Amoxicillin-Clavulanate vs Ciprofloxacin for the Treatment of Uncomplicated Cystitis in Women

A Randomized Trial
1. Thomas M. Hooton, MD; 2. Delia Scholes, PhD; 3. Kalpana Gupta, MD, MPH; 4. Ann E. Stapleton, MD; . Pacita !. "o#e$ts, MS; %. &alte$ E. Stamm, MD '() Autho$ A**iliations 1. Author Affiliations: Department of Medicine, School of Medicine (Drs Hooton, Gupta, Stapleton, and Stamm and Ms Roberts), Department of Epidemiolo ! (Dr Scholes), School of "ublic Health and #ommunit! Medicine, $ni%ersit! of &ashin ton, Seattle' and the #enter for Health Studies, Group Health #ooperati%e Seattle, &ash (Dr Scholes). Dr Gupta is no( (ith the Department of Medicine, )ale $ni%ersit!, *e( Ha%en, #onn. 1. Corresponding Author: Thomas M. Hooton, MD, Ha$#o$+ie, Me-ical .ente$, 32 /inth A+e 01o2 3 33345, Seattle, &A 36144

Abstract
Context The hi7h p$e+alence o* $esistance to t$imethop$im8sul*ametho2a9ole an- othe$ antimic$o#ials amon7 Escherichia coli causin7 acute c:stitis in ,omen has le- to inc$ease- use o* alte$nati+e anti#iotics. ;ne such anti#iotic, amo2icillin8cla+ulanate, has not #een ,ell stu-ie-. b!ective To compa$e the e**icac: o* a 38-a: $e7imen o* amo2icillin8cla+ulanate to that o* a 38 -a: $e7imen o* cip$o*lo2acin in the t$eatment o* acute c:stitis in ,omen. The p$ima$: stu-: h:pothesis ,as that the amo2icillin8cla+ulanate an- cip$o*lo2acin t$eatment 7$oups ,oul- -i**e$ in clinical cu$e. "esign# $etting# and %atients "an-omi9e-, sin7le8#lin- t$eatment t$ial o* 3<4 ,omen, a7e- 16 to 4 :ea$s, ,ith s:mptoms o* acute uncomplicate- c:stitis an- a u$ine cultu$e ,ith at least 14 2

colon:8*o$min7 units o* u$opatho7ens pe$ millilite$ *$om a uni+e$sit: stu-ent health cente$ o$ a health maintenance o$7ani9ation. &nterventions &omen ,e$e $an-oml: assi7ne- to $ecei+e amo2icillin8cla+ulanate 0 44 m7=12 m7 t,ice -ail:5 o$ cip$o*lo2acin 02 4 m7 t,ice -ail:5 *o$ 3 -a:s an- ,e$e *ollo,e- up *o$ 4 months. 'ain utcome 'easures The main outcome measu$e ,as clinical cu$e. Secon-a$: stu-: outcomes o* inte$est ,e$e mic$o#iolo7ical cu$e an- +a7inal E coli coloni9ation at the 28,ee> *ollo,8up +isit. Results .linical cu$e ,as o#se$+e- in 33 0 6?5 o* 1%4 ,omen t$eate- ,ith amo2icillin8 cla+ulanate compa$e- ,ith 124 0<<?5 o* 1%2 ,omen t$eate- ,ith cip$o*lo2acin 0"@.4415. Amo2icillin8cla+ulanate ,as not as e**ecti+e as cip$o*lo2acin e+en amon7 ,omen in*ecte- ,ith st$ains suscepti#le to amo2icillin8cla+ulanate 0% '%4?) o* 143 ,omen in the amo2icillin8 cla+ulanate 7$oup +s 114 '<<?) o* 143 ,omen in the cip$o*lo2acin 7$oup; " A .4445. The -i**e$ence in clinical cu$e $ates occu$$e- almost enti$el: ,ithin the *i$st 2 ,ee>s a*te$ the$ap:. Mic$o#iolo7ical cu$e at 2 ,ee>s ,as o#se$+e- in 116 0<%?5 o* 1 % ,omen t$eate- ,ith amo2icillin8cla+ulanate compa$e- ,ith 1 3 03 ?5 o* 1%1 ,omen t$eate- ,ith cip$o*lo2acin 0"@.4415. At this +isit, 4 ? o* ,omen in the amo2icillin8cla+ulanate 7$oup compa$e- ,ith 14? in the cip$o*lo2acin 7$oup ha- +a7inal coloni9ation ,ith E coli 0"@.4415. Conclusions A 38-a: $e7imen o* amo2icillin8cla+ulanate is not as e**ecti+e as cip$o*lo2acin *o$ the t$eatment o* acute uncomplicate- c:stitis, e+en in ,omen in*ecte- ,ith suscepti#le st$ains. This -i**e$ence ma: #e -ue to the in*e$io$ a#ilit: o* amo2icillin8cla+ulanate to e$a-icate +a7inal E coli, *acilitatin7 ea$l: $ein*ection.

KEB&;"DSC AM;DE.E!!E/8P;TASSEFM .!AGF!A/ATE .;M1E/ATE;/, .EP";H!;DA.E/, .BSTETES, "A/D;MEIED T"EA!S, F"E/A"B T"A.T E/HE.TE;/S, &;ME/JS HEA!TH.

