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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$ersity o+ Melbourne,
Melbourne /'.&.C.0 5 all in Australia.
Address reprint re9uests to Dr. Craig at the
Children4s Hospital at West6mead, Centre
+or 3idney #esear"h, o"(ed Bag :;;0 !as
updated on Mar"h
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ANTI$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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ANTI$IOTIC PROPLAI% AND PEDIATRIC URINAR TRACT IN7ECTION
: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 h e NEW ENGL A ND JOUR NA Lo f MEDICINE
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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ANTI$IOTIC PROPLAI% AND PEDIATRIC URINAR TRACT IN7ECTION
T,'e 1% (C&")i"ue*%$
A")i,i&)i! Gr&u# P'!e,& Gr&u#Cr!)eri+)i! (N/ 011$ (N/ 011$#esults o+ renal s"anning 5 no. /0
Abnormal /=>0 /=>0
'ormal
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T h e NEW ENGL A ND JOUR NA Lo f MEDICINE
=>
(2$
UTI
=; Pla"ebo
S3(#)&()i!
=
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ANTI$IOTIC PROPLAI% AND PEDIATRIC URINAR TRACT IN7ECTION
Su,gr&u# A'' Ci'*re" 4i) UTI Ci'*re" 4i) UTI "* Fe7er
F$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 ?
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T h e NEW ENGL A ND JOUR NA Lo f MEDICINE
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 $arious results !ho under!ent renal s"anning at < year. #esults o+ re6nal s"anning at < year !ere not (no!n +or == "hildren in the antibioti" group and
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ANTI$IOTIC PROPLAI% AND PEDIATRIC URINAR TRACT IN7ECTION
&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)-
=
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T h e NEW ENGL A ND JOUR NA Lo f MEDICINE
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
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ANTI$IOTIC PROPLAI% AND PEDIATRIC URINAR TRACT IN7ECTION
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