50%) for penicillin-susceptible S. pneumoniae. However, none of the cephalosporins achieved the T>MIC goal against penicillin- intermediate or -resistant pneumococci. Of the newer cephalosporins, both cefpodoxime and cefixime achieved sufficient T>MIC against H. influenzae, but only cefixime achieved sufficient T>MIC against M. calarrhalis. The older cephalosporins, cefuroxime axetil, cefprozil, and cefaclor, failed to achieve adequate T>MIC against these 2 pathogens. Only amoxicillin/clavulanate was able to achieve the T>MIC target against all AOM pathogens, including penicillin- intermediate and -resistant strains of S. pneumoniae. Thus, based on PK/PD profile alone, cephalosporins are not ideal antimierobials for AOM because their penetration at the site of infection (MEF) and duration of time that the serum concentration exceeds the MIC of S. pneumonias are less than those of the penicillin-class agents, especially against penicillin-nonsusceptible strains.

Figure 4. Serum and middle-ear fluid (MEF) levels of select oral β-lactam antimicrobials commonly used in the treatment of acute otitis media (adapted from reference 25, with permission). * Concentration stated is that of amoxicillin.

Efficacy of Cephalosporins in the Treatment of Acute Otitis Media

A review of randomized clinical trials of the newer, orally available cephalosporins (i.e., cefdinir, cefpodoxime, ceftibuten, and cefiximc) supports the fact that none of these broad-spectrum antimicrobials has been shown to be any more clinically effective than the gold standard treatment, amoxieillin/clavulanate; however, many of these trials were \conducted in the late 1980s and early 1990s, before penicillin-resistant S. pneumoniae was a real problem in AOM.26-31 Only 2 of these trials performed tympanocentesis before the start of therapy and included bacteriologic eradication as an outcome measure;27,31 however, in both studies, bacteriologic eradication was presumed based on improvement of clinical symptoms of AOM. Overall presumed bacteriologic eradication rates in these 2 trials were comparable (cefpodoxime vs amoxieillin/clavulanate and cefdinir vs amoxieillin/clavulanate). Further comparison of the bacteriologic eradication rates found that presumptive eradication of S. pneumoniae 2-4 days after completion of therapy was significantly higher in patients treated with amoxicillin/ clavulanate (40/10 mg/kg/day) than in patients treated with twice- daily (BID) cefdinir (7 mg/kg BID) (89.5% vs 55.2%, p=.0019).27

Table 3

PERCENTAGE OF DOSING INTERVAL THAT SERUM LEVELS OF ORAL β- LACTAMS ARE ABOVE THE MIC^sub 90^ OF PATHOGENS RESPONSIBLE FOR ACUTE OTITIS MEDIA

Pollyanna Phenomenon

"Pollyanna phenomenon" is a term coined by Marchant and colleagues32 to describe how differences in bacteriologic eradication between 2 agents can actually be greater than those demonstrated in clinical trials, because of flaws inherent in the design and conduct of most comparative clinical trials of AOM.33 Because AOM has a high rate of spontaneous bacteriologic (~30%) and clinical (~70%) cure, discriminating between 2 antimicrobials based on clinical outcome alone can be very difficult. Studies that enroll patients based on a clinical diagnosis only, as opposed to using tympanocentesis for bacteriologic diagnosis, and then assess efficacy on clinical grounds (eg, symptom improvement) would find that placebo is effective in 70-80% of patients. In contrast, an antimicrobial that is 100% effective in eradicating bacteria from MEF after 3-5 days might appear only 90% effective at the follow-up visit 2-3 days later because of new infection, simultaneous viral infection, or persistence of symptoms, such as middle-ear effusion. Therefore, such a study might find only a 10-20% difference (70-80% vs 90%) in efficacy between placebo and a highly effective drug. A 10-20% difference between 2 antimicrobials, although involving a small number of patients in the typical AOM study, would translate into approximately 2-4 million patients (of 20 million total treated cases) in the United States who would be expected to fail therapy if they were treated with the less effective drug. Calculated outcomes associated with the 3 different strategies that can be used in the design of AOM clinical trials are shown in Figure 5.

