Treatment of Acute Otitis Media in Children Under 2 Years of Age

8/21/2019 Treatment of Acute Otitis Media in Children Under 2 Years of Age

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Treatment of Acute Otitis Media in Children under 2 Years

of Age

Alejandro Hoberman, M.D., Jack L. Paradise, M.D., Howard E. Rockette, Ph.D., Nader Shaikh, M.D., M.P.H., Ellen R.

ald, M.D., Diana H. !earne", R.N., #.#.R.#., D. !athleen #olborn, $.S., Marcia !%rs&Lask", M.S., Sonika $hatna'ar,

M.D., M.P.H., Mar" Ann Haralam, #.R.N.P., Lisa M. (o))el, #.R.N.P., #arl" Jenkins, R.N., Marcia A. Po*e, R.N., +rac" L.

$alentine, R.N., and !aren A. $arbadora, M.+.

N En'l J Med -/ 0123-4&4Jan%ar" 0, -D563 -.-417NEJMoa-842

#omments o*en thro%'h Jan%ar" 9, -

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Abstract Article

Re)erences#itin' Articles :;0<#omments :9<Letters

Enrollment, Randomi=ation, and >ollow&%* o) #hildren in the St%d".

Resol%tion o) #hildren?s S"m*toms d%rin' the >irst ; Da"s o) >ollow&%*.

Ac%te otitis media is the most )re@%entl" dia'nosed illness in children in the nited States and the

most commonl" cited indication )or antimicrobial thera*" in children/ in the nited States, most

children with ac%te otitis media haBe ro%tinel" been treated with antimicrobial dr%'s. HoweBer, a

watch)%l&waitin' strate'", in which treatment is reserBed )or children whose condition does notim*roBe witho%t medication, has lon' been a**lied in seBeral E%ro*ean co%ntries in the interest o)

minimi=in' the %se o) antimicrobial dr%'s.0 6n the Netherlands and Scotland, that strate'" has

been recommended o))iciall" )or children as "o%n' as 1 months o) a'e.2,4 6n --2, a clinical

*ractice '%ideline iss%ed b" the American Academ" o) Pediatrics and the American Academ" o)

>amil" Ph"sicians endorsed watch)%l waitin' as an o*tion )or children 1 to 0 months o) a'e in

whom illness is CnonseBere :de)ined, in an ada*tation o) an earlier de)inition,1 b" the *resence o)

mild otal'ia and a tem*erat%re o) less than 08# d%rin' the *recedin' 2 ho%rs< and in whom the

dia'nosis o) ac%te otitis media is %ncertain.; A similar recommendation, b%t witho%t re)erence to

dia'nostic certaint", was iss%ed recentl" b" the 6n)ectio%s Diseases and 6mm%ni=ation #ommittee

o) the #anadian Paediatric Societ".9

+he ado*tion o) a strate'" o) watch)%l waitin' has been based on the res%lts o) clinical trials0 that

showed relatiBel" hi'h rates o) s*ontaneo%s im*roBement in children with ac%te otitis media.

HoweBer, in those trials, as in earlier trials inBolBin' children with otitis media, there were

s%bstantial limitations F most notabl", the lack o) strin'ent dia'nostic criteria, the incl%sion o) )ew

Ber" "o%n' children, and the %se o) an antimicrobial dr%' that had limited e))icac" or that was

administered in s%bo*timal doses.8 MoreoBer, rates o) s*ontaneo%s im*roBement similar to the

rates seen in those st%dies amon' children receiBin' *lacebo haBe not been )o%nd %ni)orml".1

+here)ore, )or children with ac%te otitis media, the circ%mstances in which immediate antimicrobial

