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APhA Drug Treatment Protocols Management of Pediatric Acute Otitis Media
FEATURE
APhA I)rug Treatment Protocols: Management of Pediatric Acute Otitis Media Annual costs for treatment of this painful childhood disorder exceed $3.5 billion. Introduction by Daniel H. Albrant Protocol developed by APhA Pediatric Disorders Protocol Panel
Introduction
Protocol Development Process
All of the protocols developed through APhA are subject Acute otitis media (AOM) is defined as an acute infection of to the following process: the middle ear. Its onset is rapid, with pain, fever, irritability, • A preliminary-draft protocol author, consultant, and project anorexia, or vomiting. 1 Otitis media (OM) is the most common director work collaborative1y to select and narrow the reason for medical office visits in childhood. 2 It is estimated that topic, thoroughly review and evaluate the scientific evi62% of children will have had at least one episode of OM by their dence, defme the target patient population, defme the clinifIrst birthday, and more than 80% will have had an attack by 3 1 cal interventions, and develop a preliminary-draft protocol. years of age. The financial impact of treating AOM is substan• An interdisciplinary panel then reviews the draft protocol tial, although antibiotics contribute to only a small portion of the and additional scientific evidence; if necessary, redefines the overall treatment costs. 3,4 topic and targeted population; and prepares a second draft Streptococcus pneumoniae and Haemophilus injluenzae infecfor further peer review. The panel's decisions are based on tions account for 60% to 80% of all cases of- AOM. Penicillinscientific evidence; in areas where evidence is inconclusive resistant Streptococcus pneumoniae is a growing problem, and . or controversial, recommendations are based on consensus. the newest dosing recommendations for amoxicillin and amoxi• The panel's draft is reviewed by an interdisciplinary cillin-clavulanate are twice as large as before (amoxicillin 80 to of peer reviewers as well as the author of the pregroup 90 mg/kg/day). liminary draft. These experts critically evaluate the draft The protocol begins with a pediatric patient who presents with a for content, validity, and applicability to patient care. diagnosis of AOM. If the child is < 3 months old, he or she should Taking this second group's recommendations into be referred to ·a physician due to the risk of AOM in association account, the draft protocol is then revised, reviewed, and with systemic infections, including meningitis. Patients with ultimately approved by the original panel. chronic suppurative OM should also be referred to an otolaryngol• Finalized protocols are published in the APhA Guide to ogist or other specialist for further evaluation and management. Drug Treatment Protocols and sold individually for a Drug therapy decision making begins with a determination of nominal fee. Again, it is intended that the template be medication allergies. If the patient is able to take penicillin, amoxadapted to increase the protocol's specificity and applicaicillin in usual doses (40 to 45 mg/kg/day) is initiated. Standard bility to local needs. dosing of amoxicillin (40 to 45 mg/kg/day, two or three times daily) is acceptable in children older than 2 years, who have not 5 received antibiotics within the last 1 to 3 months, and who are not cefuroxime axetil, or intramuscular ceftriaxone. Other options, attending day care. 5 High-dose therapy (80 to 90 mg/kg/day, determined by the allergy profile, include trimethoprim-sultWice daily to three times daily) should be initiated in other famethoxazole, certain cephalosporins, and the fluoroquinolones. After 48 to 72 hours the patient should receive a follow-up groups not amenable to standard dosing because of the increased 5 contact to assess for treatment adherence and possible treatment risk of penicillin-resistant S. pneumoniae. Patients who have If the patient has not improved, then switch to another failure. received antibiotics within 1 month of this course of treatment if the patient (or caregiver) has been adherent to the antibiotic should receive high-dose amoxicillin, amoxicillin-clavulanate,
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therapy. The usual course of therapy is 10 days. Patients who do not respond to multiple antibiotic courses, or those with persistent effusion, should be referred to an otolaryngologist for further evaluation and treatment. Thanks go out to our friends at Daiichi Pharmaceuticals for the unrestricted educational grant that enabled APhA to revise this drug treatment protocol. This revision will join the 44 other drug treatment protocols in a new edition of the Drug Treatment Protocols book due out by the end of this year. Daniel H. Albrant, PharmD, is editor-in-chief, APhA Drug Treatment Protocols Project.
References 1. Berman S. Otitis media in children. New Engl J Med. 1995; 332(23): 1560-5. 2. Cantor RM. Otitis externa and otitis media: a new look at old problems. Emerg Med Clin North Am. 1995;13(2)445-55. 3. Wandstrat TL, Kaplan B. Pharmacoeconomic impact of factors affecting compliance with antibiotic regimens in the treatment of acute otitis media. Pediatr Infect Dis. 1997;16:S27-9. 4. Kaplan B, Wandstrat TL, Cunningham JR. Overall costs in the treatment of otitis media. Pediatr Infect Dis. 1997;16:S9-11. 5. Dowell SF, Butler JC, Giebink GS, et al. Acute otitis media: management and surveillance in an era of pneumococcal resistance-a report from the Drug-Resistant Streptococcus pneumoniae Thera peutic Working Group. Pediatr Infect Dis J. 1999;18(1 ):1-9.
American Pharmaceutical Association Pediatric Disorders Protocol Participants
Comprehensive Reviewers Donna M. Kraus Associate Professor Departments of Pharmacy Practice and Pediatrics Pediatric Clinical Pharmacist University of illinois at Chicago Chicago, ill.
Kelley R. Lee, PharmD Clinical Pharmacy Specialist LeBonheur Children's Medical Center Assistant Professor College of Pharmacy University of Tennessee Memphis, Tenn.
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Protocol Revision Reviewers Seth M. Pransky, MD, FAAP Pediatric Otolaryngologist Children's Hospital San Diego, Calif.
Editor-in-Chief Daniel H. Albrant, PharmD President Pharmacy Dynamics Arlington, Va.
Lisa Hammer Rieg, PharmD Infectious Diseases Pharmacist, CA Division Drug Information Services, CA Division Kaiser Permanente Downey, Calif.
Elaine C. Taylor, PharmD Cliriical Assistant Professor University of Texas at El Paso/Austin Cooperative Pharmacy Program El Paso, Tex.
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APhA Drug Treatment Protocols Management of Pediatric Acute Otitis Media
Pediatric patient with diagnosis of acute otitis media (AOM).
2 Confirm the diagnosis of AOM. Review history, physical exam, and lab tests.
3 Review probable organisms. If patient is < 3 months old, refer to a physician.
4 Develop treatment plan with patient and caregiver. Use an analgesic as needed.
5 Does the patient have chronic suppurative otitis media?
6 Yes~
Refer to otolaryngologist. Exit protocol.
No 8
7 Does the patient have a documented penicillin allergy?
No
Yes
Does the patient have a documented sulfa allergy?
Go to Box 12.
No
10~------~------~
First course: amoxicillin. Second course: amoxicillin and clavulanate or alternative agent as dictated by local resistance patterns. Go to Box 12. 12~------~------~
Educate caregiver; give compliance tools. Follow up with phone calls. Instruct caregiver on environmental and feeding factors. Assess patient in 48-72 hours.
Go to Box 13. This protocol is a tool designed to help health professionals make decisions related to patient therapy. It is not intended to replace professional judgment or to establish the only approach to a problem.
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From Box 12.
15
13
14~------------~
Are symptoms improved or improving at 48-72 hours?
Complete current treatment regimen. Reassess patient in 4-6 weeks.
Yes
,
161-------- . . . .
Has the effusion resolved in 4-6 weeks?
I
Exit protocol.
,
No
No
17
18
19~------------~
Has the caregiver been compliant?
No
Reeducate. Institute compliance measures. Continue treatment. Reassess in 48-72 hours.
Consider antibiotics ± corticosteroids. Consider prophylactic antibiotics. Consider referral to an otolaryngologist.
I
Yes
Go to Box 13.
20~-----L------~
Initiate alternative antibiotic. See Boxes 7-11.
21 Does the patient have symptoms 48-72 hours after a second antibiotic is started?
22~-------------
Yes
Consider referral for myringotomy and culture.
, I
No
[
Go to Box 14.
J
This protocol is a tool designed to help health professionals make decisions related to patient therapy. It is not intended to replace professional judgment or to establish the only approach to a problem.
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Note: For purposes of this protocol, a pediatric patient is defined as a person from term to 18 years of age.
Box 1 Otitis media (OM) is the most common reason for medical office visits in childhood, accounting for 33% of all visits. 1 It is estimated that 62% of children will have had at least one episode of OM by their first birthday, and more than 80% will have had an attack by 3 years of age. 1 The financial impact of treating acute otitis media (AOM) is substantial, with direct and indirect costs exceeding $3.5 billion annually.2 Although antibiotics are prescribed in over 95% of cases, they contribute to only a small portion of the overall treatment costS. 2,3 AOM is defined as an acute infection of the middle ear. Symptoms develop rapidly, with pain, fever, irritability, anorexia, or vomiting. 4 The diagnosis is made by direct visualization with a pneumatic otoscope to assess tympanic movement and color. 4 AOM lasts less than 3 weeks; subacute OM lasts between 3 weeks and 3 months; and chronic OM lasts longer than 3 months. Otitis media with effusion (OME) accounts for 25% to 35% of all OM cases. 5 OME is defined"as fluid in the middle ear without clinical signs of active infection.
Box2 Confirm the diagnosis of AOM. The early development of AOM will show diminished translucency, tympanic membrane bulging, and poor tympanic membrane mobility when examined using a pneumatic otoscope. Patients may complain of muffled hearing or pull on the infected ear( s) as fluid accumulates behind the membrane and causes otalgia (ear pain), fever, and malaise. As fluid continues to accumulate, symptoms of nausea, vomiting, anorexia, and diarrhea may ensue. Otalgia may interfere with patients ' sleep. The tympanic membrane i~ erythematous and bulging by this time. 1 Left untreated, the membrane may perforate, and the patient may develop acute mastoiditis, bacteremia, chronic purulent otorrhea, or permanent loss of hearing.1,6 Review the patient's history, physical examination, and lab tests. Assess medication history and recent history of antibiotic use.
