Genito urinary jounal

8/12/2019 Genito urinary jounal

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T h e NEW ENGL A ND JOUR NA Lo f MEDICINE

ORIGINAL ARTICLE

Antibiotic Prophylaxis an R!c"rr!nt Urinary

Tract In#!ction in Chilr!nJonathan C. Craig, M.B., Ch.B., Ph.D., Judy M. Simpson, Ph.D., Gabrielle

J. Williams, Ph.D., M.P.H., Alison o!e, B.S"., Graham J. #eynolds, M.B., B.S.,

Ste$en J. M"%aggart, M.B., B.S., Ph.D., &lisabeth M. Hodson, M.B., B.S.,

Jonathan #. Carapetis, M.B., B.S., Ph.D., 'oel &. Crans!i"(, M.B., B.S.,

Grahame Smith, M.B., B.S., es M. )r!ig, M.B., B.Ch., Ph.D.,

Patrina H.*. Cald!ell, Ph.D., Sana Hamilton, M.P.H., and eslie P. #oy, M.B.,

B.S., +or the Pre$ention o+ #e"urrent rinary %ra"t )n+e"tion in Children !ith

-esi"oureteri" #e+lu and 'ormal #enal %ra"ts /P#)-&'%0 )n$estigators

A$%TR ACT

1rom the S"reening and %est &$aluation

Program /J.C.C., G.J.W., .M.).0 and the

S"hool o+ Publi" Health, /J.C.C., J.M.S.,

&.M.H., .M.).0, ni$ersity o+ Sydney2 the

Centre +or 3idney #esear"h, Children4s

Hospital at Westmead /J.C.C., G.J.W.,

A.., &.M.H., P.H.*.C., S.H., .P.#.02 and

the Department o+ rology and Surgery,

Children4s Hospital at Westmead /G.S.0

5 all in Sydney2 the Department o+ Pae6

diatri"s and Child Health, Australian 'a6

tional ni$ersity Medi"al S"hool, Canberra

/G.J.#.02 7ueensland Child and Adoles6"ent

#enal Ser$i"e and the ni$ersity o+

7ueensland, Brisbane /S.J.M.02 Men8ies

S"hool o+ Health #esear"h, Charles Dar6!in

ni$ersity, Dar!in /J.#.C.02 and Mur6do"h

Children4s #esear"h )nstitute and #oyal

Children4s Hospital, ni$ersity o+ Melbourne,

Melbourne /'.&.C.0 5 all in Australia.

Address reprint re9uests to Dr. Craig at the

Children4s Hospital at West6mead, Centre

+or 3idney #esear"h, o"(ed Bag :;;0 !as

updated on Mar"h


2/16

Downloaded from nejm.org on April 27, 2014. For personal use only. No other uses without permission.

Copyright 2009 Massachusetts Medical Society. All rights reserved.


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ANTI$IOTIC PROPLAI% AND PEDIATRIC URINAR TRACT IN7ECTION

URINAR TRACT IN7ECTION I% A FERco''on illn!ss in chilr!n+ a##!ctin) 4> o#

boys an 0> o# )irls by th! a)! o#

9 y!ars./ Urinary tract in#!ction is associat!

&ith lon)*t!r' 'orbiity+ &ith r!nal a'a)! r!*

port! in abo"t :> o# a##!ct! chilr!n.4 Th!

obs!r(ation that "rinary tract in#!ction an (!si*co"r!t!ral r!#l"x ar! associat! &ith r!nal a'*

a)!?*:

l! to th! stanar clinical practic! o# as*s!ss'!nt &ith (oiin) cysto"r!thro)raphy #orth! pr!s!nc! o# (!sico"r!t!ral r!#l"x in chilr!n

&ho ha ha "rinary tract in#!ction;+9

an th!a'inistration o# aily lo&*os! antibiotics #or

'any y!ars0to pr!(!nt #"rth!r "rinary tract in*

#!ctions an r!nal a'a)! in th!s! chilr!n. Ithas b!!n r!co)ni2! that oth!r chilr!n &itho"tr!#l"x ar! also at ris- #or r!c"rr!nt "rinary tractin#!ction an s!,"!la!+ an th! "s! o# lon)*t!r'antibiotics has also b!!n r!co''!n! #or s"ch

chilr!n.8 o&!(!r+ sinc! a!,"at!ly po&!r!

an &!ll*!si)n!+ plac!bo*controll! trials o#

lon)*t!r' antibiotics #or th! pr!(!ntion o# "ri*nary tract in#!ction in chilr!n ar! lac-in)+

/5+//

c"rr!nt clinical practic! has b!!n &i!ly ,"!s*

tion!./4+/?