http://www.nejm.org/toc/nejm/364/2/http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#discussionhttp://www.nejm.org/doi/full/10.1056/NEJMoa0912254#discussionhttp://www.nejm.org/doi/full/10.1056/NEJMoa0912254#t=abstracthttp://www.nejm.org/doi/full/10.1056/NEJMoa0912254#t=articlehttp://www.nejm.org/doi/ref/10.1056/NEJMoa0912254#t=referenceshttp://www.nejm.org/doi/citedby/10.1056/NEJMoa0912254#t=citedbyhttp://www.nejm.org/doi/full/10.1056/NEJMoa0912254#t=lettershttp://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref1http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref1http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref2http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref2http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref3http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref4http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref6http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref7http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref8http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref3http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref3http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref9http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref6http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref6http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#discussionhttp://www.nejm.org/doi/full/10.1056/NEJMoa0912254#t=abstracthttp://www.nejm.org/doi/full/10.1056/NEJMoa0912254#t=articlehttp://www.nejm.org/doi/ref/10.1056/NEJMoa0912254#t=referenceshttp://www.nejm.org/doi/citedby/10.1056/NEJMoa0912254#t=citedbyhttp://www.nejm.org/doi/full/10.1056/NEJMoa0912254#t=lettershttp://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref1http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref2http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref3http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref4http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref6http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref7http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref8http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref3http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref9http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref6http://www.nejm.org/toc/nejm/364/2/


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treatment is the *re)erred strate'" haBe remained %nclear. e %ndertook this clinical trial to

determine the eGtent to which antimicrobial treatment a))ects the co%rse o) both s"m*toms and

si'ns o) ac%te otitis media, irres*ectiBe o) the a**arent seBerit" o) the disease, amon' children 1

to 0 months o) a'e in whom the dia'nosis o) ac%te otitis media is @%ite certain. $eca%se

amoGicillinclaB%lanate has been shown to be the most e))ectiBe treatment )or ac%te otitis media,

we chose it as the actiBe treatment in o%r st%d".;,-

METHODS

Eligibility and Enrollment

e cond%cted this trial between NoBember --1 and March --8 at the #hildren?s Hos*ital o)

Pittsb%r'h and Armstron' Pediatrics, an a))iliated *riBate *ractice in !ittannin', Penns"lBania. +he

st%d" *rotocol was a**roBed b" the instit%tional reBiew board at the niBersit" o) Pittsb%r'h/

written in)ormed consent was obtained )rom a *arent o) each enrolled child. +he *rotocol, incl%din'

the statistical anal"sis *lan, is aBailable with the )%ll teGt o) this article at NEJM.or'. +he a%thors

attest that the st%d" was *er)ormed in accordance with the *rotocol and the statistical anal"sis

*lan.

+o be eli'ible )or enrollment in the st%d", children were re@%ired to haBe receiBed at least two

doses o) *ne%mococcal conj%'ate Baccine and to haBe ac%te otitis media that was dia'nosed on

the basis o) three criteria3 the onset, within the *recedin' 29 ho%rs, o) s"m*toms that *arents rated

with a score o) at least 0 on the Ac%te 5titis Media SeBerit" o) S"m*toms :A5M&S5S< scale,

:on which scores ran'e )rom - to 2, with hi'her scores indicatin' 'reater seBerit" o) s"m*toms


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administered in two doses *er da". +he *lacebo was *re*ared b" the research *harmac" at the

#hildren?s Hos*ital o) Pittsb%r'h accordin' to the )orm%la )or *lacebo s*eci)ied in the a**lication to

the >ood and Dr%' Administration )or the labelin' in)ormation )or A%'mentin ES and was similar to

that *rod%ct in a**earance and taste. +he *arents, the research *ersonnel, and the health care

*roBiders who were not associated with the st%d" remained %naware o) the children?s 'ro%*

assi'nments thro%'ho%t the st%d". Parents were adBised to administer acetamino*hen as needed

)or the relie) o) s"m*toms.

Assessment of Symptoms

e assessed s"m*toms with the %se o) a str%ct%red interBiew o) one o) the child?s *arents/

assessments were *er)ormed b" tele*hone eBer" da" %ntil the )irst )ollow&%* Bisit and in *erson at

each Bisit. e also asked the *arents abo%t loss o) time at work or the need )or alternatiBe da"&

care arran'ements beca%se o) the child?s illness. Parents were asked to record their child?s A5M&

S5S scores and other *ertinent clinical in)ormation in a diar" twice a da" )or 0 da"s and once a

da" therea)ter.

