938 Mini-Re iews in Medicinal Chemis y,2009, 9,938-955
1389-5575/09 $55.00+.00 © 2009 Ben ham Science Publishe s L d.
An imic obial De elopmen in he E a o Eme ging Resis ance
An onio So lozanoa, C is ina Ca ascoa, Jose Cabezab, En ique Villegasa and Jose Gu ie eza,*
aDepa men o Mic obiology, School o Medicine, Uni e si y o G anada, Spain; bSe ice o Pha macy, San Cecilio
Uni e si y Hospi al, G anada, Spain
Abs ac : An ibio ics cu en ly unde s udy by he Food and D ugs Adminis a ion include: a openem ( o ea men o
sinusi is, b onchi is, and communi y-acqui ed pneumonia), dalba ancin ( o ca he e in ec ions), ela ancin ( o ea men
o nosocomial pneumonia), o i a ancin ( o bac e emia), ce obip ole and iclap im ( o pneumonias). Mo eo e , all o
hem would be use ul o skin and so issue in ec ions.
Key Wo ds: Fa openem, dalba ancin, ela ancin, o i a ancin, ce obip ole, iclap im.
INTRODUCTION
Resis ance among pa hogens commonly esponsible o
bo h nosocomial and communi y acqui ed in ec ions is in-
c easing a an ala ming a e. In ec ions due o hese esis an
o ganisms a e associa ed wi h g ea e cos s, highe mo bid-
i y, and highe mo ali y han in ec ions due o simila non e-
sis an o ganisms [1]. The pas ew yea s ha e seen a majo
ise in esis ance o an ibio ics among G am-nega i e bac e-
ia (be a-lac amase [ESBL]-p oducing en e obac e ia, ca -
bapenem- esis an P. ae uginosa and A. baumannii …) [2]
and, especially, among G am-posi i e bac e ia (me hicillin-
esis an S. au eus [MRSA], glycopep ide-in e media e
[GISA] o esis an S. au eus [GRSA], ancomycin- esis an
en e ococci [VRE], mul i-d ug esis an S. pneumoniae
[MDRSP]) [3]. This end has conside ably educed he a-
peu ic op ions and b ough abou a need o no el an ibio ics.
An ibio ics cu en ly unde s udy by he Food and D ugs
Adminis a ion (FDA) o skin and so issue in ec ions
caused by G am-posi i e (including MRSA) and, in some
cases, G am-nega i e bac e ia include: dalba ancin ( o
ca he e in ec ions- phase II), ela ancin ( o nosocomial
pneumonia- in phase III ial), o i a ancin ( o bac e emia-
phase II), ce obip ole ( o pneumonias- phase III) and icla-
p im ( o pneumonias- phase II). Fa openem may be applied
in he u u e o ea mild espi a o y in ec ions (sinusi is,
b onchi is, and communi y-acqui ed pneumonia).
The objec i e o ou s udy will be o e iew he in i o
an ibio ic ac i i y, ac ion mechanisms, and esis ance (i e-
po ed) o he abo e an ibio ics.
FAROPENEM
S uc u e
Fa openem (SY5555) o 4- hia-1-azabicyclo [3.2.0] hep -
2-ene-2-ca boxylic acid, 6-(1-hyd oxye hyl) 7-oxo-3-( e a-
hyd o-2- u anyl)-, monosodium sal (Fig. 1) is a new o al
penem an imic obial agen , which has an unsa u a ed hia-
*Add ess co espondence o his au ho a he Depa men o Mic obiology,
School o Medicine, A da de Mad id 11, E-18012 G anada, Spain;
E-mail: E-mail: joseg @ug .es
Fig. (1). S uc u e o a openem.
zole ing and is a s uc u al hyb id be ween he penicillin and
ca bapenem nucleus [4-6]. A p esen , a openem is he only
ep esen a i e o his subclass ha is ei he in i s p e egis a-
ion phase (as a openem medoxomil in USA) o is comme -
cially a ailable (as a openem sodium in Japan) [7, 8].
Thus, a openem as a ep esen a i e o he penem sub-
class is chemically dis inc om he ca bapenems. The in o-
duc ion o a C-2 side chain (which is a chi al, a basic e a-
hyd o o u an ing) o he penem skele on led o he de el-
opmen o a openem, wi h unique cha ac e is ics dis inc
om ca bapenems and o he be a-lac am d ugs [9]. The s a-
bili y and neu al C-2 side chain o a openem e sus he
ins abili y o ca bapenems and posi i ely cha ged side chain
a physiological pH ha e clinical ele ance in ha . Fi s ,
ca bapenems as injec able d ugs ha e a limi ed dosing lexi-
bili y. Second, exci abili y o he cen al ne ous sys em is
closely co ela ed o he posi i e cha ge o he molecule.
Thi d, he p o ona ion s a e (and hus cha ge) o he C-2 side
chain has an impac on he an ibac e ial spec um o he
penems [4].
The subclass o ca bapenems co e s hospi al pa hogens,
whe eas he penem subclass ep esen a i e a openem is
ac i e agains pa hogens causing communi y-acqui ed in ec-
ions. In his con ex i is wo h no ing ha all he ca bap-
enems ha e o be adminis e ed pa en e ally; howe e , a o-
penem medoxomil has e y good o al bioa ailabili y. The e-
o e, a openem medoxomil may be a sui able candida e o
sequen ial he apy and a s ep-down he apy ollowing p e i-
ous in a enous ea men o in ec ions like communi y-
acqui ed pneumonia wi h e.g., e apenem [4].
Mechanism o Ac ion
Fa openem, like he o he -lac am an ibio ics, ac s by
blocking cell wall syn hesis h ough binding o PBPs. I
Me
N
S
O
COOH
OH H
OH
H
An imic obial De elopmen in he E a o Eme ging Resis ance Mini-Re iews in Medicinal Chemis y,2009, Vol. 9, No. 8 939
shows g ea e a ini y o hose o high molecula weigh .
Thus, o example, i shows g ea e a ini y o PBP1, ol-
lowed by PBP3 and PBP2 o S. au eus and S. pneumoniae;
g ea e a ini y o E. coli PBP2 han o E. coli PBP1A,
PBP1B, PBP3 and PBP4, as well as a g ea e a ini y o P.
ulga is PBP4 and o S. ma cescens PBP2 and PBP4 [10].
Spec um o Ac i i y
Fa openem is ac i e agains S aphylococcus spp., wi h
he excep ion o MRSA isola es; agains S. pneumoniae (in-
cluding MDRSP isola es), S. mille i, S. i idans (excep
penicillin- esis an isola es) and o he -haemoly ic s ep o-
cocci o he A and B g oups, and agains Neisse ia spp. [11-
15]. Howe e , i is no ac i e agains En e ococcus spp. [15,
16].
Ac i i y agains G am-nega i e bac e ia is less ma ked,
pe haps due o he absence o cha ge in he posi ion 2 subs i-
u e [17, 18]. E en so, a openem has shown good ac i i y
agains some species o En e obac e iaceae (including
ESBLs o AmpC-p oducing isola es) [19],as well as agains
H. pylo i [7] and wo o he mos common espi a o y pa ho-
gens, i.e. H. in luenzae and M. ca a halis (including -
lac amase-p oducing isola es) [20-23]. Howe e , bac e ia
such as En e obac e spp., P o eus spp., P o idencia spp.,
Se a ia spp. o Mo ganella spp. show educed suscep ibili y
agains his an ibio ic [13]. Addi ionally, a openem is no
ac i e agains P. ae uginosa o S. mal ophilia, amongs o he
non- e men ing G am-nega i e bacilli [13, 15, 16, 24].
Fa openem is equally ac i e agains some anae obic bac-
e ia such as C. pe igens, B. sub ilis, B. o sy hus, B. u e-
oly icus,P e o ella spp., F. nuclea um and P. gingi alis,
including -lac amase-p oducing isola es [25].
Table 1 shows he in i o ac i i y o a openem agains
di e en bac e ia o clinical in e es .
Resis ance
Like he o he -lac am agen s, he bac e ial mechanisms
o esis ance agains a openem include inac i a ion h ough
ca bapenemases, al e a ion o PBPs, educ ion o pe meabil-
i y o he ex e nal memb ane and ac i e e lux.
Fa openem is highly s able agains he majo i y o -
lac amases, including ESBLs and AmpC [4, 15, 16, 24, 26].
Said s abili y may be de i ed om he p esence o he 1-(R)-
hyd oxye hyl g oup in he C6 posi ion o he bycyclic mole-
cule [4, 9]. Some -lac amases o he A-class, such as Imi-I
om E. cloacae, main ain a ce ain hyd oly ic capaci y
agains ca bapenems and penems; no wi hs anding, he only
-lac amases eally ac i e agains his an ibio ic a e me allo-
-lac amases [4, 16].