O"r st"y+ call! th! Pr!(!ntion o#R!c"rr!nt Urinary Tract In#!ction in Chilr!n&ith F!sico"r!t!ric R!#l"x an Nor'al R!nalTracts 3PRIFENT6+ &as !si)n! to !t!r'in!&h!th!r th! lon)*t!r' "s! o# lo&*os! antibiot*ics pr!(!nts r!c"rr!nt "rinary tract in#!ction inchilr!n.

METOD%

STUDY DESIGN

Chilr!n &ho ha co'pl!t! short*t!r' tr!at*

'!nt+ ha "n!r)on! r!nal tract i'a)in) 3i# s"ch

a st"y &as r!co''!n!6+ an ha b!!n clini*

cally asy'pto'atic b!#or! r!cr"it'!nt &!r! ran*

o'ly assi)n! to r!c!i(! !ith!r tri'!thopri'1

s"l#a'!thoxa2ol! 3$actri'+ Roch!6 3antibiotic

)ro"p6 or plac!bo 3'atch! #or color+ tast!+ ant!xt"r!6 "rin) /4 'onths o# #ollo&*"p. Th! a*

'inistration o# th! st"y r") c!as! &h!n a

sy'pto'atic "rinary tract in#!ction occ"rr!.

Tri'!thopri'1s"l#a'!thoxa2ol! &as chos!n as

th! st"y r") b!ca"s! it is consist!ntly r!co'*

'!n! as th! #irst*lin! a)!nt #or th! pr!(!ntion

o# "rinary tract in#!ction &orl&i!.;+9+/:+/;

In(!sti)ators+ pati!nts+ phar'acy sta##+ o"t*co'!

ass!ssors+ an th! trial biostatistician &!r! all

"na&ar! o# st"y*)ro"p assi)n'!nts. Th! ran*

o'i2ation s!,"!nc! &as co'p"t!r*)!n!rat! an

strati#i! accorin) to c!nt!r+ r!#!rral so"rc!+ #r!*,"!ncy o# pr!(io"s "rinary tract in#!ction+ r!#l"x

stat"s+ a)!+ an s!x+ accorin) to th! '!tho o#

'ini'i2ation./9

Rano'i2ation &as p!r#or'!

c!ntrally by t!l!phon! by an in!p!n!nt clinical

trials c!nt!r a#t!r par!nts o# all pati!nts pro(i!

&ritt!n in#or'! cons!nt.

Th! st"y &as #"n! by th! National !alth

an M!ical R!s!arch Co"ncil o# A"stralia an

th! 7inancial Mar-!ts 7o"nation #or Chilr!n o#

A"s*tralia. All r")s that &!r! "s! in th! trial

&!r! p"rchas!. PRIFENT in(!sti)ators &!r!

r!sponsi*bl! #or all asp!cts o# th! trial.

URINARY TRACT IMAGING

PATIENTS

At #o"r c!nt!rs in A"stralia+ &! r!cr"it!chilr!n #ro' birth to /0 y!ars o# a)! &ho haha at l!ast on! sy'pto'atic "rinary tract

in#!ction./ con#i!nc! int!r(al.4/

To !t!r'in! &h!th!r th! tr!at'!nt !##!ct

(ari! accorin) to th! chilr!ns r!#l"x stat"s+ a

priori s"b)ro"p analysis &as plann! &ith chil*r!n

strati#i! accorin) to th! pr!s!nc! an s!*(!rity o#

r!#l"x+ an a t!st o# int!raction &as p!r#or'! in aCox 'o!l. Post hoc s"b)ro"p analys!s &!r! also

con"ct! &ith th! "s! o# oth!r strati#yin)

(ariabl!s+ incl"in) &h!th!r th! in!x in#!ction

&as s!nsiti(! or r!sistant to tri'!tho pri'1

s"l#a'!thoxa2ol!. Tr!at'!nt !##!cts &!r!

!scrib! in t!r's o# ha2ar ratios an absol"t! ris-

i##!r!nc!s &ith 8:> con#i!nc! int!r(als. All

r!port! P (al"!s ar! t&o*si! an ha(! not b!!n

aK"st! #or '"ltipl! t!stin).

/9:5 ' &'G J M&D ?


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:E= Patients !ere assessed +or eligibility

EE Were e"luded?>== Were ineligible

E Did not meet "lini"al "riteria

>; Had other reasons= Were eligible Had parti"ipation re+used by parent

E; Had other reasons

?:> Were in"luded in run6in enrollment

? Were e"luded? Had sul+a allergy

=: Had di++i"ulties ta(ing antibioti"? nder!ent randomi8ation

=EE Were assigned to re"ei$etrimethoprim sul+amethoa8ole

=EE #e"ei$ed inter$ention /? !ere ineligible0

= Were ta(ing medi"ation at 6mo re$ie!