Finding a statistically significant difference between 2 antimicrobials that differ in outcome by just 10% would require the following patient sample sizes, depending on study design:33

Figure 5. Comparison of 3 different strategies for evaluating antimicrobial efficacy in acute otitis media: the "Pollyanna phenomenon" (adapted from reference 32, with permission).

Although most AOM studies use the latter study design (clinical diagnosis and clinical outcome), even the largest studies have included just a few hundred patients. These studies are almost always powered to show noninferiority, rather than superiority, based on regulatory requirements for product licensing.33 Exclusion of patients at greater risk for infection (e.g., young age, daycare attendees and/or children with siblings at home, recurrent or nonresponsive AOM) also may produce the desired outcome of noninferiority based on clinical cure rather than bacteriologic eradication. It is important for clinicians to familiarize themselves with these study design flaws to accurately assess the choices presented to them before making prescribing decisions based on current publications.

Short-Course Therapy for Acute Otitis Media

In the United States, 10 days has traditionally been considered the standard duration of treatment for AOM.34 Recently, however, several studies have attempted to demonstrate that shorter courses of therapy are just as effective as the standard 10-day course. Many studies, reviews, and meta-analyses evaluating short-course antimicrobial treatment of AOM are available.34-39 Generally, these studies demonstrate that shorter courses of treatment for AOM are either equally, or slightly less, effective than standard 10-day therapy. None of these studies has shown shortcourse treatment to be more effective. Many studies evaluating short-course treatment of AOM have excluded high-risk patient populations. This has resulted in several investigators cautioning against using short-course treatment in high-risk patients (e.g., chronic or recurrent otitis media, tympanic membrane perforation, children <2 years of age, or patients with more severe infection).3,37,39,40

The ultimate in short-course treatment of AOM with a cephalosporin involves singledose intramuscular ceftriaxone (50 mg/ kg). Single-dose ceftriaxone was found to be no more effective than a 10-day course of oral amoxicillin/clavulanate (80/10 mg/kg/day) in 1 comparative study,36 and may be more likely to result in a positive nasopharyngeal culture for S. pneumoniae following treatment. In the nasopharynx, single-dose ceftriaxone appears to eradicate primarily penicillin-susceptible S. pneumoniae, leaving the penicillin-nonsusceptible strains behind to colonize the nasopharynx.41 Nasopharyngeal colonization with penicillin- resistant S. pneumoniae is thought to be a potential risk for transmission of penicillin-resistant bacteria between children, and for future episodes of AOM caused by this pathogen.42 Carriage of penicillin-resistant S. pneumoniae was associated with a significantly higher rate of clinical failure (p=.008).43 Some investigators have tried to overcome this problem by implementing a regimen of 3 consecutive daily doses of intramuscular ceftriaxone.44 However, they concluded that even the impact of the 3-day regimen was short-lived, and was followed by rapid recolonization of the nasopharynx. Thus, cephalosporins may not be ideal antimicrobials for patients with recurrent AOM or those at risk for resistant or recurrent AOM because of their inability to eradicate pneumococci from the nasopharynx. However, if ceftriaxone is used for the treatment of AOM, a 3-day course, not a 1-day course, should be used.19

Appropriateness of Cephalosporins in the Treatment of Acute Otitis Media

None of the available cephalosporins is approved by the FDA for use in patients with moderate to severe AOM, or in infections caused by penicillin-nonsusceptible S. pneumoniae, a leading cause of AOM.45-48 One agent, ceftibuten, is not approved for use at all in patients with AOM caused by S. pneumoniae because its efficacy against pneumococcal pneumonia was 23% lower than control in clinical trials.45 Of the oral agents, single daily doses are approved only for a 10-day treatment duration and shorter courses are approved only with BID dosing regimens. Although ceftriaxone is approved for 1 or 3 intramuscular doses, the inconvenience of intramuscular administration may not be desirable for young patients or their caregivers. Furthermore, only the 3-day regimen is recommended for the treatment of AOM in patients who have failed previous antimicrobial therapy.19

