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V O R I C O N A Z O L E - B h t t k r ClTANC'.ES f o r P a t i e n t s w i t h

I n v a s i v e M y c o s e s

M. A. (dhannoum d U. \E Kuhn1-’

r h \U >ii ,i' \ h > ><!i w \ l v Ki'U < o u e I ,,b> i>mi > . 1 k p v m c n i ..,i De r , ;i.i’ ,-1 in im ifi i t I;i Uv; it.1. Dim jm n, ( ><. pv ! tiii lit > - ! M-.'.hi i n 1, \ is i *'i mi •' 11'*-* pi n l > ■ *< <. I'.1'. I an J , and

< A'.', \\ i. W 01 iv, v i ' S lll.i IMU, 1 k v run j. t i l (, I S \

.‘I h i t ’jL i: The pas; t w o decades have w iutessed an

in crease in serious lunâ l mlcet h >ns, \\hIi>hii n«r-

respond ing grow th in awihab le a i u dunga ! agents.

Vor ic onazo le (YR<d) is a m>vcl i r i a /u lc a m i t u n ^ a h

recent!v approx cd in Iztinipe lor m a u m - n t ol se

r ious 1 fifccih>hs e.lust'd b\ ,•!'■/V'y jilfit, i n f i r m

Sa 'dospo ru iw , and resist ant ( ,tud i< lj species,

V o r ic onazo le h is in v i t ro act ivi ty against vcasts

and \ eastdike hmgt s imi lar , or supe> n w i i >, l l iuo-

na/ o le (FLC} , : iracoitaznk- (! ! ( ’) and u np i n >tcr;~

ciu B (AMB) . (A tnd id j a l l ' l l .a h is general ly ihe

most suscep 1 1 hie \ easi (YRC, M K . t , 0 o f 0,0?.

jUi;/ind; C kmst-i often has low M K.s e\en in the

face ol F L U / I T C . resistance. Vo r ic onazo l e has de

mons ! rated comparab le , or 1 teller, in v i t ro acti\ t-

ty t han r i ’C and A M B against A<pc> ilins (mean

M I C s 0.19-038* / i t ;/ml) , Ascouiyeeies, H tp a ijr iv

F iss jr iitm , d v n u jn t id n , ( M iad in idcs

i in m ita , dermatophytes , / ItUopl-tsHhi upsiildlnn,\

ALii.isse/.hu and Sicdnspurunn j/ryu't/u r>nn>n ( / ’.

hoydti). The dn tg poviesscs po ien l lung ic ida i ac

t iv i ty against n tonids stt J u d m g A ^p ay jd u ^ ,

Sivdvi>pf>i'hiUh and I 'u s ju iin i . h'migH idal at 1 1 ?is is

Hktdv due to the h igh a! I i n i n ol Y R ( ! lot tungal

t4-«-demetlu htse, a i oncept suppor ted by ultra-

structural and b i ochemica l analvsis. A n im a l si ti

dies coi i l ’i r i rnd t h e ,icti\il\ ot \' R i again-a in fec

t ions me!' .idnti; pu l tm mat y and m\ asi\ e aspei gd-

losis (I A 1; J . !a})it\\ans endocardi t is; tiisariosts;

p u lm o n a r y crvpti>nio. 'oms; and i i n a s i u ' ( andidia-

sts. Most imp) i r u n t l v , wci l-dcM^ned hun ian c11 1 1 1 -

cal t i iais h,i\e conh rn ie d die el t icaty ol \ K( m

tite treat m em o- cand ida l es< tphaî l is, ! \, and fe-

hri le neurropei i i a. Smal ler studies and case reports

have shown \ R(. is l isUui ler saKa;ê therapv ot

f'\, cervhr.i i asperî l losis, Srffiu^pom ^ti, and ut l ier

tunâ ! in iect ions. C l in ic d iesi inj ; has s hown \'Kt ,

is saie and well tuk-raied; i he most c> unn io n -^de

efiect is b r n ’. p i , sell-l imited \ isual disturhance

/\r’t ccfio/o \'oi'ii ona'/oie; ( andida; Asptau,ii'u>.;

Scedospctrnnn; I'usarturn; a/oie; t laa/oic; hhlo\cs;

treat nient

1. I\ I Ha i| i[ t TIi IN

Recent vt a is havi- w i messed a s i p n i n asn increase

in she incidcnce oi Iunt;a! inlectiotis, im l u d n i i ;

thi 'Sf cau't d hv \ east and h l am en ton s tung i . In

the L ntied btates L ,u id u i j species are n o w the

t iuirth most commc>n nosocomia l b lood stream

pathogen wi th ihi- highest crude mor ta l i ty

{40"-.<} [251. In Eu rope , i ' .a n d u ij spp. are the eighth

niosi c o m tno n cause (2 .S"ti) o f blood-stream intec-

t ions (whether nosocom ia l ur commnni t\ -ac-

qutred). In a re\ iew ot 11,330 autopsies conducted

at a U im ers i t } ' Hosp i ta l in Europe , G r o l l et al.

(48] d o cum en ted an im rease in invasive mycoses,

larêlv due to a rise in Aspergilla? infect ions

([' < D.COn. The incidence oi invasi's e aspergillosis

( IA) an ions tran.splattt pat ienrs mcrejNed t r om 6 'H<

io 11 % between I% ’3 and 1992. A s imda r increase

in the incidence ol organisms o the r than

Aspffxdhis has been repor ted by Singh et al., w h o

showed that hmgt o ther than Aspergillus a c coun t

ed lor 37% ol ail mou lds [93]. Ed i tor !una te l y , the

increase in the incidence ol funga l in fec t ions is as

sociated wi th a dramat ic increase in mor ta l i ty .

M cN e i l el al. [70] reported a 3 .4-1 old increase in

mor t a l i ty due to huigal infect ions f r om 1980 to

I MM7. The%e authors showed tha t fungal in ject ions

c l imbed 1 t o m ihe 1C'1, to 7;!l pos i t ion in a rank ing

0 1 infect ious causes ot death in the US, du r i ng the

same t ime period.

The increase in the incidence oi k m gal infec

t ions and assouated m o r t a l i u , an si the emerge nee

oi resistance to c u r r e m h used anr i tunâ l agents

[tor reviews see re fennces 42 and ICb] mtens i l ied

t lu scan.h lor new, sa.ê and broad-spectrum

auents. These ct iorts led to the in t r rnlnc t ion • >1

ter lur ial ine (belonîni ; to the a l l y l am m c class c4

ccit ipi amds) toi the t rea tment o l elermatophvto-

s is , and antphotc r ic in B (A m B j l ip id i o rm u ia t io ns

Us,4 . \belce' and Am K isom e) wirh impro\cd saie-

n poh i le s compa red to nanc lard A n iB [4 3. 511]-

\dddtc.nal iv. members nt a new class o! ami tun-

i; d agents, the echinocai td ins htch target iunga l

cell walls), arc beuy4 developed. Caspo fu t igm has

been a ppnnev l tn the F D A l ior tine t rea tment ot

I \ in pat ients ref rac ton ' tc>, or iu i o l e r am t>i.

other [her.tpn s'; micci tungin (Fuj isawa) and am-

d i d a iu ngu i (\'cisitori are unde rgo i ng phase I I ' ’111

d i n i c a ’l trials.

How ever , wi rh 15 d i f te ient drugs mark^ t ed

w orldc’t ide , and at least three new invest igat ional

drugs under deve lopment [vor iconazo le {Vfettd • M;

M ,n J l . 2002 L U R C l ' L A N J O U R N A L OF M L D lC A I . R ES EARCH 2 t3

i ' l i / e r ) , p < > s , H - o n a i ' i ' ) l r ( S c h e r i n g - P l o u g h ) . a n d r a \ u -

e u u a ^ o l e ( h r i s r o l - M y e r s - S q u i h b ) j , t i n a / o l e s a r e

c u r r e n t l y t h e m o s t w i d e l y u s e d a n d s t u d i e d c l a s s

o t a n t i f u n g a l a g e n t s f o r t o p i c a l a n d s ^ s t y m i e i m •

c r i s e s [ 5 3 ] . T h i s r e v i e w w i l l p r o v i d e a n o v e r v i e w

o i i l i e p t ' u p e r t l e s o i \ o i i c o n a x . o l e ( Y R C ) , a h i g h . l v

p r o m i s i n g f l e w , s e c o n d - g e n e r a t i o n t r i a / o l e . \ X Y

a r e l o c u s i u g o n t h i s a g e n t s i n c e i r h a s r e c e n t l y

b e e n a p p r o v e d b y ! h e 1: U l o r d i e t r e a t m e n t o f i n -

v a s n e a s p e g i l l o s i s , S i t ' t i o s p o r i i i / a , a n d F u ^ m u m i n -

l e e t i o n s , a s w e l l a s l l u e o n a y o l e - r e s i s i a n i s e r i o u s

i . j H t i i d j i n i e c i i o n s , a n d d u e t o o u r e x t e n s i v e i n

v o l v e m e n t i n U s n t v i t r o a n d i n v i v o e v a l u a t i o n [ 8 ,

2 8 , 4 1 , 6 I , ^ 0 ] , T h e i n f o r m a t i o n c o n t a i n e d i n t h i s

r e v i e w h a s W e n o b t a i n e d h o n i o v e r 1 0 0 p e e r - t v •

v i e w e d a r t i c l e s , a b s t i a c t s p r e s e n t e d a t n a t i o n a l

m e e t i n g s , a n d P f i z e r i n t e r n a l d a t a ( s u p p l i e d t o i n

v e s t i g a t o r s ) .

2. H i s i o r h a l P r r m -l c t iv f

A l t h o u g h t h e f i r s t a z o i c a m i i t m g a l a g e n t w a s t e -

p o r t e d i n 1 ^ 4 4 [ 2 ^ ] , i i w a s n o t u n t i l l ' ^ 3 S' t h a t t o p

i c a l c h l o n n u l a z o l e b e c a m e a v a i l a b l e t o r c l i n i c a l

u s e 1^ 2 ] . T w o m o r e t o p i c a l a z o i c a n t i f u n g a l

a g e n t s , m i c o n a z o l e a n d c l o t r i m a z o l e , w e r e i n t r o

d u c e d i n 1% T f o l l o w e d b v e e o n a z o l e t i t I ‘ >7 4 [<f2 j ,

a n d a p a r e n t e i a l i o r i n u l a r i o n o i m i c o u a / o k m t i n -

l a t e J 9 7 C s ( i C , 4 ( i J. [ o d a y . t h e s e t h r e e a g e n t s r e

m a i n t h e m a i n s t a y o l t o p i c a l t h e r a p y t o r m a i n '

s u p e r f i c i a l m v c o s e s s u c h a s t i n e a p e d i s a n d c a n d i

d a l v a g i n i t i s ,

B v 1 9 8 0 , t h e o n h n e w a / o l e i n t r o d u c e d i o r t h e

t r e a t m e n t o l s y s t e m i c f u n g a l i n f e c t i o u s w a s *>r a I

k e t o e o n a / o l e ( K T ' ( d ( S ' - ) ] . I t w o u l d h e m o r e t h a n

13 r e a r s b e l o r e e i t h e r f l u c o n a z o l e > H C | o r i t r a -

c o n a / o l e ( T*T <„ ' ) b e c a m e a v a i l a b l e l o r t h e t r e . i m i e i u

o l s y s t e m i c m v c o . s e s [ 7 ] , I t r a c o n a z o l e , f i r s t l i

c e n s e d i n 1 k^ 2 , w a s i n i u a J h a v a i l a b l e o n l y i n a

c a p s u l e f o r m t h a t w i s p l a g u e d b \ p o u r a n d e r r j i i i

b i o . n a t l a b i h t v [ 4 ^ ] . H o w e v e r , i n t h e F D A

a p p r o v e d a n o r a l s o l u t i o n l o n r m l a t e d w i t h a v e h i -

i l e t h a t f a c i l i t a t e d a b s o r p t i o n , a n d i n i l r t v , , m

i n t r a v e n o u s l o r m w i t h t h e s m i e v e h i c l e w a s a p

p r o v e d . T h e i n t r o d u c t i o n o t 1 l . C a n d E T C i n i -

p i 1 1 \ e c i o u r a b i l i t y t o m a n a g e t u n g a l t u l e c t h m s ,

p a i t i c u l a r l v e a n d i d i a s i s . H o w e v e r , t h e s e I t r s i g e n -

e r u i o n r r i a / o l c s s u l i e r f r o m a t i a n e i w s p e c t r u m o t

a c t i v i t y ( F I X ’, h a s a p o o r a c t i v i t y a g a i n s t s o m e

v e a s t s a n d m o u l d s ) , a n d t h e e m e r g e n c e o f r e s i s -

! a t i e c , T o e i r e u m v c n l t h e s e s h o r t c o m i n g s a n e x

t e n s i v e r e s e a r c h p r o g r a m w a s u n d e r t a k e n b v

P l i / e r P h a r m a c e u t i c a l s t h a t l e d s o i h e d i s c . >v e r y o f

