()!

-"1S

:;

1'.

S·e

..S

1'1

"...

ttJ.

I~'

if.

~JFS

f~·

:ti

l.1i

!rl.•...~.

~h

..!J·~I~

I-.·_.l

!1,·lf

~..h1i

~@ttS5

I.

tr

~.•.1'

1[11:

1..

1..;<

t.iQ

J.

Jl.:Ii

JO'll!

t=nI

II,·;

.,II·

tIJ

III!

~~ti

fll&:f

llI;

If~

!l"'ll

r~III'

~l!~g1 1-11

1h..i

l11

.alfltr

rl..

It_

I,H

ItII

;.,hh

.IlL

bil

f~Jl

it·I

I~~..

:'":f-

"!(i

-fflJ

i·in

lr

'll"

i-Unn

li'Jn

l'oUICliltioal MicN&NoIeu'...

Uftivcnity ofFlorida [2IJ. ARM is. eqoinl project desipcd to do8umcnt ....... inantimicrobial svsaptibtlity patterns in illpatient and outpatient isolates and to i_lilyNlatioDships betwCOJlantibiotic use _ resistance ..... The plttieiplnts ine'"qualifyins US hospitals that..... in the pro.-, and the data bKomc p8It of.1IIIdoaa1 ............. to provide benchmarks. As ofApril 11.2005.21. (79%)noa-teaehinl and 74 (21%) teaehiftlhospitals have putieipetcd in ARM. Each hospitalprovida • minimum ofthno yean ofsonsitivity report data while individual aRtihiotiesand orpnisms are cepftIIed in the datatJue.

The Applieant providls chins that depict the national susccpdbility/resistane:e tnmds forP. ."",mMtl. So tIfII'eIU. and E. Goll an4 P. mirtlbil& to rcprestftt Gram-ncptiv. entericrods (see section 5.].$.4.4. pp 12-11. in this submission). nese~ IN basedon thei~ criteria "lisJMrd for the systemic ... ofeiprofloucin.

The followina t8bIe depicts tho percemaae ofciproftoxaci" ..istanee c......natioIuIlly for ..h orpai_ sbown•

...... ,.s.........

Ofconccm is the dceliftinlsensitivity ofthe~. bacterial ,..,.... shownat»vc, to ejpIot1oxacin. The ev_. and misuse, ofquiftOloMs has ltd 10 some ofthis....... To limit the increased raismRcc to ..timicro&»als, such &I t1uoIOquinoloMs,..... the close sumitJane. ofsuscepeil)itities at the tocallevel. the deY......ofpolieia that ratricl unneceaary use. hetter useof~ _~ic data of1Il1ibiotics..IlION systematic GOl"n ofMIC ............to JIlOI'C 111 of (25.26).

As lIIic lo SUIYCiI_. nelWodscotteet ,..., prifnarily" hospital micJoIMoloty~...........~..coIIec1ionsconcaiRsipif of~

..... However.....o/these .....can make"way..1M SUIIOUIICIiaa......_L ~_olthe,......._of ....." it1tleprn__01 ., ex possible to lri.. loule.......uof_~ ActdiIioMIIy, \tIC oftopiallJditJiftcs.limics the apesurc 01......· v ...,....,....-...w "'i..c ift '''-ditcussionof

~llUI

Iff"II!

'.i.I'.Ut

iI"nIl

.l.lllI

OJIlil

!l.•i~l.i..·~(

filiI

-I

JJ'fi.1

~)1"

h' 1

2J"i

l'lll'

llJ~;

I:;::.

1..·iI

J1

1_

Ief!li

•I

~•.j

_8

_...

..J

_~

...........

'IQ,

I·"~a.

_Ii'i

...~

Ifll

l.i.,l

i\llll

rt:!

;'1~~i!n~jJ

I.~i.·i

-ll.~Jf

l'>J"

f-~••

It-

t.~.

~!t

ll!

Sl.-l

i.!

IS-tt

llta

.~r~

Il:t

l'r:

iut

~..

JIUiltJ

inJR

unuin

fUUiU

lunnn

tI

1'<1'1

IIf1.1

;11-'-.

(!.~~

I.-~~

11::·-

rI.:

i:.11

·1;1.

t(.-

,f

Ififf

II

r...

s:.s.

