Otite - Tratamento - Treatment and Prevention OM

Pediatrics
Treatment and Prevention of Otitis Media

John Erramouspe and Catherine A Heyneman
OBJECTIVE:
To review and summarize recent advances in the treatment and prevention of otitis media (OM).
A MEDLINE search (1996March 2000) was performed to identify relevant primary and review articles. References from these articles were also reviewed if deemed important.
STUDY SELECTION AND DATA EXTRACTION: English-language primary and review articles focusing on the treatment and prevention of acute otitis media (AOM) were included. Studies focusing exclusively on OM with effusion or serous OM and chronic suppurative OM were excluded. Information regarding prevention and drug therapy was reviewed, with an emphasis placed on advances made in the last two years. DATA SYNTHESIS: Recently, an expert panel of the Centers for Disease Control and Prevention recommended use of only three of 16 systemic antibiotics approved by the Food and Drug Administration for treatment of AOM: amoxicillin, cefuroxime axetil, and ceftriaxone. Controversy exists over the importance of key selection factors used by the expert panel in determining which antibiotics to recommend in a two-step treatment algorithm, that is, in vitro data, pharmacodynamic profiles, and necessity for coverage of drugresistant Streptococcus pneumoniae at all steps of empiric treatment. Additional antibiotic and patient selection factors useful for individualizing therapy include clinical efficacy, adverse effects, frequency and duration of administration, taste, cost, comorbid infections, and ramifications should bacterial resistance develop to the chosen antibiotic. Presumed or past patient/caregiver adherence (especially when antibiotic failure has occurred) is also paramount in selecting antibiotic therapy. A three-step treatment algorithm for refractory AOM that employs amoxicillin, trimethoprim/sulfamethoxazole (TMP/SMX), or high-dose amoxicillin/ clavulanate (depending on the prior dose of and adherence to amoxicillin therapy), and ceftriaxone or tympanocentesis at steps 1, 2, and 3, respectively, appears rational and cost-effective. The recent upsurge in antimicrobial resistance is highlighted, and recommendations are presented for the treatment of AOM and prevention of recurrent otitis media (rAOM).
DATA SOURCES:
Amoxicillin remains the antibiotic of choice for initial empiric treatment of AOM, although the traditional dosage should be increased in patients at risk for drug-resistant S. pneumoniae. In cases refractory to high-dose amoxicillin, TMP/SMX should be prescribed if adherence to prior therapy seemed good or complete, or high-dose amoxicillin/clavulanate if adherence was incomplete or questionable. Ceftriaxone should be reserved as third-line treatment. The increasing prevalence of drug-resistant S. pneumoniae emphasizes the importance of alternative medical approaches for the prevention of OM, as well as judicious antibiotic use in established cases. Removal of modifiable risk factors should be first-line therapy for prevention of rAOM. We support the use of conjugate pneumococcal vaccine per guidelines for prevention of rAOM from the Advisory Committee on Immunization Practice of the Centers for Disease Control and Prevention, with consideration given to influenza vaccine for cases of rAOM that historically worsen during the flu season. Sulfisoxazole prophylaxis should be reserved for children who are immunocompromised, have concurrent disease states exacerbated by AOM, or meet the criteria of rAOM despite conjugate pneumococcal and influenza vaccination. Therapy should be intermittent, beginning at the first sign of an upper respiratory infection, and should continue for 10 days. The invasive nature and risks of anesthesia relegate myringotomy, tympanostomy tubes, and adenoidectomy to last-line therapies for rAOM.
KEY WORDS: otitis media, antibiotics, prophylaxis, resistance, Streptococcus pneumoniae, oligosaccharides, xylitol, conjugate pneumococcal vaccine, influenza vaccine.
CONCLUSIONS:
Ann Pharmacother 2000;34:1452-68.

ACPE UNIVERSAL PROGRAM NUMBER:
407-000-00-028-H01
titis media (OM) is second to the common cold as an O infectious cause of disease in infants and children. Established risk factors include male gender, Native Amer1
Author information provided at the end of the text.
ican or Eskimo descent, pacifier use, larger-group day care settings, exposure to tobacco smoke, and lack of breastfeeding.2 The medical and surgical costs associated with treatment of OM within the US have been estimated at between $3 billion and $4 billion annually.3,4 This review summarizes and highlights recent advances in the treatwww.theannals.com
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The Annals of Pharmacotherapy
2000 December, Volume 34
ment and prevention of OM, with an emphasis placed on information reported over the past two years. More detailed background information regarding the etiology, epidemiology, pathophysiology, and pharmacoepidemiology of OM is beyond the scope of this article. Thorough reviews of these topics are available.2,5-7 The objectives of this article include updating the reader regarding the rationale behind current acute OM (AOM) treatment guidelines, as well as reviewing and ranking alternative medical approaches for the prophylaxis of recurrent OM (rAOM) in a treatment algorithm. Treatment of Acute Otitis Media Streptococcus pneumoniae (pneumococcus) is the most important bacterial cause of AOM, followed closely by nontypable Haemophilus influenzae and Moraxella catarrhalis.8 In recent years, there has been a worldwide increase in strains of pneumococcus that are resistant to penicillins as well as other antibiotics. The National Committee for Clinical Laboratory Standards (NCCLS)9,10 defines breakpoints for susceptible, intermediate-resistant, and resistant pneumococci according to minimum inhibitory concentrations (MICs) of 0.06, 0.121.0, and 2.0 g/mL (for penicillin G) and <1.0, 1.0 2.0, and >2.0 g/mL (for amoxicillin), respectively. The increasing resistance of pneumococcus to many of the antibiotics typically used in treating AOM has affected recent treatment guidelines in the US. In 1999, a panel of experts convened by the Centers for Disease Control and Prevention (CDC) recommended new guidelines for treating AOM with antibiotics (Table 1).
FIRST STEP: HIGH-DOSE AMOXICILLIN
The CDCs expert panel8 advocated amoxicillin as firstline treatment of AOM but recommended increasing the initial dosage used for empiric treatment from 40 to 45 mg/kg/d (usual or standard dose) to 8090 mg/kg/d (high dose). The rationale behind this recommendation is that,
unlike H. influenzae and M. catarrhalis, S. pneumoniae does not produce -lactamase.2 The mechanism of pneumococcal resistance is alteration in penicillin-binding proteins, a genetic ploy that could theoretically be overcome by simply increasing penicillin/amoxicillin concentrations in the middle ear fluid (MEF). What clinical evidence exists to support such a dosage increase? Lister et al.11 employed an in vitro pharmacodynamic model to study the killing of three strains each of penicillin-susceptible (MIC 0.06 g/mL), penicillinintermediate-resistant (MICs 1 strain, 0.25 g/mL; 2 strains 0.5 g/mL), and penicillin-resistant (MIC 4 g/mL) pneumococci. Three different peak amoxicillin concentrations, 3, 6, and 9 g/mL (achieved every 12 h) and an elimination half-life of 1.6 hours were simulated. Extrapolated from a concentrationtime curve, it appeared that the percentages of the dosing interval during which the amoxicillin concentration exceeded the MIC for the susceptible, intermediate-resistant, and resistant pneumococcal isolates were 67%, 4755%, and 0% (3 g/mL peak profile); 100%, 70 84%, and 10% (6 g/mL peak profile); and 100%, 7988%, and 22% (9 g/mL peak profile), respectively. These results suggested that peak amoxicillin concentrations of 6 and 9 g/mL might be sufficient for elimination of penicillin-nonsusceptible pneumococcal strains, especially those of intermediate resistance. Canafax et al.12 administered a single oral dose of amoxicillin 25 mg/kg (following 23 d of standard oral dosing of amoxicillin 13.3 mg/kg/dose every 8 h) to 30 children with AOM. The regular morning dose of 13.3 mg/kg had been withheld prior to administering 25 mg/kg. At least one MEF sample per patient (37 total samples) was collected between 0.5 and four hours after dosing. An MEF concentration mean of approximately 9.5 g/mL (range, undetectable to 20.6 g/mL) occurred three hours after 25 mg/kg was administered. The estimated time that the MEF amoxicillin concentrations were above 1.0 and 2.0 g/mL was approximately four and 2.5 hours (50% and 31% of an 8-h dosing interval), respectively. The MEF amoxicillin penetration tended to be lower in patients with concurrent
Table 1. Recommended Antibiotics for Treating Acute Otitis Media in Children8