V R ( ! , a n o v e l , b r o a d - s p e c t r u m a n t i f u n g a l a g e n t

w i n c h d e m o n s t r a t e d a c t i v i t y a g a i n s t ,v/< > ! e - r e s i b . t -

j i i t s p e c i e s o l C . j n d n i i , i n d n d i n g C . n n l n i . i kr;t>< /

a n d ( ' . g L i b m t j , a s w e l l a s a c t i v i t y a g a i n s t m o u l d s

s u c h a s A ^ p n j i i i h i s [ 5 4 ]

5 , CTf f F M I S [ K )

Y m i t o n a z o l e has eh>se s t r uc tu r a l s i n u l a r i t v l o

F ! f (Fig. 1), w i t h a m o l e c u l a r f o r m u l a ol

C:,, I I t\ O l c o r r e s p o n d i n g to a m o l e c u l a r

weighl of M T v ft is a w hit e po wde r that is solu

ble (at room temperature) in Z. I M 1 {( .1 (2T«j

m g / m l ) . w i t h a mel t in g po int ol I38-P4 "C . For

sit v it to experimenta l purposes, stock soUmons id

1 mg. ’ ml van be made up in dsmetl ivi \u1lo\ide

( P M S O ) . The IV prepara t ion >4 Y R C is prepared

w i t h su l phobu ty l ether jTcyelodev! rin (SBKCD) . t

no\ el s o l u l n l i /m g ageni,

4 . A \ n i a n \ ; . \ l A c ;11 \ i t y

is 1 \ Yi r f . i )

I n t e ns i ve tn vu ro suscept ibi l i ty testing ol Y E C

(more than (>C00 fungal isolates were tested, i n

c lud ing verots. veast-lih.e organisms . and mou lds !

cSearh demonstra ted the broad-spectrum aai\it\

ol tli is drug. In genera!, \ R C had in v i t ro act ivi ty

against most \ easts and veastdike lung i [ m i n im u m

m h ib i t o i n c> <ncer:rat ion ( M K i ) o! < 2 nio'm!] that

wa*. s imi lar or superioj io that ol ld.1, , ITT , and

A n iB [f>, 8, 12, 13, I T b0, 75, 7h, 84, 84, 901

C f t ; (//</.? jih n .tfJs is ênerahv the most susceptible

yeast, w i th a V R C M i l ’ (the <. oneeut i al ton ot

druj ; (.atisini; a KK''lo ” n >w th i n h i b i t i o n ol o rgan

isms) o f O.Cfa whde C. is ihe least

sensitive wi th an MIC, , of 2.0 [H3j,

\ o r i u j iM / i <le has dennms tra ted compa i able, or

belter, m v i t r o activi 'n than ITC tnd A m I I against

f i l amentous and d im o r p h i c futnp mc lud in t ; Aspcr-

spp., Ascom veetes, HipnLr> if spp,, f jn j r i i tm

spp., B inttur: ue- (/e; w .in i i i f a , f Jiccuhm.'iiy nr,-

m /th , d e nna i ophy ie s , fh> !up !,^ /N j t jp ^ it l.tt it iv ,

spp. , Siaiosptifni/)? jt!£!ospcm nfi> i (P.

b o yd i’A, R ln,:r,p ii‘i ,o>-Tv. /.ov Sporoihrix »ickii,

and '\h.iuiij i ; i lo, p , 2'n 4^, uS. i,'>, 77,

Sh, 1C7, SCHi a l t hough acti\iit\ against t iu latter

t inee species was m u ch less than against o i l ier or-

gara’ s m s [58. t o j.Urn- to t in 1 im reased i lie isle rk e ymd li l e,h a t t r ib

u tab le m o i t a l i i v I ot f i i anientous lungal inieei ioi is.

potent act ivi ty againsi m ou lds is an i m p o r i a m pa-

ranu'tt-r lor aiu' new ant T imba l agent. Studies

w i t h \TR C has e demonstra ted its h igh aei ivi iv

against .4 spa^tH as species in v i t ro (mean MIC is

C. I ^'3.58 j.i£,/ml). Im po r t a n t l y , published, reports

repealed ihal \ R C possesses a p>>teiH Jnt ioic id j !

activi i \ (at tissue c o m c n t ratif n n a p p r o x i a u t e h

twi ia' the M I C ) against mou lds me h id ing

A 'pc i'^ ilh i? spp, S^vJu\pori(ini {Ptcttdit/L^cl.n'rij)

spp. and F i's ir u ru spp. j m i n i m u m Inngicidal c on

cern rat ion (M K 4 o t C i7-1 /<g/rnf j (5, 6, 1 h. 53, 71.

S9J, li has been postu laled that sti uetural changes

m l is>dtu;ed in 3 'R C residt in a higher a l f i n m

(co’Tipared to oi l ier a/- 4esi io!' t he iungal 14«-de-

nn- thvlase, leading to cell deal h il>r. C . A .

H i t c l n ock, personal eomnu in iea? um) . ’There does

nut appear to be cross-resistance w ith Ani l*, hke l y

due to ihe d i l le rent sites o l act ion ot the two

agents [ 1 j, and in tact one stad\ f m m d \ R i . to be

elteetive in v i t ro against AmB-resisiant A^pi-iyjiliiy

fc)4]. The f ind i ng ot lung icidal activity"

against mou lds may have i m p o n a m cl inical im p l i

cations, since to date a/<ties have been considered

I ! Hi ' I T \ N j t O F M I i D k A i Kl SI AK> M \ 1 , i v ; 1. 2ZZ2

>N v— N

Iniisla/dh’ fria/ole

A — N

N-1' ‘!: //

A -N

l f > N A - N s

Fs.

O H V

- N\ N f

/> V f i\\F

F - v

/ / \' x) ON

■Vwiu/ttk* VorKvrwi’ie R : n uc i >nj .7\'»ic

- O <

/-<-U /si, I A"A-- N._.

% <>— N\\, // \

l;r;ic<ma,'L'k‘

/ — \

N

c r

o

N,N,

Cl

F '

OH

';s>. I. Si rUCturLS o| new

ri aaoics.

1u!Ji;isi,(1 u ' agents, ’I Ins has been at leaî a theoreti

cal l im itation (i’i ,1/1 >ie therapy, \inct' rrad itionalh

staiic a «,11s h aw been leh snicnur to cij.il agents

hi n u i n s e n n i t IvkUtia I and kmgai infections.

The amduni;a l activity o) \'RC' against a small

number m* / l7('s spp. was evaluated m

v i!r .>, ,ind compared to ih.n oi A m B and IT C . O l

the three agents, i>ii|v AtnPi had >od aritslunga!

activit y: M K a rang 'd Inittt 2 in > 52 /ig/ml ami

t r o n i O.Ofi to H pg/'in] to r V R C and AmB. respec

tively. H n w i ' v n , t he a c t n i n ol FTC appeared

more species-dependent, wiih some organisms

bein ;4 su^Lt'piible fM R A from C.25 to 2 |tg/ml),

whde others rest m ani (M I ( ’ > >2 /.(i;/ ml). Overall,

it may In1 assumed thai V R< ’ has poor activn y

against '/vômveeus. An extensive summary, nt

V R ( M K icsiint; lor \anrms organisms w>b re

m i t l v p u b l i s h e d j’27].

n ; I \ ' !'■ i '

Yorie* ma/-ole i>, i lunina'*. d much less r ap i dh it)

uuinea pic,''. \han in . m hct small l abora tory m a m

mals (e,£. m i a , rats, .tod rabbits), wh i ch tend t><

exhibi t hu < ‘-indue! if its o! i tKiabol isrn. The pro-

iuiic,ed s' s ie in 11 \d\t', le\eh in guinea pi;4S ate

comparab le i»> f'nuse ub'H'rx ed i n h iunans [57], As

s u e h , d i e g u i n e a pii ; w a s ê iee ied as t h e m n s i a p p r o p r i a t e a n n u a l mutk-1 lor e\ a l u a n o n of the in

y iy <* r t i i t a e \ uj \ R l . t ' s i n " this mode l , t h e e i1 tea- e\“ (>l \ RC 1 has t 'een de ni nn ' i i r a t ed agai i i s i a wide

\ a r i r i \ o! iunâ l in i i e i i o n s i n c l u d i n g i n v a s i v e a n d p u l m * > ; u n a ^ p e r g d h ’ sis (301: -1. funiigjii/s endt^- cardit is p n l n i o n . i r v e r 1. p i o e n c e o s i s [9r j: and

i n ’; a s n l e a u d u t i a s i s t a used b\ (', jib ic ii/is . C, t-Jj'h-

r u i . h and ( k> U i v t |?,S, SH. 9 7 j

Taken lujêihi 'r, data h'uin these studies sinewed

Y R C ’ cou ld be an e f le c t iw t reatment tor aspergi l

losis in bo !h inun iuio-co inpetent and immui io-

coniproi i i iset l anitnal models, and thus by exten

sion, h u m a n patients. Moreove r , it appeared elii-

eai ' ioiK lor the t rea tmem oi in jec t ions caused by

^-suseeptible and -resistant C a n d id a species.

I ' i n a lh , an ima l m o d e l < sug^csied \ R C was super i

or m A m B in crvptoci>ccosis f io i a detai led de-

•.eriptii>!i oi these si udies please see relereuce 54],

M l «, 11 \ \ J N \ t ( >!■ A C l I O X

A / o l e an: i t unâK are dnrided intri t v\- o groups on

thi- basb v'l siriu turi : the im ida/o les (clotrima-

/<>le, niicsina/ole. K 1 ( ). vs inch have a tne-mem-

be red r-.n w i ih tv. o uit roêns; and the trnK'ok-,

iFL( , f I t , \ R( ,, pi>s,Kona/o le , r.ivueona/ole],

M.n- 5 s, \:o: I I ' R O I ' I ' A N f U l ' K \ A 1 S L R I- S !• \ R f . H 11'

\\ hirli have a ti\e-im mbetcd ring w ith three ni-

tro^fii.s (Hg. i). 1 hese drags exert their effects pri

marily b\ inhibitm*; ihe fungal o l o t brosne P450

\ cnyvmL- l.au >su-rol 14-( ! hvlase, pre-

venunt; the c<nn ersif>n t»t ano\itro! to crgosferol,

(The main a/<>le fargei is l ikeh the heme protein

which co-eauU/cs the I 4-</-deinetii' lai ioti ot !,i-

nostero! [ 5 2 ] ‘{his in turn leads u ■ depletion oi ergosterol (a regulatoi of lun^.il cell membrane

idtiidin and ,is\ in m e in ) and act, iin iuLnion o| ster

ol ptvee,root's, including tho 14-c/.-nkilsvLtU'd ster

ols Lmosterol, 4J4-diniethvl/\u i o s U t o ] , and 2 !-

melhx lenediln drolatiosteroh As .1 result oi erôs*

terol depletion, ibe sotc^rit\ and h im tion ol the

fungal cell membrane is disrupted, eventually

leadiii'j, to cell 1) sis [ W|. Figure 2 is a summary ni

the cr;4uste*«'l I>i.• *5.\ n thc tu pathway '•howini; Mies

oi action oi ami fungal agents, including, V RC ,

Ai ,i genetic level, d a u supportuii; this micha-

nism ot aeti.ii! comes irom several eh-âni studies

bv Cieher el a!. [30]. I Isese aut hors cloned 1 lie S4-t7.-

niethvS sieroJ dcniel(nd.isr {I }\( '•! 0 and /^ ' ' ’-slerol

dt saiurase {£. H ( ;dJ genes fre>n! f . i:.i, r.dd in

u i r n usetl theu i 1 0 ere,He de le ! ion mutam.s lack ing

one or bo th êfies. Phe i ior . pie a n a h sis revealed

that the E K (J J delet ion m u u m remained ■susccpti-

Ide to f 'LC and IT C . In contrast , the I : R G / / and

L R C H I R G . ' delet ion inu tan ls vs ere resistant lo

F*LC 1 i CC/.g^'tnn, I M 1 •< /-ip'mij atid A m B

( J f i g / !!)!}._

A t a biochemical level, our gun ip investigated

the iniliienee oi sub-inhibitorv ecmcenirations ol

\'RC" and FI.C/ on sterol bios\ tuhcNis oi I :L.C!-re

sist am and -su.seeprtble C. iilhuan^ and C, krusei [93], Voricona/fde-treaied ( j i hi utns strains

showed p ro found changes 111 sterol protile, m-

cdudin” complete jnh ib i i io j i o! erô.sterol svnfbe-

sis and accunndation oj its precursors [90]. In (

\’K C treatment resulted in siîtilieam in h i

b it ion of ergosterol synthesis ( > 73% inh ib it ion)

and aecumnlation ol methylated intermedia!es.