Although some, but not all, of the clinical trials involving cephalosporins found that the cephalosporin was better tolerated than amoxicillin/clavulanate,26-31 dropout rates between treatments were generally similar. Important factors to consider when prescribing cephalosporins include interactions with food and drugs, and high incidences of specific adverse events. For example, food delays time to peak concentration (T^sub max^) and reduces the peak concentration (C^sub max^) and area under the concentration versus time curve (AUC) of ceftibuten, thus necessitating administration 2 hours before or 1 hour after a meal.45 No adverse events were reported by more than 5% of patients in clinical trials with ceftibuten. Food also reduces the C^sub max^ and AUC of cefdinir, but the reduction is not considered clinically significant; cefdinir may be taken without regard to meals.46 However, administration of cefdinir with multivitamins containing iron reduces absorption of cefdinir; therefore, cefdinir should be administered 2 hours before or after the multivitamin. Diarrhea was the only adverse event reported by more than 5% of patients in clinical trials (15% with cefdinir capsules [adults and adolescents]; 8% with cefdinir suspension [children]). Cefpodoxime tablets should be taken with food because they increase the absorption, C^sub max^, and AUC of the antimicrobial.48 Food does not significantly increase the C^sub max^ or AUC of the suspension formulation, but it docs decrease the rate of absorption (T^sub max^ nearly doubles); cefpodoxime suspension may be taken without regard to food. Diarrhea also is a common adverse event associated with cefpodoxime and was reported by more than 5% of patients in clinical trials (7% with tablets, 6% with suspension). Because ceftriaxone is administered intramuscularly, food and drug interactions are less of a concern than with orally administered cephalosporins; however, injection- site reactions may occur.47 Food interactions with high-dose amoxicillin/clavulanate have not been studied, but patients are encouraged to take the medication with food or a snack to reduce gastrointestinal upset.49

There were no adverse events reported by more than R% of patients in clinical trials with highdose amoxicillin/clavulanate. Clinicians should be aware of tolerability issues, but the most important issues when choosing therapy should be bacteriologic and clinical efficacy. When the impact of treatment failure (missed school, missed work for parents, return physician office visits, increased bacterial resistance) is considered, shor\t-lived tolcrability issues become quite manageable.

Conclusions

AOM is one of the most common infections experienced by young children. It is also the most common reason that antimicrobials are prescribed for children in the United States, and is a significant burden to the healthcare system. The changing etiology of AOM and the dramatic increase in antimicrobial resistance among S. pneumoniae, H. influenzae, and M. calarrhalis in recent years has complicated treatment. The clinical utility of several commonly used antimicrobials has been compromised by these resistance patterns, reducing the number of antimicrobials available to treat patients with AOM. Clinical trials have shown that bacteriologic failure translates into clinical failure, and the risk of failure is higher in patients infected with penicillinnonsusceptible S. pneumoniae when they are not treated with effective agents. Thus, risk of infection with a resistant pathogen, especially S. pneumoniae, must be considered in all children presenting with AOM.