The in insic esis ance o P. ae uginosa o a openem
en ails a leas h ee mechanisms: mul id ug ac i e expulsion
sys ems, mainly he MexAB-Op M sys em, he inabili y o
en e h ough he Op D po ine and he low binding a ini y
o he penem o su ace PBPs. The absence o exp ession o
jus one o hose mechanisms in he bac e ia would be
enough o imp o e he ac i i y o a openem agains his
pa hogen. This is he eason why he applica ion o mem-
b ane pe meabilize s, such as ca ionic polypep ides, o o
e lux sys em inhibi o s, cu en ly unde de elopmen , would
be one solu ion o he lack o ac i i y o his an ibio ic
agains P. ae uginosa [27].
Fa openem is no likely o selec o e lux-media ed ca -
bapenem esis ance. Al hough a openem is pumped ou by
he MexAB-Op M e lux sys em, i appea s o ha e a dis inc
binding si e since i does no in e ac wi h o he MexAB-
Op M subs a es (i.e., -lac ams, -lac amase inhibi o s, qui-
nolones, chlo amphenicol, sulphame hoxazole, no obiocin)
[4]. Thus, i may be said ha he he apeu ic use o a o-
penem has no eason o a ec he suscep ibili y o imipenem
and me openem in he ea men o hospi al-acqui ed in ec-
ions caused by non- e men ing G am-nega i e bacilli [4].
Las ly, in ela ion o c oss- esis ance be ween his penem
and o he -lac am an ibio ics, i has been obse ed ha , in
espi a o y pa hogens, such as S. pneumoniae and H. in luen-
zae, he highe he esis ance o penicillins, he lowe he
ac i i y o a openem [6, 9, 20, 23, 28]. In mos cases, said
c oss- esis ance is de e mined by PBPs al e a ion so ha in
M. ca a halis, in which he p edominan mechanism o e-
sis ance is he ac i i y o -lac amase, his phenomenon is
less ema kable [6].
Pha macology
Bioa ailabili y o a openem is app oxima ely 70-80%. I
binds o plasma p o eins in abou 90-95% and he heo e ical
olume o dis ibu ion is low. I s Cmax and Tmax a e 13-14
mg/l and 1-2 hou s, espec i ely, a e a single dose o 300
mg and i s adminis a ion wi h ood does no al e i s Cmax o
AUC. Fa openem medoxomil is hyd olized o a openem
a e abso p ion and no e idence is a ailable on he p oduc-
ion o me aboli es wi h an imic obial ac i i y. Fa openem
elimina ion hal -li e is app oxima ely 1 hou . Elimina ion is
mainly by enal ubula sec e ion and 14-20% o he dosage
adminis e ed may be eco e ed in u ine. Age and sex do no
a ec a openem hal -li e. In young adolescen s (12-18 yea s)
pha macokine ic pa ame e s a e simila o hose o young
adul s [17, 29-31].
Ad e se E ec s
The sa e y p o ile o a openem, acco ding o clinical
ials ca ied ou up o da e, is excellen , wi h a minimum
incidence o ad e se e ec s, mainly gas oin es inal (al-
hough i is no associa ed o pseudomemb anous coli is)
which may be p e en ed by concomi an adminis a ion o
a openem wi h o he an ibio ics o he p io inges ion o
p obio ic agen s ha may main ain he balance o in es inal
mic obio a o he indi idual ecei ing he ea men [7, 12,
17, 23, 32]. O he sligh e ec s, wi h an e en lowe inci-
dence, we e aginal candidiasis and headaches [32].
Unlike wha happens wi h ca bapenems, a openem does
no ha e se e e ad e se e ec s such as ca dio oxici y o sei-
zu es [12, 23].
Clinical Indica ions
Fa openem has a wide spec um o ac i i y agains bo h
ae obic and anae obic mic oo ganisms and, unlike ca bap-
enems and hanks o i s good o al bioa ailabili y, i is e y
use ul in he ea men o communi y-acqui ed in ec ions
940 Mini-Re iews in Medicinal Chemis y,2009, Vol. 9, No. 8 So lozano e al.
Table 1. In Vi o Ac i i y o Fa openem Agains Va ious Human Pa hogenic Bac e ia [9,11,13,15,16,20-22,25,26,28]
Mic oo ganism MIC50
(in mg/L)
MIC90
(in mg/L)
S. au eus
MSSA
MRSA
Coagulase nega i e s aphylococci
0.06-0.12
2- >32
0.06-0.12
0.12
2- >32
0.06-4
S. pneumoniae
PSSP
PRSP
G oup A be a-haemoly ic s ep ococci
G oup B be a-haemoly ic s ep ococci
Vi idans g oup s ep ococci 0.004-0.016
<0.12-1
0.015-0.03
0.03-0.06
0.12
0.008-0.03
0.5-2
0.015-0.03
0.03-0.06
1
E. aecalis
E. aecium
1
>32- 64
2-8
>32- >128
N. gono hoeae
N. meningi idis
0.03-0.06
0.008
0.06-0.25
0.008
Co ynebac e ium spp. 0.25 4
H. in luenzae
Be a-lac amase-nega i e
Be a-lac amase-posi i e
0.25-0.5
0.25-0.5
0.25-0.5
0.5-1
0.5-1
0.5-1
Mo axella spp. 0.03-0.12 0.125-1
En e obac e iaceae
Ci obac e spp.
En e obac e spp.
E. coli
Klebsiella spp.
M. mo ganii
P o eus spp.
P o idencia spp.
Salmonella spp.
Se a ia spp.
Shigella spp.
0.5
2
0.5
0.5
1-4
1
2
0.5
2
0.5
4
16
1
2
2-8
4
8
0.5
32
0.5
P. ae uginosa 32- >128 32- >128
Acine obac e spp. 4-32 8- >32
B. cepacia 16 >32
S. mal ophilia 32- >128 32- >128
Bac e oides spp. 0.25-2 0.25-4
Fusobac e ium spp. 0.015-0.5 0.06-1
P e o ella spp. 0.06-0.25 0.5-1
Pep os ep ococcus spp. 0.06-0.125 0.12-1
An imic obial De elopmen in he E a o Eme ging Resis ance Mini-Re iews in Medicinal Chemis y,2009, Vol. 9, No. 8 941
(Table 1. Con d….)
Mic oo ganism MIC50
(in mg/L)
MIC90
(in mg/L)
Po phy omonas spp. 0.015-0.12 0.06-1
C. di icile
C. pe igens
4-8
0.5
8-16
0.5-1
P. acnes 0.06 1
Veillonella spp. 0.25 4
Ac inomyces spp. 0.06 0.5
[22, 24, 26, 28, 33]. This is why, a e i s ma ke ing, a o-
penem may be indica ed in he ea men o communi y-
acqui ed in ec ions, especially acu e bac e ial sinusi is, acu e
exace ba ions o ch onic b onchi is, communi y-acqui ed
pneumonia and sligh skin and so issue in ec ions (includ-
ing hose de i ed om bi es) [17, 24, 26].
Howe e , in Oc obe 2006 he FDA decla ed i s dissa is-
ac ion wi h he clinical ials ca ied ou ill hen. Acco ding
o he epo ed, clinical ials ca ied ou in pa ien s su e ing
om acu e bac e ial sinusi is and wi h exace ba ions o
ch onic b onchi is should ha e been con as ed wi h placebo
g oups. In addi ion, samples om pa ien s wi h communi y-
acqui ed pneumonia we e no conside ed alid and, las ly,
he e was no su icien e idence on he e ec i eness o
a openem in he ea men o skin and so issue in ec ions
[24].
DALBAVANCIN
S uc u e
Dalba ancin (BI-397) o 5,31-dichlo o-38-deme hoxy-
ca bonyl-7-deme hyl-19-deoxy-56-O-[2-deoxy-2-[(10-me hyl-
1-oxoundecanoyl)amino]-b-D-glucopy anosyl]-38-[[[3-dime-
hylamino)p opyl]amino]ca bonyl]-42-O-D-mannopy anosyl-
N15-N-me hyl- is omycin-aglycon (Fig. 2) is a semisyn-
he ic glycopep ide o pa en e al use de i ed om a na u al
molecule syn hesized by Nonomu ia spp. and s uc u ally
ela ed wi h eicoplanin [34-37]. I is p oduced in h ee
s ages. Fi s , he N-acylaminoglucu onic acid unc ion was
selec i ely es e i ied by incuba ion in me hanol in he p es-
ence o sulphu ic acid a 0-58C o 24 h. Second, he pep-
ide-ca boxy g oup was amida ed wi h 3-dime hylamino-1-
p opylamine in dime hylsulphoxide in he p esence o ben-
zo iazolyloxy- is-py olidinophosphoniumhexa luo o-phos-
pha e. Finally, he suga me hyl es e was saponi ied wi h
15% sodium hyd oxide, wi h he esul an compound being
dalba ancin [35, 36]. The di e ences wi h eicoplanin ap-
pea in apolip o eins 1 and 3, as well as in he numbe and
posi ion o suga moie ies, chlo ine molecules and a ious
me hyl and hyd oxyl g oups. Thus, he molecule imp o es
i s ac i i y wi hou al e ing he unde lying D-alanyl-D-alanine
backbone, which is undamen al in he an imic obial ac i i y
o his an ibio ic [36].
Fig. (2). S uc u e o dalba ancin.