In cotiu as\. treatment hail a m in ima l ellect

on (', h m s a sterols. These result" support 1 he

premise that V R C is a superior in h ib ito r ol lutt-

Jig, \ 'JdMnsiiiissioi] eleel 1 on nm n<-

'j,raphs s he wi n g the el let t t4 mu h t>n- . i ?o !e i re . i t n ie t i l ■ ':i ; in ni< irp{;> T ^ v

<a ( t'ulaiA u.u 1 A ) Norri. iL un-

treated eotitntl; (?i) \ in-n.'on.r'nIt-

rreaii i i ieUs. Nt.iuniiic sticci \ 1 V'tcT.

I 1 'Rt H ’ K W )s. U ' R N A L * >1’ X I F n i l W ! R r ^ K X R C H M a y 3 k 2002

/?,.'. 4 V a n n i n g electron m i e n i p ' ’,ph\ -.lieu in "

ihe lMci.'i • it vi .riL.»n,’'7i >k‘ i re.Hmeiit e n d ie iimt-

J'!’ < ilri^y n i I D h l u i j ,?//>it.’.f»,T.'. IA ) k m re u ed con-

i i 1'! -tp-A\m sm < >. 'ill, tii'niial nn •rpl- < >i‘ '£v: iB)

\ i >i’k ( -na/j tk'*f ro u e d cells shmeirn ; Leikckurf; t-

u . ’ ii .inu i i u b i h n !*.• J m J i ’ ; K j \ n r k i >na?f k-

li't'.u^d ce lk -dv I'viiii; enlargement or C, rk’.\ .<>•■- S'ks; »>pi':v- ^ ith \oni!,j u u icr cnvel ; ye prt'tri>->,. 1 «. H !!. ,.

gal 14-C^dcii i t ‘tSi} l.lsc, c o m p a r e d i n i radi i ; ona l

azoies.

[ j l f r . n i ruc iu r . i l . n u k scs ( m m i ; s iM im m j : a n d

t r a n s m i s s i o n t*lcc! r«_>n i i n c n >M‘op\ ) have re\ eaied

t hat t h e d e p l e t i o n id eru,>>siend In V R i u-suhs in

s t p m h e a n l changes in the u m r p f i o l o p <>i susccp-

t i b l e specie1'. Y o t k ««u, ! / ide l rea led f '.. k n f ' i ' i , iml

C. isol aies e x h i b i t e d p r o n o u n c e d separ.i*

l i o n ill ilk- cel! wa l l a n d < \ lop i . i s i n , veil m e m

b r a ne d e g r a d a t i o n , a n d s h i n n i n g i d the cel! w. i l l

[see Fig. 5 ,ss we l l as re lercnee 8], U n l i k e c o n t r o l

(F i ^ . 4A ) , \ o n c o i u z o l e t r e a t m e n t a l so caused a

i ess.tt i i !n ot cell d i v i s i o n m a n i t e s t e d k v elonga-

11on i lk ” , 4B) and enlargement of C. jih ic jt?* bktv

t os pn re s I Fit;, 4 ( ' k I n con t ras t , F L C h a d n o effect

ni l tl ie u l t r . i s l r t i c tu re o f t h e i m r i n s i c a l l v FkC.-re

sist ,mt ( ' , K - r i / c e i . These m i c r o s c o p i c images a p

pear i o c lea r ly d e m o n s t r a t e th e i nc r eased p o t e n c y

o i \ R ( ! (over F L C ) against C. k r ; t ? e i 14-re-de-

met heh i s e .

M , n M , !CC2 I ' l iKt >r*h\\ ( O l i R N A I ( H' MF.l >1< Ai RUM A R f H 247

\\ h d e the a/<>les also b l o c k m a m n i a l u u t eholes-

rerol svnt hesis j t 14-c/. dernet l iy l a t i o n , t he dose f t -

q u i red 1 o cause the v u i i i ’ decree of i n h i b i t i o n is

m u c h h i g h e r t h a n t l iai req u i re d tor f u n g i j 52. CD,

1 Ci j. F o r r t . i m p l i 1, l i u c h c o c k et al. [ ^ 1 s h o w e d

tli.iL Y R C h ad an i n h i b i t o r y e m u ent ra t mss (IC.--J

o i 7.4 /(M against t he ! 4 -«-5 i e i o l demet h\ lase ol

rat li\er, w h i l e the I t ' _ against I In l u n g a i e n z y n u

was as l i iw as 0.23 f i \ \ . d i m s Y R C is a b o u t 232-

told m o r e ac t i ve a ga in si t he intv4 .1 I t h a n 1 h r m a m

m a l i a n He m e 1 I n lase c i i / v m e . Y R 1 ' a nd FT.C art

less a* l ive t h a n K T C a nd F I X against m a m m a l i a n

P-450-dependein, steroid h o r m o n e bn>syuthesis,

suggesting the former u n i agents arc more .selec

tive inh ib i tors of l itugal P-45C sterol b iosvndiesis .

Indeed. cl inicai etieci s of in h ib i t io n 1 if h u m an

sterol hiosvnthesis are most p r o m ine n t l y seen

w i t h K T C .

h, R i sis I A\< I

A n u m b e r o i m e c h a n i s m s o f C . v h l i t L i r e s i s t a n c e t o

a z o l e s base been we l l d e s c r i b e d . 1 he s e i n c l u d e a l t e r a t i o n s in t he drugs ' 1 arget (14 ‘fi ,-demeih\ lase) . m o d i f i e a t i o n s o l sterol s\ n t h e s t s , r e d u c t i o n o r

o \ e i - e x p r e s s i o n o l t he target e n / v m e , and i n d u c t i o n o l d r u g c l I ! u k p u m p s [ t en1 rev i e w w e reicren-

ces 42 a n d 1Cf>j. S i m i l a r m o l e c u l a r m e c h a n i s m ' '

u n J e i K m g A s/M 'rv jlhh r e s i s t a n c e 1 0 FTC ha r e been

f o u n d 12 y 44, c2. ^ ‘>j.

S ince hi e a k p o m t s h a w n o t been es tab l i shed fo>-

the m v e s t i g a t i o n a l t n a z o l e s ( Y R C , ra\ u e o na z o l e ,

a n d p o s a e o n a / o l e ) , d e t a i l ed d i seuss ion of re,sis-

t a nee is no t possib le . H o w eve r. ear i v data suggest

that ( . ' isolates resistant to I T t o r F I .C

are j K o less sum . ept ibk- to the n e w invest i ga t i ona l

t r i a / o l e s [14, 18]. M o r e o v e r , FI A.-resistant C.

g/d/yj , ' , ' isolates arc a lmos t aiw avs resistant to

IT C ; a n d less susccpt id l e to the i n ve s t i ga t i o na l

azoles (X2]. H o w e v e r , cross-resistance is no t a for-

"(' in- c o n c l u s i o n , a n d i l te actual i m p a c t o n c l i n i ca l

eHseac\ r em a i n s to be d e t e r m i n e d f ti2, 72, 9SJ.

Interest ingly, n o cross-resistam e ts obscr\ ed in

the ease ol C. krusvi; this species t ends to have l o w

M K \ to \"R even in the face o| resist a nee to

F L C and H ( 1 'O], I n an elegant ana lys i s o l cross,

resistance a m o n g l icensed and m\ estig.it tona l trt-

azoles, P l a l l e r s h o w e d thai to express h ig h M I C s

to YRC , C, and ( . g/,?br,n‘ ? isolates had to

be resistant to bo th Ft Ad and F I X I s o l a t e s that are

resistant t o F L C alone tend to have low V R (

M I C s {l O C ’h ol the isolates i n h i b i t e d at C.5 / / g /m l )

[82] M e c h a n i s m s u nde : l r i n g th i s phcn<n n e n o n

arc u t i k n o w n , but I t o m P faber ' s da ta it can be

postulated that lor an isolate to b e c o m e resistant

to Y R C , more than one resistance m e e h .m i s m

inns! be i n d u c e d s i r a uhan e ousK (e.g. a l t e ra ’ ior; ot

14-</-d,:methyias(j and over-expression of drug el

f in x p u m p s ) .

? . P i ! A R M At ‘ IKS.M i i< C r > \ M D i ; R \ F l o X S

V or ie o i i a /o l e ’.s pha rmacok ine t i c prol i le has been

characteri zed l o l l ow ing oral and in t ravenous ad-

m i n i s i r a i i < m m di i lerci i ! a m m a l species i n c l u d i n g

m k e , rat.s, g u in e a pigs, r abb i t s , and dogs. FIow-

ever these wi l l no t be ilisctissed in tlii.s article, and

i n te rested readers are tetvrred to the f o l l o w i n g

two relercnces [34, 57], 1 tere w e wi l l instead toe us

o n h u m a n data.

d l i e p h a r m a c o k i n e t i c s ol Y R C have been invest

t igated in more than ?Z2 h e a l t h y vo l u n te e r s ha l

l o w i n g single and m u l t iple-dosc. o ra l (PO) and

ini ravenous (IV) dos ing [80], These studies

s h o v e I \ R f is i a p i d h ab sorbed l o l l iawing oral

ad m i t ds t rat iem, veuh a t ime to max ima l concen tr a

t ion 0 ’1;!i,d o l < 2 hours and a halt due ( t , d o[ a p

p r o x i m a t e 1,}’ b hours. Hue t o s a tu r a t i o n ol m e tab

o l i sm, Y R C exhibi ts non- l i ne ar p h a r m ac o k i n e t i e s ,

7 he b io a v a i l . i b i l i tv ol oral \ R t ( up to ^ i s

better than that ot I T C [SCh F u r t h e r m o r e , t he a b

sorpt ion is not altected b y gastr ic p i I, and hence

antacids, as is die caê w i t h F l 'C eapsides (al

though the n e w e r I I ( ‘ so l u t ion does not sui ter

f rom th is p r o b l e m ) . Subjec ts given V R ( ’ ^00 m g

twice da l le had a C... r ( m a x i m u m co nce n t rat ion

1 d dsug in p lasma! o! 5.2 i n g / b , 1, , , ol 3,2 h, and

\lT< tatea u n d e r the corKtmirai ion-t ime cur\-e) 0 }

40.5 t n g * h / F on d av i I ['Jj. 7 ’he \’o l u m e ol distri-

bu t i i m was 4Ai 1 / k g , i m p h d n g w ide tissue distrt-

bm io i i . The 1. o m entra t i o n o l Y R t in the saliva is

app rox imate ly r>t t hat in plasma, consistent

« i t h a pla.sma p r o t e i n b ind in g ol 5SlX» . I d i e t j : o)

a b o u t <■> b o u t s alter a single d o s e suggests that

tw i ce-dadv d o s m g >s requ i red .