Newer cephalosporins (i.e., cefdinir, ceftriaxone, cefpodoxime, and ceftibuten) generally have good in vitro activity against H. influenzae, M. calarrhalis, and (with the exception of ceftibuten) penicillin-susceptible strains of S. pneumoniae. However, in vitro activity against S. pneumoniae decreases as the penicillin MIC increases, limiting the use of these agents against penicillin- nonsusceptible pneumococci, a leading cause of AOM. The question that needs to be asked, then, is what is the place, if any, for use of cephalosporins in AOM? It is well established that cephalosporins should not be used as empiric therapy because of their limited activity against penicillin-nonsusceptible S. pneumoniae. The fact that some of these agents have good activity against both H. influenzae and M. calarrhalis suggests that they may be considered alternatives (after high-dose amoxicillin/clavulanate) in patients with documented failure caused by one of these bacteria, a situation that would require tympanocentesis and culture of MEF drainage (which unfortunately is not performed very often in clinical practice in the United States). However, patients failing high-dose amoxicillin or high-dose amoxicillin/clavulanate therapy are probably infected with highly penicillin-resistant S. pneumoniae and would therefore not benefit from treatment with a cephalosporin. Thus, the current role of cephalosporins in therapy is not clear. Further investigation is warranted before an accurate determination of which patients with AOM may be appropriately treated with a cephalosporin can be made. At present, high-dose amoxicillin/ clavulanate remains the best antimicrobial for use in children with AOM at risk for infection with S. pneumoniae with reduced susceptibility to penicillin and β-lactamase-producing strains of H. influenzae or M. calarrhalis.

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20. Appelbaum PC. Microbiological and pharmacodynamic considerations in the treatment of infection due to antimicrobial- resistant Streptococcus pneumoniae. Clin Infect Dis. 2000;31 (suppl 2):S29-S34.

21. Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis. 1998;26:1-12.

22. Craig WA, Andes D. Pharmacokinetics and pharmacodynamics of antibiotics in otitis media. Pediatr Infect Dis J. 1996:15:255-259.

23. Jacobs MR. Optimisation of antimicrobial therapy using pharmacokinetic and pharmacodynamic parameters. Clin Microbiol Infect. 2001;7:589-596.

24. Liu P, Millier M, Derendorf H. Rational dosing of antibiotics: the use of plasma concentrations versus tissue concentrations. Int J Antimicrob Agents. 2002;19:285-290.

25. Harrison CJ. Using antibiotic concentrations in middle ear fluid to predict potential clinical efficacy. Pediatr Infect Dis J. 1997;16(suppl):S12-S16.

26. Adler M, McDonald PJ, Trostmann U, et al. Cefdinir versus amoxicillin/ clavulanic acid in the treatment of suppurative acute otitis media in children. Eur J Clin Microbiol Infect Dis. 1997;16:214-219.

27. Block SL, McCarty JM, Hedrick JA, et al., and the Cefdinir Otitis Media Study Group. Comparative safety and efficacy of cefdinir vs amoxicillin/ clavulanate for treatment of suppurative acute otitis media in children. Pediatr infect Dis J. 2000;19:S159- S165.

28. Gooch WM III, Philips A, Rhoades R, et al. Comparison of the efficacy, safety and acceptability of cefixime and amoxicillin/ clavulanate in acute otitis media. Pediatr Infect Dis J. 1997;16(suppJ):S21-S24.

29. Mandel EM, Casselbrant ML, Kurs-Lasky M, Bluestone CD. Efficacy of ceftibuten compared with amoxicillin for otitis media with effusion in infants and children. Pediatr Infect Dis J. 1996;15:409-414.

30. McLinn SE, McCarty JM, Perrotta R, et al., and members of the Ceftibuten Otitis Media United Slates Study Group. Multicenter controlled trial comparing ceftibuten with amoxicillin/clavulanate in the empiric treatment of acute otitis media. Pediatr Infed Dis J. 1995;14:S108-S114.

31. Mendelman PM, Del Beccaro MA, McLinn SE, Todd WM. Cefpodoxime proxetil compared with amoxicillinclavulanate for the treatment of otitis media. J Pediatr. 1992; 121: 459-465.

32. Marchant CD, Carlin SA, Johnson CE, Shurin PA. Measuring the comparative efficacy of antibacterial agents for acute otitis media: the "Pollyanna phenomenon." J Pediatr. 1992;120:72-77.