R
1
H
N
OO
OH
OCO
2
H
OH
OO
Cl
H
OH
N
H
HH
NN
H
H
N
OH H OH
N
H
H
N
H
O
O
NH
O
O
H
OH
O
NH
H
N
HO O
OOH
OH
OH OH
Cl
HO
OH
O
942 Mini-Re iews in Medicinal Chemis y,2009, Vol. 9, No. 8 So lozano e al.
Mechanism o Ac ion
Glycopep ides inhibi bac e ial wall syn hesis by p e en -
ing he syn hesis o pep idoglycan [38]. They p esen a ini y
o he D-alanine-D-alanine esidue o he ca boxy- e minal
end o pep idoglycan p ecu so s and hus p e en hei bind-
ing. Consequen ly, he e is an accumula ion o p ecu so s
and he inhibi ion o eac ions ca alyzed by anspep idases
and ca boxypep idases, which do no ecognize he sub-
s a es needed o syn hesizing he pep idoglycan, akes place
[34, 37].
The high a ini y and an ibio ic po en ial o dalba ancin
a e also based on a pa icula abili y o dime iza ion and
binding o he an ibio ic o he lipophylic la e al chains ha
a e in he bac e ial memb ane. Thus, his glycopep ide shows
an in i o bac e icide ac i i y agains esis an G am-
posi i e bac e ia ha is s onge han ha o ancomycin and
eicoplanin [34, 35].
Spec um o Ac i i y
I s in i o spec um o ac i i y is simila o ha o o he
glycopep ides. Howe e , dalba ancin has demons a ed a-
ou able in i o ac i i y agains MSSA, MRSA, VISA,
VRSA, and linezolid- esis an S. au eus, as well as agains
me hicillin- esis an coagulase-nega i e s aphylococci and
in e media e- esis an glycopep ides [36, 39]. Simila ly, dal-
ba ancin is mo e ac i e han eicoplanin and ancomycin
agains s ep ococci, including mul i esis an S. pneumoniae
[34-46].
Rega ding en e ococci, and simila ly o wha happens
wi h eicoplanin, dalba ancin is mo e ac i e han ancomy-
Table 2. In Vi o Ac i i y o Dalba ancin, O i a ancin and Tela ancin Agains Va ious Human Pa hogenic Bac e ia [40-46,68-
73,97-101]
Dalba ancin O i a ancin Tela ancin
Mic oo ganism MIC50
(in mg/L)
MIC90
(in mg/L)
MIC50
(in mg/L)
MIC90
(in mg/L)
MIC50
(in mg/L)
MIC90
(in mg/L)
S. au eus
Me hicillin-suscep ible
Me hicillin- esis an
Coagulase-nega i e s aphylococci
Me hicillin-suscep ible
Me hicillin- esis an
0.06-0.12
0.03-0.12
0.03
0.03
0.06-0.12
0.06-0.12
0.06
0.06
2
2
1
1
4
4
2
2
0.25-0.5
0.25
0.25
0.25-0.5
0.25-0.5
0.25-0.5
0.25-0.5
0.25-1
S. pneumoniae
Penicillin-suscep ible
Penicillin- esis an
MDRSP
S. pyogenes
S. agalac iae
Vi idans g oup s ep ococci 0.016
0.016
0.016
0.03
0.03-0.06
0.016-0.25
0.016-0.03
0.016-0.03
0.016-0.03
0.03
0.03-0.125
0.016-0.5
0.004-0.03
0.004-0.03
-
0.12
-
-
0.008-0.125
0.015-0.125
-
0.25
-
-
0.016
0.015
0.015
0.03-0.125
0.06-0.125
0.03-0.06
0.016-0.03
0.03
0.03
0.03-0.125
0.06-0.125
0.06-0.12
E. aecalis
Vancomycin-suscep ible
Vancomycin- esis an
E. aecium
Vancomycin-suscep ible
Vancomycin- esis an
0.03
4-32
0.06
16
0.06
32
0.12
32
0.5
-
0.06-0.12
1
1
-
0.25-0.5
2
0.25-0.5
2-4
0.12-0.25
1-2
0.5-1
4-8
16
0.25-0.5
2-4
Co ynebac e ium spp. 0.12-0.25 0.25-1 - - 0.03 0.06
L. monocy ogenes - - - - 0.125 0.125
Ac inomyces spp. 0.025 0.5 - - 0.25 0.25
Clos idium spp. 0.03-0.125 0.5-2 0.5 1 0.25 8
Eubac e ium spp. 0.25 1 - - 0.125 0.25
P opionibac e ium spp. 0.25 0.5 0.125 0.25 0.06 0.125
Pep os ep ococcus spp. 0.125 0.25 0.125 0.5 0.06 0.25
An imic obial De elopmen in he E a o Eme ging Resis ance Mini-Re iews in Medicinal Chemis y,2009, Vol. 9, No. 8 943
cin agains ancomycin-suscep ible en e ococci and agains
en e ococci wi h VanB and VanC pheno ypes; howe e , i is
no ac i e agains VanA en e ococci [34-39, 41, 45, 47-49].
Addi ionally, i was obse ed ha ac i i y agains E. aecium
is sligh ly lowe han agains E. aecalis and E. hi ae [39, 41,
46, 49].
O he G am-posi i e dalba ancin-suscep ible bac e ia a e
Ac inomyces spp., Bacillus spp., Co ynebac e ium spp.,
Clos idium spp. (excep o C. clos ido o me), Eubac e-
ium spp., Lac obacillus spp. (excep L. acidophilus and L.
casei), Lis e ia spp., Mic ococcus spp., Pep os ep ococcus
spp. and P opionibac e ium spp. [34,36,39,41,44]. On he
con a y, dalba ancin does no show any ac i i y agains
G am-nega i e bac e ia, including anae obic bac e ia [34,
39].
Table 2 shows MIC50 and MIC90 alues ob ained in i o
agains some human pa hogenic bac e ia.
Resis ance
En e ococci we e di ided in o se e al pheno ypes based
on hei deg ee o esis ance, induc ion and ans e ence o
esis ance o ancomycin and eicoplanin. In all o hem,
esis ance is owed o he syn hesis o a p ecu so ha is di -
e en om he D-alanine-D-alanine dipep ide, which may be
D-alanine-D-lac a e o D-alanine-D-se ine [37].
En e ococci wi h VanA pheno ype ha e a high deg ee o
esis ance o ancomycin (MIC 64 mg/l) and o eicoplanin
(MIC 16 mg/l), a esis ance which may be induced by bo h
glycopep ides. Genes p oducing his pheno ype a e loca ed
wi hin he Tn1546 ansposon in eg a ed in sel - ans e able
plasmids. T ans e o hese plasmids o o he sensi i e en-
e ococci isola es o o o he G am-posi i e bac e ia, such as
S. pyogenes and L. monocy ogenes, o e en o S. au eus, has
been p o en [48].
Isola es wi h VanB pheno ype show mode a e esis ance
o ancomycin (MIC o 32-64 mg/l) and hey emain sensi-
i e o eicoplanin (MIC 1 mg/l). This esis ance is no
ans e able and he gene in ol ed is ch omosomal. Resis-
ance may only be induced by ancomycin bu no by eico-
planin [48]. Isola es wi h VanC pheno ype a e mode a ely
esis an o ancomycin (MIC o 8-32 mg/l) bu sensi i e o
eicoplanin (MIC 1 mg/l). I is a cons i u ing, non- ans-
e able esis ance [48]. A VanD pheno ype has also been
desc ibed [48].
In s aphylococci, on he o he hand, esis ance o glyco-
pep ides is a ibu able o he abno mal s uc u e o he cell
wall, due o an inc ease in pep idoglycan p oduc ion, which
esul s in an abno mal hickening o he wall, hus limi ing
he binding o hese an ibio ics o hei a ge [37, 48]. How-
e e , he exis ence o MRSA isola es wi h a high deg ee o
esis ance o glycopep ides ha acqui ed he Tn1546 ans-
poson ha e been p o en [48].
No wi hs anding, no case o esis ance o dalba ancin
was obse ed [36]. In addi ion, in i o esis ance es s in
s aphylococci ha e no ob ained mu an s ha a e esis an o
his an ibio ic, a ac which p o es he low powe o selec-
ion o esis ances, in compa ison o eicoplanin and anco-
mycin [50, 51]. Fo Le o e al., his would be explained by
he s ong ac i i y o dalba ancin agains GISA isola es, he
high se um d ug concen a ion/MIC a io and he pe sis en
ac i i y agains he eicoplanin- esis an de i a i e [52].
Howe e , as poin ed ou by Benne e al., a ailable da a a e
limi ed because hey a e no om isola es subjec ed o p o-
longed he apeu ic le els o he an ibio ic [39].