'I

':wg

Ira

i.~

190nlCIiBiaI~'"

not eonsiataIt acJOSI all species. At Iowa'vaIues, the AUC24A'MIC ratio HcamC morepredictive, pcmaps bee_of" doeR_tel '* oft.ctorial kill...

Due 10"ininl rata offailuN and ........ ofrcsi.... to ciprofloucin when...... infections caused· by orpnbms widl an MlC close .. the braItpoints with thecantIDOftly used low...(2 X 200 IftI), alarp-scalc clinical s&ucIy wu performed that ..... to _tiM the PO ,.,...... tMt we.. pmtictors ofdfiacy Univariate analysisshowed thIt .... AUC24hlMIC ntit> (>125) linkad best wAh both the clinical andmicJObioloaical outcollMS, _ that a Cmu/MIC ratio of< 4 was associated sipirJantlywith a sub-optimaI ouWomc. HowevOl. the UN oftwice _ ............ daily dosin.schedules did not allow analysis ofthc hcncrJfs ofhi'" peak~ns since thesewere infRqUC8l After a second expcrimellt stmsod the~of. CmaxlMlCratio, Rlost invatipt.on and dnl,..Jllftia ad8pIed the AUC24hlM1C ratio as a,..mat pRdktivc ....... for efIicIley .. this .......appeINd to be linbclIbOnIIY 10 clinical ot*orM aM was Iy indlpcndcnt of_ dosina inWYaJ, thefluoroquinolone use4 the .....spoe_ the site of infectioIL

EvaIuMina both expcrimtntalst1ldia..c~ data, Inels ofcIrut exposure cJIpcndcritically upon tM daiNd d'..Mev.. &om .. EC50 to III Ec.dTect with ill YiIToclyMmie models ........ an inc... ofabout )o-fold in AUCIMIC ntios. CJinieaJ dataalto point to the same condusion by showin anAUC2~JC ratio of125 winyield eW..y by day seven, but thathi'"val (>2JO) will prNaec fUlCf bMtcrialII'IdicItioft. Therefo... ti.......... evCllll must also he .... _ contidIntion. This....y imply that aimin. at *iaimal valuts..y he dullCIOUf; however the Cmax/MICratio may 1M critical ift JRV-''' .....fIU ofresistItncc and quinoIones wRh ataipei Cmax lie probIWy ..... in thit CQIIInt. Table I Oudina~iveAUC24WMIC·based liInits ofsasitiY--' for ciproflo,.m (he druc~_

.~ do not JIIftic...dinrdy ift Mtivity):

Table'- ............,.,.....fvcl...........forpn......PXIID.......01...14...

,...... "'Iit AUCIat ......,...,.., .... ~ _iii.., ., IUCM'T CUI..... •..... ..1iIfI'Nt ,... Uti'..". 2.itUI 24ftI c~l~ b(4)

1t 1hac ...,ay to systalic cipIo8oucin when......... "Y or·ONI' Ex · PKi'PD cIIta toa1OpicaIIy .-sucIIas C acia Otic SoIuIieII&.2% polIS cMlJenta,MIt it is liMIy CiMxIMIC ,.... plays an inIp an-"hiPGMC of "... in audiWiy .However, the...-ortime 1)' adnlia._ho in 1M

NDA No.2'I-')ICi,..,....OticLah.....w.

24)0"1ctiMaI Miadie'. Jtniew

..... auditory canal may vuy~Iy,AUCIMIC andJcntth oftiIM a'ove M1Cmay play las pncIietablo l'Olu. In any event, at no. from the rauIu of1hc eliDkalstudy undIr review for this NDA and..ofpreviously puWished studies, favotUlePKlPD pIRIIMtcrs an present liven the hip hMtorioloaic cra4iccion ...fer theCOJIUrK)ft pMhopns associaaodwida OE..............As stIted in Sec&ion 2.4.3 ofthis submission, the pharmacokinetics, adIoIptioa,distribution, metabolism. and exorctioa ofeiprotloucin after systemic lldIIIiftistnltion arcwell known _ smnmari2ed in the litcratunl (32]. While the~ics fottopical ciplofloucin is more relcY_ to 111I cunent submission, ..s"'" levels of.,obtairMd after ototopical admiai ant too low for ysis.

