242 l-URoI'I- .AN j u T K N A t 4 M F IH C A I R F . S I ' W H M av31 ,2C02
Eur j .\U-d Res {2Z2'2i ,.M2 23)-, i'< I. 1 fulzapfel Pubh'.hi rs 2ZQ2
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 lun^a 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< tpha^i l is, ! \, and fe-
hri le neurropei i i a. Smal ler studies and case reports
have shown \ R(. is l isUui ler saKa;^e therapv ot
f'\, cervhr.i i asper^i l losis, Srffiu^pom ^ti, and ut l ier
tun^a ! 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,
lar^elv 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 tun^a l agents
[tor reviews see re fennces 42 and ICb] mtens i l ied
t lu scan.h lor new, sa.^e and broad-spectrum
auents. These ct iorts led to the in t r rnlnc t ion • >1
ter lur ial ine (belon^ini ; 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 ^enerahv 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 lea^i 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 '/v^omveeus. 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 ^e 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! iun^a 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 luj^eihi '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 un^aK 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 ro^ens; 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 er^os*
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-^ani 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 ^efies. 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! er^o.sterol svnfbe-
sis and accunndation oj its precursors [90]. In (
\’K C treatment resulted in si^itilieam 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 ca^e 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'f^i ,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 jpinspc^ann,’ 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. ^I . 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
(T^Ai 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 ^o 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 A^eit 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> a^ai 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 ■> a^ains". 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 ^eo . 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 d^eP^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 ^a 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 asjier^il 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'^i 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) a^amst 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
UHt"AA m -'H ',HH f M R ’ k j jr rpu ' i iv ) isii u j p- i p j t ’.d pvp vij Jp p ^ i s
-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 : » ’
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K on .uo lc- r t ’si^iaiti l a b o ra to rv isolates of Asper
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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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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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'na^i'- . i l i n b i l e s ! I)«s > 1: <t~ ' iAT7
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t h r r 42: 4 ' i-4"2
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lates: in-vitrri e t l i r a rv t o m p a r c d v, itii t b.it ol ti t a-
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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
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iilaris ar.d A spen ;t ib is km i i^anss u e.>ttlerred In
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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
Drrrn,iu:> 1 Dcp,irt mcu i
Casi1 Western Rt". erse LAm m sn H I :C 1 U' In V'i < lint. ! kS 5' 2 8
ClcveljH'l, 1 *i! H i »'•, L'S A L-nuil: niJS’ji'i-'tj.i. ■■a : u.ohi