Otoscopic Examination, Overall Assessment, and Management

All the st%d" clinicians were otosco*ists who had s%ccess)%ll" com*leted an otosco*ic Balidation

*ro'ram,0 and their )indin's on otosco*ic eGamination determined the dia'noses )or the st%d"/

wheneBer *ossible, howeBer, we also obtained otoendosco*ic *hoto'ra*hs o) the children?s

t"m*anic membranes :see >i'%re , 0, and 2 in the S%**lementar" A**endiG


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All o%tcome meas%res were *res*eci)ied. +he *rimar" o%tcome meas%res were the time to

resol%tion o) s"m*toms and the s"m*tom b%rden oBer time. +he time to resol%tion o) s"m*toms

was meas%red in two wa"s3 the time to the )irst recordin' o) an A5M&S5S score o) - or and the

time to the second o) two s%ccessiBe recordin's o) that score. +he s"m*tom b%rden oBer time was

meas%red b" calc%latin' the mean A5M&S5S score in the two 'ro%*s each da" oBer the )irst ;

da"s o) )ollow&%* and the 'ro%*s? wei'hted mean scores )or that *eriod. +he secondar" o%tcomes

were oBerall clinical e))icac", the %se o) acetamino*hen, the occ%rrence o) adBerse eBents,

naso*har"n'eal coloni=ation rates, and the %se o) health care reso%rces.

Statistical Analysis

e estimated that with a sam*le o) - children who co%ld be eBal%ated in each st%d" 'ro%*, the

st%d" wo%ld haBe 9- *ower to detect a 11 lower rate o) resol%tion o) s"m*toms in the *lacebo

'ro%* as com*ared with the amoGicillinclaB%lanate 'ro%*. All the anal"ses were based on the

intention&to&treat *rinci*le, were *er)ormed with the %se o) two&sided tests, and incl%ded

adj%stment )or the st%d" strati)ication Bariables. e com*ared the time to the resol%tion o)

s"m*toms between the st%d" 'ro%*s %sin' li)e&table *lots, and we cond%cted tests o) e@%al ha=ard

)%nctions %sin' a *ro*ortional&ha=ards model. e com*ared the mean A5M&S5S scores in the

two 'ro%*s at indiBid%al assessments each da" oBer the )irst ; da"s o) )ollow&%* %sin' 'enerali=ed

estimatin' e@%ations, and the 'ro%*s? wei'hted mean scores )or that *eriod :takin' into acco%nt

that obserBations were made twice dail" d%rin' the )irst 0 da"s o) )ollow&%*< %sin' re'ression

anal"sis. >or anal"ses o) clinical s%ccess or )ail%re, we %sed lo'istic re'ression. +o determine

whether Bariables were *ro'nostic or e))ect modi)iers, we %sed the *ro*ortional&ha=ards model orlo'istic&re'ression models, as a**ro*riate. e %sed McNemar?s test )or anal"ses o)

naso*har"n'eal coloni=ation rates.

RES!"TS

Stdy #oplation

A total o) 094 children were screened/ 289 o) the children were eli'ible )or the clinical trial and

8 were enrolled :>i'%re $%&!RE ' Enrollment, Randomi=ation, and >ollow&%* o)

#hildren in the St%d".


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*arents withheld consent or between the children in the two st%d" 'ro%*s. e )o%nd no si'ni)icant

correlation between children?s A5M&S5S scores at entr" and the de'ree o) b%l'in' o) their

a))ected t"m*anic membranes. A total o) 81 o) the children com*leted all sched%led st%d" Bisits,

and 94 re*ortedl" receiBed all sched%led medication doses d%rin' da"s thro%'h 0 and at least

9- o) doses oBerall.

Efficacy of Treatment

Symptomatic Response

+he children?s s"m*tomatic res*onse d%rin' the )irst ; da"s o) )ollow&%* is s%mmari=ed in >i'%re

$%&!RE ) Resol%tion o) #hildren?s S"m*toms d%rin' the >irst ; Da"s o) >ollow&%*.. +he time to

resol%tion o) s"m*toms is shown accordin' to two criteria3 the time to the )irst recordin' o) an

A5M&S5S score o) - or :>i'%re Ai'%re #


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#6, 4 to 24/ P-.--


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*asop+aryngeal olonization and Ot+er Otcomes