In \itro studies using h u m a n mtcrosomes ha\ e

show n that V R C is metabo l i zed primari l\r by the

hepat ic ev tochi i>me I ’450 iso-en/1-,mes C d P 2 C 19.

Cdi P2< and ( " ) P3.\4, wi th C Y P . l C l ^ be ing the

ma jo r metabo l ic iso-ett/vmc f951. I d im im i l i o n ol

V R C siccurs p r im a r i h ’ via metabo l ic clearance by

the l iver; less 1 han 2,|n is excreted unchanged in

die ur ine or teces. 1 bus e\ tm, about 8C'-w of the

or iginal dose is excreted in the ur ine, and 20% in

the jeees, im p l v i n g that dosage ad jus iments i t n i

be necessar) fe>r ci ther teital or hepat ic failure [3],

O n e p l u r a i , k okme t ie stud}’ in patient s wi th

chron ic hepat ic impa i rmen t c o n t i n u ed ih.it whi le

such pati-nts shou ld receive the no rmal load ing

dose (402 m g o r a d v evet'A 12 l u m r s 0 1 1 dav IS, the

m a i n i e n a n c e dose should be cut in hal l ( to ICO mg

tw ic e dai ly) [93], C o n v e r s e l y , the cquiwdct it ped i

atric 1Y m a i n t e n a n c e dose s h o u l d be 4 m g /kg , in

stead of 3 m g / k g (the adult IV m a i n t e n a n c e dose),

ledlcct i t tg higher rates ol clearance in chi ldren

[102]. Fight metabol i tes of Y R C h a w been eharac-

te r i ?ed C mai>»r and 3 minor ) , t s ing a r tn ge cd

methodo log ies , none ol die m e ta b o l i t e s have been

s h o w n to exhibi t appreciable a n t i i u n g a l activity.

1 l u m a n s t u d i e s s h o w e d th a t ach ie vab le p l a s m a

steadv st.ite ci m c e m r a t K m s { > 2/<g-rnl ) o l Y R C

a l te r P( > and 1Y a d im m ss r a t i o n an- we l l abo\ e its

M I C s l o r (\'autiiclj spp, (0.00 t-C, ^9 / i g / m l ) ,

A sfcy ^ iih if (C.35-03S /eg'did ) ( 1 1 y wocc/.-v th nfor-

ai.r j , ' (C.24 i c ^ /m l ) a nd imsst c m e i ^ i n g n i t coses

|see a bove , a nd al so reierence 53]. H o w e v e r , these

invest igai i ons also revealed tha t t hen* was instable

inter-subject v a r i a l u i i u in C „ . f o l l o w i n g b o t h

24S t - l H i il*l- \ \ It H h ' \ \ l < >1; M F P T C A L RfcSF \ R i " H

o ra l a n d i r u r . u cm his t d m m io , r,ui< >n. Such v.ui-

,1 bi 111 i n C , a l ter < n.il d o s in g im p l i e s d iHerences

in b n u v a i l a h i l i t v and-' o r v o l u m e ol J im n b t u i o n

(Yd ) . A n v v a v h i h i i u v in ( al t er IV d o s in g

o n l y d ue to d i f fe rences hi Yd . 1 he l i n d i t i ” ot

inrer-Mibiect \ a n a b i l u v in \ R ( ’ \I 1C ' m.i\ h r ai-

t r i h u t a b l e to dif t e rem es in t in' a b i l i t y of i n d i v i d u

als to i i i l*iabol i / .e ( A PdCT'^ ' l ib ' l l ra tes (see he l uw ) .

Tissue penetrat ion n u v hi1 an impo r tan t deter

m in an t in cl inical ou teonn . W h o l e b<niv au to ra

d iog raph v was used i< t assess i ho dist n b u i i o n ot

radio, ict iv i ty in (he tissues of rats (both females

and males) alter a single IV adm imst rat ion ol

[u C]-VR<j ,it j Jose level of 10 n t^ /kt ; [57 j. R a d i o

act ivi ty vuts rapid)\ am! extensive!) d is tr ibuted

t h roughou t 1 issues. D r u g concern rat ions were

highest iti l he l iver and adrenal cortex. There were

n o di l lerenees between male and leniale an imals.

Tissue concern rai inii.s ol radioai t i\ity at S m i n

utes post tn lus ion were (ill figeq/i;): 4 . ’ m b lood ,

8.1 in hi .ut i , 13 in eve (retinal, 1C.4 u; kidnev (cor

tex j, 21.1 in l iver, and AX in buui;. The high leveK

in brain and ocular tissue n u y have cl inical im p l i

cations. since ti aditii ' i talf \ i (iese are verv d d t k u h

areas to treat suet. esslullv. In hu t , t in re are n o w

sl veral anecdotal otsc i Lpori s ol stnccs.sful therapy

oi . ly/Yi\;,'/;o, Yo/m/Hio'nw. , and / ; ;v?n.vm intes-

t ions ai these sites {74, X?, '*i j. The high » ( incentra

t ions in l n v r nn\ also have sij;mi n auee in the

t rea tmem ot hepatosp ienk c a n d id i a s i s [5n|.

The toxiut\ oS the c v c h u lex tran \eh idc has

al.so been studied, i n a n i m a l studies us in g repeai-

ed-dosc 1\ SHIT I >, \ acuohitH m ol renal t u b u l a r

epithel ia l cells i n rats a n d dogs ’Acre seen, w h i c h A

c o m m o n in an imals receiving M ihs t i tm e d (YcycIo-

dextrans, H o w e v e r there was no degenerat ion, ne-

crosis, oi' pscudocryM. i l lo rn ta l ion in renal e p i t h e

l ial cells a n d no de ter iur a t nm ot renal iunc t io n

[}]. I n (ittinan \ohuueers (s ingle a n d mu l t ip le dose

studies), t here were n o changes in ur inarv pro te in ,

NAicet vb j jucoseamimdase . and (IT n i i c a tg l obu i i n

l evels, w h i c h w o u l d have i ndicated cllccts on

r a t a l in tegr i ty ’ oi l ena l tu bu l a r sma l l p r o t e i n re

s o r p t i o n . O v e r a l l t h e s tu dn s d o no! s u r e s t ,i p,

t e n t i a l rox ic eitect to the k idnex . It was als> * i< m in t

that SBEC'D is well tolerated ami f a p i d h Ueared

[%]. A i n e n -live perceiu <4 tin i ottipi u m d is re-

na l lv excreted, and the nui«>rh\ i leared w i t h i n n

hrs.

S. D paA i - D r i a ; f\ s i k -a -n, >\s

As d i scussed above . \ BA' p r i m a i d\ i n h i b i t s i he

f u nga l c v r o c h i o m e P 4 5 j < A T 5 A c i i / v o t e l am >stc-

ro! 14-o-deme i l iyhise, preven t i s i " the c o nv e r s i o n

ol l a n o s ie r o l t o ere os ie ro l , and t h u s d i s r up t im,; the

m t e g r i t v an d f u n c t i o n ol t h e funga l cell m e m

brane . H o w e v e r , t he d r u g ( l ike o i l i e r a /o les ) is

b o t h a .substrate an d i n h i b i t o r ol h u m a n

C Y P 2 C 1 9 , C Y P 2 C T and ( A T 3 A 4 . W 'h i l e V R C

has greater atfinit\ ( and hence i n h i b i t i o n p o t e n e v j

for t h e l o r m e r 2 i so-enzvines, n o t a b l ) Us m h d n -

t i o n poteiiL\- against C Y F 3 A 4 ( l i h c l v t he mos t

c l i n i c a l l y s i g n i b c a m e f fect i is , ictn, i l ly lt*NS i h an

K T C a n d 11 (T T i n s is prol«abl\ the mo s i t l inn.al-

J\' r c k w a n t co n s i d e r . n i o n , Mi ne the a / o l e ’s a d m i t }

l o r m a m m a l i a n Cl VI A \ is d ie primar\' basis for

dru;4*dnis4 i n t e r a c ! i o n s w i th o ih e i i V P 3 A - d e p e n

den t c r . m p o u n d s su ch a.s i \ i h » s p o r i t ? J 4 ’ J I In po-

t e n c v o f \ K C ’ in i n h i b i t i n g ( A P3 \4 m e t a b i d i s m

v a r i e s amonu , o t h e r snbst : ate sirups such a>» 11A p r o tease i n l n b i u n s am i im m im o se . p p r c s s . n u s ,

C Y P 2 C 1C( e xh ib i t s gene t i c p<»K m o r p h i s m :

cd C a u c a s i a n s a r t pot»r m e t a b o ! i / e r s ot ( A ’P C T ‘4

snb i t ra tes , w h i l e to : \ m .iii p o p u h i t i o n s t h i s is as

h ig h as 15-2C,,.( [4j . The l i t t e r mu. 1' i t u i i v i dua l s

s h o u l d h . n e h i gh e r YFU ’ l ew Is i han n o r m a l n n -

t a b oh ze rs . A ^ a i n , the v h in c a l s ig tn l n a i u e o i such v a r i a t i o n s is n u c l e a r .

Because ol such c .n i cc tns , t h e a b i l i n o! \ R l t o

i nterac t w i t h o t h e r agen ts has beet? assessed b <h h

in v i t r o a nd in v i v o . D n r j , i n t e r a c t i o n s iud ies d e m

o ns t r a te d tha t \ R ( m a v i n h i b i t t ' Y l A A em /yme s ,

w h i c h iti s om e i ases n i . u tesul t in ch n t s a l l v M g n i b

i cant d ru i ; m i e r v n tioii.s. D r u g - d r u ^ i n t e r a c t i o n s

w i t h o t h e r subst rates id these eti/\ mes , as wel l as

T.il'L' K \ ' a to m,iv, iU vlruj'-dnii; intcr.kiions.

IVn^-.

ei ml rauidfi J ! o i With Y RC '

A s: f i u j / i > ‘ r

F. irbii ur.its ■.( long acting)

Carbaniazepi

Cisapride

P u n e / ;d<

<Ai:i i! Id 11 ]i1

RtlaiujMT1

S, ri’T n i o

Terfenadin. 1*

\ -1 dusc ad j ice merit

u hen \'R( o m

with the I-,eh'wint;

1 eruMitime

1 h ^ n n i

Indinavi r \Lk r. Tdt

a nt j oio ticsfA vise, -■ T ilie

Rani t id ine

Dosend;usi mem of

YRC' lequired

Rifabuu

Cl in iced mui i i ior i i i i i uid. 'o

d<ise a^hiistnKtn rc*|uned

wdu r, g i ’.a-ii with \'R<

A ariarit; Ipr. a h n i i u h i n

i inu-i

n c r T o s p o i ine , i at i s i h n n o

i h h >od !c\els I

S ahm is b i n a ' (i; 1 uci *sci

Siatnw .,C ! ’K i

f ' c i i ^ r . d i a / , pen-s

\lnc.i a l ha l a d ’.

I >i iso ,ul|usi n icu i ( il

\ K l ’ a u d ' ' ( >r i 1 1-aJll iKHMi’trii<ji iic, 5 ( (|un i‘d

i hni'fî ,i/' >h (h,ii( do^

of omeprazo le , no

A ia n i ' c i «t V K C

I T c i n t o m Stin a m o !

p lnan ' . ten les ch' and

ad' io; \ IA 1

-- \ i aa, i ‘ u.i / ( T

M . i v 3 ! . 2222 L k R O i C A N J U U R X M < MI-1 J l CAl Rf S E A R CH .49

e n z y m e - m d u c e r s l ike p b c n v t o i n a nd n h i m p i n .

ha\c been documen ted , and .ire detai led in '[ able I

i 54 J. Aga in , the cl inical impor tance <>i these imer-

, u t i o n s is u nknm v n, ( M - ^ 8 ],C l i n i c a l Y R C drng-drt i g i n te r a c t i o n s have been

e xp lo r ed ex tens ive ly , in i ^ \t ud ies i m l a d i n g ^n5

\'i t l umeers w h er e i nterac t i ons ol V R C and 20

m h e r d n i ^ s were assessed |3j, Based on t hese s tm b

ses. Y R C d rug-drug i n t e r a c t i o n s v\ ere c l ass ined

i m o tin* f o l l o w i n g categor ies; 1} c o n n . l i n dn a d o n

(c.g- r i l a m p i n , w h i c h decreases Y R C exposu re ,

w h i l e YRf . increases t e r i c n a d m e levels) , 2) dose

ad j u s t m e n t u i Y R C or e o n c o m i t a m med ica l ii >ns

(e.g. eotici m u t a n t i he of r i l a b u l i u i e qm r e s i nc reas

i n g t he V R C dose t o 5 m g / k g I V , o r 400 m g o r a l h

e\ crv 12 hours ) , 3) m o n i t o r concern ra t i on s o r el-

lects o] c o n c o m i t a n t m e d i c a t i o n s (e.g. m o n i t o r

p r o t h r o m b i n t u n e w i t h w a t t a n n ) , a n d 4) n o ad

just m e n i i n q u i r e d (i\g, d ig ox i n ) .