Antibiotics in Prior Month Initial Alternative Choices Clinical Treatment Failure Day 3 Days 1028
b
No
HD amoxicillin standard-dose amoxicillin
HD amoxicillin/clavulanate cefuroxime axetil im ceftriaxonec
HD amoxicillin/clavulanateb cefuroxime axetil im ceftriaxonec HD amoxicillin/clavulanate cefuroxime axetil im ceftriaxonec or tympanocentesis
Yes
HD amoxicillin HD amoxicillin/clavulanate cefuroxime axetil
im ceftriaxonec clindamycind or tympanocentesis
HD = high-dose. 8090 mg/kg/d. b Requires formulation not yet commercially available or two separate prescriptions: amoxicillin/clavulanate (from 6.4 to ~10 mg/kg/d of clavulanate) and amoxicillin to boost the cumulative dosage to 8090 mg/kg/d. c 50 mg/kg im once daily for three days. d Not effective against Haemophilus influenzae or Moraxella catarrhalis.
a
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viral infection compared to those without. One weakness of the study was the lack of measurement of baseline amoxicillin concentrations prior to the 25-mg/kg dose. Single doses of amoxicillin 15 mg/kg have generated mean peak values of 36 g/mL.11 Using this information, the contribution from a dose of 13.3 mg/kg given at least eight hours earlier is estimated at 1 g/mL according to the 3- and 6g/mL peak profiles generated by Lister et al. Another weakness of this study12 was the exclusion of 13 MEF samples in which the amoxicillin concentration was undetectable. These samples were excluded because of low volumes (e.g., 8 of 13 were <60 L) and the dilutions required to analyze them (6- to 50-fold dilutions), which probably diluted the original amoxicillin concentrations below the assay sensitivity. The authors concluded that the current amoxicillin dosing recommendation of 40 mg/kg/d is inadequate to effectively eradicate resistant pneumococci, especially when viral coinfection exists. They suggest an initial dosing regimen of 7590 mg/kg/d for treatment of AOM. Amoxicillin MEF concentrations obtained one to three hours after single doses of amoxicillin/clavulanate, 35/5 mg/kg (6 patients) or 45/3.2 mg/kg (14 patients) in infants and children with AOM with effusion, have been reported.13 MEF concentrations of <1, 12, 2 4, and >4 g/mL occurred in two (10%), three (15%), seven (35%), and eight (40%) patients, respectively. At the higher dose, the amoxicillin breakpoints for intermediate-resistant (1 g/mL) and resistant (2 g/mL) strains of pneumococci were exceeded by at least threefold in nine of 14 (64%) and four of 14 (29%) MEF specimens, respectively. The authors stated that the 45-mg/kg dose of amoxicillin, whether or not it was combined with clavulanate, would likely be effective treatment for approximately two-thirds of intermediate-resistant and one-third of resistant pneumococci strains causing AOM. Controversy exists as to whether the dosage of amoxicillin should be doubled only on the basis of laboratory data (and no clinical evidence) and what effect this dosage change will have on the incidence of adverse effects, such as rash, vomiting, and diarrhea.14 To our knowledge, no prospective, randomized, comparative trials of standardversus high-dose amoxicillin exist, and high costs will most likely preclude pharmaceutical companies from seeking Food and Drug Administration (FDA) approval for high-dose amoxicillin therapy. In addition, many children with AOM respond to standard-dose amoxicillin.15 The CDC panel of experts8 suggested that standard-dose amoxicillin is still a worthy first-line consideration in patients at low risk for drug-resistant S. pneumoniae (DRSP) (e.g., no antimicrobial exposure in preceding 3 mo, age >2 y, no day care attendance). We support the routine empiric first-line use of highdose amoxicillin in children at high risk for DRSP-mediated AOM who are not truly allergic to penicillins. Our support is based on the following information. First, S. pneumoniae is the most common cause of bacterial AOM (40 50%8) and the increasing incidence of DRSP in the US.16
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Second, there is a need to eradicate pathogenic bacteria from the middle ear rather than simply produce clinical improvement (clinical improvement alone may reflect the high natural spontaneous cure rate for AOM rather than an antibiotics effectiveness). A meta-analysis17 of 33 randomized trials involving 5400 children with AOM reported a spontaneous cure rate of 81% (95% CI, 69% to 94%) as part of the natural history of untreated AOM. Antibiotic therapy statistically raised this cure rate by only 13.7% (95% CI, 8.2% to 19.2%). The high spontaneous cure rate for AOM is the reason practitioners in the Netherlands and Scandinavian countries generally first treat AOM in children older than two years of age symptomatically with analgesics alone, reserving antibiotic therapy for patients whose AOM fails to resolve after three to four days.18-20 Conclusions about antibiotic efficacy for AOM based solely on either clinical improvement or bacteriologic eradication should be viewed with suspicion since they are not always correlated.21,22 Both should be distinct goals of antibiotic therapy for AOM and documented in clinical trials. Comparative trials using only clinical outcome criteria to assess efficacy between antibiotics have generally not demonstrated differences, quite possibly because they lacked adequate sample size or power. Larger sample sizes are necessary to show true clinical differences between two antibiotics, assuming they do exist. For example, assuming a power of 90% and an of 0.05, one would need to enroll a total of at least 2054 subjects to confirm the suspicion that antibiotic A has 5% greater clinical efficacy than antibiotic B.23 The number of subjects required decreases, but only to 473, if a difference in clinical efficacy of 10% is assumed. Adequate funding for larger, solely clinically based outcome studies is usually difficult to obtain. Clinical coupled with bacteriologic outcome criteria may be more sensitive in detecting true differences between antibiotics and more acceptable for the funding agency. Third, amoxicillin displays a favorable pharmacodynamic profile (i.e., longest time above MIC90 for DRSP of any commercially available oral antibiotic).24 The pharmacodynamic profile of an antibiotic used for AOM is considered its ability to penetrate into and persist in MEF above the MIC of typical AOM bacteria. Antibiotics that exceed the MIC90 of typical AOM bacteria in MEF for at least 40 50% and 60 70% of the dosing interval have been associated with bacteriologic eradication rates of 80 85% and approaching 100%, respectively. The time that an antibiotic persists at the site of action in a concentration greater than the MIC of a pathogenic organism is a surrogate marker of microbiologic and clinical efficacy that appears appropriate to use in selecting antibiotics that demonstrate concentration-independent killing (e.g., amoxicillin, cephalosporins). Finally, amoxicillin has traditionally been a well-tolerated antibiotic, even at high dosages. No difference was detected in adverse effects among 274 children, aged three to 10 years, randomly allocated to receive either amoxicillin 125 mg three times daily for seven days or 750 mg twice daily for two days.25 Although no weights were reported
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for these patients, it is likely that some children receiving the higher dosage may have been taking approximately 75100 mg/kg/d, assuming an average weight range of 1520 kg for children three to six years old. Only one case of diarrhea was reported out of 43 infants and children with OM who received amoxicillin 150 mg/kg/d.26
SECOND-STEP: WHEN AMOXICILLIN INITIALLY FAILS
What is the recommended second-line therapy for AOM when high-dose amoxicillin appears to have failed? Controversy exists regarding recommendations made by various authors for antibiotics to treat AOM refractory to highdose amoxicillin.8,15,27-29 The main controversy dwells on the need to provide coverage for DRSP if high-dose amoxicillin has already been prescribed. The traditional strategy has been to prescribe an oral antibiotic that is effective against -lactamaseproducing bacteria (but not necessarily DRSP), is dosed infrequently (usually once to twice daily), is low cost, and has acceptable palatability. However, some practitioners believe that this strategy may not be optimal in the present era of increasing prevalence of DRSP.8 Two bacteriologic studies30,31 highlight this dilemma. Gehanno et al.30 identified S. pneumoniae in 67 of 170 bacterial isolates (39.4%) taken from 126 AOM patients in the Paris region who had failed prior oral antibiotics. The most frequently prescribed prior antibiotic was amoxicillin/clavulanate in 43% of cases. Reduced susceptibility to penicillin (MIC 0.125 g/mL) was present in 52 of the pneumococcal isolates (77.6%). Similarly, in Washington, DC, pneumococcus has been found to be responsible for approximately one-third of the bacterial isolates cultured from the MEF of children not responding to other oral antibiotics. Antibiotic resistance among these pneumococcal isolates was >60%.31 The CDC panel of experts8 believed that empirically prescribed second-line antibiotics should be effective against not only -lactamaseproducing H. influenzae and M. catarrhalis, but also DRSP. One exception to this dual-coverage guideline would be a culture of the MEF in which a single pathogenic bacteria was identified. In this case, antibiotic therapy could be definitively narrowed (as opposed to broad empiric therapy). For example, clindamycin is not effective against H. influenzae or M. catarrhalis, but is potentially very useful for culture-confirmed pneumococcal AOM, especially when caused by penicillin-resistant S. pneumoniae (PRSP). The additional requirement for effectiveness against both DRSP and -lactamaseproducing bacteria is extremely limiting. Only three of the 16 systemic antibiotics presently approved by the FDA for OM32 are acceptable according to the CDCs expert panel.8 The other systemic antibiotics32 (i.e., amoxicillin, trimethoprim/sulfamethoxazole [TMP/ SMX], erythromycin/sulfisoxazole, azithromycin, clarithromycin, cefixime, ceftibuten, cefdinir, loracarbef, cefprozil, cefpodoxime, cefaclor, cephalexin) were not endorsed because of limited data showing these agents capable of eradicating DRSP from the middle ear and/or little -lactamase
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coverage. The three antibiotics recommended by the expert panel8 include high-dose amoxicillin/clavulanate (presently requires additional prescription of amoxicillin to boost the dose to 80 90 mg/kg/d while limiting the clavulanate to 10 mg/kg/d), cefuroxime axetil, and intramuscular ceftriaxone (Table 1). Amoxicillin/clavulanate 40 mg/kg/d in three divided doses has been suggested24 as the best oral antibiotic available for maximizing the time in which the concentration remains greater than the MIC (T > MIC) for the full spectrum of AOM bacteria (i.e., S. pneumoniae, H. influenzae, M. catarrhalis). The T > MIC for DRSP is increased by supplementing this usual dose of amoxicillin/clavulanate with a second prescription for additional amoxicillin. In the future, high-dose amoxicillin/clavulanate (90/6.4 mg/kg/d, twice daily) will likely be commercially available to facilitate adherence to and coverage of both -lactamaseproducing bacteria and DRSP.33 Cohen et al.34 found no difference in efficacy between a 10-day course of high-dose amoxicillin/clavulanate (80/10 mg/kg/d divided in 3 doses daily) and a single dose of ceftriaxone (50 mg/kg im) in the treatment of newly diagnosed patients with AOM in France (an area with a high rate of PRSP isolated from patients with AOM, >50% as of 1995). A weakness of the study is that tympanocentesis was not done to identify MEF bacteria, although culture and sensitivity tests using samples from nasopharyngeal swabs were performed prior to treatment and on days 1214 to study the effect of treatment on bacterial carriage. No difference existed in the carriage of S. pneumoniae, M. catarrhalis, and H. influenzae between the two groups prior to treatment. The reduction of S. pneumoniae and M. catarrhalis carriage at days 1214 was significantly greater for the amoxicillin/clavulanate group compared with the ceftriaxone group (42.6% vs. 14.9% and 47% vs. 12.9% reductions, respectively; p < 0.0001 for both). Amoxicillin/clavulanate has a high acquisition cost compared with older, low-cost antibiotics (i.e., amoxicillin, TMP/SMX, erythromycin/sulfisoxazole [Table 2]).35 Although diarrhea was a major problem with the original formulations of amoxicillin/clavulanate (4:1 ratio), the newer formulations (7:1) have substantially lessened this problem.36 The next generation of amoxicillin/clavulanate formulations (14:1) should maintain a similar reduced incidence of gastrointestinal problems since they should contain a similar amount of clavulanate per dose as the 7:1 formulations.33 Cefuroxime axetil was included as a viable second-line antibiotic by the CDCs expert panel8 due primarily to one prospective study of children with pneumococcal AOM. Gehanno et al.37 treated 84 children with AOM with cefuroxime axetil 30 mg/kg/d in two divided doses for eight days. Treatment failure, defined as persistent signs of infection for >10 days (fever, otoscopic abnormalities, pain), occurred in three of 42 penicillin-susceptible (7%, MIC <0.1 g/mL), one of 10 intermediate-resistant (10%, MIC 0.11.0 g/mL), and eight of 32 highly resistant (25%, MIC 2.0 g/mL) pneumococcal isolates. The failure to repeat tympanocentesis to verify bacteriologic eradication
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and lack of a comparison/control group were methodologic weaknesses of this study. In a double-blind taste comparison of 22 antimicrobial suspensions,38 cefuroxime axetil as well as oxacillin, dicloxacillin, cefpodoxime, and erythromycin/sulfisoxazole, were judged as having the worst aftertastes, which the authors believed could potentially jeopardize compliance. Cefuroxime also has a high acquisition cost relative to older, low-cost antibiotics (Table 2).35 When coverage of both -lactamasepositive H. influenzae and DRSP is necessary, we recommend high-dose amoxicillin/clavulanate rather than cefuroxime (Table 3).38,39 Our selection is based on greater palatability; similar cost, even with the additional amoxicillin prescription (Table 2); and higher pharmacodynamic profile of amoxicillin against DRSP.24,35,38 The most recent commercially available amoxicillin/clavulanate formulations (7:1) should be prescribed at an amoxicillin/clavulanate dosage of 45/6.4 mg/kg/d; additional amoxicillin should be prescribed to boost the cumulative dosage to 8090 mg/kg/d. Occasionally, some patients or caregivers find it too difficult to administer two antibiotics at the same time. In these cases, cefuroxime axetil is an appropriate choice. Controversy exists as to what place the oral antibiotics excluded by the CDCs expert panel8 should hold in AOM therapy. TMP/SMX has long been beneficial for treating AOM due to its twice-daily dosing schedule, lack of admixture requirement for the suspension, low cost (Table 2),
and broad effectiveness against most middle ear pathogens.35 Recently, however, 11.9% of all isolates of S. pneumoniae were found to be resistant to TMP/SMX (13.4% and 40.4% TMP/SMX resistance for penicillin intermediate- and highly resistant pneumococcal isolates, respectively).40 Even isolates of H. influenzae have been found to be resistant to TMP/SMX in up to 9% of cases.41 Despite the concerns raised by results of in vitro studies, we are not aware of any randomized, comparative trial that demonstrates TMP/SMX to have less clinical and bacteriologic effectiveness than another antibiotic for initial treatment of AOM. In addition, no randomized, comparative trials of any antibiotics have been published addressing the treatment of AOM initially unresponsive to high-dose amoxicillin. Given the lack of comparison with other antibiotics and trends toward greater in vitro resistance, it is probably appropriate to reserve the use of TMP/SMX to special AOM situations, such as initial treatment of AOM in amoxicillinallergic/intolerant patients who lack risk factors for DRSP (antibiotic use in the preceding month, age <2 y, day care attendance, recent hospitalization, infection during the late winter or spring), AOM refractory to at least a three-day regimen of high-dose amoxicillin where adherence was good or complete, and situations when high acquisition cost of the antibiotic is likely to result in the caregiver not filling the prescription.42 Although AOM has traditionally been treated with a 10day course of antibiotics, the evidence to support this dura-
Table 2. Selected Antibiotic Suspension Costsa