Pha macology
The pha macokyne ics o dalba ancin is linea and p o-
po ional o he dosage, as may be de i ed om s udies ca -
ied ou in heal hy olun ee s and in a dosage ange be ween
140 and 1120 mg. Table 3 shows he main pha macokine ic
pa ame e s o his an ibio ic a e he adminis a ion o
1 g am on day 1 and 500 mg on day 8, due o a p olonged
hal li e (6 o 10 days). Cmax is achie ed 30 minu es a e
adminis a ion and plasma concen a ion o dalba ancin is
main ained o e MIC90 o esis an isola es o s aphylococci
and s ep ococci o a leas 12 days [53, 54]. To al dis ibu-
ion olume is 15.7 l a s eady-s a e, wi h 4.5 l in he cen al
compa men and 11.4 l in he pe iphe al compa men [55].
Binding o plasma p o eins is 93%. Dalba ancin is exc e ed
by enal and non- enal pa hways; app oxima ely 42% o he
dosage adminis e ed is exc e ed unal e ed in u ine [54]. Es-
ima ed clea ance is 0.06 l/h [55]. Faecal concen a ion o
dalba ancin is 6.8-73.4 mg/kg (day 5) and 7.4-26.4 (day 14)
Table 3. Pha macokine ics o Dalba ancin and Tela ancin [54,74]
Tela ancin
Pa ame e Dalba ancin
5 mg/kg 10 mg/kg 12.5 mg/kg
Cmax (mg/l) 278.3 (day 1)
166.3 (day 8) 44.9 ± 3.2 87.5 ± 6.0 112.0 ± 18.0
AUC0- (mg*h/l) 33851 426 ± 49 859 ± 109 1143 ± 195
Vdss (l) 18.3 (day 8) 106 ± 5 115 ± 6 116 ± 13
Cl (l/min) 0.0466 11.9 ± 1.5 11.8 ± 1.4 11.3 ± 2.3
T (h) 321 6.9 ± 0.6 7.5 ± 0.9 7.9 ± 0.9
Cmax: maximum plasma concen a ion, AUC: a ea unde he cu e concen a ion- ime, Vdss: appa en olume o dis ibu ion a s eady s a e, Cl: o al clea ance, T: e minal plasma
hal -li e.
944 Mini-Re iews in Medicinal Chemis y,2009, Vol. 9, No. 8 So lozano e al.
a e a 1 g am dose [56]. Pha macokine ic pa ame e s a e
simila in pa ien s wi h sligh kidney ailu e and in heal hy
olun ee s, so no dose adjus men is equi ed. Nei he is dose
adjus men equi ed in pa ien s wi h sligh (class A Child-
Pugh), mode a e (class B Child-Pugh) o se e e (class C
Child-Pugh) li e ailu e [54].
Ad e se E ec s
Dalba ancin was gene ally well ole a ed du ing he
clinical ial phase [57]. The mos common ad e se e ec s
we e e e (18.2-50%), headaches (1.9-25%), dia hoea (2.5-
21.2%), low blood p essu e (21.2%), anaemia (18.2%),
dyspnoea (15.2%), o al and aginal candidiasis (12.1%),
insomnia (12.1%), nausea (3.2-9.1%) and skin eac ion a he
si e o he injec ion (2.8%) [57-60]. Amongs he mos se-
e e, hough less equen , ad e se e ec s we e leucopaenia,
mode a e hype glycaemia and se e e pancy opaenia, which
spon aneously clea ed up. Simila ly, al e a ions we e no
equen in lab pa ame e s: LDH ele a ion, ALT ele a ion
and h ombopaenia. No case o ed man synd ome was ob-
se ed [57-59].
The neu o oxici y and o o oxici y obse ed wi h o he
glycopep ides we e no obse ed du ing ea men wi h dal-
ba ancin [59, 61]. Acco ding o No d e al., con a y o wha
happens wi h mos an ibio ics, he use o dalba ancin does
no signi ican ly a ec human in es inal mic obio a [56].
Clinical Indica ions
In i o ac i i y o dalba ancin agains MSSA and MRSA
in he a g anuloma pouch in ec ion model, endoca di is
caused by ancomycin-suscep ible s aphylococci and VISA,
and pneumonia caused by penicillin esis an S. pneumoniae
was p o en in animal expe imen s [34, 36, 37, 39].
I s u ili y agains skin and so issue in ec ions caused by
G am-posi i e bac e ia, as well as in sepsis ela ed o coloni-
za ion o ca he e s by coagulase-nega i e s aphylococci,
MSSA o MRSA was con i med in humans [34, 36, 39].
O he possible u u e applica ions o dalba ancin may be
endoca di is, os eomyeli is, diabe ic oo and espi a o y in-
ec ions [62].
TELAVANCIN
S uc u e
Tela ancin (TD-6424) (Fig. 3) is a bac e icidal lipogly-
copep ide wi h mul iple mechanisms o ac ion cu en ly un-
de clinical de elopmen (phase III s udies). I is a ancomy-
cin de i a i e ob ained h ough he alkyla ion o he an-
cosamine subs i uen wi h a la e al hyd ophobic chain (de-
cyl-aminop opyl) and he p esence o an aminome hyl sub-
s i uen (phosphonome hyl) on he cyclic pep idic co e a he
eso cinol posi ion [63-65]. These new inco po a ions o he
molecule con e i imp o ed ac i i y agains MRSA isola es
and VanA pheno ype en e ococci, in addi ion o imp o ing
he pha macokine ics o he an ibio ic [63].
Mechanism o Ac ion
Tela ancin inhibi s he cell wall syn hesis wi h a po ence
ha is 10 imes highe han ha o ancomycin. Tela ancin
inhibi s bac e ial cell wall syn hesis h ough igh binding o
he aglycone co e s uc u e o D-alanine-D-alanine-con aining
pep idoglycan p ecu so , lipid II, and nascen nonc osslinked
pep idoglycan in e media es, hus inhibi ing la e s ages o
cell wall biosyn hesis [64]. No wi hs anding, unlike anco-
mycin, ela ancin does no only ac a his le el and i s
mechanism o ac ion is mo e complex: ela ancin in e ac s
wi h he G am-posi i e bac e ial memb ane o e ec changes
in memb ane po en ial and pe meabili y in a concen a ion-
dependen manne , in a p ocess media ed by he decylami-
noe hyl la e al chain [63-67]. This mul imodal ac ion mecha-
nism, dependen on he an ibio ic concen a ion, is esponsi-
ble o he imp o emen o i s ac i i y agains s aphylococci
(including MRSA, GISA, hGISA and VRSA isola es),
Fig. (3). S uc u e o ela ancin.
NH
HN
O
HO
Me
O
O
HO
HO
O
HO
OHN
H
NMe
MeNH
Me
O
O
NH
O
ONH2
Cl
O
O
ClHN
HO NH
O
OH
N
H
O
OH
CO2H
OH
H
NP
OH
OOH
OH
Me
An imic obial De elopmen in he E a o Eme ging Resis ance Mini-Re iews in Medicinal Chemis y,2009, Vol. 9, No. 8 945
S. pneumoniae (including MDRSP) and VanA en e ococci,
among o he s [63, 65].
Spec um o Ac i i y
Tela ancin is ac i e agains an ample g oup o G am-
posi i e pa hogens such as s aphylococci (MSSA, MRSA,
hVISA, VISA, VRSA isola es, hose esis an o linezolid o
dap omycin, MSCoNS, MRCoNS, ancomycin/ eicoplanin-
esis an S. epide midis and bio ilm-p oducing s aphylococci);
and haemoly ic s ep ococci and, especially, agains S.
pneumoniae (including mul i esis an isola es); en e ococci
(bo h suscep ible and esis an o ancomycin); L. monocy o-
genes and some species o Lac obacillus spp., including an-
comycin, linezolid o dap omycin esis an isola es (excep
o L. casei) [67-73]. I also shows ac i i y agains G am-
posi i e anae obic bac e ia, such as some species o he
Clos idium spp. (mainly C. di icile,C. pe igens and C.
amosum), Eubac e ium spp., P opionibac e ium spp. and
Pep os ep occus spp. [63]. Howe e , like o he glycopep-
ides, i is no ac i e agains G am-nega i e bac e ia [63, 65].
I has also been p o en ha co-adminis a ion o ela a-
ncin wi h ce epime, imipenem o pipe acillin- azobac am
p oduces a syne gic e ec agains VISA and VRSA isola es.
The clinical use o hese combina ions is ye o be de e -
mined [65].
Table 2 e lec s he in i o ac i i y o ela ancin agains
some o he abo emen ioned mic oo ganisms.
Resis ance
Tela ancin shows a low po en ial o he selec ion o
esis an isola es among S. au eus, en e ococci (including
VRE) and mul i esis an S. pneumoniae. The de e minan s o
an esis ance p esen in en e ococci and s aphylococci ha e
ela i ely li le e ec on he ac i i y o ela ancin, mainly
inc easing MIC alues in 2-4 imes [65].
Pha macology
The pha macokine ics o ela ancin is linea and dose-
independen when adminis e ed once a day, o 7 days, in a
ange o 7.5 o 15 mg/kg o weigh [74, 75]. The mean al-
ues o he pha macokine ic pa ame e s o ela ancin a e
lis ed in Table 3. I binds o plasma p o eins in abou 93%
[74, 76]. I s pene a ion in skin blis e luids is app oxima ely
40% o plasma le els [77]. A maximum concen a ion o
3.7 mg/l is ob ained in pulmona y epi helial luid and
45 mg/l in al eola mac ophages, while i las s wi h concen-
a ions o 42 mg/l up o 24 hou s a e s a o adminis a-
ion. In addi ion, i s ac i i y is no a ec ed by he pulmona y
su ac an [78]. I s elimina ion is mainly enal and wo hi ds
o he dosage adminis e ed a e collec ed unal e ed in u ine in
48 hou s [74, 75].