Box3 In clinical trials, bacteria are cultured from middle ear aspirates in approximately 70% of children with AOM.7 Streptococcus pneumoniae accounts for the majority of isolates, ranging from 40% to 50%.1,8 The most common serotypes are 3, 6, 14, 19, and 23, with these five groups accounting for 63% to 77% of-all pneumococcal isolates. 9 Penicillin-resistant Streptococcus pneumoniae (PRSP) is an emerging public health issue, with rates of resistance ranging from 8% to 34% across the United States. 8 The prevalence of PRSP is greater in children less than 2 years of age, especially those attending day care, and in children who have
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received antibiotics within the preceding 1 to 3 months. 8 Haemophilus injluenzae is the next most prevalent organism associated with AOM (20% to 30%). 8 Nontypable H. injluenzae accounts for 85% to 90% of these cases, while type B is only responsible for 10% to 15%.10 ~-lactamase producers constitute 35% to 50% of H. injluenzae strains, although endemic areas exist with a higher prevalence of these enzyme producers. 8,lI Other causative organisms include Moraxella catarrhalis (10% to 15%), Staphylococcus aureus (1 % to 11 %), and Streptococcus pyogenes (1 % to 5%).7 While many antibiotics are marketed to treat M. catarrhalis, infections from this organism are usually self-limited.8,12 Although AOM is commonly associated with bacterial infections, viruses may also playa pathogenic role. Viruses associated with AOM include respiratory syncytial virus, rhinovirus , influenza A and B, adenovirus, enterovirus, and parainfluenza viruS.13 Although not completely understood, concomitant viral infection is thought to promote or prolong AOM by altering eustachian tube function or impairing cellular defense mechanisms. 14 In:(ants less than 3 months of age with AOM must be given special consideration. These infants may have isolated AOM, or the disease may be associated with bacteremia, meningitis, or pneumonia. 15 Possible bacterial pathogens in this group, in addition to those previously mentioned, include group B streptococcus (27%), Escherichia coli (5.5%), Klebsiella pneumoniae and Enterobacter sp. (4.9%), and Pseudomonas aeruginosa (1.6%). These patients should be evaluated by a physician because of the risk of systemic infections and meningitis.
Box 4 It is very important to discuss treatment plans with the caregiver, taking into account the issues of history of allergy or sensitivity to any antibiotic, compliance, affordability, palatability, and frequency of administration when choosing antibiotics. The caregiver's understanding of these issues can help to maximize adherence to the treatment. Secondary to the increase in prevalence of PRSP, antibiotics should be chosen as detailed in Boxes 9-11. 8 Table 1 lists the most common antibiotics used in OM and the recommended clinical course of therapy. The standard course of treatment for AOM is 10 days. However, shorter courses of therapy (i.e., 5 to 7 days) may be considered in children over the age of 2 years whose symptoms improve within 72 hours and who have no other complications, such as a perforated tympanic membrane. 8 Give adjunctive agents as necessary to control pain, fever, and ear discomfort. It is estimated that fever is present in 23% to 67% of patients with AOM, and high fever (> 40°C) is seen in 0.3% of infants « 1 year of age).1 6 No association appears to exist between fever and a particular infecting organism. A combination regimen that alternates analgesic agents does not produce a greater benefit than single-agent therapy. 17
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Table 1. Antibiotics Commonly Used to Treat Acute Otitis Media Generic Name
Brand Name
Dose B
Frequency!Duration
Amoxicillin high dose
Various generics
40-45 mg/kg/day 80-90 mg/kg/day
2-3 times daily for 10 days
Amoxicillin and clavulanate high dose
Augmentin
40 mg/kg/day 45 mg/kg/day (bid) 80-90 mg/kg/day "+ 6.4 mg/kg/day
2-3 times daily for 10 days
Azithromycin
Zithromax
10 mg/kg/day 1
1 time daily for 5 days
5 mg/kg/days 2-5 Cefaclor
Ceclor and generic
40 mg/kg/day
3 times daily for 10 days
Cefdinir
Omicef
14 mg/kg/day
1-2 times daily for 10 days
Cefixime
Suprax
8 mg/kg/day
1-2 times daily for 10 days
Cefpodoxime
Vantin
10 mg/kg day
1-2 times daily for 10 days
Cefprozil
Cefzil
30 mg/kg/day
2 times daily for 10 days
Ceftibuten
Cedax
9 mg/kg/day
1 time daily for 10 days
Ceftriaxone
Rocephin
50 mg/kg/day for 1-3 days
1 time daily intramuscular
Cefuroxime
Ceftin
30 mg/kg/day
2 times daily for 10 days
Cephalexin
Various generics
75-100 mg/kg/day
4 times daily for 10 days
Clarithromycin
Biaxin
15 mg/kg/day
2 times daily for 10 days
Erythromycin and sulfisoxazole
Various generics
50 mg/kg/day erythromycin
4 times daily for 10 days
Loracarbef
Lorabid
30 mg/kg/day
2 times daily for 10 days
Ofloxacin
Floxin Otic
0.25 mL
2 times daily for 10 days
Trimethoprim and sulfamethoxazole
Various generics
8 mg/kg/day trimethoprim
2 times daily for 10 days
Bin children weighing more than 40 kg, do not exceed adult doses.
Acetaminophen at a dose of 10 to 15 mg/kg every 4 to 6 hours or ibuprofen at a dose of 5 to 10 mg/kg every 6 to 8 hours will usually bring significant relief. Topical analgesic agents (e.g., Auralgan) should not be used when the tympanic membrane has ruptured, because these agents could damage middle ear tissue. 4 Oral antihistamines and decongestants have been prescribed together and alone to prevent eustachian tube obstruction or to decrease the amount of effusion. However, studies have shown that these agents are no more effective than a placebo. 4 ,5,18 Thus, the routine use of a decongestant, antihistamine, or both cannot be recommended at this time.
Because of the long-term sequelae if inappropriately treated, an otolaryngologist should be consulted if available--or another specialist if unavailable; exit the protocol.
Box 7 Does the patient have a documented history of an allergy to penicillin? If yes, go to Box 8 to assess for an allergy to sulfa. If no, amoxicillin is the drug of choice; go to Box 10.
Boxes 8 and 11 Boxes 5 and 6 Does the patient have chronic suppurative otitis media (CSOM)? CSOM is defined as chronic inflammation of the middle ear with otorrhea and perforated tympanic membrane but generally without pain or fever. 19 Persistent inflammation secondary to infection may result in structural changes of the middle ear. These physiologic changes of chronic inflammation and discharge are believed to result from intermittent or continuous reflux of nasopharyngeal secretions into the middle ear, or contamination from the external ear through tympanostomy tubes.2o
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The patient has a documented penicillin allergy. Is the patient allergic to sulfa? If yes, go to Box 9. If no sulfa allergy is identified, initiate trimethoprim and sulfamethoxazole (TMP-SMX) or erythromycinand sulfisoxazole. TMP-SMX and erythromycin-sulfisoxazole are good choices for empiric treatment of AOM. TMP-SMX offers the advantage of twice-daily dosing, has good penetration in the middle ear, and is inexpensive. 21,22 TMP-SMX also provides good coverage for most AOM organisms, except S. pyogenes and S. aureus. ll In addition, TMP-SMX is effective against ~-lactamase-producing H. injluenzae. 4 For pediatric patients weighing 40 kg or more, use
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normal adult dosing recommendations. The most common adverse effects associated with TMP-SMX are gastrointestinal (GI), with an incidence similar to amoxicillin.ll Although feared, the incidence of severe dermatologic skin reactions is rare. 11 Photosensitivity reactions may occur, and caregivers should be instructed to use sunscreen on the patient if prolonged sun exposure is expected. The bitter aftertaste of the suspension may contribute to its relative lack of palatability. Giving a glass of water after administration, or giving the medication from an oral syringe, can lessen this aftertaste. Go to Box 12.