Acute uncomplicate- u$ina$: t$act in*ections 0FTEs5 a$e amon7 the most commonl: encounte$e#acte$ial in*ections in ,omen. Mana7ement o* these in*ections has #een ma-e mo$e complicatein $ecent :ea$s #: inc$easin7 antimic$o#ial $esistance, especiall: to K8lactams an- t$imethop$im8 sul*ametho2a9ole. The cu$$ent stan-a$- *o$ the empi$ical t$eatment o* acute uncomplicatec:stitis is t$imethop$im8sul*ametho2a9ole *o$ 3 -a:s. 1ecause the p$e+alence o* $esistance to t$imethop$im8sul*ametho2a9ole amon7 u$opatho7ens is inc$easin7, ho,e+e$, *luo$oLuinolones a$e inc$easin7l: #ein7 use- as empi$ical the$ap: *o$ the mana7ement o* c:stitis.182

Enc$easin7 *luo$oLuinolone $esistance in man: patho7ens causin7 health ca$eMassociate- ancommunit:8acLui$e- in*ections has $aise- conce$ns a#out the *utu$e use*ulness o* this potent an*$eLuentl: p$esc$i#e- class o* anti#iotics.3 Et is impo$tant, the$e*o$e, that *luo$oLuinolone8spa$in7 anti#iotics #e use- ,hen app$op$iate. En the case o* acute c:stitis, nit$o*u$antoin an- *os*om:cin t$omethamine ha+e #een a-+ocate- as *luo$oLuinolone8spa$in7 alte$nati+es to t$imethop$im8 sul*ametho2a9ole.4 Amo2icillin is not $ecommen-e- *o$ the empi$ical t$eatment o* FTEs #ecause o* the hi7h p$e+alence o* $esistance associate- ,ith this -$u7, 4 #ut use o* amo2icillin8cla+ulanate is inc$easin7.2 Ho,e+e$, the$e a$e *e, -ata on the e**icac: o* sho$t8cou$se amo2icillin8 cla+ulanate $e7imens *o$ t$eatment o* c:stitis, an- the$e a$e no pu#lishe- stu-ies on the e**icac: o* amo2icillin8cla+ulanate in the t$eatment o* acute c:stitis in the cu$$ent e$a o* hi7h8le+el amo2icillin $esistance. &e the$e*o$e compa$e-, +ia a sin7le8#lin- $an-omi9e- t$ial, 38-a: $e7imens o* amo2icillin8cla+ulanate an- cip$o*lo2acin *o$ t$eatment o* ,omen ,ith acute uncomplicate- c:stitis an- use- lon78te$m *ollo,8up to e+aluate $ecu$$ent in*ection. &e also e+aluate- the e**ects o* these anti#iotics on +a7inal coloni9ation ,ith Escherichia coli an- the $elationship o* these e**ects to $ecu$$ent in*ection.

'(T) "$
$tudy %opulation
The stu-: ,as con-ucte- at the Fni+e$sit: o* &ashin7ton Stu-ent Health .ente$ an- at G$oup Health .oope$ati+e *$om Nul: 1336 to Ma: 2442. The Fni+e$sit: o* &ashin7ton Stu-ent Health .ente$ p$o+i-es p$ima$: ca$e *o$ app$o2imatel: 6 ? o* the 34 444 stu-ents en$olle- in the uni+e$sit:. G$oup Health .oope$ati+e is a mi2e-8mo-el health maintenance o$7ani9ation ,ith app$o2imatel: 4< 444 en$ollees locate- in ,este$n &ashin7ton State. This t$eatment t$ial *ul*ille- 1 o* the p$ima$: aims o* a la$7e $an-omi9e- lon7itu-inal stu-: to e2amine the e**ects o* antimic$o#ials on FTE $ecu$$ence an- +a7inal *lo$a. Ho$ in+esti7atin7 the Luestion o* -i**e$ence in FTE $ecu$$ence #et,een the anti#iotic t$eatment 7$oups, the sample si9e ,as estimate- to p$o+i-e 7$eate$ than 34? po,e$ to -etect a -i**e$ence o* 24? o$ mo$e #et,een the 2 7$oups. &omen ,e$e eli7i#le *o$ en$ollment i* the: ,e$e health:, #et,een 16 an- 4 :ea$s o* a7e, anha- -:su$ia, *$eLuenc:, an-=o$ u$7enc:. &omen ,e$e ineli7i#le *o$ en$ollment i* the: ,e$e p$e7nant o$ i* the: ha- e+i-ence o* p:eloneph$itis 0such as tempe$atu$e 7$eate$ than 36O., se+e$e #ac> pain, o$ costo+e$te#$al an7le ten-e$ness5, histo$: o* si7ni*icant alle$7: to a *luo$oLuinolone o$ penicillin, a ch$onic illness $eLui$in7 me-ical supe$+ision, a >no,n anatomic o$ *unctional a#no$malit: o* the u$ina$: t$act, o$ ha- $ecei+e- s:stemic o$ +a7inal topical antimic$o#ials ,ithin the p$e+ious 14 -a:s. The Human Su#Pects "e+ie, .ommittees o* the Fni+e$sit: o* &ashin7ton an- G$oup Health .oope$ati+e app$o+e- the stu-:, an- all patients 7a+e ,$itten in*o$me- consent.