Dollar Costb (optimal patient weights where no wastage occursc) Daily Dose (mg/kg/d) Weight Range (kg) 05 510 1015 1520 20
Antibiotic
Low cost amoxicillin, HD (generic) amoxicillin, SD (generic) ery-sulf (generic) TMP/SMX (generic) Moderate/high cost amoxicillin/clavulanate, HDd amoxicillin/clavulanate, SD azithromycin cefaclor (generic) cefdinir cefixime cefpodoxime proxetil cefprozil ceftibuten cefuroxime axetil clarithromycin loracarbef
90 45 50 (ery) 8 (TMP) 90/6.4 45/6.4 10 (loading dose), then 5 once daily for 4 d 40 14 8 10 30 9 30 15 30
1.94 (4.2) 2.25 (4.4) 7.46 1.38 (3) 18.80 (4.4) 16.55 (4.4) 27.74 10.13 (4.7) 33.26 32.85 18.11 15.26 (4.2) 27.17 15.40 (4.2) 16.13 15.07 (3.3)
2.78 (8.3) 1.94 (8.3) 7.46 (8) 2.30 (5) 26.42 (6.7) 22.10 (6.7) 27.74 19.13 (9.4) 33.26 32.85 18.11 (5) 22.77 (6.3) 27.17 (6) 26.80 (8.3) 16.13 (8.3) 25.16 (6.7)
5.03 (13.9) 2.25 (11.1) 10.73 (12) 4.59 (10) 44.83 (13.3) 42.05 (13.3) 27.74 (10) 36.37 33.26 (10.7) 32.85 (12.5) 34.45 (10) 41.61 (12.5) 35.29 (12) 53.59 30.70 35.22 (10)
5.56 (16.7) 2.78 (16.7) 13.66 (16) 6.89 (15) 68.42 (17.8) 61.85 (17.8) 27.74 36.37 (18.75) 52.80 (17.8) 52.44 (18.75) 51.55 (15) 54.92 (16.7) 56.41 (18) 53.59 (16.7) 30.70 (16.7) 60.38 (16.7)
8.34 (25) 4.50 (22.2) 18.19 (20) 9.18 (20) 78.10 (22.2) 73.60 (22.2) 27.74 (20, 30, or 40) 55.50 (28.1) 66.52 (21.4) 66.11 (25) 65.54 (20) 69.92 (20.8) 71.18 (24) 80.39 (25) 56.85 (33.3) 75.50 (23.3)
ery-sulf = erythromycinsulfisoxazole; HD = high dose; SD = standard dose; TMP/SMX = trimethoprim/sulfamethoxazole. a Costs for treating infants and children within various weight ranges in 5-kg increments up to 20 kg, and 20 kg. b Average wholesale price (brand) or federal upper limit price (generic)35 for 10-day regimen at listed dose (azithromycin 5 d). c Dollar cost plus the optimal patient weight in parentheses (i.e., weight where no wastage occurs when given at listed dose for 10 d); dollar cost listed alone indicates the closest larger bottle size with the least wastage. d Requires two prescriptions, amoxicillin/clavulanate plus amoxicillin; lack of wastage based on amoxicillin/clavulanate.
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tion is practically nonexistent and is probably more an extrapolation from the 10-day penicillin regimen used to treat streptococcal pharyngitis.43 A meta-analysis44 of 32 randomized, controlled trials of the treatment of AOM in children with antibiotics of different durations suggested the efficacy of a five-day course of antibiotic. Dowell et al.43 recommended that uncomplicated AOM (i.e., absence of perforated tympanic membrane, underlying medical conditions, chronic/recurrent OM) may be treated with a five-day course of antibiotics in children two years of age or older. Theoretical advantages to this shortened regimen include a reduction in selective pressure favoring resistant bacteria and greater adherence to therapy. We support the use of the five-day oral antibiotic regimen (high-dose amoxicillin included) for the initial treatment of uncomplicated AOM in children at least two years old. However, if the AOM fails to clear with the initial regimen, subsequent oral regimens should be 10 days long until resolution occurs (exception: azithromycin requires only 5 d of treatment). If the initial antibiotic chosen to treat AOM is standard-dose amoxicillin or TMP/SMX and symptomatic improvement (e.g., decreased ear pain, irritability, fever, sleeplessness, anorexia) together with a reduction in tympanic membrane inflammation, redness, bulging, and/or
otorrhea have not occurred by day 3, resistant -lactamaseproducing H. influenzae and/or pneumococcus should be suspected. In this case, the second-step antibiotic chosen should cover both types of bacteria. Disadvantages of the older macrolide/sulfonamide combination product erythromycin/sulfisoxazole include its requirement for dosing three to four times per day, potential for gastrointestinal upset, and unpleasant taste.38 As with TMP/SMX, the incidence of in vitro resistance of pneumococcus to erythromycin has increased in recent years.41 Advantages of erythromycin/sulfisoxazole for AOM include low cost and coverage of comorbid infections caused by atypical bacteria (e.g., Mycoplasma or Chlamydia pneumoniae). Neither erythromycin/sulfisoxazole, clarithromycin, nor azithromycin were recommended by the CDCs expert panel8 due to concerns of resistance to pneumococcus (~10% of isolates), substantial cross-resistance with lactams, and the inability to overcome pneumococcal resistance by increasing the dosage. Other authors15 have expressed concern about potentially inadequate extracellular MEF concentrations of erythromycin, clarithromycin, and azithromycin to treat H. influenzae and have not recommended them as second-line agents for treatment of refractory AOM. Although these antibiotics concentrate intracel-
Table 3. Recommended Antibiotics for Treating AOM in Childrena