Because cl the i in ' idencf ol fungal i n fe c t i ou s ni

pa t i en t s u n d e r p i n , ; h e m a t o g e n o u s a n d sol i d

org an t r a n sp la n t s . i n t e r a u n m s oi \ R C wi th t.om-

m o n l v used t r ansp lan t ruedic.u i on s is ol par t icular

interest, S o m e drugs do not i cqu i r t dosage adjus t

ments, tm h i d i n g p i e dn i v » h> ne ( Y R k increases its

A l , C i n 13-34".i) |3|] and m v e o p h e n o l a t e molc-

t i le [110], C o n c o m i t a n t \’R C a d m i n i s t r a t i o n i n

creases c\ c l o ^ p o r i n A and tac ro l imus exp osur e

(•\l/Cs useceasing I n I T and 3.2 told, respect iw-

l y j , requi r ing close m o n i t o r i n g ol dt ug levels and

probab le dose reduct ion j 38 t i l } , S i ro l imus is

i o n t r a u u l i c a t f d because vor iconazo le increases its

C\. ails.! A L A ‘ In- 55CY and l ,C14‘'.i res pec tn ci v

1,3]-

lK F O R M l ' l . A T H >\S, R O f IT O F

A l > M I X is i n \Th ' X \ X D D t )S,\GF

V o r i c o n a z o l e is ava i l ab le as tab let s (50 m g o r 200

nit:) o i IV p r e p a r a t i o n . T h e I V h e m u l a t i o n is a

K o p h i l e c o n t a i n i n g 2 DC me, Y R C w i t h 32CC m g

S R l ’ C D , a n d is r e cons t i t u te d in steri le wa ter . 1 he

IV f o r m u l a t i o n is s table in i l ie p resence o f wa te r ,

si .-dium ch l o r i d e , s o d i u m I n dt o x v c a r b o na t e , pcp-

t i de, r i n ger s ’ l ac tate , D-,. a n d D ;_ so lu t i o n ' . [3].

D o s i n g s t ra tcgv calls tor a lo ad i ng (first 24

hours) and a m a i n t e n a n c e (alter first 24 hou rs )

dust r e g im e n . This dosing; regimen targets i l ie

m a x i m u m to l e r a te d dose and p r o v i d e s p lasma

concern i anuns above i h e M I C f o r c o m m o n luti-

gal pa thogens, O r a l dos i ng r e c o m m e n d a t i o n s

varv a u o r d i n g to t h e pa t i en t ’s b o d v weight , I ;o r

pat ients w e i g h i n g less than 4C kg, the l o a d i n g

dose consists ot tw o doses of 2DO m g separated In

12-hour interval o n first day , whi l e the m a i n t e

n a n ce dose i-. ICC m g e v e n 12 hours, b 1 r pat ients

w h o a:v g n u i e r than 42 kg. the load in g and main-

ienance doses shou ld be 40C m g and 20C mi ;, re

spect ively. The l oad ing dose l o r V R C in t ravenous

a d m i n i s t rat i o n consists ot tw o doses of 6 m g / k g

12 hours apart , b i l lowed In a ma i n tenance dose

ol 3 m g / k g every 12 hou rs (for serious Cd/idu'ui

i n !e c t i on s /emp i r ic mvcoses therapy) or 4 m g / k g

i s tTv 12 hou rs (for 1A < Scedo<noi•'mm and

F t'S j^nw : i n S e a i o n s . 0 1 o t h e r ser ious m o u l d mlee-

ttons). Ii is po ss ib le to increase t h e m a i n t e n a n c e

doses ( to 4 m g / k g every 12 ho u r s , IV; 300 m g q 12

hours ( pa t i en ts > 4 0 kg); or S50 m g *]12 hours

(pat ients < 4 2 kg')], in wises v here i nadequate p a

t ient response occurs. If p a t i c m s art enab le to t o l

e rate the h igher doses, then increment . i l dose re

d u c t i o n s (1 m g / k g I V. 50 n ig I ’O ) to the or iginal

dose a ie r e c o m m e n d e d .

10, C l i n i c a l E f f c a c y

The cl inical e i i i c a n of VR(_ ior the Heatmei i t «>!

f A, C .m diti.t infect urns, and those caused In

An do^pofntm and Ftisiuntm was assessed ttt Phase

[ l / I I l cl inical trials [2, 22. 51 j, Addi t iona l ly , VRC,

was recenth' comparc i ! w i t h l iposomal A m B lor

empi r ic a m d u n g a l t reatment ol pat ients wi th kb-

rite neutropen ia despite appropr ia te an t ib io t ic

t i terapv [ 1 ;5], Patient popu la t ions studied have in-

, h u l f d those w i t h bone m a r r o w and solid < ugan

irai tsplants, hematogenous tna i ignan i i i s, Hl\3'

Af f )S , ch ron i c gr anuJomatous disease, and o ther

im m um . ie om prom is ed states.

D e n n n i g et ah [ 2 I j c o n d u i t e d an e l i t cacv and

saieU s tudy ol \’R t in I \ in an open , non-com

par .u iv c m u l t i cen te r s ludy ot 1 In patients, For t

o n e percent had p r o v e n 1A, whi le the rest had

probab le disease. V o i a o n a ? o ! e dos ing 'A as as d e

scr ibed abo\ e, anei t he drug was g iven as p r im a ry

therapy in n0 pat ients (52%) , O v e r a l l response

rates were 11, 54, anil 2L% tor c o m p l e t e , part ial ,

and stable responses, respect ive]\. T h i r i v one pe r

cent o f the i n f e c t i o u s fai led to respond to V R C

therapy. W h e n V R C was used as p r i m a n th e r a p y ,

the response rates v.ere 17, 42, and 18 % — equa l to

or bet te i than that prev ious ly noted for A m B in

1A, X o t a b h , ‘"good” responses (de f i ned as c o m

plete or part ial im p rovem en t ) occurred in 6 0 % ot

p u l m o n a r y or t racheobronch i a l disease (n = 84),

bTn w i th b ra i n I A (n - i ' C VKk, ot those wi th he

m a t o l o g i c disorders, and 2 n % ol a l l ogene ic s tem

cel! transplant recipients. The authors c o n c l u d e d

thai V R C js cU ieac ious in t rea t ing a e u u I \, and

most so when used as p r i m a r y the rap ) . Readers

are encouraged to read t he excel lent discussion

pro\ id ed in she paper,

A simi lar , smal ler, open-labeled s l u d v ol the ef

f icacy and i o l e ra b i l i t c ot ora! \ R C {2ZZ m g tvrice

d a i h ) tor (he t rea tment o f i h r o n i c IA was c o n

du c te d in 25 n u n - n e u t r o p e n i c pat ients 124], O n e

quar ter of 1 he patients had A I D S an d 1/2 received

V R C as salvage t b e r a p v . l i a v m g tai led 1’1 C or

YmB . T h e tn a i o r i t v ot patterns had c h r o n i c p u l

m o n a r y aspergillosis. A t i n t e r i m analysts , 53% oi

the eva lu ab l e pat ients (n = 1^) had a response (2

complete, 5 part ial , 3 stable!

A d d i t i o n a l l y , there have been a n u m b e r of en

courag i ng sma l l e r studies and case report s. These

im h id e studies o f V R C t rea tment o i resistant or

rare i u n ga l p a t h o g e n s [44. 5Cj, \ R C as salvage

t h e r a p v ot 1A [81], use as t rea tment m ch i l d r e n

wi th invas ive ftmgal disease , successful therapy

lot C N S aspergillosis (23, 44, n2, n3], disseminated

f V R O f M ' - W It H R \ \1 i M' M l i Hi \ ! R i M \ R ( I I

aspergi l losis in chron ic gramdoma t f ms disease and

disseminated ScL'tio.woria/n jpinspcânn,’ jHcschvria hoy tiii] in a cancer pal it tit (4'],

Cl iructans shou ld hi* m a r c ) hat Pf i /er m a im ains

an ongo in g compass ionate use prog ian t .

The above studies suggest Y R ( is .in effective

o p t i o n ior the treatment of am te a n d c h r o n i c as

perg i l los i s , as well as o ther p r o b i e m a t t c f u ng a l i n

fections, w i t h response rares c o m p a r a b l e u r . super

i o r to i r a d i n o n a l t hr rapv , I n st.nie cases (e.g. cere

b ra l disease}, Y R C m . n fil ler a un ique t rea tment

o p t i o n . Because of these results, Phase HI m u l t n

center c o m p a r a t i v e tr ials have been un d e r t a k e n .

T h i e e large phase I I I trials have c o n f i r m e d

V R C s status as a useful a n t d u u g a l d ru g . The first

was a mu l t i-cen t er , r a n d o m i z e d , placeb< i-run-

t r o l l e d , d o u b l e - b l i n d e d ( o n i p a r i s o n w i t h bd .C as

t r e a tm e n t i o r esophageal cand i d i a s i s in i m m u n o

c o m p r o m i s e d pat ients [2]. Both arms showed s im

i l ar e f i i caev and t o l e r a b d i l v. Primary elftcacv

ana lys is ol esophagea l l r e a tm e n t , as assessed I n es-

o p h a g o s e o p v , revealed success rates (cure o r i m

pr ovemen t ) o i 9 S. 3 % and 95.1 % w i t h Y R ( and

F L C , respec t i vely . There was no s ign i f i c an t d i f lei -

etiec b e t w e e n the tw o a m i f un gals, Based o n these

f i n d i n g s the authors e o n e l u d i d that V R t 2 at 230

m g twice da i l y , is at least as el feet i\ e as F I .<2 in

t he t r e a t m e m ol b io ps x -p ro ven esophageal c a n d i

d iasis in i m m u n o c o m p r o m i s e d patients.