$tudy %rocedures

At the initial +isit, pa$ticipants un-e$,ent a -i$ecte- histo$: an- ph:sical e2amination, an inte$+ie, usin7 a stan-a$-i9e- stu-: Luestionnai$e, a mi-st$eam u$ine specimen collection to e+aluate #acte$iu$ia an- p:u$ia, an- a +a7inal s,a# specimen collection to e+aluate #acte$ial coloni9ation. "ace an- ethnicit: ,e$e sel*8$epo$te- on the Luestionnai$e. Pa$ticipants ,e$e $an-omi9e- to t$eatment assi7nments #: the statistician, usin7 a #loc>e- $an-omi9ation scheme ,ith +a$:in7 #loc> si9es not $e+eale- to clinic pe$sonnel. Assi7nments ,e$e place- in seale-, seLuentiall: num#e$e- en+elopes, ,hich ,e$e opene- at the time o* en$ollment. &omen $ecei+e- eithe$ amo2icillin8cla+ulanate 0 44 m7=12 m7 t,ice -ail:5 o$ cip$o*lo2acin 02 4 m7 t,ice -ail:5 each *o$ 3 -a:s. The: ,e$e as>e- to $etu$n to the clinic e+e$: 2 ,ee>s *o$ 4 months o$ until the: ,e$e $et$eate- *o$ s:mptomatic pe$sistent o$ $ecu$$ent FTE. At each +isit, the tests pe$*o$me- at the initial +isit ,e$e $epeate-. At the *i$st *ollo,8up +isit 02 ,ee>s5, pa$ticipants ,e$e as>e- ho, man: stu-: pills the: ha- ta>en.

*aboratory $tudies
Metho-s *o$ collectin7 u$ine an- +a7inal specimens an- isolatin7, i-enti*:in7, an- Luanti*:in7 u$ine an- +a7inal u$opatho7ens ha+e #een p$e+iousl: -esc$i#e-. 8% Ga7inal cultu$es ,e$e consi-e$e- positi+e *o$ E coli i* the$e ,as Q1( 7$o,th on a semiLuantitati+e scale. The Ki$#:8 1aue$ -isc metho- ,as use- to -ete$mine antimic$o#ial suscepti#ilit: o* causati+e st$ains. The leu>oc:te este$ase test ,as pe$*o$me- on each mi-st$eam u$ine specimen an- cate7o$i9e- as positi+e i* at least t$ace. Genomic D/A isolation, $est$iction en-onuclease -i7estion, 7el elect$opho$esis, an- Southe$n #lot h:#$i-i9ation ,e$e pe$*o$me- as p$e+iousl: -esc$i#e-.< Total E coli $i#osomal "/A 0Si7ma, St !ouis, Mo5 ,as $a-ioacti+el: la#ele- #: e2tension o* $an-om p$ime$s usin7 $e+e$se t$ansc$iptase.6 "i#ot:pin7 ,as pe$*o$me- usin7 "%uEE an- Eco"E. ;nl: isolates sho,in7 144? match in the $est$iction *$a7ment len7th pol:mo$phism patte$ns ,e$e classi*ie- as i-entical to each othe$.

'ain

utcome 'easures

The p$ima$: stu-: outcome ,as stu-: -$u7 e**icac: #ase- on clinical cu$e. &omen ,e$e consi-e$e- to ha+e clinical cu$e i* the: -i- not ha+e s:mptomatic pe$sistent o$ $ecu$$ent FTE. A ,oman ,as consi-e$e- to ha+e a pe$sistent FTE i*, *ollo,in7 stu-: -$u7 t$eatment, she hape$sistent s:mptoms ,a$$antin7 $et$eatment. A ,oman ,as consi-e$e- to ha+e a $ecu$$ent FTE i* she ha- $esolution o* he$ initial FTE s:mptoms a*te$ t$eatment #ut then -e+elope- $ecu$$ent s:mptoms ,a$$antin7 $et$eatment. A pe$sistent o$ $ecu$$ent FTE ,as consi-e$e- to #e cultu$e8 con*i$me- i* the$e ,e$e at least 142 colon:8*o$min7 units 0.HF5 o* u$opatho7ens pe$ millilite$ o* u$ine. Secon-a$: stu-: outcomes ,e$e 015 stu-: -$u7 e**icac: #ase- on mic$o#iolo7ical cu$e at the *i$st postt$eatment +isit 02 ,ee>s5; 025 +a7inal coloni9ation ,ith E coli at all postt$eatment +isits; an035 the association #et,een +a7inal coloni9ation ,ith E coli an- s:mptomatic pe$sistent o$ $ecu$$ent FTE. &omen ,e$e consi-e$e- mic$o#iolo7icall: cu$e- i*, at an as:mptomatic 28,ee> *ollo,8up +isit, the: ha- less than 14 .HF=m! o* all u$opatho7ens an- at least a 18lo7 -$op in colon: count o* the causati+e u$opatho7en compa$e- ,ith the u$ine cultu$e at en$ollment.