Step 1 Good/Completeb Step 2a Adherence to Step 1 HD Amoxicillin Treatment Poor/Incompletec Step 3
Preferred
HD amoxicillin (8090 mg/kg/d) or SD amoxicillin (40 mg/kg/d)d TMP/SMXd
TMP/SMX
HD amoxicillin/clavulanatee
ceftriaxonef or tympanocentesis
Alternative(s)
SD amoxicillin/clavulanate cefdinirg cefixime cefpodoxime proxetilh ceftibuten cefuroxime axetilh azithromycinj clarithromycinj ery-sulfh,j
cefdinirg cefpodoxime proxetilh cefprozili cefuroxime axetilh
AOM = acute otitis media; DRSP = drug-resistant Streptococcus pneumoniae; ery-sulf = erythromycinsulfisoxazole; HD = high dose; SD = standard dose; TMP/SMX = trimethoprim/sulfamethoxazole. a Steps 2 and 3 indicated for clinical treatment failure after three days of antibiotic from prior step. Clinical treatment failure defined as lack of clinical improvement in signs and symptoms (e.g., ear pain, irritability, fever, sleeplessness, anorexia) together with tympanic membrane findings of inflammation, redness, bulging, or otorrhea. b Covers only -lactamasepositive Haemophilus influenzae. c Covers -lactamasepositive H. influenzae and DRSP. d Acceptable if low risk of DRSP (see text); failure of this antibiotic as the initial treatment of AOM warrants treatment with a second-step antibiotic that covers both -lactamasepositive H. influenzae and DRSP. e Presently requires patient/caregiver adherence to the concomitant administration of amoxicillin/clavulanate (45/6.4 mg/kg/d) and amoxicillin to boost the cumulative dose to 8090 mg/kg/d. f Three-dose regimen (50 mg/kg im once daily for 3 d). g Not clinically investigated for refractory AOM, although it possesses in vitro activity similar to that of cefpodoxime proxetil. h Taste may jeopardize compliance.38 i Although questionable in vitro activity against -lactamaseproducing H. influenzae, no difference in clinical efficacy was seen in one study with AOM patients harboring -lactamasepositive and negative H. influenzae.39 j Reserve for possible comorbid atypical bacterial infections (prescribe ery-sulf, clarithromycin, or azithromycin) or concerns of caregiver/patient adherence (prescribe azithromycin).
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lularly, the inflammatory cells in which they concentrate may be delivered in high amounts to the site of infection/ inflammation (e.g., the inner ear).45 A recommendation has been made that macrolide/azalide antibiotics be considered for AOM refractory to amoxicillin.45 Clarithromycin and azithromycin have moderate patient acquisition cost; azithromycin is especially competitively priced for children weighing 20 kg (Table 2).35 Azithromycin has other advantages over erythromycin/sulfisoxazole and clarithromycin, that is, an extended half-life (3060 h), permitting once-daily dosing for five days, relative lack of association with significant drug interactions, and better taste.38 Due to concern for inducing resistant H. influenzae and, especially, pneumococcal isolates from macrolide/azalide antibiotic overuse, we recommend that erythromycin/sulfisoxazole, clarithromycin, and azithromycin be reserved for situations when, despite good or complete adherence to high-dose amoxicillin, treatment failure has occurred, and either coverage of atypical bacteria for a comorbid infection is necessary or concerns of adherence by the patient/caregiver dictate that oral therapy for a short duration is warranted (azithromycin is recommended in this instance). Loracarbef, cefaclor, and cefprozil have excellent tastes and may be administered, conveniently, twice daily.38 However, these antibiotics have acquisition costs in the moderate (cefaclor) to high range (Table 2).35 Among the three antibiotics, cefprozil appears to have the most in vitro activity against DRSP, with one noncomparative, openlabel trial suggesting clinical effectiveness for children with persistent and recurrent AOM. Pichichero et al.39 treated AOM in 262 children aged six months to 12 years with cefprozil 30 mg/kg/d in two divided doses for 10 days. Eighteen percent of the children had persistent AOM (i.e., antibiotic used 7 d before study entry); 37% had recurrent AOM (i.e., 4 episodes/12 mo or 3 episodes/ 6 mo immediately preceding study entry). All children underwent tympanocentesis and had pretreatment cultures of the MEF performed. Subsequently, the clinical signs and symptoms of AOM were assessed by one telephone contact (days 3 6) and during two return visits (days 1115 and 28 40). Single and multiple bacterial pathogens were identified in 57% and 11% of the MEF samples, respectively. Satisfactory clinical responses in the children occurred in 13 of 14 with M. catarrhalis (93%), 56 of 75 with H. influenzae (75%), and 70 of 93 with S. pneumoniae (75%). There was no difference in the clinical success of patients harboring -lactamasepositive (30/42, 71%) and -lactamasenegative (26/33, 79%) H. influenzae. The clinical response rates for patients infected with penicillin-susceptible (MIC 0.06 g/mL; 39/50, 78%), intermediate-resistant (MIC 0.11 g/mL; 11/12, 92%), and -resistant (MIC 2 g/mL; 21/31, 68%) S. pneumoniae were similar to those reported from France by Gehanno et al.37 who used cefuroxime axetil to treat DRSP AOM. Both studies failed to include a comparison/control group and repeat tympanocentesis after completion of therapy.
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A major concern when using loracarbef, cefaclor, and cefprozil for AOM refractory to high-dose amoxicillin is their in vitro coverage of H. influenzae. A recent US surveillance study46 of the activity of oral antibiotics against pneumococcus and H. influenzae used pharmacodynamically derived breakpoints to determine susceptibilities. For the -lactams tested, the breakpoints for susceptibilities were based on drug concentrations in serum that maintained serum concentrations greater than the bacterias MIC for 4050% of the dosing interval. It has not been determined whether this new susceptibility testing method should someday replace the method presently used by the NCCLS.9,10 Out of 1676 clinical isolates of untypable H. influenzae (41.6% of the isolates produced -lactamase), the percentages of isolates reported susceptible to cefaclor, loracarbef, and cefprozil were 2%, 9%, and 14%, respectively, compared with 57%, 78%, 98%, and 100% for amoxicillin, cefuroxime, amoxicillin/clavulanate, and cefixime, respectively. Among 1476 strains of S. pneumoniae, over half (50.4%) were resistant, with roughly twothirds of these (64.5%) displaying high-level resistance. The overall susceptibilities of all S. pneumoniae isolates were 11% (loracarbef), 22% (cefaclor), 52% (cefixime), 63% (cefprozil and cefuroxime), 69% (azithromycin and clarithromycin), and 94% (amoxicillin and amoxicillin/ clavulanate). This study46 highlights a disturbing trend the increased resistance of key pathogens of AOM to antibiotics extensively used in the past for treating this infection. At present, the use of cefaclor and loracarbef for AOM refractory to high-dose amoxicillin seems difficult to support, unless sensitive bacteria have been identified. Cefprozil might be used in refractory patients whose adherence to high-dose amoxicillin was poor or incomplete, since the clinical response rate for DRSP appears similar to that of cefuroxime axetil.37,39 In addition, despite questionable in vitro susceptibility, the clinical response rate for -lactamaseproducing H. influenzae to cefprozil has not been proven to differ from -lactamasenegative H. influenzae.39,46 The CDCs expert panel report8 has been criticized for not giving greater consideration to advocating a secondstep approach to AOM initially refractory to amoxicillin, which concentrates on -lactamaseproducing bacteria alone.28 Use of this approach assumes that good adherence to an adequate regimen of amoxicillin has occurred as the initial AOM step and, therefore, -lactamaseproducing H. influenzae or M. catarrhalis are the most likely bacteria to have persisted. TMP/SMX seems the most cost-effective choice with this approach unless palatability and/or adverse effects preclude its use, or the community in which the patient lives has a high incidence of resistance of H. influenzae to TMP/SMX. In vitro resistance rates to TMP/ SMX of only 9.0% for H. influenzae and 6.5% for M. catarrhalis have been reported.47,48 Oral antibiotics considered as acceptable alternatives to TMP/SMX, albeit with greater acquisition costs, include standard-dose amoxicillin/clavulanate (45 mg/kg/d), cefuroxime, azithromycin, clarithromycin, erythromycin/sulfisoxazole, cefdinir, cefwww.theannals.com
ixime, cefpodoxime, and ceftibuten (Table 2).35 The last four antibiotics (third-generation cephalosporins) may be given once daily, have high acquisition costs (Table 2), and, with one exception (cefpodoxime), good taste.35,38 Cefpodoxime and cefdinir have similar in vitro antibacterial activity to organisms including penicillin-susceptible and intermediate-resistant S. pneumoniae, although neither antibiotic has been extensively evaluated in children with refractory AOM due to DRSP.49 Cefixime and ceftibuten are less active against pneumococci, especially DRSP, than cefpodoxime and cefdinir.
THIRD-STEP: CEFTRIAXONE AND TYMPANOCENTESIS
Presently, ceftriaxone is FDA-approved as only a singledose regimen for the treatment of AOM. Studies34,50-53 of treatment with single-dose ceftriaxone are limited to patients with new AOM. The CDC panel of experts8 believed that this duration may not be sufficient to treat refractory AOM due to PRSP and advocated a three-day regimen of ceftriaxone (50 mg/kg/dose im once daily for 3 d). Three studies21,54,55 have investigated this regimen in patients who initially failed oral antibiotic therapy; however, comparison with the single-dose regimen occurred in only one of these studies.55 Leibovitz et al.21 prospectively studied 92 pediatric patients with AOM who did not respond to treatment with either amoxicillin, amoxicillin/clavulanate, or cefaclor. MEF was collected prior to beginning the three-day ceftriaxone regimen and again on days 4 to 10. Among bacteria isolates recovered from the MEF, eradication occurred in 54 (100%) H. influenzae, 13 (100%) penicillin-susceptible pneumococcus, 28 of 34 (82%) penicillinintermediate-resistant pneumococcus (MIC 0.11.0 g/mL), one of two (50%) M. catarrhalis, and two (100%) S. pyogenes with treatment. Although all isolates of pneumococcus were susceptible to ceftriaxone (MIC <0.5 g/mL), four cases of bacteriologic failure (defined by a positive culture on days 410) and two cases of relapse (defined as a recurrence of the same organism before the end of follow-up of 17 2 d) occurred. All four patients who experienced bacteriologic failure of pneumococcus showed clinical improvement at the day 4 10 follow-up tympanocentesis; three of these patients experienced successful eradication with an additional five to seven days of ceftriaxone, and one patient was lost to follow-up. Another study54 evaluated the three-day ceftriaxone regimen in 186 children who clinically failed oral antibiotic therapy. Prior to ceftriaxone, an MEF specimen was obtained by either tympanocentesis or otorrhea pus suction. A second MEF specimen on days 35 was obtained only if PRSP (MIC 1 g/mL) was isolated with the initial tap and an effusion persisted. Clinical cure occurred in 145 of 173 (83.8%) evaluable patients on days 1012 (81.4% and 87.5% for S. pneumoniae and H. influenzaeinfected children, respectively). Thirteen patients were excluded from analysis of the clinical response for various reasons (e.g., 4 patients because of antibiotic treatment for intercurwww.theannals.com
rent diseases before day 10). Among 59 patients infected with pneumococci, 36 had PRSP isolates. The bacteriologic eradication at three to five days and clinical cure at 10 12 days occurred in 88.9% of patients with PRSP (24/27 evaluable patients and 32/36 patients, respectively). The final study55 was comparative and prospectively randomized 60 patients, aged three to 36 months, with nonresponsive AOM (persistent or relapsing AOM for which an antibiotic was administered for any period of time >48 h during the 14 d preceding tympanocentesis) to receive one day (group A, n = 29) or three days (group B, n = 31) of intramuscular ceftriaxone 50 mg/kg/d. Amoxicillin and amoxicillin/clavulanate were the main antibiotics administered before randomization (45% and 21% for group A; 32% and 35% for group B, respectively). Bacteria recovered included pneumococcus (n = 37), H. influenzae (n = 36), and Branhamella catarrhalis (n = 2). Pneumococcal isolates in group A were intermediately resistant to penicillin (MIC 0.11.0 g/mL) and ceftriaxone (MIC >0.5, but 1.0 g/mL) in 13 of 17 (76%) and 2 of 17 (12%) cases, respectively; two of 17 isolates (12%) were highly resistant (MIC >1.0 g/mL) to penicillin. In group B, pneumococcal isolates were resistant to penicillin and ceftriaxone (no MIC data specified) in 17 of 20 (85%) and one of 20 (5%) cases, respectively. Bacteriologic eradication occurred in all H. influenzae, B. catarrhalis, and penicillin-susceptible pneumococcal cases. Bacteriologic failure (positive culture on days 45) was seen more frequently in group A, the single-day ceftriaxone regimen (7/13, 54%), than in group B, the three-day (1/17, 6%) ceftriaxone regimen (p = 0.009). Both group A and B patients were followed until day 30 2 with no apparent difference evident in clinical (8 and 7 cases) and bacteriologic (6 and 4 cases, all with new pathogens) relapses, respectively. In conclusion, the three-day regimen was significantly superior to the one-day regimen in eradicating DRSP from the MEF of patients with nonresponsive AOM. The CDCs expert panel8 suggested that ceftriaxone might be used as second-line treatment for AOM initially refractory to high-dose amoxicillin. We believe that ceftriaxone regimens are probably better reserved as third-line treatment when both first- and second-line oral antibiotics have failed unless the risk of nonadherence to a five- to 10-day course of oral antibiotic appears very likely. Widespread use of ceftriaxone for mild infections such as AOM has the potential to select for resistant isolates, which could compromise ceftriaxones utility for moderate to severe infections. The three-day intramuscular ceftriaxone regimen has been shown to have superior bacteriologic eradication compared with the single-dose regimen.55 Ceftriaxone regimens that employ less-frequent dosing (e.g., every other day or every third day) or cumulative dosages (i.e., <3) may be just as effective but have not been evaluated. Two factors suggest that such regimens might be equally efficacious: concentration-independent killing of bacteria by cephalosporins, and high concentrations of ceftriaxone that are achievable and persist in MEF for extended periods.56 In one study,56 the maximum ceftriI
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axone MEF concentration (35 g/mL) from a single 50mg/kg intramuscular dose given to children with chronic middle-ear effusion occurred 24 hours later and was 35580 times higher than the MIC90 for the three major bacteria causing AOM, including PRSP. The estimated half-life in the MEF was 25 hours, and the T > MIC90 varied between 100 and >200 hours depending on the bacteria. Therefore, it might be possible to achieve the same level of bacterial eradication with fewer doses administered over a more prolonged period. The effect on adherence of ceftriaxone regimens employing fewer doses administered less frequently also needs to be investigated. Until additional studies are done, the three-day ceftriaxone regimen should generally be considered the preferred empiric thirdline treatment if tympanocentesis is not done. The CDCs expert panel8 suggested a diagnostic tympanocentesis be done when treatment failures occur in patients who have recently received multiple courses of antibiotics. Tympanocentesis is not a new or unique procedure.57 It is our opinion that, presently, few primary care physicians have been adequately trained to perform tympanocentesis. This lack of skilled training is probably the result of decades when the standard practice to counteract most AOM failures has been to treat empirically with a different antibiotic rather than perform tympanocentesis. Even manufacturers of antibiotics for AOM have voiced difficulties in finding physicians willing to perform tympanocentesis on children participating in studies.58 Undoubtedly, some physicians will remain reluctant to view tympanocentesis as necessary. Physician concerns regarding tympanocentesis may include the time and costs required to perform it and the attendant bacteriologic studies, caregiver/patient acceptance, liability in the event of a bad outcome, and lost clientele should they choose to refer patients for tympanocentesis. Despite these concerns, we recommend tympanocentesis as a viable third-line option and encourage physicians to improve their skills in this area. In summary, we recommend high-dose amoxicillin for initial empiric treatment of AOM in patients at risk of DRSP (Table 3).38,39 If patient risk factors for DRSP appear low, standard-dose amoxicillin or TMP/SMX are also appropriate for initial therapy, although symptomatic failure with either of these two regimens should warrant coverage of both -lactamasepositive H. influenzae and DRSP with the next antibiotic prescribed. If failure occurs after three days of good or complete adherence to high-dose amoxicillin, -lactamasepositive H. influenzae seems the most likely organism, and we recommend TMP/SMX for treatment. If there is a reason to avoid TMP/SMX in this situation, appropriate alternatives include standard-dose amoxicillin/clavulanate, oral third-generation cephalosporins, cefuroxime axetil, erythromycin/sulfisoxazole, azithromycin, or clarithromycin. Poor or incomplete adherence to and failure of high-dose amoxicillin as a first-step antibiotic should prompt coverage for both -lactamasepositive H. influenzae and DRSP. We prefer high-dose amoxicillin/ clavulanate, provided the patient/caregiver can adhere to the administration of two antibiotics at the same time. If
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adherence seems to be a potential problem, cefdinir, cefpodoxime proxetil, cefprozil, or cefuroxime axetil can be considered. We do not recommend loracarbef or cefaclor for empiric treatment of AOM due to the array of antibiotic alternatives available that have superior in vitro activity and pharmacodynamic profiles. The three-day intramuscular ceftriaxone regimen is the preferred empiric third-step choice. However, tympanocentesis-directed antibiotic therapy is also appropriate at this point, and we advocate its use although we suspect that, at present, few physicians feel comfortable performing it. Given the present risks and difficulties associated with treating AOM, renewed efforts at prevention appear warranted. Prevention of Otitis Media
ANTIBIOTICS
rAOM has been defined as three or more distinct episodes of AOM in a six-month period, or four occurrences within a single year.59 Prevention of rAOM is unarguably superior to treatment after the fact, particularly when the possible sequelae of hearing loss and potential long-range learning disabilities are considered.60,61 Continuous antimicrobial prophylaxis for rAOM has generally been considered efficacious. The most commonly recommended regimens have included oral amoxicillin 20 mg/kg/d or sulfisoxazole 3575 mg/kg/d given either once daily at bedtime or in two divided doses.5,61-63 Several reports64-67 assessing prophylactic antibiotic efficacy in children with rAOM have documented a two- to threefold reduction in AOM recurrences compared with placebo. One study68 reported no statistical difference in recurrences between treatment and placebo groups, despite use of amoxicillin 20 mg/kg/d. A 1993 meta-analysis of nine studies69 found an overall reduction of 0.11 AOM episodes per patient per month (95% CI 0.03 to 0.19) attributable to prophylactic antibiotic use. Considering the outer ranges of the 95% CI reported, this suggests that the prophylactic use of antibiotics could, on average, reduce yearly occurrences of AOM by approximately 0.4 2.3 episodes per child. These unimpressive results must be considered in light of the documented emergence of DRSP. Baquero et al.70 reported a clear and direct correlation between annual aminopenicillin use and the incidence of S. pneumoniae resistance. A recent Canadian study71 noted an increasing prevalence of pneumococci with reduced susceptibility to fluoroquinolones and postulated that this increase has occurred secondary to selective pressure from increased use of this antibiotic class. The use of prophylactic antibiotics has been documented as a risk factor for nasopharyngeal carriage of DRSP (p < 0.001).72 A meta-analysis73 reported that antibiotic use increases the risk of nasopharyngeal carriage of DRSP two- to fivefold. The importance of increasing pneumococcal resistance patterns is highlighted by the fact that penicillin-resistant species are, more often than not, resistant to multiple antibiotics and -lactams (includwww.theannals.com