A phumacokiMdc study in'" ._.ed levcl of of,iprof1oucin iIItothe systemic ciNvlation [SALVAT dot PK soetion 2.6.5.4, this su......J. ThisstucIy~ levels olablerplion ofeiJl'Ofioucin after otic application isneatilible etap- a hi.... thM that ofthe eli""'" Aaay scntiIivity wuOM ofthe fac:ton that may have affected the outcoJM of this study. C~in levelsin"'"WON....... It)' hip ,...,.liauKt~y(HPLC) \¥iIh UVdItation which had 'a Ibnit ofdaeetioft of J'alml [Tah" 2.6.$.2, SALVAT b(4)Analytical Method]. nis study .... CctnxaI Oticd u .. tat..1t _1hisproducthas • dift'crent fonnulaUon ...CiJllOftoueill Otic Solution 0.2%. Dc acipiIIatdill.....were SUIIIIMIizecl__", Section 2.4.1.1 ..... _ ...... to·....

die Incl ofeiproftouciA 1bsodJId. The study used a mpe conccntIa1iun ofciPofloucin Chan the drul product, Whieh i---'.. libIiIaoocIo'..... in 1Mplasma.

Dis low IYsteiltic exposure is supported by a study yay liute ofthe ciprotloxMin passed die .,.puic mcrnbnne appticaIicm to ....tympanic dscIf [TaWe 2.6.'.3, 33). The.. artie 11 in 0.9"-saliM, whiGlt is di 110m that oICiJnfIoxacin Otic SoIutiaD t.2%.

No otic specific tiIsuc distlilMleion studies were· con4uctc4. " 4~ia,however, is CXJMded to to~ the ...diSCriltution doN ofeiplofloueift.

FoitowinI.,. cnI.., cipmt10ucift reIaIad ,.."..vitydislra••rI..,wty intothI __ ....,aa1JDIIItS. e-,..wty hi.1cftls wtn fGunct ia .... DtnIy, 1iYcr,.....-Ie, J*ICNU, ..... Mel.... retativeto ....... l.ow .................... CJClaIIf8d in'" tJniIt;'lO," _pos.c". AsiInilu·,.... 01~was .... aa."ava:_~ IfiPatCOllClt8b ...olumelll OIIC hour post" (TUIe 2-'.$.'., .._.isIioIl). It is ,.. aftIr.......bn••siIaiI8r ......oI WWW· ....No Iism llliaClnplrisolt weN C'lJIIOf1oudais,...wJy izcd in die lw-a.y modif of,...-, idenIifW

1~1~!

IJll

lltl

l'I!

!I!

~tllrll

rf~i

t!IIII~~l~

IIilf

I', ..

,,,Iil

~I:I"..

'11r'1

·S

l;'l..r

ll'C·t.I

IIIr

I'I~

,.

tt~a-

.'I'e

Iell

~=

i.'

if11 _.

,II'

-t.t·

f=.

•i'

a°:!

.....

it.:I

J:..

t5

'"2"

i:ilit

I:_

,<!I

"I'

!.-li'

.~

g..

---

_•

I:I

2ae:

1.--

!.'~~

&I"

,.1';

i5

Ii::

..:1Ii

:I.~

!l!

~--i

i'...

.I

Ir:I

JlI~1

_.I--

.I

I.~

S,..

IS'

~i

JI"J'-

••ll'l

f....

i:f

if~5

'S"

!l,,

=-1t

rp'.t

hI~

!l.

,sl

t-;1

.=1

"iIt)

>~!.

l~i

'§,

t(I'(i~H

f

I..1:

•.111

1..•

.•:til

l1<

f'rt-

lrw

°

'11.i,I

~i:'1.

1r·

I·I.

ir~I

.Sa•S

'.

oSfA l·

.'I:~

ll.

JiJ.

°

"r

~11;

~..

tIt

.1Sa

I.J

aI:

I.:

Ii'

t

lI11·1

'~fJI

ifr

Itl'J

f~'

ffII·

ltl~~i

~~I

I·¥.

,I.I

ii

lII.

°~I·

rI·

.i"~.

J&I

=-~

:II

fA'F

5ij

'Sa

,j

':<jo~