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1、儿童急性中耳炎的治儿童急性中耳炎的治疗疗第1页，本讲稿共70页SOURCE INFORMATIONN Engl J Med,2011,364:105-115(had been cited by 16 articles)From the Department of Pediatrics,University of Pittsburgh School of Medicine,USA.Correspondence author:Dr.Hoberman E-mail:hobermanchp.edu.2第2页，本讲稿共70页美国科学信息所（美国科学信息所（ISI）公布）公布 3第3页，本讲稿共70页BA
2、CKGROUNDAcute otitis media(AOM)is the most frequently diagnosed illness in children in the US.Most children have routinely been treated with antimicrobial drugs in the US.1.Tahtinen PA,et al.A placebo-controlled trial of antimicrobial treatment for acute otitis media.N Engl J Med 2011;364:116-126 2.
3、Klein JO.Is acute otitis media a treatable disease?N Engl J Med 2011;364:168-1695第5页，本讲稿共70页nA watchful-waiting strategy has long been applied in several countries to minimize the use of antimicrobial drugs.-Netherlands and Scotland4,5 -USA,2004,6,7 -Canada 8 4.Appelman CL,et al.Otitis media acuta:N
4、HG-standaard(eerste herziening).Huisarts Wet 1999;42:362-366 5.Scottish Intercollegiate Guidelines Network.Diagnosis and management of childhood otitis media in primary care.Guideline no.66.Edinburgh:Royal College of Physicians in Edinburgh,2003.8.Forgie S,Zhanel G,Robinson J.Management of acute oti
5、tis media.Paediatr Child Health(Oxford)2009;14:457-4646第6页，本讲稿共70页AOM in children aged 6 to 23 months is“nonsevere”6(mild otalgia and T 39 during the preceding 24 hours)Diagnosis of AOM is uncertain.7Indications of Watchful Waiting 6.Kaleida PH,et al.Amoxicillin or myringotomy or both for acute otit
6、is media:results of a randomized clinical trial.Pediatrics 1991;87:466-474 7.American Academy of Pediatrics Subcommittee on Management of Acute Otitis Media.Diagnosis and management of acute otitis media.Pediatrics 2004;113:1451-14657第7页，本讲稿共70页OBJECTIVESTo evaluate the extent to which antimicrobial
7、 treatment(Amoxicillin-clavulanate)and placebo treatment affect the course of both symptoms and signs of AOM in children aged 6 to 23 months.11第11页，本讲稿共70页METHODS1.Eligibility and Enrollment2.Randomization3.Assessment of Symptoms4.Otoscopic Examination,Overall Assessment,and Management5.Outcomes6.St
8、atistical Analysis12第12页，本讲稿共70页 Inclusion Criteria Eligible children(1)will be aged 6 to 23 months,(2)have received pneumococcal conjugate vaccine,and(3)have evidence of AOM defined as:A.Recent(within 48 hours),onset of signs and symptoms and a score of 3 on the AOM-SOS scale.B.Presence of middle-e
9、ar effusionC.Moderate or marked bulging of the tympanic membrane or slight bulging accompanied by either otalgia or marked erythema of the membrane.14第14页，本讲稿共70页AOM-SOSThe Acute Otitis Media Severity of Symptoms(AOM-SOS)scale11,12 The AOM-SOS scale consists of seven items:tugging of ears,crying,irr
10、itability,difficulty sleeping,diminished activity,diminished appetite,and fever.As“none,”“a little,”or“a lot,”with corresponding scores of 0,1,and 2scores range from 0 to 14,with higher scores indicating greater severity of symptoms 11.Shaikh N,et al.Development and preliminary evaluation of a paren
11、t-reported outcome instrument for clinical trials in acute otitis media.Pediatr Infect Dis J 2009;28:5-8 12.Shaikh N,et al.Responsiveness and construct validity of a symptom scale for acute otitis media.Pediatr Infect Dis J 2009;28:9-12 15第15页，本讲稿共70页AOM-SOS16第16页，本讲稿共70页Exclusion Criteria(protocol)
12、(1)certain signs or symptoms(e.g.,toxic appearance,otalgia 48 hours,spontaneous perforation of the tympanic membrane and drainage or temperature 105F);(2)clinical or anatomical characteristics that might obscure response to treatment(e.g.,tympanostomy,submucous cleft palate,high-arched palate,or Dow
13、ns syndrome);(3)underlying systemic problems that might obscure response to infection(e.g.,serious underlying disease e.g.,cystic fibrosis,neoplasm,juvenile diabetes),concomitant infection,known renal insufficiency,known hepatic insufficiency,history of immune dysfunction,chronic gastrointestinal co