&omen ,ho ha- pe$sistent o$ $ecu$$ent FTE s:mptoms ,a$$antin7 $et$eatment #e*o$e the 28,ee> +isit ,e$e also classi*ie- as mic$o#iolo7icall: cu$e- i* thei$ u$ine cultu$es ha- less than 14 2 .HF=m! an- the: ,e$e not ta>in7 anti#iotics at the time o* the u$ine cultu$e. The associations #et,een antimic$o#ial suscepti#ilit: o* the initiall: in*ectin7 st$ains an- clinical an- mic$o#iolo7ical outcomes ,e$e e+aluate-. Ho$ cultu$e8con*i$me- FTEs, u$opatho7ens ,ith the hi7hest colon: count ,e$e consi-e$e- the causati+e patho7en, #ut i* 2 o$ mo$e o$7anisms hathe same colon: count 0,ithin @1 lo75 the: ,e$e consi-e$e- copatho7ens. .oa7ulase8ne7ati+e staph:lococci, R8hemol:tic st$eptococci, lacto#acilli, -iphthe$oi-s, an- mi2e- 7$am8positi+e *lo$a ,e$e cate7o$i9e- as nonu$opatho7ens at en$ollment an- *ollo,8up.

$tatistical Analyses
All ,omen ,ho ,e$e en$olle- an- $an-omi9e- to $ecei+e t$eatment ,e$e inclu-e- in anal:ses o* -emo7$aphic an- #eha+io$al cha$acte$istics an- FTE histo$:, usin7 means an- *$eLuenc: -ist$i#utions. &omen ,e$e inclu-e- in the anal:sis i* the: met en$ollment c$ite$ia, ha- at least 142 .HF=m! o* u$opatho7ens in thei$ en$ollment u$ine, an- $etu$ne- to the clinic *o$ at least 1 post$an-omi9ation clinic +isit. En*ectin7 u$opatho7ens at the en$ollment FTE ,e$e also -esc$i#e-, as ,ell as thei$ anti#iotic suscepti#ilit: p$o*iles. Kaplan8Meie$ cu$+es ,e$e const$ucte- to e2amine the cu$e $ates o+e$ the *ollo,8up pe$io-, anthe li>elihoo- $atio test ,as use- to test *o$ -i**e$ences #et,een t$eatment 7$oups. .ompa$isons o* p$opo$tions #et,een the 2 t$eatment 7$oups ,e$e teste- usin7 the S2 statistic. &omen ,e$e *ollo,e- up until the: ,e$e $et$eate- *o$ pe$sistent o$ $ecu$$ent FTE s:mptoms o$ the en- o* the stu-:. SAS +e$sion 6.2 0SAS Enstitute, .a$:, /.5 ,as use- *o$ all anal:ses. Statistical si7ni*icance ,as consi-e$e- to #e "@.4 .

R($U*T$
$tudy %opulation
Th$ee hun-$e- se+ent: ,omen 033 at the stu-ent health cente$ an- 3 at G$oup Health .oope$ati+e5 ,e$e en$olle- an- $an-omi9e- to $ecei+e t$eatment 0Hi7u$e 15. &omen $an-omi9eto the 2 t$eatment 7$oups an- inclu-e- in the e**icac: anal:ses ,e$e simila$ ,ith $espect to #aseline cha$acte$istics 0Ta#le 15. Ho$t:8ei7ht ,omen ,e$e e2clu-e- *$om the anal:sesC 33 haless than 142 .HF=m! at en$ollment an- 3 ha- no *ollo,8up. The 322 ,omen eli7i#le *o$ the anal:ses 01%4 $an-omi9e- to $ecei+e amo2icillin8cla+ulanate an- 1%2 $an-omi9e- to $ecei+e cip$o*lo2acin5 ,e$e *ollo,e- *o$ a me-ian o* 143 -a:s 0$an7e, 2812 -a:s5. .ompliance ,ith at least o* the % -oses o* stu-: -$u7 ,as 33? in #oth 7$oups. &omen ta>in7 *e,e$ than % -oses o* stu-: -$u7 ,e$e inclu-e- in the anal:ses.

+igure ,. Patient Assi7nment an- Hollo,8up Assessment TMi-st$eam u$ine cultu$e collecte- at time o* en$ollment u$ina$: t$act in*ection :iel-e- less than 142 colon:8*o$min7 units pe$ millilite$. Gie, this ta#leC Table ,- .ha$acte$istics o* Stu-: Pa$ticipants Enclu-e- in the E**icac: Anal:ses #: T$eatment "e7imen

Uropathogen "istribution and $usceptibility at (nrollment

Amon7 the 3<4 ,omen en$olle-, 331 ,omen ha- 1 o$ mo$e u$opatho7ens p$esent in Luantities o* at least 142 .HF=m!. Escherichia coli ,as the onl: patho7en o$ copatho7en in 2<4 062?5, 7$oup 1 st$eptococci in 26 06?5, Staph!lococcus saproph!ticus in 2% 06?5, ente$ococci in 6 02?5, an+lebsiella species an- "roteus mirabilis in < 02?5 each. ;+e$all suscepti#ilit: -ata *o$ the 323 isolates teste- a$e sho,n in Ta#le 2. Suscepti#ilit: -ata *o$ the E coli st$ains ,e$e almost i-entical. Amon7 the 33 isolates that ,e$e $esistant to ampicillin, 3%? ,e$e suscepti#le, 33? ,e$e inte$me-iate, an- 34? ,e$e $esistant to amo2icillin8cla+ulanate. Amon7 the 31 isolates that ,e$e inte$me-iatel: $esistant to ampicillin, % ? ,e$e suscepti#le to amo2icillin8cla+ulanate. Gie, this ta#leC Table .- Antimic$o#ial Suscepti#ilit: o* 323 F$opatho7ens Esolate- H$om &omen at En$ollment, #: T$eatment "e7imenT