Box9 If the patient is allergic to both penicillin and sulfa, then a macrolide (i.e., erythromycin, clarithromycin, or azithromycin) or possibly a cephalosporin should be prescribed. (See Table 1 for dosing.) Patients who demonstrate a severe or potentially severe allergic reaction (i.e., anaphylaxis) to penicillins need to be carefully assessed before cephalosporin therapy is initiated. Crosssensitivity between penicillins and cephalosporins is reported at 5% to 14% for patients with severe allergy.1 1 Cephalosporins are effective against most organisms associated with AOM; however, they are not effective against highly resistant pneumococci. 4 Thus, cephalosporins offer no advantage over amoxicillin in a "typical" AOM case. Furthermore, if the patient is less than 6 months old, the following cephalosporins should not be prescribed due to lack of established safety and efficacy: cefixime, cefprozil, cefpodoxime, cefdinir, and loracarbef. Occasionally, patients will have AOM primarily because of H. influenzae or M. catarrhalis. In these cases second-generation oral cephalosporins (i.e., cefac1or, cefuroxime axetil, cefpodoxime, cefprozil, loracarbef) are preferable, because they appear to provide better gram-positive coverage and comparable coverage of M. catarrhalis and H. inJluenzae when ~ompared with third-generation cephalosporins (i.e., cefixime, ceftibuten, cefdinir, ceftriaxone). Cefuroxime axetil and ceftriaxone (intramuscular for up to 3 days) are now recommended as second-line therapy for clinical treatment failures. 8 Certain cephalosporins offer the advantage of once- or twice-daily dosing; however, the newer macrolide antibiotics (i.e., clarithromycin, azithromycin) offer the same feature and have expanded bacterial coverage (versus erythromycin) to include H. injluenzae and M. catarrhalis. Two new agents in the treatment of AOM are c1arithromycin and azithromycin. Both appear to be effective against major causative AOM organisms, including p-Iactamase-producing H. inJluenza e. 23 ,24 Potential benefits include once-daily (azithromycin) and twice-daily (clarithromycin) administration that might benefit patients with compliance issues. Although azithromycin is indicated for a total course of 5 days, a 3-day regimen has been shown to have comparable efficacy to a 10-day amoxicillin-c1avulanate course. 22 A potential disadvantage of these agents is cost and, for clarithromycin, a lack of palatability
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as well. GI side effects are the most common adverse effects. For children with tympanostomy tubes or perforated tympanic membranes and AOM, an alternative topical therapy was recently approved by the Food and Drug Administration. Ofloxacin otic solution (3 mglmL) 0.25 mL (equivalent to 5 drops) twice a day for 10 days was compared with amoxicillin-c1avulanate 40 mglkglday for 10 days in patients aged 1 to 12 years with tympanostomy tubes and otorrhea. Cure rates were similar (76% versus 69%, P = .169), but pathogen eradication rates were superior (96% to 67%, P < .001) in the ofloxacin group.25 In another study of children with tympanostomy tubes and otorrhea, which was open-label and compared with historical controls, ofloxacin otic was shown to be effective.26 Ofloxacin otic achieves high middle ear concentrations, has limited systemic absorption and thus limited side effects, and is neither ototoxic nor chondrotoxic in animal studies.27 There are currently no published randomized, controlled trials of ofloxacin otic compared with high-dose amoxicillin, high-dose amoxicillin and c1avulanate, or other antimicrobials, in patients with tympanostomy tubes or perforated tympanic membranes. A patient presenting with allergies to all of the previously mentioned antibiotics poses a therapeutic dilemma. The first option would be supportive therapy only (e.g., analgesics). Only 11 % of S. pneumoniae cases resolve without antibiotic therapy. Therefore, it would appear that treatment targeted against S. pneumoniae would be most practical. Agents such as c1indamycin or parenteral vancomycin could be used. It has been shown that approximately 60% of patients will have spontaneous resolution of AOM without antibiotic treatment. 28 It is reported that 52% of nontypable H. inJluenzae and 75% of M. catarrhalis will spontaneously resolve in 3 to 6 days:12
Box 10
Amoxicillin is considered the drug of choice in AOM. 1,4,8,11,29 Amoxicillin has good activity against the major causative organisms, has good penetration into middle ear fluid, and is a costeffective agent. 21 ,22 The incidence of adverse effects (e.g., Gl upset, diarrhea, rash) is low at 8%.11 Amoxicillin is not effective against p-Iactamase-producing organisms. Although concerns exist about the incidence of p-Iactamase-producing organisms, this group still accounts for only 4% to 6% of all AOM cases; thus, amoxicillin is a good choice for empiric therapy. Standard dosing of amoxicillin (40 to 45 mg/kg/day, twice a day or three times a day) is acceptable in children older than 2 years, who have not received antibiotics within the last 1 to 3 months, and who are not attending day care. 8 High-dose therapy (80 to 90 mg/kg/day, twice a day to three times a day) should be initiated in other groups not amenable to standard dosing because of the increased risk of PRSp. 8 The addition of clavulanic acid to amoxicillin expands antibiotic coverage to include p-Iactamase-producing organisms, especially M. catarrhalis and H. inJluenzae. In comparative studies with other oral antibiotics, this combination product is generally
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equivalent or superior to other agents for AOM. If the patient fails low-dose amoxicillin, then high-dose amoxicillin-clavulanate, cefuroxime axetil, or intramuscular ceftriaxone is suggested as the next course of therapy. 8 Patients who have received antibiotics within 1 month of this course of treatment should receive high-dose amoxicillin, amoxicillin and clavulanate, cefuroxime axetil, or intramuscular ceftriaxone. 8 (See Table 1 for dosing.) New formulations of amoxicillin (875 mg tablets) and amoxicillin and clavulanate (875 mg + 125 mg tablets; 400 mg + 57 mg and 200 mg + 28.5 mg chew tabs and suspension) have been approved to easily accommodate this higher dosing and to reduce 01 intolerance from clavulanic acid. Other second-line choices include TMP-SMX, erythromycin-sulfisoxazole, or other antibiotics as dictated by local resistance patterns. However, there are data to suggest that resistance to TMPSMX and erythromycin is significant, 25% and 10%, respectively. Therefore, patients who have failed amoxicillin may not respond to TMP-SMX or erythromycin in areas where resistant organisms are prevalent. 8
Box 12 Can the caregiver comply with multiple drug administrations per day? For children in day care, giving doses three times a day may present problems. Day care centers may elect not to administer medications or may be unable to reassure parents of proper compliance. In this situation, prescription of a once- or twicedaily antibiotic should avoid potential problems and allow parents to supervise medication administration. (See Table 1 for other agents with less frequent dosing.) Recently, amoxicillin and clavulanate was approved for twice-daily dosing. Amoxicillin is most often given three times a day; however, doses greater than 45 mg/kg/day are approved for twice-daily administration. Other sources of noncompliance include the poor taste of the antibiotic suspension, a lack of understanding of the disease, and a poor understanding of the risks of noncompliance. 30,31 Palatability of antibiotic suspensions may be improved by following administration with water, juice, or chocolate milk. For the noncompliant caregiver, provide education on the disease, reminders for medication administration, or a change to a more palatable antibiotic or administration from an oral syringe. Telephone calls to remind caregivers of the importance of compliance have been shown to increase compliance. 30 Counsel the caregiver about environmental and feeding factors that could influence the resolution of AOM. Environmental factors that have been examined range from passive smoke to feeding practices. Passive smoking appears to have a moderate association with OM with effusion, probably because of alterations in the mucociliary transport between the nasopharynx and eustachian tube. 5 Although data are somewhat limited, caregivers should be instructed to limit the patient's exposure to smoke, if possible. Postural factors during feeding have also been examined, suggesting that infants fed in the supine position are more
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likely to reflux nasopharyngeal secretions into the middle ear.32 Although available research is inconclusive, patients having recurrent episodes of OM may benefit from elevation of the head during feeding. Finally, an association appears to exist between OM and attendance at child care facilities, with some studies showing a twofold increase of OM in these children.5 It is unknown at this time whether removing the child from such facilities speeds resolution or prevents OME. Assess the patient in 48 to 72 hours for symptom improvement.
Boxes 13 and 14 Are symptoms improved or improving at 48 to 72 hours? If yes, complete the current antibiotic regimen. In approximately 60% of patients an effusion will resolve within 4 weeks, so the patient without symptoms should be seen again in 4 to 6 weeks. 33 Those continuing to have effusion should be managed as noted in Box 15.33 If the patient's symptoms are not improving, go to Box 18. If symptoms have not begun to resolve after 3 days of therapy, consider noncompliance or treatment failure. Treatment failure is defmed by a lack of clinical improvement characterized by persistent ear pain, fever, or drainage, and red or bulging tympanic membranes. 8 Children who continue to have persisting middle ear effusions, coryza, or cough should not be considered treatment failures and should continue their antibiotic regimen. 8
Boxes 15-17 Has the effusion resolved at the 4- to 6-week visit? If yes, exit the protocol. If no, consider the treatments outlined below or referral to an otolaryngologist for further evaluation. Patients who have not had resolution of their effusion(s) within 2 months may be candidates for antibiotics with or without systemic steroids. The management of OME is controversial because spontaneous resolution occurs in 65 % of all cases within 3 months without antibiotic therapy. 33 Thus, the appropriateness of drug therapy, time to initiate therapy, and duration of this therapy remain undefined. Concerns over long-term effusion are based on possible delays in the development of language skills if the child is not hearing the pronunciation of words clearly. The Agency for Health Care Policy and Research (AHCPR) evaluated randomized, controlled, clinical trials examining antibiotics alone, antibiotics with steroids, and steroids alone. 5 The AHCPR panel examined 18 randomized studies and 2 meta-analyses concerning the use of antibiotics in OME. A meta-analysis of all blinded studies (n = 10) showed a 14% increase in resolution of OME with antibiotics versus placebo. The panel also reviewed antibiotic and steroid combination therapy versus antibiotics alone in the treatment of OME. A metaanalysis of five studies indicated a high probability that the combination therapy was more effective than antibiotics alone, although ' statistical significance was not reached. The panel did not recommend combination therapy, although a minority report
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disagreed with this recommendation. 4 If combination therapy is to be used, oral prednisone at 1 mg/kg/day (in two divided doses for 7 days) plus concurrent antibiotics is recommended.34 Finally, three studies comparing steroids with placebo showed no long-term improvement with steroids. Thus, the panel did not recommend steroid therapy alone for OMB. Patients who respond to antibiotics for OME may benefit from prophylactic antibiotics. See Appendix 1 for further discussion.
Boxes 18 and 19 Symptoms are still unresolved-Has the caregiver been compliant with the medication administration? If yes, go to Box 20. If no, reeducate the caregiver and institute compliance measures. Once the reason for noncompliance has been identified, it can be resolved. Continue treatment and reassess symptoms in 48 to 72 hours. Go to Box 13. Noncompliance is a major source of therapeutic failure. In the absence of extensive verbal and written counseling, patient compliance has ranged from 5% to 49% with profound improvement in compliance (51 % to 82%) with aggressive patient education and follow-up compliance reminders. l ,2,3o,35 Regimens requiring multiple daily doses are detrimental to compliance. Drug regimens that require dosing more than two times a day may result in decreased compliance by patients or parents, and some day care centers may refuse to administer the medication, making such frequent dosing prohibitive.
Box 20 Patients who continue to demonstrate symptoms of AOM or Whose symptoms are worse after 72 hours of antibiotic therapy could be considered unresponsive to initial treatment. l A common question in the symptomatic patient is whether bacterial eradication has occurred. One study examined the bacteriology of AOM that is clinically unresponsive to antibiotics within the first 36 hours of treatment. These authors noted that approximately 60% of children had bacteriologically negative middle ear fluid, 20% had bacteria sensitive in vitro to prescribed antibiotic(s), and 20% had bacteria resistant to prescribed antibiotic(s).36 It is important to realize that patients may still have clinical symptoms of AOM after sterilization of the middle ear fluid, secondary to the effusion exerting pressure on the tympanic membrane. Therefore, When evaluating the patient's response, worsening of fever or otalgia may be the only indication that the prescribed antibiotic is not effective, and switching to another agent is warranted. 37 On the basis of the previously listed study, this unresponsiveness should occur only about 20% of the time. 36 Return to Boxes 7-11 and initiate another round of antibiotic therapy.