14、nditions,malignancy;18第18页，本讲稿共70页(4)sensorineural hearing loss;(5)comedications(e.g.,systemic corticosteroids at any point while enrolled in the study,more than one dose of systemic antimicrobial therapy within 96 hours,any investigational drug or vaccine;(6)hypersensitivity to penicillin,amoxicill
15、in or amoxicillin-clavulanate,or phenylketonuria or known hypersensitivity to aspartame;(7)unable to complete the study protocol or not having access to a telephone;and(8)current enrollment in another study or previously enrolled in this study.aspartame阿司帕坦阿司帕坦;phenylketonuria苯丙酮酸尿苯丙酮酸尿19第19页，本讲稿共70
16、页2.RandomizationStratification according to history of recurrent AOM(defined as 3 episodes in 6 months or 4 episodes in 1 year)and according to their exposure or nonexposure to three or more children for at least 10 hours per week.At each study site,within each stratum,we randomly assigned children
17、in blocks of four,in a 1:1 ratio20第20页，本讲稿共70页Amoxicillinclavulanate(Augmentin ES,GlaxoSmithKline),90/6.4mg/kg/day in 2 divided doses for 10 days.Placebo was similar to Amoxicillinclavulanate in appearance and taste.The parents were unaware of the childrens group assignments.Parents prepared acetami
18、nophen as needed for the relief of symptoms.21第21页，本讲稿共70页3.Assessment of SymptomsStructured interview by telephone every day until the first follow-up visit and in person at each visit.Parents record their childs AOM-SOS scores and other pertinent clinical information in a diary twice a day for 3 d
19、ays and once a day thereafter.22第22页，本讲稿共70页4.Otoscopic Examination,Overall Assessment,and ManagementOtoscopy on day 1,day 4-5,day 10-12,day 21-25.SlightOtoscopic Photographs Moderate markedbulging of tympanic membrane23第23页，本讲稿共70页Overall AssessmentTo categorize clinical success or clinical failure
20、 at each visit.Clinical failure at or before the day 45 visit:a lack of substantial improvement in symptoms,a worsening of signs on otoscopic examination,or both.Clinical failure at the day 1012 visit:the failure to achieve complete or nearly complete resolution of symptoms and of otoscopic signs.13
21、.Kaleida PH.Assessment of otoscopists accuracy regarding middle-ear effusion:otoscopic validation.Am J Dis Child 1992;146:433-435 24第24页，本讲稿共70页Management for clinical failure casesA standardized 10-day regimen of orally administered amoxicillin,at a dose of 90mg/kg/day,and cefixime,at a dose of 8mg
22、/kg/day.Once a child had met the criteria for clinical failure,he or she remained in that category for the analyses.25第25页，本讲稿共70页Relapse at the day 2125 visit:the reappearance of AOM in a child who had previously been categorized as having met the criteria for clinical success.26第26页，本讲稿共70页To obta
23、in nasopharyngeal specimens from the children for culturing,at study entry and at the day 1012 and day 2125 visits.27第27页，本讲稿共70页5.OutcomesThe primary outcome measures A.The time to resolution of symptoms:-The time to the first recording of an AOM-SOS score of 0 or 1 -The time to the second of two s
24、uccessive recordings of that score.B.The symptom burden over time:-The mean AOM-SOS score of each day over the first 7 days of follow-up -The groups weighted mean scores for that period.28第28页，本讲稿共70页The secondary outcomes:A.Overall clinical efficacyB.The occurrence of adverse eventsC.Nasopharyngeal
25、 colonization ratesD.The use of acetaminophenE.The use of health care resources.29第29页，本讲稿共70页RESULTS1.Study Population2.Efficacy of Treatment -Symptomatic Response -Clinical Failure -Prognostic Factors and Effect Modifiers -Relapse and Residual Middle-Ear Effusion3.Nasopharyngeal Colonization and O
26、ther Outcomes4.Complications and Adverse Events33第33页，本讲稿共70页1.Study Population1385 Children were assessed for eligibility887 Were not eligible498 Were eligible291 Underwent randomization207 Had parent who declined participation144 Were assigned to and received amoxicillinclavulanate147 Were assigne
27、d to and received placebo34第34页，本讲稿共70页 Selected Demographic and Clinical Characteristics(1)1.Age at entry 611 mo 1217 mo 1823 mo2.Sex Male Female3.Race White Black Other4.Maternal level of education Less than high school High-school graduate College graduate5.Type of health insurance Private Medica