The second Phase III t l imcal trial comp le ic d

eva lua t ing Y R C efficacy was a miahi center, < -pen

label r a n d o n u / e d compa r ison wi th -\mP» lor i he

p r im a ry thesapy o l IA [51]. Th iee hundred and

n inety-two pati t nts were enrol led over a vyear

per iod . Pat ients w ere r andom i zed in tveeb e \mR

I m g / k g / d a y in t r avenous ly vs. Y R C h m g / k g

even- 12 h r ior tw o doses t«i Slowed hv -I m g / k g

e v e n 12 hr, and then 2C3 m g orai lv twice dai ly ii

desired. Af te r mitta! r a ndom t / ed thef. ip\. phvsi-

eians had the op t i o n to change the 11 eat tnem to

any l icensed am i funga ! therapv ior IA l l i p id ur

non-l tpid A m B oi I 1’*'). At ',\iek I 1 52,K"., ot p a

t ients treated in i t i a l ly w i t h \ RC, had a comple t e

or part ial response, vs. Î . iVC o! pat ients treated

i u i n a l h wi th An iB (€? t d for t he d i l l e r em e •-

32,9 to IC.4*%»J. S u n n a! of patients receiving Y R ( "

was 70.8"-. vs. 57'.1)'’.. l or A m B fHaz. ird Ra t io =

1.59, w i t h sHA. Cf of ZAZ - C.KH). The ini t ial ther

apy was con t i n ued for a med ian ol 7^ dial's m pa

t ients on Y R C vs. i i da\ s in those on A mi l , w i t h

satisfactory en dp emu o m c o mc-s in 5 3 . o| \ RC-

treated pat ients vs. 2 ! . S <’«* of AmB-t tcated patients

(TÂi C I lor di fference --- *!2,n to d l . C w , 7 he

au thors conc luded t li at \ R l is snore id feci b e

thati A m B for IA, result m g in u n p n wed patient

s u rv jva i .The th i rd Phase III cl inical trial tondt ic ied w as

an in ternat iona l mult i-center, randt un i /ed , opets-

label stuck' com pa r in g Y R C wi th l iposomal A m B

(amRisome) ten' empir ic au t i funga l therapy in p a

t ients w i t h n eu t t o pe m a and persistent te\er de

spite appropria te an t ib io t i r iherap\ ' IG ^ ]. A total

of 837 pat ients were e\ aluated ' I ! assigned to

Y R C and 422 to l iposomal A m B ) lor treatment

success, f’be ( i\ e r a II success rate ( a c co r d i ng to a

c o m p o s i t e si. o re ! was 2b ’A and 3C'.f>l'o f o r Those re

d o i n g \ R( and amB isume . respect tvc-bc. T he

c ; nnp os i t e score etu <mip. issed the fo l l ow mg : treat

ment was eo t iode i ed successful if pat ients d i d ran

have a break th rough fungal infect ion , s u tv i v e d tor

da\s b e n m d the t’tul of therapy, d u l not d i s con

t inue therapy p r e m a t u r e l y , had reso lut ion o! .’ever

d u n n g the pern>d <d neutropenia , a nd *.\ere suc

cess ltd lv treated ft»r a n v base-l ine funga l i n fect ion.

A m o n g the J o e compin ien ts in, the compos i te

score, t he o i t l v s igmf l ean t difleta'iiae l o u n d was in

the f requence ed b r e a k t h r o u g h l u n g a l infect ions,

d 'here were fewer b r e a k i h r o u g h i n fe c t i o n s in the

\ Rc ’ arm compa red to the A m B arm (1.9 w .

5.0".;.. respectively), w i t h the largest d i f f e re nce in

,-b/ier(t>/77//5 itdett tons {-? v->. H patients, respecti^'e-

h' j . Based on these f i n d in g s , the au thors c o n c l u d

ed that Y R C is a suit able al ternat ive to A m B prep

arat ions tor empir ica l a n t i l u n g a l therapy in p a

tients wi th neutropen ia and persi s ten t fever.

NX bite a m o r e tietailed ana lyse of the article is be-

\ oitd t lie scope ol this review, it shou l d be noted

the F D A has exp iessed reserva t i ons regarding the

use of Y R C h>r this i n d i c a t i o n , at least in part due

to t he we igh t ed smeess rates based o n ini t ial p a

tient s t i a t i l i e a t i o n {risk of fungal infect ion , +

aru i fu t tga l p ta>phylaxis , a nd dnrattott of neu trope-

nia}, wh ich was not p u sen ted in the final article ,

I’he au thors urge interested readers to careful ly

read the or iginal paper, the blk\ response, and

the accom pany i ng editorial [66],

1 hi a hove M tidies indicate that V R C is l ikelv at

least as ef fk ,n ions, and tit some cases more so,

than t rad it ional therapies for serious fungal infec

t ious caused in- a wirteiy of organ isms. W he the r

this is also th i case for t rea tment o f febri le n eu t r o

penia seems l ikely, but has yet to be fu l lv deter

m ined ;Olij. Nonetheless , gt\'cn ihe -.uperiortr.- cd

l\” l l C ,md l iposomal A m B [12^, 12(>j to conven-

t nmal Am i ) , l he addit ion of \’R ( to the antitun-

gal annan te n t .m m m tttav spell the end of coin-en-

t nma l A m B use in set n ms mte i t io i t s .

I I . S \ f f A \M • 1 o ! I K \P.11 !'IA

T h e sjfepv atul t o le rab i l i t s ot \'RC was assessed in

bo th healths volunteers and pat ients enro l led in

cl inical i rials. In gem-ral , t hesc 'tu-Jies revealed

that Y R C ha> ,u\cpiable t o l e r a b d t f i . d'he chief

ads’erse effects observed inc luded t ransient visual

d is t u r b ane e , hepa io tox i c i tv , and skin reactions,

r h e m o s t t icquctH ulverse drug react ion is visa-

al dnstui 'bant e, described as enhanced l ight pereep-

i ion, b lurred v i s io n , ph o t i . p hob ia , vr Ck'har visiein

changes, d ’iuse \ isual ev t t i l s ocenn' t ’d in 23A.-35'’m

of pat ients (3 j, general!} occur ear ly (w i t h i n 32

minutes nf dosing! , a n d mos t f requent ly d u r i n g

the first week of t h e r a p v |2^“v. of pa t i ents) , ’[“he

majon;\ of these events v ere m i l d a n d resolve

w i th in 'C m i n u t e s . M o r e o v e r , w h i l e f u n c t i o n a l

visual changes are revers ible after d i s c o n t i n u a t i o n

■ d \ R i i h e ’‘ap\, s v m p t om s gene ra l h ' resolve even

if treatment is c<m in u t e d [2j. lit cl inical trials, vis-

M n t*1, 2 FI l i t J l 'FAN j< >( ' K \ M. OP M h D K . AI KHSEARC 'I I

i n] changes ra re ly necessi tate d i s c o n t i n u a t i o n ol

the d r a g [21, 24, Fh\ r o j r e n n o g r a p f n {b R G }

has s h o w n ( In' re t i na to be th e mu- ot t h e s e el leets ,

w i t h decreased a m p l i t u d e ot F . R C w a v e l n r m s m

h u m a n s a nd dogs [9h|. Six a n d ! 2 - m o n th doj ; s tu d

ies s i i (m cd i li.it n o ' U u crura l a l t e ra t i o n s in the

i c i i n a n r v i sual p a t h w a y s occu r as a result ot \'RC

a d m i n i s t r a t i o n . N o h u m a n h i s m p a t h o l o g v has

been J * m u d , a n d o cu l a r h i o m i c r o s c tpv has not de

tected i i cu l a r lesions,

H e p a t o t o v i e i t v o t Y R C was assessed in Phase

I I I c l i n i ca l i r ials [2, 51, i 05] b v m o n i t o r i n g l ive r

I n n c t i o n test ( L F T ! a b n o t ma i n ie s , i n c l u d i n g e l eva

t i o n s in s e r u m a l a n i n e t r . u isaminse ( A L T ). asp.tr-

ta tc am i n o t ra n s fe r a se . a l k a l i n e p h osp ha ta s e and

b i l i r u b i n levels. These s tudies s h o w e d that f . FT

a b n o r m a l i t i e s m i g h t be associated w i t h h igher

p l a sm a co nce t t i r a t to n s a n d / o r d>>scs o| A R C ,

T w e l v e and 2 ! “>» ot subjects h a d a b n o r m a l

a n d t o t a l b i l i r u b i n l evels, respei i i v e h . Tl ie m a j o r

i t y t«t a b n o r m a l F FTs resolved d u r i n g treat m e m

wi t h u n t dose a d j u s t m e n t <>r t ‘>l1o\v m g dose adjust-

m e n f . b u l in s o m e cases o c cu r r e d a t i e r dt-.com inu-

a t ioi i o f t h e r a p y . I n east's w h e r e d i s c o n t i m u u ion

i >1 Y R C is necessary, e leva t i ons in L F T s w i l l l i k e

ly be i h e chief cause [21, 24. r>7 ] I l o w e v e r ii is i m

p o r t a n t to i i d i e i h a i t here R a s im i l a r t requencv o!

adverse hepa t i c even ts t o r V R C and A m R lorrnu-

l a i i ons . I n co n t ra s t , he pa t i c adverse el lects oc

c u r re d at a grea ter f r e q ue n cy in \ R C t h a n F L C

t reated pa t i en ts . S ince Y R C h a - been i n f r e q u e n t l y

associated w i t h ser ious hepa t i c t o x i c i t y in pa t i en ts

wi t h o th e r sub s t an t i a l under l y i ng ; e o n d i t i o n s , p a

t i en ts w h o d e v e l o p e l e v a u d L F T s d u r i n g 1 h e i a p y

wi t h t he a n t i l u n g a l s h o u l d be c lose ly m o n i t o r e d ,

and d t s c o n l i u u a t i o n ol Y R C co n s i d e r e d it c l i n i ca l

st^ns a n d s y m p t o m s c msts ient w i i h l i ve r disease

dev eh ;p that n ia v be alt r i bu f . i b l e i n t he d ray .

T w o t vnes of adeerse sk in react u ms haw. been

n o t e d w i i n Y R C a d m i i m t r a t i o u d u r i n g p r e-ma r

ket ing, s tudies: rash a n d p h o t o s e n s i t i v i t y . Rashes

nou-d as a resul l <>1 Y R ( , m c l u d e ; facial and gener-

a i i / e d e r y t h e m a , e x a m h e m , a n d d e r m a t i t i s ( i n

c l u d i n g I ease ol psori as i s w i t h e o s in o ph i l i a } ;

there have been several cases ol er\ t h e m a mu l t i -

f o r m e a n d non- ia ta l S t ev en s- Johu son s y n d r o m e .

F r i a n h t o 25"';. o l pa t i en ts o n \ R C exp e r ie n ce d

s om e t o r m o l i ash, w i t h an i n c i d e n c e si m i l tr t o

t ha t o bse rv ed t o r A t n B i o r m u l a i i o n s (e.g. 2 3 %

and 2 5 % l o r Y R C a m i l i p o s o m a l A t n B , respec-

l i v e h t [3j. Ii is i m p o r t a n t to> n o t e th a t tn Phase I I

c l i n i ca l t r ia l s i n v o l v i n g 217! pa t i e n ts ( i n c l u d i n g

1A5 H F V + pa t i en ts , w h o are at h i g h e r r isk o l

d r u g rashes) , o n l y 1 w i t h d r e w I r o m t r e a t m e n t

d u e to an adverse sk in r ea c t i on I ’ I, 24, j. T h e

i n c i de nee oi rash appears c o m p a r a b l e w i t h that ot

F I C [ 2 ] , P h o t o s e n s i t i v i t y o c c u r r e d ai a m u c h

k iw er l evel that) rash (b e tw ee n 1 -2 % ) , ,u i d was

m o r e f r e q u e n t l y obs e rv ed m pa t i e n ts receiving:

g reater t h a n 12 c o nse cu t i v e w e e ks o t \’R k t h e r a

p y | 3 1- S ince ph o t o s e n s i t ivi tv o c c u r r e d o n 1 it^hr-

exposed areas ol the s k in , it is r e c o m m e n d e d i h a t

pa t i en ts a vo id stt o n g s u n l i g h t w h e n t a k i n g \ R C ,

as we l l as t a k i n g o t h e r a p p r o p r i a t e m e a s m es (m-

C u d i n g tile use oi sunscreen and , ipp topr i .de

c l o t h i n g ) .

A n o t h e r area ot p o t e n t i a l side effects is card iae,

p a r t i c u l a r b a r r h y i h m i as. O t h e r a? ales have been

im p l i c a t e d in l o n g Q T s y n d r o m e s . p a r t i c u l a r l y

K T C , t h r o u g h its i n h i b i t i o n o i t he hepa t i c

t Y P 3 A 4 i so-en zvnu [71’ , fit stud ies e < m i p a n n g

Y R C w i t h KT'C , t he f o r m e r s h o w e d m i n i m a !

changes in t h e cor rec ted C?T i n t e rv a l ( Q T c ) , w i t h

n o pa t i e n ts h a v i n g Q T c i ncreases greater t h a n h Z

ni sec [3), f 'here appears to be n o increase m Q C

changes desp i te i nc reas ing d r u g doses, fit pre-ehui-

eal tr ials, t here has been o n e ep i sode ol s udden

s ardtae dea th a l t er Y R C i n f u s i o n , W h i l e the s p o n

sor c o u l d not exc lude the c o r n n b u t i on ol \ R t J |i(

t h is even t , it is we»rth in . ' t ing t h a t t he pa t i e n t had

p r e v i o u s d i l a te d eardh unv < n v n l n a n d a r r h y t h m i a s

Hke lv d ue to i d a r u b i c i n t h e r a p t . In s u t n m a r v ,

w h i l e Y R C does not appear to cause s t ^n i i i can t

changes in Q T c , d ue to th e d rug ' s ei ieets o n l he

( Y P 3 A4 lso-en'/vm-', it w o u l d l i k e l v be p r u d e n t

t n a v o i d c o - a d m i n s s i e n n g o t h e r d rug s ie.i;. astemi-

/ o l e a n d cisapr ide? w h i c h h.tv i- t h e p o i e n u a l to

cause Q T p r o l o n g a t i o n .