ing cephalosporins) as well as non--lactam agents (e.g., macrolides, TMP/SMX).74 The importance of judicious antibiotic use is emphasized by the French study conducted by Gehanno et al.30 These authors evaluated the bacteriologic epidemiology of treatment failures for AOM in infants. While the percentage distribution of causative organisms isolated from MEF remained similar to that seen overall in AOM (40% S. pneumoniae, 36% H. influenzae, 5% M. catarrhalis), more than 75% of the S. pneumoniae isolates had reduced susceptibility to penicillin. In contrast, estimates of penicillin resistance in S. pneumoniae cultures obtained from US children are approximately 31%.74 Compelling evidence of the dangers of prophylactic antibiotic overuse has been reported recently.75 In this study, nasopharyngeal cultures were obtained from children taking daily or every-other-day oral TMP/SMX prophylaxis for at least six weeks and were compared with those from children taking no antibiotics. While the overall S. pneumoniae colonization rate was similar in the two groups, increased resistance to penicillin and multiple antibiotics was identified more frequently in the prophylaxis group (82% vs. 7% for penicillin resistance, p value NR; 82% vs. 0% for multiple-drug resistance, p = 0.00001, respectively). Overuse of antibiotics for AOM, rAOM, and OM with effusion is postulated to act as a natural selective pressure toward resistance.42,74 The use of strict criteria for patient selection has been advocated before prophylactic antibiotics are administered.30,42 Given that >90% of AOM cases are preceded by a respiratory tract infection, intermittent dosing of prophylactic antibiotics seems rational.76 The evidence supporting intermittent versus continuous prophylaxis is equivocal, however. One study77 comparing oral administration of azithromycin 5 or 10 mg/kg/wk with amoxicillin 20 mg/kg/d over a six-month period reported that the recurrence rate with azithromycin 10 mg/kg/wk was significantly lower (p < 0.05) than with amoxicillin. Treatment with azithromycin 5 mg/kg/wk was terminated early, however, due to a high AOM recurrence rate (55.5%). The only head-to-head comparison of continuous versus intermittent AOM prophylaxis in children with rAOM compared oral amoxicillin 10 mg/kg/dose given twice daily either continuously for four months or at the first sign of an upper respiratory tract infection and continued for two weeks.78 Continuous amoxicillin therapy was found to be superior to intermittent prophylaxis. Seventy-three percent of the continuous prophylaxis group had no AOM episodes; 52% of the intermittent prophylaxis group remained free of recurrences (p value NR). Two groups of investigators79,80 compared intermittent prophylaxis in OM-prone children with placebo. Prellner et al.79 reported a 50% decrease (p = 0.025) in AOM recurrences compared with placebo when children were given prophylaxis with penicillin V 25 mg/kg twice daily for 10 days initiated at the first sign of a respiratory tract infection. Another group of investigators,80 using a similar study design, failed to show a statistical difference
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in AOM recurrences when comparing administration of placebo with amoxicillin/clavulanic acid 20 mg/kg orally given twice daily for seven days at the first appearance of symptoms of respiratory tract infection. Low sample size (n = 104) and shorter treatment time (7 vs. 10 d) may have contributed to the lack of observed effect in the latter study. We support the criteria for antibiotic prophylaxis proposed by Paradise.59 Patients should meet the basic criteria for rAOM (at least 3 episodes of AOM during the preceding 6 mo or at least 4 occurrences within the preceding year). Some authors have cautioned against the use of sulfonamides for AOM prophylaxis on the basis of increased risk of severe cutaneous eruptions, blood dyscrasias, and hemolytic anemia in patients with glucose-6-phosphate deficiency. However, Gutman81 reviewed 14 studies using TMP/SMX in children and found that, of 2061 children treated for seven to 10 days, three (0.15%) discontinued therapy because of an adverse drug reaction, and all three reactions (rash, vomiting, leukopenia) subsided upon discontinuation. Current data82,83 confirm that serious hematologic, hepatic, and cutaneous reactions to sulfonamides are rare in children, and compare reasonably with the adverse effect profiles of many other antibiotics. Sulfisoxazole seems a rational first choice given its lengthy and convincing safety record, availability in liquid form, and some rather convincing data suggesting that, compared with amoxicillin, sulfisoxazole may be less likely to promote nasopharyngeal colonization with DRSP or -lactamase producing bacteria.42,84 Amoxicillin is a good alternative for patients allergic to sulfonamides. Azithromycin may be considered for prophylaxis in patients with sulfonamide allergies and a pathogen known to be resistant to amoxicillin or for patients allergic to both sulfonamides and -lactams. Intermittent dosing, although not proven superior to continuous prophylaxis, has nevertheless been documented to decrease recurrences of AOM by 50%79 and should be less likely to promote the selection and spread of resistant bacteria. Continuous antibiotic prophylaxis would probably also result in poor compliance when compared with intermittent prophylaxis, although this remains to be proven. The dosage recommended for antibiotic prophylaxis is generally half the usual therapeutic dosage and is given once daily, preferably at bedtime.85 We advocate a 10-day duration of prophylactic antibiotic therapy, regardless of the antibiotic chosen, based on the inferior results achieved in one study80 using the shorter course. Due to the nature of -lactam resistance of pneumococci (alterations in penicillin-binding proteins that may be overcome by elevated -lactam concentrations),74 the dosage of amoxicillin should depend on local prevalence of DRSP. If local resistance is low, we advocate the use of amoxicillin 20 mg/kg given orally at bedtime for 10 days, initiated at the first sign of a respiratory tract infection. If local pneumococcal resistance levels are known to be high, a dosage increase to 40 mg/kg/d for 10 days seems rational (this is still half the current recommended empiric therapy for AOM8). Breakthrough episodes of AOM require an alternative antibiotic regimen.85 For example, if a child has been treatI
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ed prophylactically at the first sign of a respiratory tract infection for at least three days and still has signs and symptoms of AOM (fever, fussiness, otalgia), it seems rational to recommend switching to a therapeutic dosage of an antibiotic with documented efficacy against DRSP and -lactamaseproducing H. influenzae and M. catarrhalis, such as high-dose amoxicillin/clavulanic acid, cefuroxime axetil, cefprozil, cefpodoxime proxetil, or cefdinir.16,86,87 Sulfonamides are not generally recommended after antibiotic treatment failure, due to diminished levels of TMP/SMX sensitivity reported in areas with a high prevalence of penicillin-resistant pneumococcus.87 When choosing an antibiotic, consideration should be given to knowledge of local levels of resistance as well as the patients risk factors and prior experience with antibiotics. Day care attendance, temperature >38 C with signs of otalgia, age less than two years, and prior antibiotic therapy with erythromycin/sulfisoxazole have been documented as independently predictive risk factors for PRSP.30
SURGICAL OPTIONS
ALTERNATIVE MEDICAL APPROACHES
Myringotomy and tympanostomy tube placement have been proposed as reasonable alternatives to repeated courses of antibiotics.88 Data comparing the efficacy of myringotomy or tympanostomy tube placement with chemoprophylaxis are sparse and equivocal, however; myringotomy has no demonstrable influence on the course of AOM.89-91 An increased incidence of retraction or atrophy of the tympanic membrane has been noted in patients who received myringotomy when compared with placebo controls.92 Gonzalez et al.93 compared tympanostomy tube insertion with sulfisoxazole 5001000 mg given orally twice daily or placebo in 65 children with rAOM. These authors reported that tympanostomy tube placement significantly reduced treatment failures when compared with placebo (23% vs. 60%, respectively; p < 0.02). The sulfisoxazole prophylaxis group reported 38% treatment failures, but this was not significantly different from either the tympanostomy tube group or the placebo group. It is important to note that these results were confounded by inclusion of 18 patients (27.7%) who had OM with effusion. In a larger trial,94 tympanostomy tube insertion was compared with amoxicillin 20 mg/kg/d or placebo in 264 children aged seven to 35 months. This study used stricter rAOM inclusion criteria, excluding all patients with OM with effusion. Both tube placement and chemoprophylaxis proved superior to placebo for the prevention of AOM recurrences (p < 0.001 for tympanostomy tubes and p = 0.03 for amoxicillin, respectively). Due to a 3.9% incidence of persistent tympanic membrane perforations in the tympanostomy tube group, however, these authors advocated amoxicillin prophylaxis over tympanostomy tube insertion for rAOM prevention. We believe the inherent risks of anesthesia and eardrum perforation, atrophy, or retraction, as well as the lack of convincing clinical evidence, relegate myringotomy and tympanostomy tube placement as last-line therapy for rAOM prevention.
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Concern regarding the spread of antimicrobial resistance has spurred interest in alternative medical approaches to AOM prevention, including the use of oligosaccharides and xylitol. In an interesting study,95 oligosaccharides administered intranasally prevented pneumococcal colonization of the nasopharynx of infant rats. The authors postulated that oligosaccharides act as ligand homologs to inhibit adherence the first step in the pneumococcal pathogenic process. If these results prove similar in human trials, oligosaccharides may be an innovative, easily administered agent for the prevention of AOM. Xylitol, a sugar substitute, has been widely used in Europe for the prevention of Streptococcus mutansmediated dental caries. While the mechanism is not clearly understood, xylitol 5% has been demonstrated in vitro96,97 to inhibit both the growth and epithelial cell adhesion of S. pneumoniae. Based on this information, Uhari et al.98,99 conducted two well-designed clinical trials investigating the usefulness of this compound in the prevention of AOM in young children attending day care centers. In the first trial,98 xylitol gum chewed five times daily (total 8.4 g/d) was well tolerated and achieved a 42% reduction in AOM episodes compared with sucrose-containing placebo gum (p < 0.04). The efficacy of xylitol was remarkably diminished in subjects who were noncompliant with the regimen, suggesting a dose-dependent effect. The second trial97 used a similar design to determine the efficacy of 8.4 10 g/d of xylitol gum, lozenges, or syrup (the latter dosage forms were included because gum is not appropriate for use in children <5 y old). The syrup and gum formulations of xylitol resulted in reductions in AOM recurrences of approximately 30% (p < 0.006) and 40% (p < 0.012), respectively, compared with placebo. Differences in AOM episodes between the lozenge formulation and placebo were not statistically significant. Lack of widespread availability (gum containing the requisite amount of xylitol is not commercially available in the US) and dosing five times a day will certainly limit the clinical usefulness of xylitol. However, further trials are certainly justified to document safety in children and to determine whether less frequent dosing, perhaps with dosage formulations containing higher concentrations of xylitol, could make this form of AOM prevention practical.
VACCINE STRATEGIES
S. pneumoniae is the most common bacterial cause of AOM; thus, it seems rational to expect that administration of a pneumococcal vaccine would reduce the incidence of AOM in children. However, the 23-valent unconjugated pneumococcal vaccine is a polysaccharide, which requires a T cellindependent antibody response in order to invoke immunity, a pathway that does not mature until the child is approximately two years old.100 Unfortunately, this is the population with the highest incidence and prevalence of AOM. Not surprisingly, administration of unconjugated
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pneumococcal vaccine to infants has not been shown to decrease the incidence of OM.101 The concept of conjugating a polysaccharide vaccine to a protein carrier molecule to enhance immunogenicity has been proven successful with the Haemophilus influenza B (Hib) vaccine. Current strategies have included conjugating seven to 11 of the 90 naturally occurring capsular S. pneumoniae polysaccharides to diphtheria or tetanus toxoid proteins or to other immunogenic proteins. The heptavalent conjugate vaccines promote immunity against 5281% of invasive pneumococcal diseases in children, including 58% of the serotypes causing AOM.102-104 Five different formulations of heptavalent pneumococcal conjugate vaccines are currently undergoing Phase II or III clinical evaluations. Prevnar (a heptavalent pneumococcal vaccine conjugated to a nontoxic mutant diphtheria toxin CRM197) has recently become the first conjugate pneumococcal vaccine to obtain FDA approval for use in infants and young children.105 Wyeth-Ayerst Laboratories plans to pursue approval for 9- and 11-valent pneumococcal formulations.105 Considerable evidence exists in support of both the safety and immunogenicity of conjugate pneumococcal vaccines in children.100,101,106-108 Dagan et al.109 documented reduction of pneumococcal nasopharyngeal carriage by three- to fivefold compared with placebo in infants after immunization with tetravalent pneumococcal vaccines conjugated to tetanus or diphtheria toxoids (p = 0.014 and p = 0.001, respectively). Data confirming the efficacy of conjugate pneumococcal vaccines in preventing AOM recurrences was published recently by the Kaiser-Permanente Vaccine Study Center.110 In this double-blind, multicenter trial, 37 868 healthy infants were randomized to receive either Prevnar or meningococcus type C CRM197 conjugate at two, four, six, and 1215 months of age. The trial was terminated prematurely and unblinded on interim analysis when 97.4% efficacy was established for the prevention of invasive pneumococcal disease in children who were administered Prevnar (95% CI 82.7% to 99.9%; p < 0.0001). Compared with the meningococcal vaccine, Prevnar was 7.0% effective overall in the prevention of OM episodes (95% CI 4.1% to 9.7%; p value NR). The vaccines efficacy in preventing OM episodes increased from 9.3% to 22.8% as the frequency of OM episodes increased from three to five per six-month time period. Infants who received Prevnar were 20.1% less likely to require tympanostomy tube placement than the control group (95% CI 1.5% to 35.2%; p value NR). The success of Prevnar in preventing invasive pneumococcal disease was tempered by its relatively unimpressive 7% overall efficacy in the prevention of OM. While the Kaiser-Permanente study110 provides some indication that the conjugate pneumococcal vaccines efficacy may be greater in pediatric patients with rAOM, early termination of the study prevented collection of further data that would have assisted in a costbenefit analysis and identification
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of patients most likely to benefit from Prevnar. The high cost of the conjugate pneumococcal vaccine (~$300 for the 4-injection series) has sparked debate concerning the establishment of administration guidelines. The CDCs Advisory Committee on Immunization Practices (ACIP) Vaccines for Children Program recently recommended the use of Prevnar for all infants and children at least six weeks of age through 59 months old.111 This resolution identified children at highest risk, as those with sickle cell disease or anatomic asplenia, chronic illnesses, immunocompromising conditions, or HIV infection. Groups at moderate risk were identified as toddlers 2435 months old, children of African-American, Native American, and Alaskan Native descent, and children 3559 months of age who attend outof-home child care. The American Academy of Pediatrics (AAP) has released a policy statement112 recommending pneumococcal conjugate vaccination for all children 23 months of age. This statement also recommends vaccination for all children 24 59 months of age at high risk for invasive pneumococcal disease. The prospect of effective immunization for the prevention of OM is especially promising for treatment of rAOM, because these children often have lower concentrations of immunoglobulin (Ig) G against certain pneumococcal antigens.113 In a study performed by Breukels et al.,114 five children with rAOM and a poor IgG2 response were immunized with heptavalent conjugated pneumococcal vaccine, followed by injection of the 23-valent polysaccharide vaccine six months later. The unconjugated booster response was dramatic, resulting in an 11.5- to 163-fold increase in IgG2 antipolysaccharide antibody titers. Hopefully, larger studies will clearly delineate the role of the 23-valent unconjugated pneumococcal product, if any, as a booster vaccine in rAOM. Some rather dramatic enhancements in mouse T cell reactivity to pneumococcal antigens have been reported,115 using heat shock proteins as highly immunogenic conjugate molecules. Another animal study116 noted successful oral immunization of mice with an S. pneumoniae polysaccharide conjugate vaccine in enterically coated microparticle form. Further research identifying alternative dosage forms as well as the best protein for polysaccharide conjugation is certainly on the horizon. The role of respiratory viruses in the etiology of AOM has been highlighted by two recent reports.117,118 Heikkinen et al.117 reported MEF prevalence rates of 74%, 52%, and 42% for respiratory syncytial, parainfluenza, and influenza viruses, respectively, isolated from children with AOM. Some children in this study had concomitant bacterial and viral infections; all eight of the children with positive S. pneumoniae cultures also had influenza virus in their MEF. Pitkaranta et al.118 used a reverse transcription polymerase chain reaction assay to detect viral RNA in nasal aspirates and middle ear effusions from children with AOM, and found evidence of infection by human rhinovirus, respiratory syncytial virus, and human coronavirus in 35%, 28%, and 17% of patients, respectively. Overall, 48% of middle ear effusion samples showed evidence of viral RNA.
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Three trials119-121 have been conducted assessing the efficacy of influenza vaccine in reduction of AOM episodes in children. All three trials reported overall reductions in AOM incidence from 3036% compared with placebo (2 studies120,121 reported p values 0.02; 1 study119 did not report a p value). Not surprisingly, Clements et al.120 discovered that the greatest protection against AOM occurred during flu season. The report by Belshe et al.121 is particularly interesting because the influenza vaccine was administered intranasally; this dosage form may become preferable to intramuscular injection in the pediatric population. Influenza vaccine has not traditionally been considered part of the prophylaxis guidelines for rAOM. However, given substantial evidence for viral etiology and pathogenesis of AOM,122 documented immunization efficacy in reducing AOM recurrences, and established safety of influenza vaccine in the pediatric population,123 it seems rational to consider viral immunization yearly (in October November) in addition to the conjugate pneumococcal vaccine for children with severe, documented rAOM that worsens in the winter months.32 White et al.124 recently estimated a net cost savings of $35 per child who was vaccinated in a group-based vaccination scenario. These cost savings were derived primarily from averted indirect costs (e.g., missed work). Prevention of potential episodes of OM was not included in the calculations, a factor that would certainly increase the estimated dollar savings. Further research and development of vaccines against respiratory syncytial virus and parainfluenzae virus are needed.
First line
appropriate, and we support its use as a third-step management option; however, there are few physicians who feel comfortable performing tympanocentesis. Efforts to prevent rAOM seem more consequential when one considers the difficulties in changing the treatment of refractory AOM from a largely empiric approach to a more definitive approach involving the increased frequency of use of tympanocentesis. As healthcare providers, we have been trained and pressured to cure disease with drugs. The concept of disease prevention is often presented last in our pharmaceutical care paradigm, when it actually is the most powerful weapon in our therapeutic armamentarium. In this era of reduced sensitivity to existing antibiotics, it is essential to realize that antimicrobial prophylaxis of rAOM is not the only option. The potential short-term benefits of prophylactic antibiotic use must continuously be weighed against the risks of furtherance and spread of antibiotic resistance.42 Practicality may dictate a stepwise approach to rAOM prevention and therapy (Table 4).125-129 Established modifiable risk factors for AOM include lack of breast feeding,125,126 exposure to environmental smoke,126,127 pacifier use,126,128 and day care in large group settings.126,129 We consider the nonpharmacologic risk factor reduction approach to be first line.
Table 4. Algorithm for Prevention of AOM5