Treatment

utcomes

Clinical utcomes- The $ate o* clinical cu$e ,as si7ni*icantl: lo,e$ in the amo2icillin8 cla+ulanate 7$oup 033 ' 6?) o* 1%45 than in the cip$o*lo2acin 7$oup 0124 '<<?) o* 1%25 0"@.4415 0Hi7u$e 25. The ,omen in the amo2icillin8cla+ulanate 7$oup ha- a si7ni*icantl: lo,e$ clinical cu$e $ate compa$e- ,ith ,omen in the cip$o*lo2acin 7$oup $e7a$-less o* ,hethe$ the

patients ,e$e in*ecte- ,ith st$ains that ,e$e suscepti#le 0% '%4?)o* 143 ,omen in the amo2icillin8cla+ulanate 7$oup +s 114 '<<?) o* 143 ,omen in the cip$o*lo2acin 7$oup; " A .4445 o$ nonsuscepti#le 034 ,omen5 0" A .441 +s cip$o*lo2acin5 to amo2icillin8cla+ulanate 0Hi7u$e 25. Althou7h the$e ,as a t$en- to,a$- a #ette$ clinical outcome in ,omen t$eate- ,ith amo2icillin8 cla+ulanate i* the: ,e$e in*ecte- ,ith st$ains suscepti#le to amo2icillin8cla+ulanate, this -i**e$ence ,as not statisticall: si7ni*icant 0" A .1<5 0Hi7u$e 25. En a--ition, amon7 the 143 ,omen in the amo2icillin8cla+ulanate 7$oup in*ecte- ,ith amo2icillin8cla+ulanateMsuscepti#le u$opatho7ens, cu$e $ates ,e$e not associate- ,ith amo2icillin suscepti#ilit: o* the in*ectin7 st$ains.

Gie, la$7e$ +e$sionC +igure .- Time to Pe$sistent o$ "ecu$$ent FTE #: T$eatment G$oup an- Amo2icillin8.la+ulanate Suscepti#ilit: o* En*ectin7 St$ain at En$ollment A, "@.441. 1, " A .444 *o$ the compa$ison o* cip$o*lo2acin +s amo2icillin8cla+ulanate 0suscepti#le5; " A .1< *o$ the compa$ison o* amo2icillin8cla+ulanate 0suscepti#le5 +s amo2icillin8 cla+ulanate 0nonsuscepti#le5. FTE in-icates u$ina$: t$act in*ection. Pe$sistent FTEs occu$$e- in 6 ,omen t$eate- ,ith amo2icillin8cla+ulanate 03 ha- suscepti#le st$ains at en$ollment5 an- in 1 ,oman t$eate- ,ith cip$o*lo2acin 0the st$ain ,as suscepti#le5 0Ta#le 35. "ecu$$ent FTEs occu$$e- in 3 ,omen in the amo2icillin8cla+ulanate 7$oup an- 3< ,omen in the cip$o*lo2acin 7$oup. Amon7 the %< pe$sistent o$ $ecu$$ent FTEs in the amo2icillin8 cla+ulanate 7$oup, 33 0 4?5 occu$$e- ,ithin the *i$st 2 ,ee>s 0Ta#le 35 an- 34 occu$$e- -u$in7 ,ee>s 3 th$ou7h 14 *ollo,in7 t$eatment compa$e- ,ith 3 06?5 an- 3 032?5, $especti+el:, o* the 36 pe$sistent o$ $ecu$$ent FTEs in the cip$o*lo2acin 7$oup. Pe$sistent an- $ecu$$ent FTEs ,e$e cultu$e8con*i$me- in 1 0<%?5 ,omen t$eate- ,ith amo2icillin8cla+ulanate compa$e- ,ith 34 0<3?5 ,omen t$eate- ,ith cip$o*lo2acin. P:u$ia ,as p$esent in 32? o* the ,omen ,ho hape$sistent o$ $ecu$$ent FTE in each o* the 2 t$eatment 7$oups.