Boxes 21 and 22 The patient has received treatment with a second empiric
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antibiotic for 48 to 72 hours. Are the AOM symptoms improved or improving? If yes, continue therapy for the full course, and reassess the patient in 4 to 6 weeks for resolution of effusion. Go to Box 14. If symptoms are not improving, consider referral for myringotomy and culture.
Appendix 1: Further Issues in the Management of OM Note: The panel members believe that although the following information is important as supporting material, it is beyond the scope of a decision tree. It is presented here for readers ' information and use as appropriate. A common problem in OM is the patient who presents 1 to 3 weeks after treatment for AOM with recurrent signs and symptoms of acute infection. The selection of antibiotics is based on whether the clinician believes this relapse is caused by the pathogen that caused the first infection or by a new organism. A recent study showed that re-infections caused by a new organism were three times more likely than were relapses. 38 Therefore, constantly changing antibiotics could be inappropriate management, resulting in increased costs and frustration for patients and caregivers as well as the potential for increased antibiotic resistance. It is common for children to have several episodes of AOM. However, children who have frequent episodes close together are problematic. It is r~commended that children who have more than three episodes of AOM within a 6-month period start prophylactic antibiotics to prevent recurrent attacks. 4,29 The duration of prophylaxis is usually no longer than 6 months. Two antibiotics evaluated for prophylaxis are amoxicillin and sulfisoxazole. While many studies on antimicrobial prophylaxis have been performed, two representative studies are highlighted here. The fIrst, a randomized, controlled trial undertaken to compare sulfisoxazole 75 mg/kg/day divided in two daily doses for 6 months versus tympanostomy tubes showed that 33% of patients with indications for tubes were successfully treated with sulfisoxazole. 39 Although 67% of patients received tubes, the authors recommended a 6-month trial of sulfisoxazole prior to placement of tympanostomy tubes because safety and cost benefits seen with sulfisoxazole outweighed the risk of tubes. More patients may have responded if they had been started earlier on antibacterial prophylaxis. The second study evaluated amoxicillin prophylaxis 20 mg/kglday given once daily for 1 month versus tympanostomy tube for prevention of recurrent AOM. 4o This study showed that amoxicillin therapy was comparable to tubes in prevention of recurrent OM and was the preferred fIrst measure. Thus, initiating prophylaxis with either agent appears to be beneficial, especially since both agents are inexpensive and cause few adverse effects. One type of therapy currently being evaluated for prevention OM is vaccination. As mentioned previously, S. pneumoniae is the most common cause of AOM; thus, pneumococcal vaccine has been evaluated for prevention. 41 The main concerns are the
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ability to stimulate antibodies against the most common serotypes (serotype 6 could be important and is not currently covered by the vaccine) and the lack of benefit seen in infants less than 6 months of age.41 Still, the use of pneumococcal vaccine could be promising if pneumococcal SUbtypes could be added. H. injluenzae vaccine has little effect on OM, because most strains are nontypable and are not covered by the vaccine. Type B (which is covered by the vaccine) accounts for only 10% to 15% of H. injluenzae cases, and thus only 5% or less of all OM cases. A new vaccine is currently being developed that includes SUbtypes that appear promising for the prevention of OM.42 The influenza A vaccine also appears promising. Because a correlation appears to exist between viral infections and AOM, studies are evaluating the effectiveness of viral vaccines in decreasing AOM incidence. Two studies evaluating influenza A vaccine for children in day care centers showed a reduction in the incidence of AOM by 30% and 36%.43.44 These preliminary data indicate that the use of viral vaccinations offers promise in reducing the incidence of AOM.
References
17. Drwal-Klein LA. Phelps SJ. Antipyretic therapy in the febrile child. Clin Pharm. 1992;11:1005--21 . 18. Cantekin EI, Mandel EM, Bluestone CD, et al. Lack of efficacy of a decongestant-antihistamine combination for otitis media with effusion ("secretory" otitis media) in children. N Engl J Med. 1983;308:297-301 . 19. Wintermeyer SM, Nahata MC. Chronic suppurative otitis media. Ann Pharmacother. 1994;28:1089-99. 20. Pelton SI, Klein JO. The draining ear: otitis media and externa. Infect Dis Clin North Am. 1988;2(1):117-29. 21 . Krause PJ, Owens NJ, Nightingale CH, et al. Penetration of amoxicillin, cefaclor, erythromycin-sulfisoxazole and trimethoprim-sulfamethoxa· zole in the middle ear fluid of patients with chronic serous otitis media. J Infect Dis. 1982;145(6):815--21 . 22. Callahan CWoCost effectiveness of antibiotic therapy for otitis media in a military pediatric clinic. Pediatr Infect Dis J. 1988;7(9):622-5. 23. Schaad UB. Multicentre evaluation of azithromycin in comparison with co-amoxiclav for the treatment of acute otitis media in children. J Antimicrob Chemother. 1993;31 (suppl E):81-8, 24. Aspin MM, Hoberman A, McCarty J, et al. Comparative study of the safety and efficacy of clarithromycin and amoxicillin-clavulanate in the treatment of acute otitis media in children . J Pediatr. 1994; 125(1 ):136-41 . 25. Goldblatt EL, Dohar J, Nozza RJ, et al. Topical ofloxacin versus sys· temic amoxicillin/clavulanate in purulent otorrhea in children with tym· panostomy tubes. IntJ Pediatr Otorhinolaryngo/. 1998;46(1-2):91-101 . 26. Dohar JE, Garner ET Nielsen RW, et al. Topical ofloxacin treatment of otorrhea in children with tympanostomy tubes. Arch Otolaryngol Head Neck Surg. 1999;125(5):537-45. 27. Simpson KL, Markham A. Ofloxacin otic solution: a review of its use in the management of ear infections. Drugs. 1999;58(3):509-31 . 28. Frenkel M. Acute otitis media-does therapy alter its course? Postgrad Med.1987 ;82(5) : ~.
1. Cantor RM. Otitis extern a and otitis media: a new look at old problems. Emerg Med Clin North Am. 1995;13(2):445-55. 2. Claessen JQPJ, Appleman CLM, Touw-Otten FWMM, et al. A review of clinical trials regarding treatment of acute otitis media. Clin Otolaryngol. 1992;17:251-7. 3. Roark R, Petrofski J, Berson E, et al. Practice variations among pediatricians and family physicians in the management of otitis media. Arch Pediatr Adolesc Med. 1995;149:839-44. 4. Berman S. Otitis media in children. New Engl J Med. 1995; 332(23):1560-5. 5. Stool SE, Berg AO, Berman S, et al. Otitis Media with Effusion. Clinical Practice Guideline, No. 12. Rockville, Md: US Department of Health and Human Services; July 1994. AHCPR Publication 95-0621 . 6. Block SL. Strategies for dealing with amoxicillin failure in AOM. Arch Fam Med. 1999;8:68-78. 7. Giebink GS. The microbiology of otitis media. Pediatr Infect Dis J. 1989;8( 1):S518-20.
8. Dowell SF, Butler JC, Giebink GS, et al. Acute otitis media: management and surveillance in an era of pneumococcal resistance-a report from the Drug -Resistant Streptococcus pneumoniae Therapeutic Working Group. Pediatrlnfect Dis J. 1999;18(1 ):1-9. 9. Palua T, Lehtinen T, Virtanen H. Pneumococcal polysaccaride capsular antigens in chronic secretory otitis media . Int J Ped Otolaryngol. 1983;6: 145--9. 10. Wald ER. Haemophilus influenzae as a cause of acute otitis media. Pediatr Infect Dis J . 1989;8( 1):S528-30. 11 . Thoene DE, Johnson CEo Pharmacotherapy of otitis media. Pharmacotherapy. 1991 ;11(3):212-21 . 12. Klein JO. Microbiologic efficacy of antibacterial drugs for acute otitis media. Pediatr Infect Dis J. 1993;12(12):973-5. 13. Henderson FW, Collier AM, Sanyal MA, et al. A longitudinal study of respiratory viruses and bacteria in the etiology of acute otitis media with effusion. N Eng/J Med. 1982;306(23):1377-83. 14. Chonmaitree T, Owen MJ, Howie VM . Respiratory viruses interfere with bacteriologic response to antibiotic in children with acute otitis media. J Infect Dis. 1990;162:546-9. 15.
Remington JS, Klein JO. In: Marks MI, Klein JO, eds. Infectious Diseases of the Fetus and Newborn Infant. 4th ed. Philadelphia, Pa: WB Saunders Co; 1995:894-8.
16. Schwartz RH, Rodriguez WJ, Brook I, et al. The febrile response in acute otitis media. JAMA. 1981;245(20):2057-8.
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29. Bluestone CD. Otitis media in children: to treat or not to treat? N Engl J Med. 1982;306(23): 1399-404. 30. Finney JW, Friman PC, Rapoff MA, et al. Improving compl iance with antibiotic regimens for otitis media. Am J Dis Child. 1985;139:89-95. 31 . Dagan R, Shvartzman P, Liss Z. Variation in acceptance of common oral antibiotic suspensions. Pediatr Infect Dis J . 1994;13(8):686-90. 32. Paradise JL. Otitis media in infants and children. Pediatrics. 1980; 65(5):917-43. 33. Caselbrant ML, Brostoff LM, Cantekin EI, et al. Otitis media with effusion in preschool children. Laryngoscope. 1985;96:428-36. 34. Berman S, Grose K, Nuss R, et al. Management of chronic middle ear effusion with prednisone combined with trimethoprim-sulfamethoxazole. Pediatr Infect Dis J. 1990;9(8):533-8. 35. Mattar ME, Markello J, Yaffe SJ. Pharmaceutic factors affecting pediatric compliance. Pediatrics. 1975;55(1 ):101-8. 36. Teele DW, Pelton SI, Klein JO. Bacteriology of acute otitis media unresponsive to initial antimicrobial therapy. J Pediatr. 1981;98(4):537-9. 37. Marchant CD, Carlin SA, Johnson CE, et al. Measuring the comparative efficacy of antibacterial agents for acute otitis media: the "Pollyanna phenomenon." J Pediatr. 1992;120(1):72-7. 38. Carlin SA. Marchant CD, Shurin PA. et al. Early recurrences of otitis media: reinfection or relapse? J Pediatr. 1987;110(1):20-5. 39. Bernard PAM, Stenstrom RJ, Feldman W, et al. Randomized controlled trial comparing long-term sulfonamide therapy to ventilation tubes for otitis media with effusion. Pediatrics. 1991 ;88(2):215--22. 40. Cassel brant ML, Kaleida PH, Rockette HE, et al. Efficacy of antimicro· bial prophylaxis and of tympanostomy tube insertion for prevention of recurrent acute otitis media: results of a randomized clinical trial. Pediatrlnfect Dis J. 1992;11 (4):278-86. 41 . Makela PH, Leinonen M, Pukander J, et al. A study of the pneumococ· cal vaccine in prevention of clinically acute attacks of recurrent otitis media. Rev Infect Dis. 1981 ;3(suppl): S124-30. 42. Wadwa RP, Feigin RD. Pneumococcal vaccine: an update. Pediatrics. 1999;103:1035--7. 43. Clements DA. Langdon L, Bland C, et al. 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. 44. Heikkinen T, Ruuskanen 0, Waris M, et al. Influenza vaccination in the prevention of acute otitis media in children. Am J Dis Child. 1991;145:445-8.