environmental modifications encourage breast feeding for at least 3 mo125,126 reduce exposure to environmental smoke126,127 minimize pacifier use126,128 discourage child care in large group settings126,129 conjugate pneumococcal vaccinea influenza vaccine for children 6 mo oldb pneumococcal vaccine for children 2 y oldc xylitol gum or syrupd intermittent antibiotic prophylaxise myringotomy/tympanostomy tube placement adenoidectomy
Summary We support the CDCs expert panel8 guideline to initially treat children with AOM who are at risk of DRSP with high-dose amoxicillin (standard-dose amoxicillin is acceptable in the absence of risk factors for DRSP). In the event of failure and poor or incomplete adherence, we recommend switching from highdose amoxicillin to second-step antibiotics that include coverage of both DRSP and -lactamaseproducing bacteria. In this situation, we recommend high-dose amoxicillin/clavulanate, provided that adherence to the concurrent administration of two separate prescriptions would not be too difficult for the patient or caregiver to achieve. TMP/SMX is our preferred second-step antibiotic if adherence to at least three days of high-dose amoxicillin appeared to be good or complete. The three-day regimen of intramuscular ceftriaxone should be reserved for third-step therapy unless nonadherence to a 10-day course of oral antibiotic seems likely. The three-day ceftriaxone regimen needs to be compared with other regimens employing less frequent dosing and cumulative dosages. Tympanocentesis-directed antibiotic therapy is also
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Second line immunizations
Third line Fourth line
drug therapy surgical interventions
AOM = acute otitis media. a Indicated for all children less than two years old. Conjugate pneumococcal vaccine is also indicated for children under the age of five years with sickle cell anemia, HIV, or chronic diseases, or who are immunocompromised, as well as for children of African-American, Native American, or Alaskan Native descent. Administration should be considered in children under age five with recurrent otitis media, those who are socially or economically disadvantaged, and those who participate in large group day care. b Consider in cases of severe recurrent acute otitis media, which historically occur or worsen in the winter/early spring months. Use the split (subvirion or purified surface antigen) vaccine, not the whole virus vaccine in children younger than 12 years. c Use only if conjugate vaccine not available. d Not available in the US. e Only if three or more episodes in six months or four or more episodes in 12 months. Consider sooner in children who are immunocompromised or who have concurrent disease states exacerbated by recurrent acute otitis media (e.g., diabetes, asthma). Therapy should begin at the first sign of an upper respiratory tract infection and continue for 10 days.
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At present, immunization with pneumococcal conjugate vaccine holds the most hope for control of recurrent pneumococcal AOM. We support the use of this vaccine per ACIP guidelines for the prevention of rAOM, with consideration given to the use of influenza vaccine for cases of rAOM, which historically worsen during the flu season (Table 4). Sulfisoxazole prophylaxis should be reserved for children who are immunocompromised, have concurrent disease states exacerbated by AOM, and for children with three or more documented episodes of AOM in six months or at least four occurrences in 12 months despite conjugate pneumococcal and influenza vaccination. Therapy should be intermittent, beginning at the first sign of an upper respiratory tract infection and continued for 10 days. Alternative prophylactic agents for children who have sulfonamide allergies or who harbor resistant organisms include amoxicillin and azithromycin. The potential for psychological trauma, invasive nature, and risks of anesthesia relegate myringotomy, tympanostomy tubes, and adenoidectomy to last-line therapies for rAOM.
John Erramouspe PharmD MS, Associate Professor of Pharmacy Practice, College of Pharmacy, Idaho State University, Pocatello, ID Catherine A Heyneman PharmD MS, Assistant Professor of Pharmacy Practice, College of Pharmacy, Idaho State University Reprints: John Erramouspe PharmD MS, Department of Pharmacy Practice, College of Pharmacy, Idaho State University, Campus Box 8333, Pocatello, ID 83209-8333, FAX 208/282-4305, E-mail johnerra@otc.isu.edu
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Antimicrob Agents Chemother 1995;39:1820-3. 97. Kontiokari T, Uhari M, Koskela M. Antiadhesive effects of xylitol on otopathogenic bacteria. J Antimicrob Chemother 1998;41:563-5. 98. Uhari M, Kontiokari T, Koskela M, Niemela M. Xylitol chewing gum in prevention of acute otitis media: double blind randomised trial. BMJ 1996;313:1180-4. 99. Uhari M, Kontiokari T, Niemela M. A novel use of xylitol sugar in preventing acute otitis media. Pediatrics 1998;102:879-84. 100. Eskola J, Anttila M. Pneumococcal conjugate vaccines. Pediatr Infect Dis J 1999;18:543-51. 101. Sloyer JL Jr, Ploussard JH, Howie VM. Efficacy of pneumococcal polysaccharide vaccine in preventing acute otitis media in infants in Huntsville, Alabama. Rev Infect Dis 1981;3(suppl):S119-23. 102. Sniadack DH, Schwartz B, Lipman H, Bogaerts J, Butler JC, Dagan R, et al. Potential interventions for the prevention of childhood pneumonia: geographic and temporal differences in serotype and serogroup distribution of sterile site pneumococcal isolates from children implications for vaccine strategies. Pediatr Infect Dis J 1995;14:503-10. 103. Karma P, Pukander J, Sipila M, Timonen M, Pontynen S, Herva E, et al. Prevention of otitis media in children by pneumococcal vaccination. Am J Otolaryngol 1985;6:173-84. 104. Butler JC, Breiman RF, Lipman HB, Hofmann J, Facklam RR. Serotype distribution of Streptococcus pneumoniae infections among preschool children in the United States, 19781994: implications for development of a conjugate vaccine. J Infect Dis 1995;171:885-9. 105. ACIP Prevnar coverage recommendation includes prioritization plan. The Pink Sheet 1999;61:13. 106. Ahman H, Kayhty H, Lehtonen H, Leroy O, Froeschle J, Eskola J. Streptococcus pneumoniae capsular polysaccharide diphtheria toxoid conjugate vaccine is immunogenic in early infancy and able to induce immunologic memory. Pediatr Infect Dis J 1998;17:211-6. 107. Sigurdardottir ST, Vidarsson G, Gudnason T, Kjartansson S, Kristinsson KG, Jonsson S, et al. Immune responses of infants vaccinated with serotype 6B pneumococcal polysaccharide conjugated with tetanus toxoid. Pediatr Infect Dis J 1997;16:667-74. 108. Rennels MB, Edwards KM, Keyserling HL, Reisinger KS, Hogerman DA, Madore DV, et al. Safety and immunogenicity of heptavalent pneumococcal vaccine conjugated to CRM197 in United States infants. Pediatrics 1998;101:604-11. 109. Dagan R, Muallem M, Melamed R, Leroy O, Yagupsky P. Reduction of pneumococcal nasopharyngeal carriage in early infancy after immunization with tetravalent pneumococcal vaccines conjugated to either tetanus toxoid or diphtheria toxoid. Pediatr Infect Dis J 1997;16:10604. Black S, Shinefield H, Fireman B, Lewis E, Ray P, Hansen JR, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J 2000;19:187-95. CDC Vaccines for Children Program. http:www.cdc.gov/nip/vfc/ACIP_ pneumo.pdf (accessed 10/27/2000). American Academy of Pediatrics Committee on Infectious Diseases. Policy statement: recommendations for the prevention of pneumococcal infections, including the use of pneumococcal conjugate vaccine (Prevnar), pneumococcal polysaccharide vaccine, and antibiotic prophylaxis (RE9960). Pediatrics 2000;106:362-6. Prellner K, Kalm O. Humoral immune response in acute otitis media. Acta Otolaryngol Suppl (Stockh) 1989;457:133-8. Breukels MA, Rijkers GT, Voorhorst-Ogink MM, Zegers BJ, Sanders LA. Pneumococcal conjugate vaccine primes for polysaccharide-inducible IgG2 antibody response in children with recurrent otitis media acuta. J Infect Dis 1999;179:1152-6. Konen-Waisman S, Cohen A, Fridkin M, Cohen IR. Self heatshock protein (hsp60) peptide serves in a conjugate vaccine against a lethal pneumococcal infection. J Infect Dis 1999;179:403-13. Flanagan MP, Michael JG. Oral immunization with a Streptococcus pneumoniae polysaccharide conjugate vaccine in enterocoated microparticles induces serum antibodies against type specific polysaccharides. Vaccine 1999;17:72-81. Heikkinen T, Thint M, Chonmaitree T. Prevalence of various respiratory viruses in the middle ear during acute otitis media. N Engl J Med 1999;340:260- 4. Pitkaranta A, Virolainen A, Jero J, Arruda E, Hayden FG. Detection of rhinovirus, respiratory syncytial virus, and coronavirus infections in acute otitis media by reverse transcriptase polymerase chain reaction. Pediatrics 1998;102:291-5. Heikkinen T, Ruuskanen O, Waris M, Ziegler T, Arola M, Halonen P. Influenza vaccination in the prevention of acute otitis media in children. Am J Dis Child 1991;145:445-8. Clements DA, Langdon L, Bland C, Walter E. Influenza A vaccine decreases the incidence of otitis media in 6- to 30-month-old children in day care. Arch Pediatr Adolesc Med 1995;149:1113-7. Belshe RB, Mendelman PM, Treanor J, King J, Gruber WC, Piedra P, et al. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine in children. N Engl J Med 1998;338:1405-12. Ruuskanen O, Arola M, Heikkinen T, Ziegler T. Viruses in acute otitis media: increasing evidence for clinical significance. Pediatr Infect Dis J 1991;10:425-7. Kramarz P, DeStefano F, Gargiullo PM, Davis RL, Chen RT, Mullooly JP, et al. Does influenza vaccination exacerbate asthma? Analysis of a large cohort of children with asthma. Vaccine Safety Datalink Team. Arch Fam Med 2000;9:617-23. White T, Lavoie S, Nettleman MD. Potential cost savings attributable to influenza vaccination of school-aged children. Pediatrics 1999;103 (6):e73. Duffy LC, Faden H, Wasielewski R, Wolf J, Krystofik D. Exclusive breastfeeding protects against bacterial colonization and day care exposure to otitis media (abstract). Pediatrics 1997;100:717. Uhari M, Mantysaari K, Niemela M. A meta-analytic review of the risk factors for acute otitis media. Clin Infect Dis 1996;22:1079-83. Stathis SL, OCallaghan DM, Williams GM, Najman JM, Andersen MJ, Bor W. Maternal cigarette smoking during pregnancy is an independent predictor for symptoms of middle ear disease at five years postdelivery. Pediatrics 1999;104(2):e16. Jackson JM, Mourino AP. Pacifier use and otitis media in infants twelve months of age or younger. Pediatr Dent 1999;21:255-60. Paradise JL, Rockette HE, Colborn DK, Bernard BS, Smith CG, KursLasky M, et al. Otitis media in 2253 Pittsburgh-area infants: prevalence and risk factors during the first two years of life. Pediatrics 1997;99: 318-33.
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EXTRACTO
OBJETIVO:
Revisar y resumir los avances recientes en el tratamiento y prevencin de otitis media.