Table /- .linical an- Mic$o#iolo7ical ;utcomes at o$ 1e*o$e Hi$st Hollo,8up 02 &ee>s A*te$ T$eatment5 En the amo2icillin8cla+ulanate 7$oup, all 3 pai$s o* initial an- pe$sistent FTE st$ains teste- an- 1% 0<3?5 o* 22 pai$s o* initial an- $ecu$$ent FTE st$ains teste- ha- the same $i#ot:pe. Hi+e ,omen in*ecte- ,ith amo2icillin8cla+ulanateMsuscepti#le st$ains o* E coli at en$ollment ,ho ,e$e t$eate- ,ith amo2icillin8cla+ulanate ha- $ecu$$ent FTEs < to 44 -a:s a*te$ t$eatment cause- #: E coli st$ains that ,e$e nonsuscepti#le to amo2icillin8cla+ulanate. Esolates *$om onl: 1 such patient ha- the same $i#ot:pe. T,o ,omen t$eate- ,ith cip$o*lo2acin ,hose o$i7inal u$opatho7ens ,e$e suscepti#le to cip$o*lo2acin -e+elope- $ecu$$ent FTE ,ith cip$o*lo2acin8 nonsuscepti#le st$ains 24 an- 23 -a:s a*te$ t$eatmentU#oth ,e$e -i**e$ent species *$om the o$i7inall: in*ectin7 st$ains. T,o ,omen in the amo2icillin8cla+ulanate 7$oup ,ho at 2 ,ee>s a*te$ t$eatment ha- pe$sistent #acte$iu$ia ,ith at least 14 .HF=m! o* E coli an- p:u$ia #ut no u$ina$: s:mptoms ,e$e su#seLuentl: -ia7nose- ,ith an- t$eate- *o$ p:eloneph$itis. 1ecause the: ,e$e as:mptomatic, these 2 ,omen -i- not $ecei+e t$eatment at the 28,ee> +isit. ;ne ,oman p$esente- 3 -a:s a*te$ he$ 28,ee> *ollo,8up +isit to the eme$7enc: -epa$tment ,ith su#Pecti+e *e+e$ an- chills anacute onset o* #ac> pain an- ,as *oun- to ha+e a tempe$atu$e o* 36. O., #ilate$al milcosto+e$te#$al an7le ten-e$ness, p:u$ia, an- 7$eate$ than 14 .HF=m! o* E coli, ,hich ,as suscepti#le to amo2icillin8cla+ulanate. He$ initial, 28,ee> *ollo,8up, an- p:eloneph$itis st$ains ,e$e i-entical #: $i#ot:pe. The othe$ ,oman p$esente- to an outsi-e hospital -a:s a*te$ he$ 28 ,ee> +isit ,ith su#Pecti+e *e+e$ an- sha>in7 chills, u$7enc:, an- lo, #ac> pain an- $epo$te- that she ha- a tempe$atu$e o* 33.6O.. &e ,e$e not a#le to o#tain he$ outsi-e me-ical $eco$-s o$ la#o$ato$: isolate, #ut he$ initial an- 28,ee> isolates ,e$e i-entical #: $i#ot:pe. 'icrobiological utcomes- Mic$o#iolo7ical cu$e ,as also in*e$io$ in the amo2icillin8 cla+ulanate 7$oup. At the 28,ee> postt$eatment +isit, mic$o#iolo7ical cu$e ,as o#se$+e- in 116 0<%?5 o* 1 % ,omen in the amo2icillin8cla+ulanate 7$oup compa$e- ,ith 1 3 03 ?5 o* 1%1 ,omen in the cip$o*lo2acin 7$oup 0"@.4415 0Ta#le 35. En the amo2icillin8cla+ulanate 7$oup, mic$o#iolo7ical cu$e occu$$e- in << 0<3?5 o* 14% ,omen in*ecte- ,ith suscepti#le st$ains compa$e- ,ith 2< 062?5 o* 33 ,omen in*ecte- ,ith nonsuscepti#le st$ains 0 " A .345. En the amo2icillin8cla+ulanate 7$oup, %%? o* the ,omen ,ith mic$o#iolo7ical *ailu$e ha- s:mptomatic pe$sistent o$ $ecu$$ent FTE compa$e- ,ith 13? in the cip$o*lo2acin 7$oup 0Ta#le 35. 0aginal Colonization 1ith E coli. Ga7inal coloni9ation ,ith E coli ,as p$esent at en$ollment in 62? 0134=1 35 o* the ,omen in the amo2icillin8cla+ulanate 7$oup compa$e- ,ith 6%? 0133=1%25 in the cip$o*lo2acin 7$oup 0Hi7u$e 35. 1: the 28,ee> postt$eatment *ollo,8up +isit, ho,e+e$, 4 ? 0%6=1 15 o* the ,omen in the amo2icillin8cla+ulanate 7$oup compa$e- ,ith 14? 01%=1 35 in the cip$o*lo2acin 7$oup ha- +a7inal coloni9ation 0 "@.4415. This -i**e$ence -i- not na$$o, until ,ee> 14 a*te$ t$eatment. Antimic$o#ial suscepti#ilit: testin7 ,as not pe$*o$me- on +a7inal isolates at en$ollment an-, thus, ,e ,e$e not a#le to -ete$mine the $elationship #et,een antimic$o#ial suscepti#ilit: o* the +a7inal st$ains at en$ollment an- the p$e+alence o* postt$eatment coloni9ation.