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APhA I)rug Treatment Protocols: Management of Pediatric Acute Otitis Media Annual costs for treatment of this painful childhood disorder exceed $3.5 billion. Introduction by Daniel H. Albrant Protocol developed by APhA Pediatric Disorders Protocol Panel
Introduction
Protocol Development Process
All of the protocols developed through APhA are subject Acute otitis media (AOM) is defined as an acute infection of to the following process: the middle ear. Its onset is rapid, with pain, fever, irritability, • A preliminary-draft protocol author, consultant, and project anorexia, or vomiting. 1 Otitis media (OM) is the most common director work collaborative1y to select and narrow the reason for medical office visits in childhood. 2 It is estimated that topic, thoroughly review and evaluate the scientific evi62% of children will have had at least one episode of OM by their dence, defme the target patient population, defme the clinifIrst birthday, and more than 80% will have had an attack by 3 1 cal interventions, and develop a preliminary-draft protocol. years of age. The financial impact of treating AOM is substan• An interdisciplinary panel then reviews the draft protocol tial, although antibiotics contribute to only a small portion of the and additional scientific evidence; if necessary, redefines the overall treatment costs. 3,4 topic and targeted population; and prepares a second draft Streptococcus pneumoniae and Haemophilus injluenzae infecfor further peer review. The panel's decisions are based on tions account for 60% to 80% of all cases of- AOM. Penicillinscientific evidence; in areas where evidence is inconclusive resistant Streptococcus pneumoniae is a growing problem, and . or controversial, recommendations are based on consensus. the newest dosing recommendations for amoxicillin and amoxi• The panel's draft is reviewed by an interdisciplinary cillin-clavulanate are twice as large as before (amoxicillin 80 to of peer reviewers as well as the author of the pregroup 90 mg/kg/day). liminary draft. These experts critically evaluate the draft The protocol begins with a pediatric patient who presents with a for content, validity, and applicability to patient care. diagnosis of AOM. If the child is < 3 months old, he or she should Taking this second group's recommendations into be referred to ·a physician due to the risk of AOM in association account, the draft protocol is then revised, reviewed, and with systemic infections, including meningitis. Patients with ultimately approved by the original panel. chronic suppurative OM should also be referred to an otolaryngol• Finalized protocols are published in the APhA Guide to ogist or other specialist for further evaluation and management. Drug Treatment Protocols and sold individually for a Drug therapy decision making begins with a determination of nominal fee. Again, it is intended that the template be medication allergies. If the patient is able to take penicillin, amoxadapted to increase the protocol's specificity and applicaicillin in usual doses (40 to 45 mg/kg/day) is initiated. Standard bility to local needs. dosing of amoxicillin (40 to 45 mg/kg/day, two or three times daily) is acceptable in children older than 2 years, who have not 5 received antibiotics within the last 1 to 3 months, and who are not cefuroxime axetil, or intramuscular ceftriaxone. Other options, attending day care. 5 High-dose therapy (80 to 90 mg/kg/day, determined by the allergy profile, include trimethoprim-sultWice daily to three times daily) should be initiated in other famethoxazole, certain cephalosporins, and the fluoroquinolones. After 48 to 72 hours the patient should receive a follow-up groups not amenable to standard dosing because of the increased 5 contact to assess for treatment adherence and possible treatment risk of penicillin-resistant S. pneumoniae. Patients who have If the patient has not improved, then switch to another failure. received antibiotics within 1 month of this course of treatment if the patient (or caregiver) has been adherent to the antibiotic should receive high-dose amoxicillin, amoxicillin-clavulanate,
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therapy. The usual course of therapy is 10 days. Patients who do not respond to multiple antibiotic courses, or those with persistent effusion, should be referred to an otolaryngologist for further evaluation and treatment. Thanks go out to our friends at Daiichi Pharmaceuticals for the unrestricted educational grant that enabled APhA to revise this drug treatment protocol. This revision will join the 44 other drug treatment protocols in a new edition of the Drug Treatment Protocols book due out by the end of this year. Daniel H. Albrant, PharmD, is editor-in-chief, APhA Drug Treatment Protocols Project.
References 1. Berman S. Otitis media in children. New Engl J Med. 1995; 332(23): 1560-5. 2. Cantor RM. Otitis externa and otitis media: a new look at old problems. Emerg Med Clin North Am. 1995;13(2)445-55. 3. Wandstrat TL, Kaplan B. Pharmacoeconomic impact of factors affecting compliance with antibiotic regimens in the treatment of acute otitis media. Pediatr Infect Dis. 1997;16:S27-9. 4. Kaplan B, Wandstrat TL, Cunningham JR. Overall costs in the treatment of otitis media. Pediatr Infect Dis. 1997;16:S9-11. 5. Dowell SF, Butler JC, Giebink GS, et al. Acute otitis media: management and surveillance in an era of pneumococcal resistance-a report from the Drug-Resistant Streptococcus pneumoniae Thera peutic Working Group. Pediatr Infect Dis J. 1999;18(1 ):1-9.
American Pharmaceutical Association Pediatric Disorders Protocol Participants
Comprehensive Reviewers Donna M. Kraus Associate Professor Departments of Pharmacy Practice and Pediatrics Pediatric Clinical Pharmacist University of illinois at Chicago Chicago, ill.
Kelley R. Lee, PharmD Clinical Pharmacy Specialist LeBonheur Children's Medical Center Assistant Professor College of Pharmacy University of Tennessee Memphis, Tenn.
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Protocol Revision Reviewers Seth M. Pransky, MD, FAAP Pediatric Otolaryngologist Children's Hospital San Diego, Calif.
Editor-in-Chief Daniel H. Albrant, PharmD President Pharmacy Dynamics Arlington, Va.
Lisa Hammer Rieg, PharmD Infectious Diseases Pharmacist, CA Division Drug Information Services, CA Division Kaiser Permanente Downey, Calif.
Elaine C. Taylor, PharmD Cliriical Assistant Professor University of Texas at El Paso/Austin Cooperative Pharmacy Program El Paso, Tex.
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APhA Drug Treatment Protocols Management of Pediatric Acute Otitis Media
Pediatric patient with diagnosis of acute otitis media (AOM).
2 Confirm the diagnosis of AOM. Review history, physical exam, and lab tests.
3 Review probable organisms. If patient is < 3 months old, refer to a physician.
4 Develop treatment plan with patient and caregiver. Use an analgesic as needed.
5 Does the patient have chronic suppurative otitis media?
6 Yes~
Refer to otolaryngologist. Exit protocol.
No 8
7 Does the patient have a documented penicillin allergy?
No
Yes
Does the patient have a documented sulfa allergy?
Go to Box 12.
No
10~------~------~
First course: amoxicillin. Second course: amoxicillin and clavulanate or alternative agent as dictated by local resistance patterns. Go to Box 12. 12~------~------~
Educate caregiver; give compliance tools. Follow up with phone calls. Instruct caregiver on environmental and feeding factors. Assess patient in 48-72 hours.
Go to Box 13. This protocol is a tool designed to help health professionals make decisions related to patient therapy. It is not intended to replace professional judgment or to establish the only approach to a problem.
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From Box 12.
15
13
14~------------~
Are symptoms improved or improving at 48-72 hours?
Complete current treatment regimen. Reassess patient in 4-6 weeks.
Yes
,
161-------- . . . .
Has the effusion resolved in 4-6 weeks?
I
Exit protocol.
,
No
No
17
18
19~------------~
Has the caregiver been compliant?
No
Reeducate. Institute compliance measures. Continue treatment. Reassess in 48-72 hours.
Consider antibiotics ± corticosteroids. Consider prophylactic antibiotics. Consider referral to an otolaryngologist.
I
Yes
Go to Box 13.
20~-----L------~
Initiate alternative antibiotic. See Boxes 7-11.
21 Does the patient have symptoms 48-72 hours after a second antibiotic is started?
22~-------------
Yes
Consider referral for myringotomy and culture.
, I
No
[
Go to Box 14.
J
This protocol is a tool designed to help health professionals make decisions related to patient therapy. It is not intended to replace professional judgment or to establish the only approach to a problem.
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Note: For purposes of this protocol, a pediatric patient is defined as a person from term to 18 years of age.
Box 1 Otitis media (OM) is the most common reason for medical office visits in childhood, accounting for 33% of all visits. 1 It is estimated that 62% of children will have had at least one episode of OM by their first birthday, and more than 80% will have had an attack by 3 years of age. 1 The financial impact of treating acute otitis media (AOM) is substantial, with direct and indirect costs exceeding $3.5 billion annually.2 Although antibiotics are prescribed in over 95% of cases, they contribute to only a small portion of the overall treatment costS. 2,3 AOM is defined as an acute infection of the middle ear. Symptoms develop rapidly, with pain, fever, irritability, anorexia, or vomiting. 4 The diagnosis is made by direct visualization with a pneumatic otoscope to assess tympanic movement and color. 4 AOM lasts less than 3 weeks; subacute OM lasts between 3 weeks and 3 months; and chronic OM lasts longer than 3 months. Otitis media with effusion (OME) accounts for 25% to 35% of all OM cases. 5 OME is defined"as fluid in the middle ear without clinical signs of active infection.