28、id6.Exposure to other children Yes No36第36页，本讲稿共70页7.AOM-SOS score(1)Baseline score35689111214(2)Mean baseline score(SD)8.Laterality of acute otitis mediaBilateralUnilateral9.Degree of tympanic membrane bulging in worse ear SlightModerateMarked Selected Demographic and Clinical Characteristics(2)uTh
29、ere were no significant differences in characteristics between the two study groups.37第37页，本讲稿共70页2.Efficacy of Treatment:2.1Symptomatic Response The proportion of children in whom symptoms had not resolved40第40页，本讲稿共70页 Day2 Day4 Day7Group A 35%61%80%Group B 28%54%74%P=0.14 for the overall comparis
30、onRates of the first recording of a score of 0 or 1Group A:children who were treated with amoxicillinclavulanateGroup B:children who were treated with placebo41第41页，本讲稿共70页42第42页，本讲稿共70页 Day2 Day4 Day7Group A 20%41%67%Group B 14%36%53%P=0.04 for the overall comparisonRates of two successive recordin
31、gs of a score of 0 or 1 In 54%of the instances in which scores fell to 0 or 1,a subsequent score was higher than 1.43第43页，本讲稿共70页44第44页，本讲稿共70页The 7-day weighted mean(SE)score was lower in the amoxicillinclavulanate group than in the placebo group(2.790.16 vs.3.420.18;P=0.01).46第46页，本讲稿共70页 Group A
32、Group B P Value*Day4-5 4%23%0.001Day10-12 16%51%0.001*At or before the day(n)Rates of clinical failure at different time2.2Clinical Failure47第47页，本讲稿共70页2.3 Prognostic Factors and Effect ModifiersAt day 10 to 12Childrens exposure or nonexposure,(P=0.007)Children with higher AOM-SOS scores at entry a
33、nd with lower scores(P=0.004)Children with bilateral AOM with unilateral AOM(P=0.002)Children with more bulging of the tympanic membrane and with less bulging(P0.001)50第50页，本讲稿共70页2.4Relapse and Residual Middle-Ear EffusionAt the day 2125 visit.Group A Group B P ValueRelapse 19/119(16%)13/70(19%)0.5
34、6 71/141(50%)87/139(63%)0.05Middle-ear effusion54第54页，本讲稿共70页3.Nasopharyngeal Colonization and Other OutcomesFrom day 1 to the day 2125 visit,there were no significant changes in either group in the rates of nasopharyngeal colonization with nonsusceptible Streptococcus pneumoniae.55第55页，本讲稿共70页There
35、 were no significant differences between the study group in either the mean daily number of doses of acetaminophen administered(0.37 and 0.43,respectively;P=0.35)or the use of health care resources.56第56页，本讲稿共70页4.Complications and Adverse EventsMastoiditis developed in one child in the placebo grou
36、p on day 5.Diarrhea and diaper-area dermatitis were more common among children who received amoxicillinclavulanate.Perforation of tympanic membraneOral thrush VomitingRash57第57页，本讲稿共70页DISCUSSIONChildren treated with amoxicillinclavulanate had consistently more favorable short-term outcomes,includin
37、g:1.A sustained symptomatic response,2.An absence of otoscopic evidence of persistent middle-ear infection,3.A reduced rate of residual middle-ear effusion.59第59页，本讲稿共70页The principal side effects were diarrhea and dermatitis in the diaper area,but the side effects were usually not severe enough to
38、discontinue the treatment of the drugs.62第62页，本讲稿共70页The differences in outcome in this trial were greater than the differences seen in most previous trials of antimicrobial agents,Not because of better outcomes among the children treated with amxicillinclavulanate but because of higher rates of cli
39、nical failure among the children who received placebo.This finding seems to be attributable to the stringent diagnostic criteria68第68页，本讲稿共70页CONCLUSIONSAmong children aged 6 to 23 months with AOM,treatment with amoxicillinclavulanate for 10 days affords a measurable short-term benefit,irrespective
40、of the initial severity.The benefit must be weighed against concern not only about the side effects of the medication but also about the contribution of antimicrobial treatment to the emergence of bacterial resistance.69第69页，本讲稿共70页Supported by a grant(3U01AI066007-02S1)from the National Institute of Allergy and Infectious Diseases.Thanks70第70页，本讲稿共70页