Gie, la$7e$ +e$sionC +igure /- Ga7inal .oloni9ation &ith Escherichia coli #: Gisit an- T$eatment G$oup The$e ,as a t$en- to,a$- p$esence o* +a7inal coloni9ation ,ith E coli at the 28,ee> postt$eatment +isit an- su#seLuent $ecu$$ent FTE o+e$ the ne2t month. Thus, $ecu$$ent FTEs occu$$e- in 44 021?5 o* 213 ,omen ,ho -i- not ha+e +a7inal coloni9ation ,ith E coli at the 28 ,ee> +isit compa$e- ,ith 22 031?5 o* <4 ,ho ha- coloni9ation 0" A .4%5. Adverse (vents- &hen as>e- an open Luestion a#out ,hethe$ the pa$ticipant ha- a-+e$se e**ects $elate- to stu-: me-ications, ,omen in the amo2icillin8cla+ulanate 7$oup ,e$e mo$e li>el: to $epo$t s:mptoms 02<?5 compa$e- ,ith ,omen in the cip$o*lo2acin 7$oup 013?5 0" A .4%5. Di**e$ences ,e$e -ue mostl: to inc$ease- loose stools an- +a7inal s:mptoms in the ,omen t$eate- ,ith amo2icillin8cla+ulanate. !oose stools ,e$e $epo$te- in 6? an- 4.%?, +a7inal s:mptoms in 3? an- 3?, nausea in ? an- 6?, an: cent$al ne$+ous s:mptoms in 3? an- %?, an- *e+e$ o$ $ash in 1? an- 4? o* amo2icillin8cla+ulanateMt$eate- an- cip$o*lo2acin8t$eate,omen, $especti+el:. T,ent:8t,o amo2icillin8cla+ulanateMt$eate- ,omen $eLui$e- t$eatment *o$ a-+e$se e**ects compa$e- ,ith 14 cip$o*lo2acin8t$eate- ,omen. ;nl: 2 ,omen in the amo2icillin8cla+ulanate 7$oup an- 1 ,oman in the cip$o*lo2acin 7$oup -iscontinue- stu-: me-ication -ue to a-+e$se e**ects.

C ''(2T
This is the *i$st compa$ison o* a 38-a: $e7imen o* amo2icillin8cla+ulanate +s a 38-a: $e7imen o* a *luo$oLuinolone *o$ the t$eatment o* acute uncomplicate- c:stitis in ,omen. Amo2icillin8 cla+ulanate ,as ma$>e-l: in*e$io$ to cip$o*lo2acin in clinical an- mic$o#iolo7ical cu$e $ates as ,ell as in e$a-ication o* +a7inal E coli. ;* conce$n, 2 ,omen -e+elope- same8st$ain p:eloneph$itis soon a*te$ t$eatment ,ith amo2icillin8cla+ulanate 0same8st$ain is p$esume- in 1 ,oman #ase- on a u$ine cultu$e -a:s #e*o$e the episo-e o* p:eloneph$itis5. The -i**e$ence in clinical cu$e occu$$e- p$ima$il: ,ithin the *i$st 2 ,ee>s o* t$eatment an- ,as most li>el: -ue to the in*e$io$ acti+it: o* amo2icillin8cla+ulanate in e$a-icatin7 E coli *$om the +a7ina. At the 28 ,ee> *ollo,8up +isit, 4 ? o* amo2icillin8cla+ulanateMt$eate- ,omen ha- +a7inal coloni9ation compa$e- ,ith 14? o* cip$o*lo2acin8t$eate- ,omen 0Hi7u$e 35. En this $e7a$-, amo2icillin8 cla+ulanate is simila$ to ampicillin an- amo2icillin, -$u7s that also -o not e**ecti+el: e$a-icate E coli *$om the +a7inal $ese$+oi$ an- a$e associate- ,ith hi7h $ecu$$ence $ates.3