Box2 Confirm the diagnosis of AOM. The early development of AOM will show diminished translucency, tympanic membrane bulging, and poor tympanic membrane mobility when examined using a pneumatic otoscope. Patients may complain of muffled hearing or pull on the infected ear( s) as fluid accumulates behind the membrane and causes otalgia (ear pain), fever, and malaise. As fluid continues to accumulate, symptoms of nausea, vomiting, anorexia, and diarrhea may ensue. Otalgia may interfere with patients ' sleep. The tympanic membrane i~ erythematous and bulging by this time. 1 Left untreated, the membrane may perforate, and the patient may develop acute mastoiditis, bacteremia, chronic purulent otorrhea, or permanent loss of hearing.1,6 Review the patient's history, physical examination, and lab tests. Assess medication history and recent history of antibiotic use.
Box3 In clinical trials, bacteria are cultured from middle ear aspirates in approximately 70% of children with AOM.7 Streptococcus pneumoniae accounts for the majority of isolates, ranging from 40% to 50%.1,8 The most common serotypes are 3, 6, 14, 19, and 23, with these five groups accounting for 63% to 77% of-all pneumococcal isolates. 9 Penicillin-resistant Streptococcus pneumoniae (PRSP) is an emerging public health issue, with rates of resistance ranging from 8% to 34% across the United States. 8 The prevalence of PRSP is greater in children less than 2 years of age, especially those attending day care, and in children who have
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received antibiotics within the preceding 1 to 3 months. 8 Haemophilus injluenzae is the next most prevalent organism associated with AOM (20% to 30%). 8 Nontypable H. injluenzae accounts for 85% to 90% of these cases, while type B is only responsible for 10% to 15%.10 ~-lactamase producers constitute 35% to 50% of H. injluenzae strains, although endemic areas exist with a higher prevalence of these enzyme producers. 8,lI Other causative organisms include Moraxella catarrhalis (10% to 15%), Staphylococcus aureus (1 % to 11 %), and Streptococcus pyogenes (1 % to 5%).7 While many antibiotics are marketed to treat M. catarrhalis, infections from this organism are usually self-limited.8,12 Although AOM is commonly associated with bacterial infections, viruses may also playa pathogenic role. Viruses associated with AOM include respiratory syncytial virus, rhinovirus , influenza A and B, adenovirus, enterovirus, and parainfluenza viruS.13 Although not completely understood, concomitant viral infection is thought to promote or prolong AOM by altering eustachian tube function or impairing cellular defense mechanisms. 14 In:(ants less than 3 months of age with AOM must be given special consideration. These infants may have isolated AOM, or the disease may be associated with bacteremia, meningitis, or pneumonia. 15 Possible bacterial pathogens in this group, in addition to those previously mentioned, include group B streptococcus (27%), Escherichia coli (5.5%), Klebsiella pneumoniae and Enterobacter sp. (4.9%), and Pseudomonas aeruginosa (1.6%). These patients should be evaluated by a physician because of the risk of systemic infections and meningitis.
Box 4 It is very important to discuss treatment plans with the caregiver, taking into account the issues of history of allergy or sensitivity to any antibiotic, compliance, affordability, palatability, and frequency of administration when choosing antibiotics. The caregiver's understanding of these issues can help to maximize adherence to the treatment. Secondary to the increase in prevalence of PRSP, antibiotics should be chosen as detailed in Boxes 9-11. 8 Table 1 lists the most common antibiotics used in OM and the recommended clinical course of therapy. The standard course of treatment for AOM is 10 days. However, shorter courses of therapy (i.e., 5 to 7 days) may be considered in children over the age of 2 years whose symptoms improve within 72 hours and who have no other complications, such as a perforated tympanic membrane. 8 Give adjunctive agents as necessary to control pain, fever, and ear discomfort. It is estimated that fever is present in 23% to 67% of patients with AOM, and high fever (> 40°C) is seen in 0.3% of infants « 1 year of age).1 6 No association appears to exist between fever and a particular infecting organism. A combination regimen that alternates analgesic agents does not produce a greater benefit than single-agent therapy. 17
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Table 1. Antibiotics Commonly Used to Treat Acute Otitis Media Generic Name
Brand Name
Dose B
Frequency!Duration
Amoxicillin high dose
Various generics
40-45 mg/kg/day 80-90 mg/kg/day
2-3 times daily for 10 days
Amoxicillin and clavulanate high dose
Augmentin
40 mg/kg/day 45 mg/kg/day (bid) 80-90 mg/kg/day "+ 6.4 mg/kg/day
2-3 times daily for 10 days
Azithromycin
Zithromax
10 mg/kg/day 1
1 time daily for 5 days
5 mg/kg/days 2-5 Cefaclor
Ceclor and generic
40 mg/kg/day
3 times daily for 10 days
Cefdinir
Omicef
14 mg/kg/day
1-2 times daily for 10 days
Cefixime
Suprax
8 mg/kg/day
1-2 times daily for 10 days
Cefpodoxime
Vantin
10 mg/kg day
1-2 times daily for 10 days
Cefprozil
Cefzil
30 mg/kg/day
2 times daily for 10 days
Ceftibuten
Cedax
9 mg/kg/day
1 time daily for 10 days
Ceftriaxone
Rocephin
50 mg/kg/day for 1-3 days
1 time daily intramuscular
Cefuroxime
Ceftin
30 mg/kg/day
2 times daily for 10 days
Cephalexin
Various generics
75-100 mg/kg/day
4 times daily for 10 days
Clarithromycin
Biaxin
15 mg/kg/day
2 times daily for 10 days
Erythromycin and sulfisoxazole
Various generics
50 mg/kg/day erythromycin
4 times daily for 10 days
Loracarbef
Lorabid
30 mg/kg/day
2 times daily for 10 days
Ofloxacin
Floxin Otic
0.25 mL
2 times daily for 10 days
Trimethoprim and sulfamethoxazole
Various generics
8 mg/kg/day trimethoprim
2 times daily for 10 days
Bin children weighing more than 40 kg, do not exceed adult doses.
Acetaminophen at a dose of 10 to 15 mg/kg every 4 to 6 hours or ibuprofen at a dose of 5 to 10 mg/kg every 6 to 8 hours will usually bring significant relief. Topical analgesic agents (e.g., Auralgan) should not be used when the tympanic membrane has ruptured, because these agents could damage middle ear tissue. 4 Oral antihistamines and decongestants have been prescribed together and alone to prevent eustachian tube obstruction or to decrease the amount of effusion. However, studies have shown that these agents are no more effective than a placebo. 4 ,5,18 Thus, the routine use of a decongestant, antihistamine, or both cannot be recommended at this time.
Because of the long-term sequelae if inappropriately treated, an otolaryngologist should be consulted if available--or another specialist if unavailable; exit the protocol.
Box 7 Does the patient have a documented history of an allergy to penicillin? If yes, go to Box 8 to assess for an allergy to sulfa. If no, amoxicillin is the drug of choice; go to Box 10.
Boxes 8 and 11 Boxes 5 and 6 Does the patient have chronic suppurative otitis media (CSOM)? CSOM is defined as chronic inflammation of the middle ear with otorrhea and perforated tympanic membrane but generally without pain or fever. 19 Persistent inflammation secondary to infection may result in structural changes of the middle ear. These physiologic changes of chronic inflammation and discharge are believed to result from intermittent or continuous reflux of nasopharyngeal secretions into the middle ear, or contamination from the external ear through tympanostomy tubes.2o
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The patient has a documented penicillin allergy. Is the patient allergic to sulfa? If yes, go to Box 9. If no sulfa allergy is identified, initiate trimethoprim and sulfamethoxazole (TMP-SMX) or erythromycinand sulfisoxazole. TMP-SMX and erythromycin-sulfisoxazole are good choices for empiric treatment of AOM. TMP-SMX offers the advantage of twice-daily dosing, has good penetration in the middle ear, and is inexpensive. 21,22 TMP-SMX also provides good coverage for most AOM organisms, except S. pyogenes and S. aureus. ll In addition, TMP-SMX is effective against ~-lactamase-producing H. injluenzae. 4 For pediatric patients weighing 40 kg or more, use
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normal adult dosing recommendations. The most common adverse effects associated with TMP-SMX are gastrointestinal (GI), with an incidence similar to amoxicillin.ll Although feared, the incidence of severe dermatologic skin reactions is rare. 11 Photosensitivity reactions may occur, and caregivers should be instructed to use sunscreen on the patient if prolonged sun exposure is expected. The bitter aftertaste of the suspension may contribute to its relative lack of palatability. Giving a glass of water after administration, or giving the medication from an oral syringe, can lessen this aftertaste. Go to Box 12.