Clea ance in heal hy olun ee s aged 65 and o e was
simila o ha in young adul s, al hough wi h a highe dis i-
bu ion olume and a longe hal li e [65]. Pha macokine ic
pa ame e s a e simila in men and women [75]. C ea inine
clea ance is ela ed o ela ancin clea ance in pa ien s wi h
sligh o mode a e enal ailu e, and he AUC and T1/2 in-
c ease such ha adjus men o he dosage is ad ised in pa-
ien s wi h mode a e o se e e enal ailu e [65]. In pa ien s
wi h mode a e li e ailu e (Child-Pugh class B) he pha ma-
cokine ic pa ame e s a e equi alen o hose o pa ien s wi h
no mal li e unc ion [65].
Ad e se E ec s
In gene al, ea men wi h ela ancin seems o be well
ole a ed [63,67]. The mos equen ad e se e ec s obse ed
du ing clinical ials we e sligh o mode a e in na u e, and
we may highligh he al e a ion o as e in 14-75% o indi-
iduals ea ed ( e e sible a e 24-31 hou s) and headaches
(8-40%). O he e ec s we e e igo (35%), p ocedu al si e
eac ion (25%), nausea (13-20%), insomnia (13%), psychia -
ic diso de s (10%), omi ing (8%), dyspnoea (7%), i ching
(6%), cons ipa ion (3-5%) and pa es hesia (4%) [78-80].
High le els o se um c ea inine we e de ec ed in some
cases, as well as cases o sligh and e e sible hypopo-
asemia [78-80]. No cases o QTc in e al leng hening we e
obse ed [79]. Acco ding o Ba ie e e al., he use o e-
la ancin en ails minimal isk o ad e se ca diac e ec s [81].
Tela ancin is accumula ed in lysosomes o euka yo e
cells, and so i can be ac i e agains in acellula pa hogens.
Howe e , and unlike o i a ancin, i does no signi ican ly
a ec cell le els o phospholipids and choles e ol, maybe
due o a di e en accumula ion a e o because o an in insic
capaci y o in e e e wi h he lipidic me abolism o bo h
molecules [82].
Clinical Indica ions
Up o he cu en momen , he use o ela ancin has been
p oposed o he ea men o in ec ions caused by s aphylo-
cocci (including VRSA isola es): endoca di is, skin and so
issue in ec ions [83-85], pe i oneal dialysis-associa ed pe i-
oni is [86], pneumonias [87, 88], bac e aemias [89], os eo-
myeli is [90]; and, as mono he apy, in he ea men agains
meningi is caused by penicillin- esis an S. pneumoniae [91].
ORITAVANCIN
S uc u e
O i a ancin (LY333328) (Fig. 4) is he N-subs i u ed p-
chlo ophenylbenzyl de i a i e o chlo oe emomycin, a na u-
al glycopep ide p oduc o Amycola opsis o ien alis e men-
a ion [92, 93]. O i a ancin was ob ained by educ i e alky-
la ion wi h 4’chlo o-biphenylca boxaldehyde o he na u al
glycopep ide chlo oe emomycin, which di e s om anco-
mycin by he addi ion o a 4-epi- ancosamine suga and he
eplacemen o he ancosamine by a 4-epi- ancosamine
[94]. The addi ion o he la e al p-chlo ophenylbenzyl chain
o he s uc u e o p ecu so chlo oe emomycin con e s an
imp o ed ac i i y agains en e ococci, bo h VSE and VRE
isola es, al hough i sligh ly educes he ac i i y agains
s aphylococci [92].
Mechanism o Ac ion
Like he es o glycopep ides, o i a ancin p oduces i s
e ec h ough he inhibi ion o he cell wall syn hesis, block-
ing pep idoglycane biosyn hesis. The g ea e capaci y o
dyme iza ion and he ancho ing o he chlo obiphenyl side
chain in o he cy osolic memb ane imp o e in e ac ion and
hus he ac i i y o o i a ancin wi h ega ds o ancomycin.
946 Mini-Re iews in Medicinal Chemis y,2009, Vol. 9, No. 8 So lozano e al.
In ac , o i a ancin also has he capaci y o inhibi he syn-
hesis o he cellula wall in ancomycin- esis an En e o-
coccus spp. isola es [92].
Al hough he bac e icide ac i i y o o i a ancin agains
bac e ia in he exponen ial phase is well es ablished, Belley
e al. explain ha o i a ancin induces depola iza ion o he
memb ane in MSSA isola es, hus inc easing pe meabili y
and causing addi ional al e a ions in he s a iona y phase.
This may explain he powe o o i a ancin agains MSSA,
MRSA and VRSA a minimal bio ilm e adica ion concen a-
ions (MBECs) be ween 0.5 and 8 mg/l [95].
Spec um o Ac i i y
O i a ancin shows a wide spec um o ac i i y, compa a-
ble o ha o ancomycin, bu wi h imp o ed ac i i y agains
ce ain mic oo ganisms [3, 37]. I is ac i e agains G am-
posi i e bac e ia, such as s aphylococci (including MRSA
and VRSA), s ep ococci (including MDRSP isola es) and
en e ococci (including VRE isola es o E. gallina um and E.
casseli la us isola es wi h VanC pheno ype) [96-101]. How-
e e , i may be no ed ha ac i i y agains VRE isola es may
be sligh ly educed in he s a iona y phase [93]. O he o i-
a ancin-suscep ible G am-posi i e bac e ia a e E. hu-
siopa hiae, L. monocy ogenes (including ancomycin- esis-
an isola es), C. jeikeium, B. ce eus and B. an h acis [92,
102].
The adminis a ion o o i a ancin in combina ion wi h
gen amicin inc eases he bac e icide ac i i y agains E. ae-
calis, in addi ion o p e en ing he appea ance o esis ance
agains bo h an ibio ics [103]. The syne gy be ween o i-
a ancin and o he an ibio ics such as linezolid, moxi loxacin
and i ampicin agains S. au eus isola es has also been e-
cen ly p o en [104].
O i a ancin is also ac i e agains anae obic G am-
posi i e mic oo ganisms, such as some species o he Pedio-
coccus spp., Pep os ep ococcus spp., P. acnes and C. pe -
ingens ypes [92, 97], and i s e ec i eness in he ea men
o in ec ions caused by C. di icile was ecen ly demon-
s a ed [105].
On he o he hand, o i a ancin, like o he glycopep ides,
has no ac i i y agains G am-nega i e pa hogens [3] o
agains mycobac e ia [92].
Table 2 shows MIC50 and MIC90 alues ob ained in i o
o o i a ancin agains some o he abo emen ioned mic o-
o ganisms.
Resis ance
Up o da e, no speci ic in i o esis ance o high deg ees
o in i o esis ance o o i a ancin ha e been de ec ed [92,
99]. In addi ion, his an ibio ic may be able o e ade he
mechanisms o esis ance o glycopep ides om s aphylo-
cocci and en e ococci [37]. In ac , i s accep able ac i i y
agains VRE isola es is due o he close binding be ween he
an ibio ic and he D-Ala-D-Lac esidues [92]. No wi hs and-
ing, en e ococci wi h VanA and VanB pheno ypes show e-
duced suscep ibili y o he glycopep ide, ei he due o he
o e exp ession o esis ance de e minan s o o he educ ion
in he le els o D-Ala-D-Ala p ecu so s [92, 93]. S udies
ca ied ou on o i a ancin show ha he poo capaci y o
induce esis ance exe cised by he glycopep ide on hese
Fig. (4). S uc u e o o i a ancin.
Cl
H
N
O
H
3
C
OH
O
CH
3
O
OH
O
OH
OH
O O
ClCl
OHO
OH
3
C
HO
H
2
NCH
3
N
H
H
NN
H
H
N
O
O
O
O
N
H
H
N
O
CH
3
CH
3
CH
3
OH
OHHO
H
2
N
O
HN
O
O
HO
An imic obial De elopmen in he E a o Eme ging Resis ance Mini-Re iews in Medicinal Chemis y,2009, Vol. 9, No. 8 953
[67] D ew, R.H. Eme ging op ions o ea men o in asi e, mul id ug-
esis an S aphylococcus au eus in ec ions. Pha maco he apy,
2007,27, 227-49.
[68] D aghi, D.C.; Ben on, B.M.; K ause, K.M.; Tho nsbe y, C.; Pilla ,
C.; Sahm, D.F. Compa a i e su eillance s udy o ela ancin ac i -
i y agains ecen ly collec ed G am-posi i e clinical isola es om
ac oss he Uni ed S a es. An imic ob. Agen s Chemo he .,2008,52,
2383-8.