>rom da" to the da" 4 Bisit, no si'ni)icant chan'es occ%rred in either 'ro%* in the rate o)

coloni=ation with nons%sce*tible strains o) Streptococcus pneumoniae :minim%m inhibitor"

concentration, -. ' *er milliliter< :see +able 0 in the S%**lementar" A**endiG )or details


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seemin'l" resolBed, we de)ined the time o) resol%tion in two wa"s3 the time at which an A5M&S5S

score o) - or was )irst recorded and the time o) the second o) two s%ccessiBe recordin's o) an

A5M&S5S score o) - or . e also meas%red the s"m*tom b%rden oBer time, and we %sed a

combination o) s"m*tomatic res*onse and middle&ear )indin's to cate'ori=e oBerall o%tcomes as

either clinical s%ccess or clinical )ail%re. +he di))erences in s"m*tom scores between the two st%d"

'ro%*s were modest b%t consistent thro%'h the )irst - da"s o) )ollow&%*/ the di))erences were

obserBed mainl" amon' the children with the most seBere s"m*toms initiall". 6n contrast, between&

'ro%* di))erences in the oBerall clinical res*onse, which incl%ded the s"m*tomatic res*onse and

)indin's on otosco*ic eGamination, were s%bstantial and were obserBed not onl" amon' the

children who had the most seBere s"m*toms initiall" b%t also amon' the children who had the

least seBere s"m*toms. +o o%r knowled'e, a dis*arit" o) this nat%re has not been re*orted

*reBio%sl". +hese obserBations, to'ether with the )act that amon' in)ants and "o%n' children,

ac%te otitis media ma" be entirel" as"m*tomatic1,; and the )act that s"m*toms ma" not

di))erentiate ac%te otitis media )rom other res*irator" illnesses,9 s%''est that oBerall clinical

res*onse constit%tes the more tellin' meas%re o) o%tcome. Re'ardless o) the initial seBerit" o)

s"m*toms, howeBer, it is %ncertain whether children who haBe become as"m*tomatic b%t haBe

otosco*ic )indin's that s%''est *ersistent in)ection are thereb" at increased risk )or illness later.

Also %ncertain is the clinical si'ni)icance o) *ersistent middle&ear e))%sion in the a**arent absence

o) in)ection. $eca%se in "o%n' children otitis media with e))%sion is o)ten a )orer%nner o) ac%te otitis

media,8 it is *ossible that the hi'her *reBalence o) *ersistent e))%sion amon' the children in the

*lacebo 'ro%* than amon' children in the amoGicillinclaB%lanate 'ro%* mi'ht haBe *laced the

children in the *lacebo 'ro%* at 'reater risk )or rec%rrent in)ection.

+he di))erences in o%tcome in this trial between the children who were treated with amoGicillin

claB%lanate and the children who receiBed *lacebo were 'reater than the di))erences seen in most

*reBio%s trials o) antimicrobial a'ents F not beca%se o) better o%tcomes amon' the children

treated with antimicrobial a'ents b%t beca%se o) hi'her rates o) clinical )ail%re amon' the children

who receiBed *lacebo. +his )indin', in t%rn, seems to be attrib%table to the strin'ent dia'nostic

criteria that we %sed to ens%re that we wo%ld st%d" onl" children in whom the dia'nosis o) ac%te

otitis media was @%ite certain.-

6n concl%sion, amon' children 1 to 0 months o) a'e with ac%te otitis media, treatment with

amoGicillinclaB%lanate )or - da"s a))ords a meas%rable short&term bene)it, irres*ectiBe o) the

a**arent seBerit" o) the illness. +he bene)it m%st be wei'hed a'ainst concern not onl" abo%t the

side e))ects o) the medication b%t also abo%t the contrib%tion o) antimicrobial treatment to the

emer'ence o) bacterial resistance. +hese considerations %nderscore the need to restrict treatment

to children whose illness is dia'nosed with the %se o) strin'ent criteria.
http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref16http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref16http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref18http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref18http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref19http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref19http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref19http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref20http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref20http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref20http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref16http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref18http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref19http://www.nejm.org/doi/full/10.1056/NEJMoa0912254#ref20

Treatment of Acute Otitis Media in Children Under 2 Years of Age

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