Box9 If the patient is allergic to both penicillin and sulfa, then a macrolide (i.e., erythromycin, clarithromycin, or azithromycin) or possibly a cephalosporin should be prescribed. (See Table 1 for dosing.) Patients who demonstrate a severe or potentially severe allergic reaction (i.e., anaphylaxis) to penicillins need to be carefully assessed before cephalosporin therapy is initiated. Crosssensitivity between penicillins and cephalosporins is reported at 5% to 14% for patients with severe allergy.1 1 Cephalosporins are effective against most organisms associated with AOM; however, they are not effective against highly resistant pneumococci. 4 Thus, cephalosporins offer no advantage over amoxicillin in a "typical" AOM case. Furthermore, if the patient is less than 6 months old, the following cephalosporins should not be prescribed due to lack of established safety and efficacy: cefixime, cefprozil, cefpodoxime, cefdinir, and loracarbef. Occasionally, patients will have AOM primarily because of H. influenzae or M. catarrhalis. In these cases second-generation oral cephalosporins (i.e., cefac1or, cefuroxime axetil, cefpodoxime, cefprozil, loracarbef) are preferable, because they appear to provide better gram-positive coverage and comparable coverage of M. catarrhalis and H. inJluenzae when ~ompared with third-generation cephalosporins (i.e., cefixime, ceftibuten, cefdinir, ceftriaxone). Cefuroxime axetil and ceftriaxone (intramuscular for up to 3 days) are now recommended as second-line therapy for clinical treatment failures. 8 Certain cephalosporins offer the advantage of once- or twice-daily dosing; however, the newer macrolide antibiotics (i.e., clarithromycin, azithromycin) offer the same feature and have expanded bacterial coverage (versus erythromycin) to include H. injluenzae and M. catarrhalis. Two new agents in the treatment of AOM are c1arithromycin and azithromycin. Both appear to be effective against major causative AOM organisms, including p-Iactamase-producing H. inJluenza e. 23 ,24 Potential benefits include once-daily (azithromycin) and twice-daily (clarithromycin) administration that might benefit patients with compliance issues. Although azithromycin is indicated for a total course of 5 days, a 3-day regimen has been shown to have comparable efficacy to a 10-day amoxicillin-c1avulanate course. 22 A potential disadvantage of these agents is cost and, for clarithromycin, a lack of palatability
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as well. GI side effects are the most common adverse effects. For children with tympanostomy tubes or perforated tympanic membranes and AOM, an alternative topical therapy was recently approved by the Food and Drug Administration. Ofloxacin otic solution (3 mglmL) 0.25 mL (equivalent to 5 drops) twice a day for 10 days was compared with amoxicillin-c1avulanate 40 mglkglday for 10 days in patients aged 1 to 12 years with tympanostomy tubes and otorrhea. Cure rates were similar (76% versus 69%, P = .169), but pathogen eradication rates were superior (96% to 67%, P < .001) in the ofloxacin group.25 In another study of children with tympanostomy tubes and otorrhea, which was open-label and compared with historical controls, ofloxacin otic was shown to be effective.26 Ofloxacin otic achieves high middle ear concentrations, has limited systemic absorption and thus limited side effects, and is neither ototoxic nor chondrotoxic in animal studies.27 There are currently no published randomized, controlled trials of ofloxacin otic compared with high-dose amoxicillin, high-dose amoxicillin and c1avulanate, or other antimicrobials, in patients with tympanostomy tubes or perforated tympanic membranes. A patient presenting with allergies to all of the previously mentioned antibiotics poses a therapeutic dilemma. The first option would be supportive therapy only (e.g., analgesics). Only 11 % of S. pneumoniae cases resolve without antibiotic therapy. Therefore, it would appear that treatment targeted against S. pneumoniae would be most practical. Agents such as c1indamycin or parenteral vancomycin could be used. It has been shown that approximately 60% of patients will have spontaneous resolution of AOM without antibiotic treatment. 28 It is reported that 52% of nontypable H. inJluenzae and 75% of M. catarrhalis will spontaneously resolve in 3 to 6 days:12
Box 10
Amoxicillin is considered the drug of choice in AOM. 1,4,8,11,29 Amoxicillin has good activity against the major causative organisms, has good penetration into middle ear fluid, and is a costeffective agent. 21 ,22 The incidence of adverse effects (e.g., Gl upset, diarrhea, rash) is low at 8%.11 Amoxicillin is not effective against p-Iactamase-producing organisms. Although concerns exist about the incidence of p-Iactamase-producing organisms, this group still accounts for only 4% to 6% of all AOM cases; thus, amoxicillin is a good choice for empiric therapy. Standard dosing of amoxicillin (40 to 45 mg/kg/day, twice a day or three times a day) is acceptable in children older than 2 years, who have not received antibiotics within the last 1 to 3 months, and who are not attending day care. 8 High-dose therapy (80 to 90 mg/kg/day, twice a day to three times a day) should be initiated in other groups not amenable to standard dosing because of the increased risk of PRSp. 8 The addition of clavulanic acid to amoxicillin expands antibiotic coverage to include p-Iactamase-producing organisms, especially M. catarrhalis and H. inJluenzae. In comparative studies with other oral antibiotics, this combination product is generally
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equivalent or superior to other agents for AOM. If the patient fails low-dose amoxicillin, then high-dose amoxicillin-clavulanate, cefuroxime axetil, or intramuscular ceftriaxone is suggested as the next course of therapy. 8 Patients who have received antibiotics within 1 month of this course of treatment should receive high-dose amoxicillin, amoxicillin and clavulanate, cefuroxime axetil, or intramuscular ceftriaxone. 8 (See Table 1 for dosing.) New formulations of amoxicillin (875 mg tablets) and amoxicillin and clavulanate (875 mg + 125 mg tablets; 400 mg + 57 mg and 200 mg + 28.5 mg chew tabs and suspension) have been approved to easily accommodate this higher dosing and to reduce 01 intolerance from clavulanic acid. Other second-line choices include TMP-SMX, erythromycin-sulfisoxazole, or other antibiotics as dictated by local resistance patterns. However, there are data to suggest that resistance to TMPSMX and erythromycin is significant, 25% and 10%, respectively. Therefore, patients who have failed amoxicillin may not respond to TMP-SMX or erythromycin in areas where resistant organisms are prevalent. 8
Box 12 Can the caregiver comply with multiple drug administrations per day? For children in day care, giving doses three times a day may present problems. Day care centers may elect not to administer medications or may be unable to reassure parents of proper compliance. In this situation, prescription of a once- or twicedaily antibiotic should avoid potential problems and allow parents to supervise medication administration. (See Table 1 for other agents with less frequent dosing.) Recently, amoxicillin and clavulanate was approved for twice-daily dosing. Amoxicillin is most often given three times a day; however, doses greater than 45 mg/kg/day are approved for twice-daily administration. Other sources of noncompliance include the poor taste of the antibiotic suspension, a lack of understanding of the disease, and a poor understanding of the risks of noncompliance. 30,31 Palatability of antibiotic suspensions may be improved by following administration with water, juice, or chocolate milk. For the noncompliant caregiver, provide education on the disease, reminders for medication administration, or a change to a more palatable antibiotic or administration from an oral syringe. Telephone calls to remind caregivers of the importance of compliance have been shown to increase compliance. 30 Counsel the caregiver about environmental and feeding factors that could influence the resolution of AOM. Environmental factors that have been examined range from passive smoke to feeding practices. Passive smoking appears to have a moderate association with OM with effusion, probably because of alterations in the mucociliary transport between the nasopharynx and eustachian tube. 5 Although data are somewhat limited, caregivers should be instructed to limit the patient's exposure to smoke, if possible. Postural factors during feeding have also been examined, suggesting that infants fed in the supine position are more
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likely to reflux nasopharyngeal secretions into the middle ear.32 Although available research is inconclusive, patients having recurrent episodes of OM may benefit from elevation of the head during feeding. Finally, an association appears to exist between OM and attendance at child care facilities, with some studies showing a twofold increase of OM in these children.5 It is unknown at this time whether removing the child from such facilities speeds resolution or prevents OME. Assess the patient in 48 to 72 hours for symptom improvement.
Boxes 13 and 14 Are symptoms improved or improving at 48 to 72 hours? If yes, complete the current antibiotic regimen. In approximately 60% of patients an effusion will resolve within 4 weeks, so the patient without symptoms should be seen again in 4 to 6 weeks. 33 Those continuing to have effusion should be managed as noted in Box 15.33 If the patient's symptoms are not improving, go to Box 18. If symptoms have not begun to resolve after 3 days of therapy, consider noncompliance or treatment failure. Treatment failure is defmed by a lack of clinical improvement characterized by persistent ear pain, fever, or drainage, and red or bulging tympanic membranes. 8 Children who continue to have persisting middle ear effusions, coryza, or cough should not be considered treatment failures and should continue their antibiotic regimen. 8
Boxes 15-17 Has the effusion resolved at the 4- to 6-week visit? If yes, exit the protocol. If no, consider the treatments outlined below or referral to an otolaryngologist for further evaluation. Patients who have not had resolution of their effusion(s) within 2 months may be candidates for antibiotics with or without systemic steroids. The management of OME is controversial because spontaneous resolution occurs in 65 % of all cases within 3 months without antibiotic therapy. 33 Thus, the appropriateness of drug therapy, time to initiate therapy, and duration of this therapy remain undefined. Concerns over long-term effusion are based on possible delays in the development of language skills if the child is not hearing the pronunciation of words clearly. The Agency for Health Care Policy and Research (AHCPR) evaluated randomized, controlled, clinical trials examining antibiotics alone, antibiotics with steroids, and steroids alone. 5 The AHCPR panel examined 18 randomized studies and 2 meta-analyses concerning the use of antibiotics in OME. A meta-analysis of all blinded studies (n = 10) showed a 14% increase in resolution of OME with antibiotics versus placebo. The panel also reviewed antibiotic and steroid combination therapy versus antibiotics alone in the treatment of OME. A metaanalysis of five studies indicated a high probability that the combination therapy was more effective than antibiotics alone, although ' statistical significance was not reached. The panel did not recommend combination therapy, although a minority report
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disagreed with this recommendation. 4 If combination therapy is to be used, oral prednisone at 1 mg/kg/day (in two divided doses for 7 days) plus concurrent antibiotics is recommended.34 Finally, three studies comparing steroids with placebo showed no long-term improvement with steroids. Thus, the panel did not recommend steroid therapy alone for OMB. Patients who respond to antibiotics for OME may benefit from prophylactic antibiotics. See Appendix 1 for further discussion.
Boxes 18 and 19 Symptoms are still unresolved-Has the caregiver been compliant with the medication administration? If yes, go to Box 20. If no, reeducate the caregiver and institute compliance measures. Once the reason for noncompliance has been identified, it can be resolved. Continue treatment and reassess symptoms in 48 to 72 hours. Go to Box 13. Noncompliance is a major source of therapeutic failure. In the absence of extensive verbal and written counseling, patient compliance has ranged from 5% to 49% with profound improvement in compliance (51 % to 82%) with aggressive patient education and follow-up compliance reminders. l ,2,3o,35 Regimens requiring multiple daily doses are detrimental to compliance. Drug regimens that require dosing more than two times a day may result in decreased compliance by patients or parents, and some day care centers may refuse to administer the medication, making such frequent dosing prohibitive.