Id nai l v. azoles have been shown fn be teraio-

Ueni-c iu an ima l studies In ra ts , h igh doses oi \'R(

fnC mg-'dsg/davl q,ave i hi■ivrel.ited tera fogemei ty ,

and there may be effects at b iwer dose levels.

Un t i l more in f o rm a t i o n is avai lable, when given

Y R C , w o m e n ot ch i ldbear ing po ien i i a l T u m i d use

comraeept ion ; pregnant we,men shou l d on lv be

admin istered the drug it the benefi ts clearly o u t

we igh the risks [3],

12. G >\ci rsn >\a

It is clear that we are enter ing a new era in amdun-

gal therapv . The uisl itv ol t rnwoie agents is on l v

liosv besom ing ful ly apparent , w n h the t'\iensum

o! thei r a c t iv nv to a broad spec i rum oi oiganisins,

as well as fungicidal activity against moulds, as evi

denced b\ \’ K C . Ir, the case of \ R C . in vi tro activ •

n v clearlv extends to in v ivo elhcacy , m boils an i

mals and man . Y o r i eona /o ie shows part icular

promise m treat ing iesssiant candidiasis and i n v a

sive aspergillosis as well as Scrdo^poriii’n and

J'/h'.o hi,-if infect ion v In this ode, tt exhibi ts less

t ox i c in ihan c o m e n t i o n a l agt nts, wdth potettt ial lv

more et l icacv . in tpor t an t l v , ii also oi lers a un ique

hope in the therapy of prev i o u s l e un treat able in-

ti-ciions, for example, invasive ( i 'NS aspcii;i l!osis.

R 1* I ' t 'RLNf TS

I Abranam O C , athu l; K, t 'i s r r t !o j I ,

0 h a u d o o v k a r !J11 i f n v ,•, ■, sii'-ci p u h d u jcs < <!

Asperg il l to spat ivs u • x ni n i ,n,i/, ilr, it r.to -h i/< -ie. and

a m p h m e i i e i n B. I >ia^n M i e n T n <! Infect f hs 33: 7-1 ’

2. A He R. Sc l iu rn ru ; n D , Krwsel VX‘, t ,.i rnsi ( i,

A g u i r re l ie n ô a K, D u p o n t H. H u d ’ fs \1. 1 roke P,

R o n i e v A j (2221! A r,md> m e /e d . A u iM r-b lnn i .

d o ub le d u m n iw (nultict-inei o u i n! vor icona/nk-

and f i iu 'onazi>!e ni d ie treatriu-nt o i es* >phaftval tan

d i si i a s i s ui H iu?u ir . i 'eomp! ‘(>n!OL\i pat n-n: s, C I A

Infect D is 33: 1.447-1454

252 I1 l rRs 1PFAM J O F .K N A L O F M E D IC .A I R F S F A R i H Mn 31, 2C'C2

3. B.i i ldou R , I’ .itH'im m 1'. !»■ itK IaT I d W , T i e n u n R , 1?

Pov, e rs j 11 (2C011 NI>\ 21 2hh, Y te n d (vo r icona

zole! T abU’is. and N 1 ' A 2 1-2o~, Vdend 1,\: . <\'t >ri-

•]>,•) ii»r m hi si o n . H i / a ( d o K d Research and

D e r e k < p n ic m , l l i i •)'!iSv’i 1 t<>r i lu ' irc . it im 'i i t ot invj-

sive aspergillosis, st- r j * > li (. and ida m lc c t io n s , iuh?c-

t ions .M in i 'J In- Si e d o s p o n u m *>pp. and P i is j r iu m 18

jp p . . iM!r and t el t actor x m k ‘i J :o n s ,md ei5ipiric.il

t i e . m u n i ■ ■! I fh r ik ' m tit fope iua , L'S F D A .

l i t ! p: ' ■ v. n w . J d, i ,e,o v 1 <-d i : in s ■ d m ke i s .1 , - 2 F' -

slides, ' > 2 s J .ht in \i i r 'v d,iu\ >12-0212

I. P<ali.,u j l >. S i d d e u ,( \ , I Ian is J W , ! K- a i'U j , Pickle

t , < 1 1 <ld\i cin j \, \\ < i . R i . I i'u k h a n I >A I

The n\ i i ."<\ \ k.t it >n i.l o m e p ra /- »!'• M'j ie kites « d h S-

i m p h e m nn m e :a bo i ism : > p< ip i ikum n s t t n n . s.Tin

P h a n n a u d Pher nhl-ht-M

y, I k m iucsi F, Res;repo M, \1< (<> t i^ h 1 FA. R in a ld i M C

( H ‘F>) In vi! !'• i .u'ts\ i' \ ol a nrw , in i ihm i; .d i n a z n lc :

F‘ R-P211, 2‘^> I’ rt>” r,un and absi rau s nt the ' 5 t h 22.

Inre i m u*tu i' i i inference on \m im k rob ia i Agents

and ( d ie inot h e t . i p s . A h Mr p 1 M . W ash ing ir«n . I ) . (2.. 21.

Amen>. .m S i i i i t lY Ii ir \1 it n >bto|i igv

ft. B a r n A I , Fin >\vn SI* ( P ' 'Fd In v im > si udies ot tw o

fr ia/.o le anulune , .d agents ( v o r k in t a /o le [U K - lO F

41?!'] and l lm o n , i / i de) against C a n d id a spt-ues,

A n t im i c m b Aêit is ( h e m o i hei 40; 1

7. Bai i n i i i J. T n rn i i i 1’ , A l p i c r o XI, P>oncoutpU‘ F.,

V e tn v t M L , ( kit t. ta- RaFund l J, F w a J (19^5) Svn-

iI icms and ,mt ihm ea ! a>.11 \ i u ol new a/<de d e rn a- 22.

m Os o m l .u n in i ; an \-,n lm< >rphobue rutj; } M r d

F h em ?H. i'M X-V)i2

.S P. i\ast t . [• s,iit i R , Sana'.i f {, ( d h a n n o u m

M {19^’’ ) \'oi'n i in . i/u lc (F K-! i nhi bi t s t he

*ri i <v.-(h andi alu-rs llii; m m phi T i ^ v ol i iu rr ir ia /ok- 23.

vaMcjmbh- and -:'i‘s;N(ai!l C a n d id a sprcic^. Anti-

m uT ' 'h ’ V ^ i i i h ( h i m i >!Ih t 4 1 ■ 1^42-1842

s1. B iu n im c ! j i . Y a n u v n d i S, S c H i n im H . R o m e r n A

(2 2 2 11 rd ia^m an 'k i iH ' tu 's iPK ) and s.uct^" r/l n n !

vi trit'i 'iia/t ik \ X i in pa! na il \ j ; risk fung.d int»ac- 24.

I ii ins: a duM' t-M da! ;i m s fudv. In Prngr .un in d

A l ’>'i!i .n iv, 4 I !a. A nnua l In'uTvicrKT- ( u ii t i ’ rcnce rifi

Ai i t in iHTchhi ! A'^rnls a nd < hami'al iir-rapy A b ’-rr.* A-1 S < Jih*a;<( •, A iiisa umii SiH ii ! v i n 5- M ie n ih io H p -

F2. Buds-', i 1 { P |l)2) \>'< iv , im i !u in ;a l , ^ r n i v C’Jin Irh-ft

I )i 14; S l i . i-SJ ia i

I I . Bi m \-1, \Fit'tU‘Us j |20CF1 ( d in i f . i i exper in ice

w i i l i ii••.U’una/.ult' in s\ su-mu fin ica l i i i fectiuns. 23.

I h UC.S (1 1 Supp l I ; 5V-4'

12. Brumr i HT !\, K an i f i K, M i v a j i M (1 V'.J8) A n t i -r r\ 'psiu nr r a l . n i i v i i v nl \->iri iama/uU' a^ j insrC rv’putc?KVti\ rit-olurni.nis car. ^.uii vs var . nendor- 2b. mans ; L'ornparisuri wi i i l t h i r n i i a / n l f ami rlti-rf of h u m a n M'runi. M\a o p . u hi ' l o^ i a M 2 : 3 -?

H . B runm it ' r F, R a n u i K. W iw i i i M ( P^.)8) D am ag e tti

\ rjsi fells ni ( d*\'pi 1 h <n ui*. iicnftfrni.Hi^ by x oricon-

a?>de and Hih > iii.i/i ilt-; a cult im- and iDu.ruseopic 27.

'■Hid} . M ed M v l ( sl 3ft; 227-2 ’ 3

i 4, td ir i It d';e j i 5 Midi;ie\ j . l i .w / a r d B'2 ! i ‘Is*7 ) C a n d i

da C i i n u all v ml;i i i I ii ail! a / id t cr^ss-resisiatu'e in

C i is d id a i ’.i dales I ft >in >si[ ;ve p a t i>• nls w i t h 28

* >r.d eamiiditsi;,. A.SI'S i j i s ' h SK4-1

H. ( h a i r / M, Pit! n .il S, \7dvi-rde (3ui ierrez MJ . Q u u k P " . (>, \Li/ tie 111' F M l:i-’,-iu'i> a d iv i tv »>'.

'.•M'reoriai'i T* (I K -1 2l*.4‘?ht, L ’i '>C^3lih u:d r.e her

antip.iii;j,al ays i l l s a-jaitisl . era! t and ida spp. isolatr s I ' -) ,

iri!«n f 1 fV 'H i le i le d j-j.i i ;e ! ! is | -Xfuiirieriah Cheniri-

! i icr 44; <-l^- 'C 2

P.. ( d a s h ’, ( j , \ ;.;inrt t) [ >X I P ' ' !M| fn vit n ’. etficae v and 32.

tum;ie ida1 aeti\ u i d v< >i i. <>n i,:ide against Asper-

u,d1us ind f-usariuni sptx ies. F u r j ( .lui M ie n -hejl

in leei Id-, 17: ' -r./^

Cuenc.i-F\irella .VI, K od t i i ;ue / T u d d a |I . M e l lado

E, KLirtine/-Sit.ire/ J\ , M o n / o n \ t p»l>K) C o in p a i i-

snn o l 1 lie iu-\ m > » .u l iv i( \ til w n ii < >n a /o le ( I K-

iC9,4 'ib), n saei m a / i >ie and ampli> tiorii in P> aâi nst

tdmieal is-d.iies of A sperg il lus !iunit; .n us. j

A i i u i i i i e t ' ib C h e m n ; her 42; ’A] ^3 •-

Fueuea- H s i ie i l i Ni, R u t / 1 >u / IF \ F in i iuv S ;:. n >j/

J \ , M o j i /o m A s J R o d r iu a e / i udela j L ■ ] C uni-

j i .u v im e in-\Hui 1 1 \ ? \ n \ , e i i n e H M / n l , ' (F K

J ! and sj\ m i n t a n ! i lu n ^ .d ap :n i ■> aâins". eiin-

K.d lsi dates oj *si ei.ii opi ir iuu i i >h! u’ans and

tCrd- ‘spi a m m apiospei m u m J An; isiih o d ’ F heir.L--

lh ri P I 1 * ’ <

Je Sevau.\ R< j, k n l l i u i ^ I*|, \'err' ,e ;d ’Fi. \aii d.e \es

j A. M ias j h , v >n dv; Mee; j\\ i j 3‘5S * M a fo -

^raiJiik 'in i'o <us a\pci t;ill> ns a pat ient v\ n i l i In oii-

se granuk in.ii I uis diM ase1 i m e w ;ih \ i >; u on .t /o le .

c 1m I n C i i I ds 2f>: W f ,

Derm me I )\K i F ii!<4 I hierape'.a ii i . u u n m e in in v a

sive aspt,r^daims. C l m In te i t H is 2 v h i i

D e n t in i i ; t)\X , del P a êo . A, ( d m l\inan P., \ or folk

I ) , R id i i i k e M , ' l o i i i m S, P io h r P, Saram is \

{LLA*5) 11K-1 dêP^t, a iurt'<4, v uie spec i n mi c r i , i/o le

d e ru at n e loj d ie 11 eai men! i>! l im â l in leU n u is ;

e h n t ia ! eliieaes in . l u i i r n n a s is e asperi;dli>ms. i5 ih

In!erst le iu t ‘ io ide i e iu e on A m inueta ibiai Agents

anti < h e n io ib e r a jn , Abs ir . f-'-NO, S.in Francisco.