[69] D aghi, D.C.; Ben on, B.M.; K ause, K.M.; Tho nsbe y, C.; Pilla ,
C.; Sahm, D.F. In i o ac i i y o ela ancin agains ecen G am-
posi i e clinical isola es: esul s o he 2004-05 P ospec i e Eu o-
pean Su eillance Ini ia i e. J. An imic ob. Chemo he ., 2008,62,
116-21.
[70] Gande , S.; Kinnai d, A.; Finch, R. Tela ancin: in i o ac i i y
agains s aphylococci in a bio ilm model. J. An imic ob. Che-
mo he ., 2005,56, 337-43.
[71] Jansen, W.T.M.; Ve el, A.; Ve hoe , J.; Mila o ic, D. In i o ac i -
i y o ela ancin agains G am-posi i e clinical isola es ecen ly ob-
ained in Eu ope. An imic ob. Agen s Chemo he ., 2007,51, 3420-
4.
[72] King, A.; Phillips, I.; Kaniga, K. Compa a i e in i o ac i i y o
ela ancin (TD-6424), a apidly bac e icidal, concen a ion-
dependen an i-in ec i e wi h mul iple mechanisms o ac ion
agains G am-posi i e bac e ia. J. An imic ob. Chemo he ., 2004,
53, 797-803.
[73] K ause, K.M.; Renelli, M.; Di un o um, S.; Wu, T.X.; Debabo ,
D.V.; Ben on, B.M. In i o ac i i y o ela ancin agains esis an
g am-posi i e bac e ia. An imic ob. Agen s Chemo he ., 2008,52,
2647-52.
[74] Shaw, J.P.; Se oogy, J.; Kaniga, K.; Higgins, D.L.; Ki , M.; Ba i-
e e, S. Pha macokine ics, se um inhibi o y and bac e icidal ac i i y,
and sa e y o ela ancin in heal hy subjec s. An imic ob. Agen s
Chemo he ., 2005,49, 195-201.
[75] Wong, S.L.; Ba ie e, S.L.; Ki , M.M.; Goldbe g, M.R. Mul iple-
dose pha macokine ics o in a enous ela ancin in heal hy male
and emale subjec s. J. An imic ob. Chemo he ., 2008,62, 780-3.
[76] Leu hne , K.D.; Cheung, C.M.; Rybak, M.J. Compa a i e ac i i y
o he new lipoglycopep ide ela ancin in he p esence and absence
o se um agains 50 glycopep ide nonsuscep ible s aphylococci and
h ee ancomycin- esis an S aphylococcus au eus.J. An imic ob.
Chemo he ., 2006,58, 338-43.
[77] Sun, H.K.; Duchin, K.; Nigh ingale, C.H.; Shaw, J.P.; Se oogy, J.;
Nicolau, D.P. Tissue pene a ion o ela ancin a e in a enous
adminis a ion in heal hy subjec s. An imic ob. Agen s Chemo he .,
2006,50, 788-90.
[78] Go ied, M.H.; Shaw, J.P.; Ben on, B.M.; K ause, K.M.; Gold-
be g, M.R.; Ki , M.M.; Ba ie e, S.L. In apulmona y dis ibu ion
o in a enous ela ancin in heal hy subjec s and e ec o pulmo-
na y su ac an on in i o ac i i ies o ela ancin and o he an ibi-
o ics. An imic ob. Agen s Chemo he ., 2008,52, 92-7.
[79] S yjewski, M.E.; G aham, D.R.; Wilson, S.E.; O'Rio dan, W.;
Young, D.; Len nek, A.; Ross, D.P.; Fowle , V.G.; Hopkins, A.;
F iedland, H.D.; Ba ie e, S.L.; Ki , M.M., Co ey, G.R. Tela ancin
e sus ancomycin o he ea men o complica ed skin and skin-
s uc u e in ec ions caused by g am-posi i e o ganisms. Clin. In-
ec . Dis., 2008,46, 1683-93.
[80] S yjewski, M.E.; Chu, V.H.; O’Rio dan, W.D.; Wa en, B.L.;
Dunba , L.M.; Young, D.M.; Vallée, M.; Fowle , V.G.; Mo gan-
o h, J.; Ba ie e, S.L.; Ki , M.M.; Co ey, G.R. Tela ancin e sus
s anda d he apy o ea men o complica ed skin and skin s uc-
u e in ec ions caused by g am-posi i e bac e ia: FAST 2 S udy.
An imic ob. Agen s Chemo he ., 2006,50, 862-7.
[81] Ba ie e, S.; Gen e , F.; Spence , E.; Ki , M.; Hoelsche , D.; Mo -
gan o h, J. E ec s o a new an ibac e ial, ela ancin, on ca diac e-
pola iza ion (QTc in e al du a ion) in heal hy subjec s. J. Clin.
Pha macol., 2004,44, 689-95.
[82] Ba cia-Macay, M.; Mouaden, F.; Mingeo -Lecle cq, M.P.; Tulkens,
P.M.; Van Bambeke, F. Cellula pha macokine ics o ela ancin, a
no el lipoglycopep ide an ibio ic, and analysis o lysosomal
changes in cul u ed euka yo ic cells (J774 mouse mac ophages and
a emb yonic ib oblas s). J. An imic ob. Chemo he ., 2008,61,
1288-94.
[83] Ba cia-Macay, M.; Lemai e, S.; Mingeo -Lecle cq, M.P.; Tulkens,
P.M.; Van Bambeke, F. E alua ion o he ex acellula and in acel-
lula ac i i ies (human THP-1 mac ophages) o ela ancin e sus
ancomycin agains me hicillin-suscep ible, me hicillin- esis an ,
ancomycin-in e media e and ancomycin- esis an S aphylococ-
cus au eus.J. An imic ob. Chemo he ., 2006,58, 1177-84.
[84] Mad igal, A.G.; Basuino, L.; Chambe s, H.F. E icacy o e-
la ancin in a abbi model o ao ic al e endoca di is due o me-
hicillin- esis an S aphylococcus au eus o ancomycin-
in e media e S aphylococcus au eus. An imic ob. Agen s Che-
mo he ., 2005,49, 3163-5.
[85] Mi ó, J.M.; Ga cía-de-la-Ma ia, C.; A me o, Y.; de-Lazza i, E.;
Soy, D.; Mo eno, A.; del Rio, A., Almela, M.; Mes es, C.A.; Ga-
ell, J.M.; Jiménez-de-An a, M.T.; Ma co, F; he Hospi al Clínic
Expe imen al Endoca di is S udy G oup. E icacy o ela ancin in
he ea men o expe imen al endoca di is due o glycopep ide-
in e media e S aphylococcus au eus. An imic ob. Agen s Che-
mo he ., 2007,51, 2373-7.
[86] Clouse, F.L.; Ho de, L.B.; Ro scha e , J.C. In i o e alua ion o
he ac i i ies o ela ancin, ce azolin, and ancomycin agains me-
hicillin-suscep ible and me hicillin- esis an S aphylococcus
au eus in pe i oneal dialysa e. An imic ob. Agen s Chemo he .,
2007,51, 4521-4.
[87] Hegde, S.S.; Reyes, N.; Skinne , R.; Di un o um, S. E icacy o
ela ancin in a mu ine model o pneumonia induced by me hicillin-
suscep ible S aphylococcus au eus.J. An imic ob. Chemo he .,
2008,61, 169-72.
[88] Reyes, N.; Skinne , R.; Kaniga, K.; K ause, K.M.; Shel on, J.;
Obedencio, G.P.; Gough, A.; Conne , M.; Hegde, S.S. E icacy o
ela ancin (TD-6424), a apidly bac e icidal lipoglycopep ide wi h
mul iple mechanisms o ac ion, in a mu ine model o pneumonia
induced by me hicillin- esis an S aphylococcus au eus. An imi-
c ob. Agen s Chemo he ., 2005,49, 4344-6.
[89] Reyes, N.; Skinne , R.; Ben on, B.M.; K ause, K.M.; Shel on, J.;
Obedencio, G.P.; Hegde, S.S. E icacy o ela ancin in a mu ine
model o bac e aemia induced by me hicillin- esis an S aphylococ-
cus au eus.J. An imic ob. Chemo he ., 2006,58, 462-5.
[90] Yin, L.Y.; Calhoun, J.H.; Thomas, T.S.; Wi z, E.D. E icacy o
ela ancin in he ea men o me hicillin- esis an S aphylococcus
au eus os eomyeli is: s udies wi h a abbi model. J. An imic ob.
Chemo he ., 2009,63, 357-60.
[91] S ucki, A.; Ge be , P.; Acos a, F.; Co agnoud, M.; Co agnoud, P.
E icacy o ela ancin agains penicillin- esis an pneumococci and
S aphylococcus au eus in a abbi meningi is model and de e mina-
ion o kine ic pa ame e s. An imic ob. Agen s Chemo he ., 2006,
50, 770-3.
[92] Allen, N.E.; Nicas, T.I. Mechanism o ac ion o o i a ancin and
ela ed glycopep ide an ibio ics. FEMS Mic obiol. Re ., 2003,26,
511-32.