Althou7h not e+aluate- in this stu-:, anothe$ *acto$ that ma: ha+e cont$i#ute- to the poo$e$ $esults seen ,ith amo2icillin8cla+ulanate is the much sho$te$ se$um hal*8li*e o* amo2icillin compa$e- ,ith cip$o*lo2acin 01.3 hou$s *o$ amo2icillin, 1 hou$ *o$ cla+ulanate, an- 4 hou$s *o$ cip$o*lo2acin5 an-, thus, the sho$te$ pe$io- o* time that amo2icillin is p$esent in hi7h concent$ations in u$ine. Althou7h conce$ns ha+e #een $aise- a#out the e**ecti+eness o* amo2icillin8cla+ulanate in the t$eatment o* FTEs cause- #: amo2icillin8$esistant E coli,14 ,e ,e$e una#le to -emonst$ate that amo2icillin8$esistant st$ains ,e$e associate- ,ith hi7he$ *ailu$e $ates. Hinall:, it has #een -emonst$ate- in an e2pe$imental mouse mo-el that E coli, *ollo,in7 inoculation o* la$7e Luantities into the #la--e$, can penet$ate into the #la--e$ epithelium anp$o-uce int$acellula$ colonies o* #acte$ia an- e+entuall: #io*ilms.11812 E* epithelial in+asion an#io*ilm *o$mation occu$s in human c:stitis, it is possi#le that amo2icillin8cla+ulanate is less e**ecti+e than cip$o*lo2acin in e$a-icatin7 u$opatho7ens *$om these sites, $esultin7 in hi7he$ clinical *ailu$e $ates. The ,o$l-,i-e inc$ease in t$imethop$im8sul*ametho2a9ole $esistance in E coli an- conce$ns a#out *luo$oLuinolone $esistance in FTEs an- othe$ mo$e se$ious in*ections 3 hi7hli7ht the nee*o$ alte$nati+e anti#iotics *o$ the t$eatment o* c:stitis. /it$o*u$antoin an- *os*om:cin t$omethamine ha+e #oth #een a-+ocate- as *luo$oLuinolone8spa$in7 alte$nati+es to t$imethop$im8 sul*ametho2a9ole, #ut neithe$ appea$s to #e as e**ecti+e as t$imethop$im8sul*ametho2a9ole o$ *luo$oLuinolones.4, 13 Althou7h K8lactam anti#iotics ha+e lon7 #een use- *o$ the t$eatment o* FTEs, lo,e$ FTE cu$e $ates ha+e 7ene$all: #een o#se$+e- compa$e- ,ith t$imethop$im8 sul*ametho2a9ole an- *luo$oLuinolones $e7a$-less o* the -u$ation o* t$eatment. 4 Amo2icillin8 cla+ulanate has #een use- *o$ the t$eatment o* FTEs an- othe$ in*ections since the ea$l: 1364s, #ut most pu#lishe- t$ials o* its e**icac: ha+e #een +e$: small, in chil-$en o$ in mi2e- populations o* patients, inclu-in7 those ,ith complicate- FTEs.14823 En stu-ies o* uncomplicate- c:stitis, a 38 -a: $e7imen o* amo2icillin8cla+ulanate an- a <8-a: $e7imen o* t$imethop$im8sul*ametho2a9ole ha+e #een sho,n to #e supe$io$ to a sin7le8-ose $e7imen o* amo2icillin8cla+ulanate. 2482 E2posu$e to amo2icillin8cla+ulanate has #een sho,n p$e+iousl: to select *o$ su#seLuent amo2icillin8cla+ulanateM$esistant E coli FTEs.2% En ou$ stu-:, ,omen o$i7inall: in*ecte- ,ith amo2icillin8cla+ulanateMsuscepti#le st$ains ,ho ,e$e t$eate- ,ith amo2icillin8cla+ulanate ,e$e *oun- to ha+e $ecu$$ent FTEs ,ith st$ains nonsuscepti#le to amo2icillin8cla+ulanate, #ut onl: one ,as 7eneticall: i-entical to the initial st$ain. &e chose to compa$e 38-a: $e7imens o* amo2icillin8cla+ulanate an- cip$o*lo2acin *o$ the t$eatment o* acute uncomplicate- c:stitis #ecause o* the nee- *o$ sa*e an- e**ecti+e *luo$oLuinolone8spa$in7 anti#iotics, the a#sence o* a la$7e t$ial compa$in7 a 38-a: $e7imen o* amo2icillin8cla+ulanate to cu$$ent stan-a$- the$ap:, an- inc$easin7 amo2icillin8cla+ulanate use *o$ the t$eatment o* FTEs o+e$ the past -eca-e. 2 The p$e+alence o* amo2icillin8cla+ulanate $esistance amon7 causati+e st$ains at #aseline 03?5 ,as in the same $an7e as that -esc$i#e- in $ecent Eu$opean count$ies 03.4? '$an7e, 4?83.3?)5.2< The $ate o* amo2icillin8cla+ulanate $esistance appea$e- to ha+e limite- impact on #oth clinical an- mic$o#iolo7ical outcomes. En *act, amo2icillin8cla+ulanate ,as *oun- to #e si7ni*icantl: in*e$io$ to cip$o*lo2acin e+en in ,omen in*ecte- ,ith u$opatho7ens suscepti#le in +it$o to amo2icillin8cla+ulanate.

St$en7ths o* this stu-: inclu-e its la$7e sample si9e, ,ell8-e*ine- stu-: population, lon7 *ollo,8 up pe$io-, lo, -$opout $ate, hi7h $ate o* me-ication a-he$ence, an- 7enetic anal:sis o* st$ains causin7 pe$sistent an- ea$l: $ecu$$ent FTEs. The sin7le8#lin- stu-: -esi7n is a potential ,ea>ness o* the stu-: i* the$e ,as a clinical #ias a7ainst amo2icillin8cla+ulanate an- a su#seLuent lo,e$ th$eshol- to t$eat ,omen in this 7$oup ,ho ha- mil- s:mptoms. This seems unli>el: since the pe$centa7e o* FTEs that ,e$e cultu$e8con*i$me- an- the pe$centa7e that ,e$e associate- ,ith p:u$ia ,e$e almost i-entical in the 2 t$eatment 7$oups. T$imethop$im8sul*ametho2a9ole shoul- continue to #e the *i$st8line t$eatment *o$ acute c:stitis i* the ,oman has no histo$: o* alle$7: to the -$u7 an- i* the li>elihoo- o* t$imethop$im8 sul*ametho2a9ole $esistance is lo,.4, 26 En a$eas ,he$e the li>elihoo- o* t$imethop$im8 sul*ametho2a9ole $esistance is hi7h 0V24?5 o$ in ,omen ,ho ha+e $is> *acto$s *o$ t$imethop$im8 sul*ametho2a9ole $esistance, nit$o*u$antoin o$ a *luo$oLuinolone is an app$op$iate choice. Amo2icillin8cla+ulanate in a 38-a: $e7imen is not as e**ecti+e as a *luo$oLuinolone *o$ the t$eatment o* acute uncomplicate- c:stitis, e+en in those ,omen ,ith FTEs cause- #: suscepti#le u$opatho7ens, an- shoul- #e consi-e$e- onl: ,hen use o* othe$ *i$st8 an- secon-8line anti#iotics is not *easi#le.
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