I
www.theannals.com
1467
FUENTES DE INFORMACIN: Se hizo una bsqueda en el sistema de bsqueda de informacin MEDLINE de enero del 1996 a marzo del 2000 para identificar los artculos relevantes. Las referencias de dichos artculos tambin se revisaron si se juzgaban importantes. EXTRACCIN DE DATOS: Se incluyeron artculos de la literatura primaria y de revisin en el idioma ingls enfocndose en la prevencin y tratamiento de otitis media aguda (OMA). Se excluyeron estudios cuyo foco exclusivo era otitis media con efusin o seroso u otitis media crnica supurativa. Se revis la informacin concerniente a la prevencin y terapia con frmacos con nfasis en los avances hechos en los ltimos dos aos. SNTESIS: Recientemente un panel de expertos del Centro para el Control y Prevencin de Enfermedades (CDC) recomend el uso de solo tres de 16 antibiticos sistmicos aprobados por la Administracin de Drogas y Alimentos (ADA). Estos son amoxicillin, cefuroxime axetil, y ceftriaxone. Existe una controversia de la importancia de los factores de seleccin claves utilizados por el panel de expertos para determinar cul antibitico recomendar en un algoritmo de dos pasos, la interpretacin de datos de pruebas in vitro, perfiles farmacodinmicos, y la necesidad de cobertura para Estreptococo pneumoniae resistente a frmacos en todos los pasos del tratamiento emprico. Algunos factores tiles para la seleccin antibiticos de acuerdo a las individualidad del paciente y el tipo de infeccin incluyen: eficacia clnica, efectos adversos, frecuencia de la dosis y duracin del tratamiento, sabor, costo, infecciones concomitantes, y consecuencias del desarrollo de resistencia con el antibitico escogido. Otra consideracin importante al seleccionar la terapia es el historial de adherencia a la terapia por parte del paciente y los que le cuidan (especialmente si ha habido falla de la terapia). Un algoritmo de tres pasos para OMA refractaria que emplea amoxicillin, trimetroprim-sulfamethoxazole o amoxicillin clavulunato en dosis altas (dependiendo de la dosis anterior y adherencia al amoxicillin), y ceftriaxone o timpanocentesis en los pasos 1, 2, y 3, respectivamente, parece una estrategia racional y costo-efectiva. Se enfatiza el surgimiento reciente de resistencia antimicrobiana, y se presentan recomendaciones para la prevencin y tratamiento de OMA recurrente. CONCLUSIONES: Amoxicillin permanece como el antibitico de eleccin inicial emprico, aunque la dosis debe ser mayor que la tradicional en los pacientes en riesgo de adquirir Estreptococo pneumoniae resistente a frmacos. En casos refractarios a dosis altas de amoxicillin donde la adherencia al tratamiento se considera buena, se debe prescribir trimetroprim/sulfamethoxazole. Si la adherencia al tratamiento fue incompleta o cuestionable, se recomienda amoxicillin-clavulunate en dosis altas. Se debe reservar ceftriaxone como un agente de tercera lnea. El aumento en la prevalencia de cepas de Estreptococo pneumoniae resistentes a medicamento enfatiza la importancia de estrategias alternas para la prevencin de otitis media as como el uso juicioso de antibiticos. La primera lnea de terapia debe ser la remocin de factores de riesgo modificables para prevenir OMA recurrente. Apoyamos el uso de la vacuna conjugada de pneumococo segn las guas del Comit Consultor para Prcticas de Inmunizacin del CDC para la prevencin del OMA recurrente, y que se considere la vacuna de influenza para los casos de OMA recurrente que histricamente empeoran durante la poca del flu. La profilaxis con sulfisoxazole debe reservarse para nios inmunocomprometidos que tienen condiciones que se exacerban por OMA y para aquellos nios que renen los criterios de OMA recurrente an despus de ser vacunados contra influenza y pneumococo. La terapia con sulfisoxazole debe ser intermitente, comenzando el tratamiento al detectar las primeras seales de infeccin respiratoria superior y debe continuar por un perodo de 10 das. La naturaleza invasiva y riesgos de la anestesia relegan la miringotomia, los tubos de timpanostoma, y la adenoidectoma a considerarse las terapias de ltima opcin para OMA recurrente.
RSUM
OBJECTIF:
Jorge R. Miranda-Massari
Revoir et rsumer les nouvelles tendances et progrs dans le traitement et la prvention de lotite moyenne. SOURCES DE DONNES: Une recherche informatise MEDLINE (janvier 1996 mars 2000) a t ralise pour identifier les articles pertinents. Les rfrences de ces articles ont aussi t rviss si juges dintrt. SLECTION DES TUDES ET EXTRACTION DES DONNES: Les articles de langue anglaise concernant le traitement et la prvention de lotite moyenne aigu (OMA) ont t inclus. Les articles se concentrant exclusivement sur lotite moyenne avec effusion ou lotite sreuse et lotite moyenne chronique avec suppuration ont t exclus. Les informations concernant la prvention et le traitement mdicamenteux ont t revues, avec accent port sur le progrs ralis les deux dernires annes. RSUM: Rcemment, un panel dexperts recommandait lutilisation de seulement trois des 16 antibiotiques systmiques approuvs par lAdministration des Drogues et Alimentaires (ADA) pour le traitement de lOMA: lamoxicilline, le cefuroxime axetil, et le ceftriaxone. Des controverses existent sur limportance de la slection des facteurs cls utiliss par le panel dexperts dans la dtermination des antibiotiques recommander dans lalgorithme de traitement cest dire les donnes in vitro, les profils pharmacodynamiques et la ncessit de couvrir les organismes rsistants la mdication tel que le Streptococcus pneumoniae chaque tape du traitement empirique. Des facteurs additionnels de slection des patients et des antibiotiques utiles pour individualiser la thrapie incluent lefficacit clinique, les effets adverses, la frquence et la dure de ladministration, le got, le cot, et les ramifications si une rsistance bactrienne se dveloppe lantibiotique choisi. Un algorithme de traitement trois paliers pour les OMA rfractaires compos damoxicilline, de trimethoprimsulfamthoxazole ou de doses leves damoxicilline/acide clavulinique (en fonction de la dose antrieure et de ladhsion lamoxicilline), le ceftriaxone ou une tympanocentse ltape 1, 2, et 3, respectivement, apparat rationnel et cot-efficace. La rcente recrudescence dans la rsistance antimicrobienne est souligne et des recommandations sont prsentes pour le traitement et la prvention des OMA rcurrentes (OMAr). CONCLUSIONS: Lamoxicilline demeure lantibiotique de choix pour le traitement empirique initial de lOMA mme si la dose traditionnelle devrait tre augmente chez les patients risque dun Streptococcus pneumoniae rsistant au mdicament. Dans les cas rfractaires aux hautes doses damoxicilline, le trimethoprim/sulfamthoxazole devrait tre prescrit si ladhsion semble bonne et complte, ou de hautes doses damoxicilline/acide clavulinique si ladhsion tait incomplte ou questionnable. Le ceftriaxone devrait tre rserv en troisime ligne. Laugmentation de la prvalence des rsistances mdicamenteuses face au Streptococcus pneumoniae met laccent sur limportance de dvelopper des approches mdicales alternatives pour la prvention de lOM, de mme que lusage judicieux dantibiotiques dans des cas tablis. Le retrait des facteurs de risque modifiables devrait tre en premire ligne de thrapie pour la prvention de lOMAr. Nous supportons lutilisation du vaccin antipneumococcique conjugu selon les guides dutilisation de lACIP pour la prvention de lOMAr et considrons lutilisation du vaccin contre linfluenza pour les cas dOMAr avec histoire de dtrioration pendant la saison des grippes. Une prophylaxie au sulfisoxazole devrait tre rserv aux enfants immunocompris, avec des pathologies concomitantes exacerbes par lOMA et pour les enfants qui rencontrent les critres dOMA malgr une vaccination antipneumococcique et contre linfluenza. La thrapie doit tre intermittente dbutant aux premiers signes dune infection respiratoire haute et doit tre poursuivie pour une priode de 10 jours. La nature invasive et les risques de lanesthsie relguent la myringotomie, les tubes de tympanostomie, et ladnoidectomie comme thrapies de derniers recours pour lOMAr.
Chantal Guvremont
1468
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Pediatrics