>> Had stopped ta(ing medi"ation


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T,'e 1% Cr!)eri+)i!+ &f )e P)ie")+ ) B+e'i"e%.

A")i,i&)i! Gr&u# P'!e,& Gr&u#Cr!)eri+)i! (N/ 011$ (N/ 011$

Age

Median 5 mo yr ?0

Cir"um"ised 5 no.@total no. /0

*es :@ /:0 >@0

'o :@ /;0 E@= /EE0

Proteus


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T,'e 1% (C&")i"ue*%$

A")i,i&)i! Gr&u# P'!e,& Gr&u#Cr!)eri+)i! (N/ 011$ (N/ 011$#esults o+ renal s"anning 5 no. /0

Abnormal /=>0 /=>0

'ormal


8/16




9/16


=>

(2$

UTI

=; Pla"ebo

S3(#)&()i!

=


10/16


Su,gr&u# A'' Ci'*re" 4i) UTI Ci'*re" 4i) UTI "* Fe7er

F$erall

Se

1emale

Male

Age

I: yr

: yr-esi"oureteral re+lu

'one

) or ))

))) to )-

n(no!n

Pre$ious %)

)nde in+e"tion

only = in+e"tions

in+e"tions

)nde %)

Sensiti$e

#esistant

=; ; > "on+iden"e inter$als.

th! n"'b!r o# chilr!n &ho r!c!i(! at l!ast on!

co"rs! o# antibiotics #or a ca"s! oth!r than "rinary

tract in#!ction &as not si)ni#icantly lo&!r in th!

antibiotic )ro"p+ a t!st #or tr!n sho&! that chil*

r!n in th! plac!bo )ro"p &!r! 'or! li-!ly to r!*

c!i(! 'or! co"rs!s o# antibiotics than &!r! chil*

r!n in th! antibiotic )ro"p 3Tabl! 46.

DI%CU%%ION

Lon)*t!r'+ lo&*os! tri'!thopri'1s"l#a'!thox*

a2ol! &as associat! &ith a 'o!st !cr!as! in th!n"'b!r o# sy'pto'atic "rinary tract in#!ctions in

pr!ispos! chilr!n+ &ith a r!"ction in ab*sol"t!

ris- o# ; p!rc!nta)! points. This #inin) '!ans that

/< chilr!n &o"l n!! to b! tr!at! to pr!(!nt on!

cas! o# "rinary tract in#!ction. Th! absol"t!

tr!at'!nt !##!ct app!ar! to b! consis*t!nt across a

&i! ran)! o# ris- #actors #or #"r*th!r "rinary tract

in#!ction. Th! patt!rn o# r!c"r*r!nc! s"))!st! that

th! b!n!#it o# antibiotic th!rapy &as )r!at!st "rin)

th! #irst ; 'onths o# tr!at'!nt+ th! 'ost li-!ly ti'!

#or r!c"rr!nt in*

#!ction. Altho")h tri'!thopri'1s"l#a'!thoxa2ol!

pr!(!nt! "rinary tract in#!ction o(!rall+ o"r ata

s"))!st that prolon)! a'inistration r!s"lt! in

chan)!s in th! s"sc!ptibility o# patho)!nic bac*

t!ria+ &ith an incr!as! ris- o# sy'pto'atic "ri*

nary tract in#!ction ca"s! by bact!ria that &!r!

r!sistant to tri'!thopri'1s"l#a'!thoxa2ol!. Th!

r!s"lts inicat! that chilr!n &ith an in!x in*

#!ction that &as r!sistant to tri'!thopri'1s"l*

#a'!thoxa2ol! 'i)ht not b!n!#it #ro' s"ch pro*

phylaxis.

Any b!n!#its o# lon)*t!r' antibiotic "s! in r!*"cin) th! ris- o# n!& -in!y a'a)! #ro' py!lo*

n!phritis r!'ain sp!c"lati(!+ sinc! o"r st"y &as

not po&!r! to analy2! this o"tco'!. o&!(!r+

)i(!n th! 'o!st r!"ction in th! ris- o# "rinary

tract in#!ction in th! antibiotic )ro"p an th! lo&

ris- o# n!& a'a)! 3:>6 occ"rrin) &ith a sin)l!

in#!ction+4th! 'a)nit"! o# th! b!n!#its is li-!ly to

b! s'all at b!st. O"r #inin)s ar! str!n)th*!n! by

th! #inin) that th!r! &as a r!"c! ris- o# #!bril!

"rinary tract in#!ction a'on) chilr!n in th!

antibiotic )ro"p. Conc!rn that th! lon)*t!r'

' &'G J M&D ?