\ menran Soeu-H !>ir \1 it robioiop^-

Dennn ip , f>\\. K d ' .m d P, \!dpied N. (. a i l lo i FF

Herbrechr R , I hie! b , I Fi.c. A, R u lu ik e M . I ■ nle FI

(2CC2) I and sale!\ :P icona '/ ide m ihie

i t . atiiie'V, oi acute im a .i\ e asjierîl losis. « d m bik-ct

DiS I; •’ (i i-A-7 |D e n n m *4 I )\\ . \ i u k Uesv. aric> k , i )akk i R F,

■\ndei'soii \tj, M .nm ny4 \ J. Ste\ eiis I>\, \\ -.rni ad;

DWA K ; lie Si '. F F ^ j pt r\H Hii.i/i d< >‘i si si a nee m

AspLT^dlus l inm ^ .u i is . \n»iimi'’ ob \t;en*s (2tiensi>-

; hei 41 :1 m>4-1 ?hH

D a p i int B, I F i isdni; 1 >\\ . 1 a nk 1 I. d on ren 5. T roke

P, Sara m is X S k 4 CF A»«,, a tn i\'ek wide-

spi c m n n i n a / n l i d i i n . i i i u 1 ' o ’- she t rea: m e m of

timi4 d mfei. t ions : idonca l t* i I i v u:’. in c h rnn ic irna,-

si cc aspergillosis. • Ai h I n te rsnepcc ( ’n p l f rence rai

A n t inde r td ' i .d A'î nis and < '.In t n o ih e rapv , Abs!r .

SFK1. San l-ra in iscn, A i n i r u a n Nocjelv fo r \licrc;-

Hi< d<

E d m o n d Ml'., \\ aliac( SP. Mc( bsh D K , P la l ler

\f A . Jones R N , W en-el K P ( i Noscur>n i. i j

blooi'.s ii i am inlcct ions nt U n i te d States hospda ls ; \

thiee-\ ear anal vsk . t 'h n Inieci D is 2'F 23^-244

Fsfdne l I n ^ t o i ! A 11 ‘>VH 1 In \ itr>i . iclivin- o l d ie new

tn . i /nk * voi'i io ii. i/ ii l*. <1'R-10'F4‘Fi) aâmst oppor-

t n n is i ie Id . i ines inms and d im o r p h ic lung : and c o m

m o n atut em erg ing \ easi pathogens . J ( d i n M ic r o

b io l PiH-202

Fspinel-ltt i ;ro lj ,A (2001) hi \ it r i> luns;ic idal ac t iv

ities nl vo ru o i i a /o i r , i t ; at o ita /tde , and a m p h o te r i

c in Pi against ■ ippor) imis l ic fin >rdb.H'eous and denia-

riacc<>us . J ( l i n M ien tb i<d ' M. riS 4 . rJSK

F ra t : i R F F Bekmi;e! 14 1, Sait tti I F < ihann i m m \! \

f he ellect «*! t ht ne'A l i i t / o k , \ n-ico ita/ok“

j fdK -1C1F4‘if 1 ) * in the in teract ions of < ,a n d id a ,dhi-

caii'. and ( and id . i k rus t i a h end< .t iielial c e l l s . J

("dietr.othi-r F2: It,

P rom t lm ^ R \ [ F ,rjSi i S-rer’, :c \ \ of m ed 'ca l lv m ipnr-

tam a i i t ik m ^ a l a/oh- di ro. ati\ 1, s. t h n M ic ro l ’md

R e ’, F 1K7--2 17

Fiebe: A. I fitcl ii ock i A . S w a n / j P . Pit: Icn PS,

Marsdeii R IF K\\ im-t l i tm ^ k j , Piennctt j i I ^ ‘451

Delei i* m ol iht- ( a n d i d i r jab ra ia l 'R» i ' in d F H G l l

(jt-nev Fit-, c! n il ! ck \daluhl’,. < ell ( rritverh,

CK-iV ' f t A r p p f t v iSu j .n r i tm r j . j - nu i Jsp ip p . isdp

ius,v, tu .nu ’d f in ;.nKr 'U U jd s i iu 'd ,p p,i

-FIH Hi iSMp l- ' J I f ' r H%(- '(,l\ \[/Vl 7« ' 'M 1 1 . 1 0 v th-.jp

u turn t j i jo vu ui . ’V [i uiiij j ( 1 GOT J M ’I 1 *!t)

‘ 1 lllA Vi u r I, ‘ A l -’A , ‘HKL ‘MA Air u pA A

'26*.! ^ A i p j -Ui.'iAU] u i d ( i s.i.xh. ,j --ti' pM

tiaj .niMMUi ilu i j-.ui io| s tt iA r p A m juuv [rumv.-'!

-uspuii \\.p\i foocn VI'M um oim rij') p qy uivssiq j -u,hs.t id. o11 -i<} p j f u j u«i j

Mil>n vpn i p 'S n r ; A m . n r ' 1 1 |t ? p [ p 1 u . ' ju ir j ^ rn uu

j i| i iu j aiciui’ p t .m s p n i r i j im i j d s q n ' i j . t q '|,;\uu

r :.>]<i/i'iknuo^ {-COD <i ■v1tUl 4V. > HJOJIl M,l I ‘Aj.n iy .it i| >, i,m is t, ur ‘i m y 7 , q«

■.nsqy • u i r i m p o i u j i f j i i r c\ p p 1 1 'umiu\. ,’<u

|UI I ) 5 lll.MJs J, ■ 1 LI | t jK j u p ]0 ^! H’ l j s q y | HI V

u u i t v ni u i . u i u p ' - p u r u t v i n e jv^nn j im r

: s » ( <1 1 ' . ! [ ! ! ! { I I ’. I I , U H I f >.U .HJ j . i l ' l 3 i u r i f i p ’>

• i j n / r m urn,;; <A ' .- p i a ' p v u . u -M(p A : i ^ p A . n f )

A i V [<A1 V IA A\!) A . J , ) lH Vs

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-n f i iu-’iHS''d.'ir ^v,f-•,i Jtti.iup-.-i\ ’ i iu v- v n i i ' i . j n u i ’

p S m q n m ' .' jo?v p> nor , ,i j >i a [ p i , ( , l i |‘( j s u i r p y

■;>_5 Mitv.q ' g j »\\<ug k\{ ->i{ j n r| j pv.

A p - t r q m iq\ m | / .u i h h , u i ' .n i u u y

) p s j i | ui-.ijsq y ‘ vdc i >i; iuui^f] ) p : » ’

MU 's'ri \ ,U\,r l i lt j ni.U.lJSl! \ ) < IUJI 'S I,MU}

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g il lus hmii»atii\. < J i n M u ’roh io l Iniect 7 : 1 '3-137

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the r 42; 161-163

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son ot v o i K o i u / o l f I l 'K - ID*>,4c'!'i and n r a c m i a / o k ’

iti p iv\ciii ion am i i r r a i n i c m ol A sp c rg d k u

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l i v i n <d \ot k o n a /a d f ai;aii)si M.'kxU'J imis;;, M e d

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p u lm o n a r y aspri ;J'1!o m s , k i u u m ro|-, \u,<, n t i

C h e n io ;h e r 41: ^'ki-o'-is

’ 4, \esks M A , MrI)fmL;al b ( , Praroi. kj b , j i (2222)

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r e p o r t a n d k tL T a tu iv rc\ u-’a u i l u i i i a l m-i vuit% ,

t o m pscudajl i. 's idt i'naî'- . i l i n b i l e s ! I)«s > 1: <t~ ' iAT7

" 5 . X g n v c i i M i l , 1 it C A i h i \ i t : < t > >> i i iparanve

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!lucoii,i7aak'-:,iiSL t p i i l ' k a n d -rt-sistaiil ( i \ pi<n . n.\ ih.

n e c d u r n i .m s ibsaknes, ,-\iumti, t <th A s i a n s C’hcn io-

t h r r 42: 4 ' i-4"2

'"ij, N g u v f i i M id , Y u ( A i ! \' oi i r o i i a /o lc ,ij;,uiivi

S lucona/o le- ' iusrrp i ib lc and n-sisiaut ( 'aridida iso

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M \ o r iL o n a / o k ’ (11k 10 lk 4 f*h| treal m e m ot

hematoi;L-nonsh’ d is s em m a lrd i .a iuhda krusei uiler-

t io n in a nem r o p t i in gum ea p i^ m ode l , i 'u 11 Congress uf i ‘i r k i lert ia tto 'ta ! S o a i e ! i o r k lnn ia i i

a n d A n im a l M v r* d o ^ v , A b ^ t :. ^ .4. S a k o m a g ^ i u r e

T v r tn e , k a l v . k i f r r i s a i i o i i a l S u e i e i r Sot H n n i . u i a n . t

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Osht-ro\ N . Ki m u\ :ann is U P , !<■ unan t A , M ay t iS

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iilaris ar.d A spen ;t ib is km i iânss u e.>ttlerred In

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the rapy , Ahmr. P 7h, W.isluii^twn, A n i i riean

Soc ie iy tor Mi«.robadoi;\

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G n u d n u i i j , A r n e l a A f20C2t A 1 and .»un /ed . d .m

kk-b ittu l t ■.unparai i\ c tr ia l eva lua t ing the s.dety oi

l ip o som a l am p h o te r ic in B versus a m p h u t e t i t i n B

l ip id co m jd e v in d u 1 em p ir ica l l u a t n i e m <d febtde

neasrup . u ; :, L A i t i p i i ' ABLC3 LnS Iabnr .un i , Stude

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f' (2001) \3>1 icon, 1 / 1 de does im i aik-ct the pharma-

cidvtnct;cs 1 ij n n ci.'phemalR ti id. 4 1st If tu.rsa.enec

F U R O P h A N J O U R N A L O F M E D I C A L R h S H A K t '! 1 \I,u- 2002

s.'t.iifers'iicr liii Ai!Ht!Vli,i'( (Li.tl A^rni^ <iml Chem o ther . ipv , Ahs i r. * V 2 4. t >, A m uruM n S<K;ujt v

tor KfivTohhilnu,\-

J11. W outl N, 1 .in. KK( Ali.ni R, Lii'khr.i!. \, Nichols D J 123C Ij Li icei lit l iM /nu ' osi ihe p f u “nuiYtk-

inr) ics of eacr*>!im>.is. 4I<; Inn-rsi ii-itct- C ; ‘nierencc nt! A m n n ie r o b i / i l A^rsi i^ ,nni < h f i?nuhc r , ip v ,

Ahsir . *\-2Z. i Iiir.i^n, Ank'nY.m SnC’t’tv tor \?n r»>r>ii>li

Received: M,tn/< 2\ 2JJ2 ■ / u , ifu-d: Annl H 200^

Add>r><t h i r ( t t y r c .p t ^ id i 'm e ;

M . ih n io u d ( ib .m n m i i is , IMi. I >,

Ci'iiU'r fnj Mt-dii/ii ,uidM \ w lo £ V R e k ’FfiKt' 1 ,ibnr,i>,nrv

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Casi1 Western Rt". erse LAm m sn H I :C 1 U' In V'i < lint. ! kS 5' 2 8

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