Box 20 Patients who continue to demonstrate symptoms of AOM or Whose symptoms are worse after 72 hours of antibiotic therapy could be considered unresponsive to initial treatment. l A common question in the symptomatic patient is whether bacterial eradication has occurred. One study examined the bacteriology of AOM that is clinically unresponsive to antibiotics within the first 36 hours of treatment. These authors noted that approximately 60% of children had bacteriologically negative middle ear fluid, 20% had bacteria sensitive in vitro to prescribed antibiotic(s), and 20% had bacteria resistant to prescribed antibiotic(s).36 It is important to realize that patients may still have clinical symptoms of AOM after sterilization of the middle ear fluid, secondary to the effusion exerting pressure on the tympanic membrane. Therefore, When evaluating the patient's response, worsening of fever or otalgia may be the only indication that the prescribed antibiotic is not effective, and switching to another agent is warranted. 37 On the basis of the previously listed study, this unresponsiveness should occur only about 20% of the time. 36 Return to Boxes 7-11 and initiate another round of antibiotic therapy.
Boxes 21 and 22 The patient has received treatment with a second empiric
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antibiotic for 48 to 72 hours. Are the AOM symptoms improved or improving? If yes, continue therapy for the full course, and reassess the patient in 4 to 6 weeks for resolution of effusion. Go to Box 14. If symptoms are not improving, consider referral for myringotomy and culture.
Appendix 1: Further Issues in the Management of OM Note: The panel members believe that although the following information is important as supporting material, it is beyond the scope of a decision tree. It is presented here for readers ' information and use as appropriate. A common problem in OM is the patient who presents 1 to 3 weeks after treatment for AOM with recurrent signs and symptoms of acute infection. The selection of antibiotics is based on whether the clinician believes this relapse is caused by the pathogen that caused the first infection or by a new organism. A recent study showed that re-infections caused by a new organism were three times more likely than were relapses. 38 Therefore, constantly changing antibiotics could be inappropriate management, resulting in increased costs and frustration for patients and caregivers as well as the potential for increased antibiotic resistance. It is common for children to have several episodes of AOM. However, children who have frequent episodes close together are problematic. It is r~commended that children who have more than three episodes of AOM within a 6-month period start prophylactic antibiotics to prevent recurrent attacks. 4,29 The duration of prophylaxis is usually no longer than 6 months. Two antibiotics evaluated for prophylaxis are amoxicillin and sulfisoxazole. While many studies on antimicrobial prophylaxis have been performed, two representative studies are highlighted here. The fIrst, a randomized, controlled trial undertaken to compare sulfisoxazole 75 mg/kg/day divided in two daily doses for 6 months versus tympanostomy tubes showed that 33% of patients with indications for tubes were successfully treated with sulfisoxazole. 39 Although 67% of patients received tubes, the authors recommended a 6-month trial of sulfisoxazole prior to placement of tympanostomy tubes because safety and cost benefits seen with sulfisoxazole outweighed the risk of tubes. More patients may have responded if they had been started earlier on antibacterial prophylaxis. The second study evaluated amoxicillin prophylaxis 20 mg/kglday given once daily for 1 month versus tympanostomy tube for prevention of recurrent AOM. 4o This study showed that amoxicillin therapy was comparable to tubes in prevention of recurrent OM and was the preferred fIrst measure. Thus, initiating prophylaxis with either agent appears to be beneficial, especially since both agents are inexpensive and cause few adverse effects. One type of therapy currently being evaluated for prevention OM is vaccination. As mentioned previously, S. pneumoniae is the most common cause of AOM; thus, pneumococcal vaccine has been evaluated for prevention. 41 The main concerns are the
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ability to stimulate antibodies against the most common serotypes (serotype 6 could be important and is not currently covered by the vaccine) and the lack of benefit seen in infants less than 6 months of age.41 Still, the use of pneumococcal vaccine could be promising if pneumococcal SUbtypes could be added. H. injluenzae vaccine has little effect on OM, because most strains are nontypable and are not covered by the vaccine. Type B (which is covered by the vaccine) accounts for only 10% to 15% of H. injluenzae cases, and thus only 5% or less of all OM cases. A new vaccine is currently being developed that includes SUbtypes that appear promising for the prevention of OM.42 The influenza A vaccine also appears promising. Because a correlation appears to exist between viral infections and AOM, studies are evaluating the effectiveness of viral vaccines in decreasing AOM incidence. Two studies evaluating influenza A vaccine for children in day care centers showed a reduction in the incidence of AOM by 30% and 36%.43.44 These preliminary data indicate that the use of viral vaccinations offers promise in reducing the incidence of AOM.
References
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1. Cantor RM. Otitis extern a and otitis media: a new look at old problems. Emerg Med Clin North Am. 1995;13(2):445-55. 2. Claessen JQPJ, Appleman CLM, Touw-Otten FWMM, et al. A review of clinical trials regarding treatment of acute otitis media. Clin Otolaryngol. 1992;17:251-7. 3. Roark R, Petrofski J, Berson E, et al. Practice variations among pediatricians and family physicians in the management of otitis media. Arch Pediatr Adolesc Med. 1995;149:839-44. 4. Berman S. Otitis media in children. New Engl J Med. 1995; 332(23):1560-5. 5. Stool SE, Berg AO, Berman S, et al. Otitis Media with Effusion. Clinical Practice Guideline, No. 12. Rockville, Md: US Department of Health and Human Services; July 1994. AHCPR Publication 95-0621 . 6. Block SL. Strategies for dealing with amoxicillin failure in AOM. Arch Fam Med. 1999;8:68-78. 7. Giebink GS. The microbiology of otitis media. Pediatr Infect Dis J. 1989;8( 1):S518-20.
8. Dowell SF, Butler JC, Giebink GS, et al. Acute otitis media: management and surveillance in an era of pneumococcal resistance-a report from the Drug -Resistant Streptococcus pneumoniae Therapeutic Working Group. Pediatrlnfect Dis J. 1999;18(1 ):1-9. 9. Palua T, Lehtinen T, Virtanen H. Pneumococcal polysaccaride capsular antigens in chronic secretory otitis media . Int J Ped Otolaryngol. 1983;6: 145--9. 10. Wald ER. Haemophilus influenzae as a cause of acute otitis media. Pediatr Infect Dis J . 1989;8( 1):S528-30. 11 . Thoene DE, Johnson CEo Pharmacotherapy of otitis media. Pharmacotherapy. 1991 ;11(3):212-21 . 12. Klein JO. Microbiologic efficacy of antibacterial drugs for acute otitis media. Pediatr Infect Dis J. 1993;12(12):973-5. 13. Henderson FW, Collier AM, Sanyal MA, et al. A longitudinal study of respiratory viruses and bacteria in the etiology of acute otitis media with effusion. N Eng/J Med. 1982;306(23):1377-83. 14. Chonmaitree T, Owen MJ, Howie VM . Respiratory viruses interfere with bacteriologic response to antibiotic in children with acute otitis media. J Infect Dis. 1990;162:546-9. 15.
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29. Bluestone CD. Otitis media in children: to treat or not to treat? N Engl J Med. 1982;306(23): 1399-404. 30. Finney JW, Friman PC, Rapoff MA, et al. Improving compl iance with antibiotic regimens for otitis media. Am J Dis Child. 1985;139:89-95. 31 . Dagan R, Shvartzman P, Liss Z. Variation in acceptance of common oral antibiotic suspensions. Pediatr Infect Dis J . 1994;13(8):686-90. 32. Paradise JL. Otitis media in infants and children. Pediatrics. 1980; 65(5):917-43. 33. Caselbrant ML, Brostoff LM, Cantekin EI, et al. Otitis media with effusion in preschool children. Laryngoscope. 1985;96:428-36. 34. Berman S, Grose K, Nuss R, et al. Management of chronic middle ear effusion with prednisone combined with trimethoprim-sulfamethoxazole. Pediatr Infect Dis J. 1990;9(8):533-8. 35. Mattar ME, Markello J, Yaffe SJ. Pharmaceutic factors affecting pediatric compliance. Pediatrics. 1975;55(1 ):101-8. 36. Teele DW, Pelton SI, Klein JO. Bacteriology of acute otitis media unresponsive to initial antimicrobial therapy. J Pediatr. 1981;98(4):537-9. 37. Marchant CD, Carlin SA, Johnson CE, et al. Measuring the comparative efficacy of antibacterial agents for acute otitis media: the "Pollyanna phenomenon." J Pediatr. 1992;120(1):72-7. 38. Carlin SA. Marchant CD, Shurin PA. et al. Early recurrences of otitis media: reinfection or relapse? J Pediatr. 1987;110(1):20-5. 39. Bernard PAM, Stenstrom RJ, Feldman W, et al. Randomized controlled trial comparing long-term sulfonamide therapy to ventilation tubes for otitis media with effusion. Pediatrics. 1991 ;88(2):215--22. 40. Cassel brant ML, Kaleida PH, Rockette HE, et al. Efficacy of antimicro· bial prophylaxis and of tympanostomy tube insertion for prevention of recurrent acute otitis media: results of a randomized clinical trial. Pediatrlnfect Dis J. 1992;11 (4):278-86. 41 . Makela PH, Leinonen M, Pukander J, et al. A study of the pneumococ· cal vaccine in prevention of clinically acute attacks of recurrent otitis media. Rev Infect Dis. 1981 ;3(suppl): S124-30. 42. Wadwa RP, Feigin RD. Pneumococcal vaccine: an update. Pediatrics. 1999;103:1035--7. 43. Clements DA. Langdon L, Bland C, et al. 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. 44. Heikkinen T, Ruuskanen 0, Waris M, et al. Influenza vaccination in the prevention of acute otitis media in children. Am J Dis Child. 1991;145:445-8.
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