[93] Len ino, J.R.; Na i a, M.; Yu, V.L. New an imic obial agen s as
he apy o esis an g am-posi i e cocci. Eu . J. Clin. Mic obiol.
In ec . Dis., 2008,27, 3-15.
[94] Coope , R.D.; Snyde , N.J.; Zwei el, M.J.; S aszak, M.A.; Wilkie,
S.C.; Nicas, T.I.; Mullen, D.L.; Bu le , T.F.; Rod iguez, M.J.; Hu ,
B.E.; Thompson, R.C. Reduc i e alkyla ion o glycopep ide an i-
bio ics: syn hesis and an ibac e ial ac i i y. J. An ibio . (Tokyo),
1996,49, 575-81.
[95] Belley, A.; Neesham-G enon, E.; Mckay, G.; A hin, F.F.; Ha is,
R.; Be e idge, T.; Pa , T.R.J .; Moeck, G. O i a ancin kills s a-
iona y-phase and bio ilm S aphylococcus au eus in i o.An imi-
c ob. Agen s Chemo he ., 2009,53, 918-25.
[96] Cabellos, C.; Fe nandez, A.; Maiques, J.M.; Tubau, F.; A danuy,
C.; Vilad ich, P.F.; Lina es, J.; Gudiol, F. Expe imen al s udy o
LY333328 (o i a ancin), alone and in combina ion, in he apy o
cephalospo in- esis an pneumococcal meningi is. An imic ob.
Agen s Chemo he ., 2003,47, 1907-11.
[97] Ci on, D.M.; Kwok, Y.Y.; Appleman, M.D. In i o ac i i y o
o i a ancin (LY333328), ancomycin, clindamycin, and me oni-
dazole agains Clos idium pe ingens,P opionibac e ium acnes,
and anae obic G am-posi i e cocci. Anae obe,2005,11, 93-5.
[98] C andon, J.; Nicolau, D.P. O i a ancin: a po en ial weapon in he
ba le agains se ious G am-posi i e pa hogens. Fu u e Mic obiol.,
2008,3, 251-63.
[99] Gosbell, I.B.; Fe nandes, L.A.; Fe nandes, C.J. In i o an ibac e-
ial ac i i y o be a-lac ams and non-be a-lac ams agains S ep o-
coccus pneumoniae isola es om Sydney, Aus alia. Pa hology,
2006,38, 343-8.
954 Mini-Re iews in Medicinal Chemis y,2009, Vol. 9, No. 8 So lozano e al.
[100] No iello, S.; Ianniello, F.; Esposi o, S. In i o ac i i y o
LY333328 (o i a ancin) agains G am-posi i e ae obic cocci and
syne gy wi h cip o loxacin agains en e ococci. J. An imic ob.
Chemo he ., 2001,48, 283-6.
[101] Zeckel, M.L.; P es on, D.A.; Allen, B.S. In i o ac i i ies o
LY333328 and compa a i e agen s agains nosocomial g am-
posi i e pa hogens collec ed in a 1997 global su eillance s udy.
An imic ob. Agen s Chemo he ., 2000,44, 1370-4.
[102] Heine, H.S.; Basse , J.; Mille , L.; Basse , A.; I ins, B.E.; Lehoux,
D.; A hin, F.F.; Pa , T.R.J ; Moeck, G. E icacy o o i a ancin in a
mu ine model o Bacillus an h acis spo e inhala ion an h ax. An-
imic ob. Agen s Chemo he ., 2008,52, 3350-7.
[103] Le o , A.; Saleh-Mghi , A.; Ga y, L.; Ca bon, C.; Fan in, B. Ac-
i i y o LY333328 combined wi h gen amicin in i o and in abbi
expe imen al endoca di is due o ancomycin- suscep ible o -
esis an En e ococcus aecalis. An imic ob. Agen s Chemo he .,
2000,44, 3017-21.
[104] Belley, A.; Neesham-G enon, E.; A hin, F.F.; McKay, G.A.; Pa ,
T.R.J ; Moeck, G. Assessmen by ime-kill me hodology o he
syne gis ic e ec s o o i a ancin in combina ion wi h o he an imi-
c obial agen s agains S aphylococcus au eus.An imic ob. Agen s
Chemo he ., 2008,52, 3820-2.
[105] Baines, S.D.; O'Conno , R.; Sax on, K.; F eeman, J.; Wilcox, M.H.
Compa ison o o i a ancin e sus ancomycin as ea men s o
clindamycin-induced Clos idium di icile PCR ibo ype 027 in ec-
ion in a human gu model. J. An imic ob. Chemo he .,2008,62,
1078-85.
[106] Bha nani, S.M.; Owen, J.S.; Lou i , J.S.; Po e , S.B.; Amb ose,
P.G. Pha macokine ics, sa e y, and ole abili y o ascending single
in a enous doses o o i a ancin adminis e ed o heal hy human
subjec s. Diagn. Mic obiol. In ec . Dis., 2004,50, 95-102.
[107] Fe e ly, G.J.; Ong, C.M.; Bha nani, S.M., Lou i , J.S.; Po e ,
S.B.; Mo ello, L.G.; Amb ose, P.G.; Nicolau, D.P. Pha macokine -
ics o o i a ancin in plasma and skin blis e luid ollowing admini-
s a ion o a 200-millig am dose o 3 days o a single 800-
millig am dose. An imic ob. Agen s Chemo he ., 2005,49, 148-52.
[108] Van Bambeke, F.; Sa an, J.; Mingeo -Lecle cq, M.P.; Tulkens,
P.M. Mixed-lipid s o age diso de induced in mac ophages and i-
b oblas s by o i a ancin (LY333328), a new glycopep ide an ibio ic
wi h excep ional cellula accumula ion. An imic ob. Agen s Che-
mo he ., 2005,49, 1695-700.
[109] Sha pe, J.N. An ibio ics as an adjunc o su gical managemen o
lowe ex emi y ulce a ions. Mic osu ge y,2004,24, 8-17.
[110] Bogdano ich, T.; Cla k, C.; Ednie, L.; Lin, G.; Smi h, K.; Shapi o,
S.; Appelbaum, P.C. Ac i i ies o ce obip ole, a no el b oad-
spec um cephalospo in, agains Haemophilus in luenzae and
Mo axella ca a halis.An imic ob. Agen s Chemo he ., 2006,50,
2050-7.
[111] Deshpande, L.; Rhombe g, P.R.; F i sche, T.R.; Sade , H.S. ; Jones,
R.N. Bac e icidal ac i i y o BAL9141, a no el pa en e al cepha-
lospo in agains con empo a y G am-posi i e and G am-nega i e
isola es. Diagn. Mic obiol. In ec . Dis., 2004,50, 73-5.
[112] Kosowska, K.; Hoellman, D.B.; Lin, G.; Cla k, C.; C edi o, K.;
McGhee, P.; Dewasse, B.; Bozdogan, B.; Shapi o, S.; Appelbaum,
P.C. An ipneumococcal ac i i y o ce obip ole, a no el b oad-
spec um cephalospo in. An imic ob. Agen s Chemo he ., 2005,49,
1932-42.
[113] De esinski, S.C. Ce obip ole: b eaking he apeu ic dogmas o he
be a-lac am class. Diagn. Mic obiol. In ec . Dis., 2008,61, 82-5.
[114] Queenan, A.M.; Shang, W.; Kania, M.; Page, M.G.; Bush, K. In e -
ac ions o ce obip ole wi h be a-lac amases om molecula classes
A o D. An imic ob. Agen s Chemo he ., 2007,51, 3089-95.
[115] Da ies, T.A.; Shang, W.; Bush, K. Ac i i ies o ce obip ole and
o he be a-lac ams agains S ep ococcus pneumoniae clinical iso-
la es om he Uni ed S a es wi h de ined subs i u ions in penicillin-
binding p o eins PBP 1a, PBP 2b, and PBP 2x. An imic ob. Agen s
Chemo he ., 2006,50, 2530-2.
[116] Da ies, T.A.; Page, M.G.; Shang, W.; And ew, T.; Kania, M.;
Bush, K. Binding o ce obip ole and compa a o s o he penicillin-
binding p o eins o Esche ichia coli,Pseudomonas ae uginosa,
S aphylococcus au eus, and S ep ococcus pneumoniae.An imi-
c ob. Agen s Chemo he ., 2007,51, 2621-4.
[117] Jones, M.E. In- i o p o ile o a new be a-lac am, ce obip ole, wi h
ac i i y agains me hicillin- esis an S aphylococcus au eus.Clin.
Mic obiol. In ec ., 2007,13(Suppl 2), 17-24.
[118] Noel, G.J. Clinical p o ile o ce obip ole, a no el be a-lac am
an ibio ic. Clin. Mic obiol. In ec ., 2007, 13(Suppl 2), 25-9.
[119] Page, M.G.P. An i-MRSA be alac ams in de elopmen . Cu . Opin.
Pha macol.,2006,6, 480-5.
[120] Chambe s, H.F. Ce obip ole: in- i o p o ile o a bac e icidal
cephalospo in. Clin. Mic obiol. In ec ., 2006,12(Suppl 2), 17-22.