33. Dagan R, McCracken GH Jr. Flaws in design and conduct of clinical trials in acute otitis media. Pedialr Infect Dis J. 2002;21:894-902.

34. Pichichero ME. Short course antibiotic therapy for respiratory infections: a review of the evidence. Pediatr Infect Dis J. 2000;19:929-937.

35. Cohen R, Levy C, Boucherat M, et al. Five vs ten days of antibiotic therapy for acule otitis media in young children. Pediatr Infect Dis J. 2000;19:458-463.

36. Cohen R, Navel M, Grunbcrg J, et al. One dose ceftriaxone vs ten days of amoxicillin/clavulanate therapy for acute otitis media: clinical efficacy and change in nasopharyngcal flora. Pediatr Infe\ct Dis J. 1999;18:403-409.

37. Cohen R, Levy C, Boucherat M, et al. A multicenter, randomized, double-blind trial of 5 versus 10 days of antibiotic therapy for acute otitis media in young children. J Pediatr. 1998;133:634-639.

38. Kozyrskyj AL, Hildes-Ripstein E, Longstaffe SEA, et al. Treatment of acute otitis media with a shortened course of antibiotics: a meta-analysis. JAMA. 1998;279:1736-1742.

39. Pichichero ME, Marsocci SM, Murphy ML, et al. A prospective observational study of 5-, 7-, and 10-day antibiotic treatment for acute otitis media. Otolaryngol Head Neck Surg. 2001;124:381-387.

40. Paradise SL. Short-course antimicrobial treatment for acute otitis media: not best for infants and young children. JAMA. 1997;278:1640-1642.

41. Heikkinen T, Saeed KA, McCormick DP, et al. A single intramuscular dose of ceftriaxone changes nasopharyngeal bacterial flora in children wilh acule otitis media. Acta Pdiatr. 2000;89:1316- 1321.

42. Dagan R, Leibovitz, E, Cheletz G, et al. Antibiotic treatment in acute otitis media promotes superinfection with resistanl Streptococcus pneumoniae carried before initiation of treatment. J Infect Dis. 2001;183:880-886.

43. Dabernat H, Geslin P, Megraud F, et al. Effects of cefixime or co-amoxiclav treatment on nasopharyngeal carriage of Streptococcus pneumoniae and Haemophilus influenzae in children with acute otitis media. J Antimicrob Chemother. 1998;41:253-258.

44. Haiman T, Leibovilx E, Piglansky L, et al. Dynamics of pneumococcal nasopharyngeal carriage in children wilh nonresponsivc acule otitis media treated wilh two regimens of intramuscular ceflriaxone. Pediatr Infect Dis J. 2002;21:642-647.

45. Cedax prescribing information. Morrisville, NC: Biovail Pharmaceuticals; 2002.

46. Omnicef prescribing information. North Chicago, IL: Abbott Laboratories; 2001.

47. Rocephin prescribing information. Nutley, NJ: Roche Laboratories; 2000.

48. Vantin prescribing information. Kalamazoo, MI: Pharmacia & Upjohn; 2003.

49. Augmentin ES-600 prescribing information. Research Triangle Park, NC: GlaxoSmithKline; 2003.

Peter C. Appelbaum, MD, PhD

ClinPediatr. 2005;44:95-107 Professor, Division of Clinical Pathology, Medical Director, Clinical Microbiology, Milton S. Hershey Medical Center, Hershey, Pennsylvania.

Supported in part through a grant from GlaxoSmithKline.

Reprint requests and correspondence to: Peter C. Appelbaum, MD, PhD, Professor, Clinical Pathology, Milton S. Hershey Medical Center, 500 University Drive, Mail Svc H160, Room C6518, Hershey, PA 17033.

2005 Westminster Publications, Inc., 708 Glen Cove Avenue, Glen Head, NY 11545, U.S.A.

Copyright Westminster Publications, Inc. Mar 2005

Source: Clinical Pediatrics

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