11/16




12/16


T,'e 0% Se!&"*r3 Ou)!&e+%

A")i,i&)i! Gr&u# P'!e,& Gr&u# Ri+6 Differe"!eOu)!&e (N/ 011$ (N/ 011$ (;/=0

= /= in the

pla"ebo group0. %!o "hildren /one in the antibioti" group and one in the pla"ebo group0 had one or more subse9uent urinary tra"t in+e"6tions that !ere "aused by entero"o""us or pseudomonas2 these organisms !ere not tested +or sus"eptibility to trimethoprimsul+ametho6a8ole but !ere assumed to be resistant. &ight "hildren /si in the antibioti" group and t!o in the pla"ebo group0 had in+e"tions "aused byba"teria that !ere resistant to trimethoprim but that !ere not tested +or resistan"e to sul+amethoa8ole. #esistan"e !as not tested in three

"hildren in the pla"ebo group. %he P $alue +or this "omparison !as "al"ulated !ith the "hi6s9uare test.

%he P $alue !as "al"ulated !ith the use o+ the MantelHaens8el test +or trend.

%he per"entages in this "ategory are the proportions o+ patients !ith $arious results !ho under!ent renal s"anning at < year. #esults o+ re6nal s"anning at < year !ere not (no!n +or == "hildren in the antibioti" group and


13/16




14/16


&ho' only ?4 ha r!#l"x+ an '!thoolo)ic

li'i*tations an th! r!portin) o# positi(! "rin!

c"lt"r!s rath!r than clinically i'portant+

sy'pto'atic "ri*nary tract in#!ction li'it! th!

applicability o# thos! trials.

D!spit! s"ch &!a- !(i!nc!+ a 45*y!ar hiat"s in

trials #ollo&!+ "rin) &hich ti'! antibiotic

prophylaxis &as consi!r! to b! )oo clinicalpractic!+ 'a-in) th! "s! o# plac!bo in a trial "n*

!thical. D"rin) th! past !ca!+ as a r!#l!ction o#

th! )ro&in) "nc!rtainty r!)arin) th! !##icacy o#

antibiotic prophylaxis #or "rinary tract in#!ction+

th! r!s"lts o# #i(! rano'i2!+ controll! trials o#

antibiotics in chilr!n &ith an &itho"t r!#l"x ha(!

b!!n p"blish!.49*?/

o&!(!r+ non! o# th!s! trials

&!r! plac!bo*controll! or r!port! ah!r*!nc!.

7"rth!r'or!+ all th! trials &!r! "n!rpo&*!r!+

&ith sa'pl! si2!s o# b!t&!!n /55 an 4/0

pati!nts./5+//+?4

Th!s! trials i not sho& a b!n*!#it

#or prophylactic antibiotics+ &ith th! abso*l"t!

i##!r!nc! in th! ris- o# sy'pto'atic "rinary tract

in#!ction in th! antibiotic )ro"p ran)in) #ro' a

r!"ction o# 5.8 p!rc!nta)! points to an incr!as! o#

;.5 p!rc!nta)! points. Th! iscoranc! o# th!s!

r!s"lts &ith o"r #inin)s 'ay b! !xplain! by th!

lac- o# ah!r!nc! to lon)*t!r' antibiotic "s!+ a lac-

o# statistical po&!r+ an "nbalanc! co

int!r(!ntions in th! !arli!r trials. W! a&ait &ith

int!r!st th! r!s"lts o# th! on)oin)+ plac!bo*

controll! Rano'i2! Int!r(!ntion #or Chil*r!n

&ith F!sico"r!t!ral R!#l"x 3RIFUR6 st"y

3ClinicalTrials.)o( n"'b!r+ NCT55

=;

UTI

Fe,ri'e

Pla"ebo

4i)-

=


15/16


nary tract in#!ction 3!.).+ thos! &ith con)!nital

hyron!phrosis or siblin)s &ith r!#l"x6.

In concl"sion+ o"r r!s"lts inicat! that lon)*

t!r'+ lo&*os! antibiotic "s! &as associat!

&ith a 'o!st r!"ction 39 p!rc!nta)! points6 in

th! absol"t! ris- o# sy'pto'atic "rinary tract

in#!c*tion in pr!ispos! chilr!n+ r!)arl!ss o#

a)!+ s!x+ #r!,"!ncy o# pr!(io"s "rinary tractin#!ction+ an conco'itant r!#l"x+ an 'ay

r!"c! th! li-!*lihoo that antibiotics &ill b!

r!,"ir! #or oth!r in#!ctions.%"pport! by )rants #ro' th! National !alth an M!ical

R!s!arch Co"ncil o# A"stralia 38859?:+ ?5/888+ an


16/16


tion o# r!c"rr!nt "rinary tract in#!ction in

chilr!n &ith lo& )ra! (!sico"r!t!ral r!*

#l"x r!s"lts #ro' a prosp!cti(! rano'*

i2! st"y. J Urol 4550=/98;9

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Genito urinary jounal

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