Treatment and Prevention of Otitis Media

Ann Pharmacother 2000;34:1452-68.

Author information provided at the end of the text.

The Annals of Pharmacotherapy

2000 December, Volume 34

Table 1. Recommended Antibiotics for Treating Acute Otitis Media in Children8

HD amoxicillin standard-dose amoxicillin

HD amoxicillin/clavulanate cefuroxime axetil im ceftriaxonec

HD amoxicillin/clavulanateb cefuroxime axetil im ceftriaxonec HD amoxicillin/clavulanate cefuroxime axetil im ceftriaxonec or tympanocentesis

HD amoxicillin HD amoxicillin/clavulanate cefuroxime axetil

im ceftriaxonec clindamycind or tympanocentesis

The Annals of Pharmacotherapy

2000 December, Volume 34

The Annals of Pharmacotherapy

2000 December, Volume 34

Treatment and Prevention of Otitis Media

The Annals of Pharmacotherapy

2000 December, Volume 34

Table 2. Selected Antibiotic Suspension Costsa

The Annals of Pharmacotherapy

2000 December, Volume 34

Treatment and Prevention of Otitis Media

Table 3. Recommended Antibiotics for Treating AOM in Childrena

HD amoxicillin (8090 mg/kg/d) or SD amoxicillin (40 mg/kg/d)d TMP/SMXd

cefdinirg cefpodoxime proxetilh cefprozili cefuroxime axetilh

The Annals of Pharmacotherapy

2000 December, Volume 34

The Annals of Pharmacotherapy

2000 December, Volume 34

Treatment and Prevention of Otitis Media

The Annals of Pharmacotherapy

2000 December, Volume 34

The Annals of Pharmacotherapy

2000 December, Volume 34

Treatment and Prevention of Otitis Media

The Annals of Pharmacotherapy

2000 December, Volume 34

ALTERNATIVE MEDICAL APPROACHES

The Annals of Pharmacotherapy

2000 December, Volume 34

Treatment and Prevention of Otitis Media

The Annals of Pharmacotherapy

2000 December, Volume 34

Table 4. Algorithm for Prevention of AOM5

Second line immunizations

Third line Fourth line

drug therapy surgical interventions

The Annals of Pharmacotherapy

2000 December, Volume 34

Treatment and Prevention of Otitis Media

The Annals of Pharmacotherapy

2000 December, Volume 34

The Annals of Pharmacotherapy

2000 December, Volume 34

Revisar y resumir los avances recientes en el tratamiento y prevencin de otitis media.

The Annals of Pharmacotherapy

2000 December, Volume 34

The Annals of Pharmacotherapy

2000 December, Volume 34

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