[121] Leona d, S.N.; Cheung, C.M., Rybak, M.J. Ac i i ies o ce o-
bip ole, linezolid, ancomycin, and dap omycin agains commu-
ni y-associa ed and hospi al-associa ed me hicillin- esis an S aphy-
lococcus au eus.An imic ob. Agen s Chemo he ., 2008,52, 2974-
6.
[122] Amsle , K.M.; Da ies, T.A.; Shang, W.; Jacobs, M.R.; Bush, K. In
i o ac i i y o ce obip ole agains pa hogens om wo phase 3
clinical ials o complica ed skin and skin s uc u e in ec ions. An-
imic ob. Agen s Chemo he ., 2008,52, 3418-23.
[123] Ande son, S.D.; Gums, J.G. Ce obip ole: an ex ended-spec um
an i-me hicillin- esis an S aphylococcus au eus cephalospo in.
Ann. Pha maco he ., 2008,42, 806-16.
[124] Bogdano ich, T.; Ednie, L.M.; Shapi o, S., Appelbaum, P.C. An-
is aphylococcal ac i i y o ce obip ole, a new b oad-spec um
cephalospo in. An imic ob. Agen s Chemo he ., 2005,49, 4210-9.
[125] Chung, M.; An ignac, A.; Kim, C.; Tomasz, A. Compa a i e s udy
o he suscep ibili ies o majo epidemic clones o me hicillin-
esis an S aphylococcus au eus o oxacillin and o he new b oad-
spec um cephalospo in ce obip ole. An imic ob. Agen s Che-
mo he ., 2008,52, 2709-17.
[126] Denis, O.; Deplano, A.; Nonho , C.; Hallin, M.; De Ryck, R.;
Vanhoo , R.; De Mendonca, R., S uelens, M.J. In i o ac i i ies o
ce obip ole, igecycline, dap omycin, and 19 o he an imic obials
agains me hicillin- esis an S aphylococcus au eus s ains om a
na ional su ey o Belgian hospi als. An imic ob. Agen s Che-
mo he ., 2006,50, 2680-5.
[127] D ees, M.; Bouche , H. New agen s o S aphylococcus au eus
endoca di is. Cu . Opin. In ec . Dis.,2006,19, 544-50.
[128] F i sche, T.R.; Sade , H.S.; Jones, R.N. An imic obial ac i i y o
ce obip ole, a no el an i-me hicillin- esis an S aphylococcus
au eus cephalospo in, es ed agains con empo a y pa hogens: e-
sul s om he SENTRY An imic obial Su eillance P og am
(2005-2006). Diagn. Mic obiol. In ec . Dis., 2008,61, 86-95.
[129] Golds ein, E.J.C.; Ci on, D.M.; Me iam, C.V.; Wa en, Y.A.;
Ty ell, K.L.; Fe nandez, H.T. In i o ac i i y o ce obip ole
agains ae obic and anae obic s ains isola ed om diabe ic oo in-
ec ions. An imic ob. Agen s Chemo he ., 2006,50, 3959-62.
[130] Issa, N.C.; Rouse, M.S.; Pipe , K.E.; Wilson, W.R.; S eckelbe g,
J.M.; Pa el, R. In i o ac i i y o BAL9141 agains clinical isola es
o g am-nega i e bac e ia. Diagn. Mic obiol. In ec . Dis., 2004,48,
73-5.
[131] Jones, R.N.; Deshpande, L.M.; Mu nick, A.H.; Biedenbach, D.J. In
i o e alua ion o BAL9141, a no el pa en e al cephalospo in ac-
i e agains oxacillin- esis an s aphylococci. J. An imic ob. Che-
mo he ., 2002,50, 915-32.
[132] Pilla , C.M.; A anza, M.K.; Shah, D.; Sahm, D.F. In i o ac i i y
p o ile o ce obip ole, an an i-MRSA cephalospo in, agains ecen
g am-posi i e and g am-nega i e isola es o Eu opean o igin. J.
An imic ob. Chemo he ., 2008,61, 595-602.
[133] Rossolini, G.M. Redesigning be a-lac ams o comba esis ance:
summa y and conclusions. Clin. Mic obiol. In ec ., 2007,13(Suppl
2), 30-3.
[134] Wang, H.; Liu, Y.; Sun, H.; Xu, Y.; Xie, X.; Chen, M. In i o
ac i i y o ce obip ole, linezolid, igecycline, and 23 o he an imi-
c obial agen s agains S aphylococcus au eus isola es in China. Di-
agn. Mic obiol. In ec . Dis., 2008,62, 226-9.
[135] Zhanel, G.G.; Lam, A.; Schweize , F.; Thomson, K.; Walk y, A.;
Rubins ein, E.; Gin, A.S.; Hoban, D.J.; No eddin, A.M.; Ka -
lowxky, J.A. Ce obip ole: a e iew o a b oad-spec um and an i-
MRSA cephalospo in. Am. J. Clin. De ma ol,, 2008,9, 245-54.
[136] Walk y, A.; Deco by, M.; Nichol, K.; Ka lowsky, J.A.; Hoban,
D.J.; Zhanel, G.G. In i o ac i i y o ce obip ole agains clinical
isola es o Pseudomonas ae uginosa ob ained om Canadian in-
ensi e ca e uni (ICU) pa ien s as pa o he CAN-ICU S udy. J.
An imic ob. Chemo he ., 2008,62, 206-8.
[137] Zbinden, R.; Pün e , V.; on G ae eni z, A. In i o ac i i ies o
BAL9141, a no el b oad-spec um py olidinone cephalospo in,
agains G am-nega i e non e men e s. An imic ob. Agen s Che-
mo he ., 2002,46, 871-4.
An imic obial De elopmen in he E a o Eme ging Resis ance Mini-Re iews in Medicinal Chemis y,2009, Vol. 9, No. 8 955
[138] Ednie, L.; Shapi o, S.; Appelbaum, P.C. An ianae obe ac i i y o
ce obip ole, a new b oad-spec um cephalospo in. Diagn. Mic o-
biol. In ec . Dis., 2007,58, 133-6.
[139] Woo on, M.; Bowke , K.E.; Hol , H.A.; MacGowan, A.P. BAL
9141, a new b oad-spec um py olidinone cephalospo in: ac i i y
agains clinically signi ican anae obes in compa ison wi h 10 o he
an imic obials. J. An imic ob. Chemo he ., 2002,49, 535-9.
[140] Bane jee, R.; G e es, M.; Basuino, L.; S ynadka, N.; Chambe s,
H.F. In i o selec ion and cha ac e iza ion o ce obip ole- esis an
me hicillin- esis an S aphylococcus au eus.An imic ob. Agen s
Chemo he .,2008,52, 2089-96.
[141] Mu hy, B.; Schmi -Ho mann, A. Pha macokine ics and pha ma-
codynamics o ce obip ole, an an i-MRSA cephalospo in wi h
b oad-spec um ac i i y. Clin. Pha macokine ., 2008, 47, 21-33.
[142] Schmi -Ho mann, A.; Roos, B.; Schleime , M.; Saue , J.; Man,
A.; Nashed, N.; B own, T.; Pe ez, A.; Weidekamm, E.; Ko ács, P.
Single-dose pha macokine ics and sa e y o a no el b oad-spec um
cephalospo in (BAL5788) in heal hy olun ee s. An imic ob.
Agen s Chemo he ., 2004,48, 2570-5.
[143] Schmi -Ho mann, A.; Nyman, L.; Roos, B.; Schleime , M.; Saue ,
J.; Nashed, N.; B own, T.; Man, A.; Weidekamm, E. Mul iple-dose
pha macokine ics and sa e y o a no el b oad-spec um cepha-
lospo in (BAL5788) in heal hy olun ee s. An imic ob. Agen s
Chemo he ., 2004,48, 2576-80.
[144] Noel, G.J.; Bush, K.; Bagchi, P.; Ianus, J.; S auss, R.S. A andom-
ized, double-blind ial compa ing ce obip ole medoca il wi h an-
comycin plus ce azidime o he ea men o pa ien s wi h compli-
ca ed skin and skin-s uc u e in ec ions. Clin. In ec . Dis., 2008,46,
647-55.
[145] En enza, J.M.; Hohl, P.; Heinze-K auss, I.; Glause , M.P.; Mo eil-
lon, P. BAL9141, a no el ex ended-spec um cephalospo in ac i e
agains me hicillin- esis an S aphylococcus au eus in ea men o
expe imen al endoca di is. An imic ob. Agen s Chemo he ., 2002,
46, 171-7.
[146] Rouse, M.S.; Hein, M.M.; Angui a-Alonso, P.; S eckelbe g, J.M.;
Pa el, R. Ce obip ole medoca il (BAL5788) ea men o expe i-
men al Haemophilus in luenzae,En e obac e cloacae, and Kleb-
siella pneumoniae mu ine pneumonia. Diagn. Mic obiol. In ec .
Dis., 2006,55, 333-6.
[147] A ias, C.A.; Singh, K.V.; Panesso, D.; Mu ay, B.E. Time-kill and
syne gism s udies o ce obip ole agains En e ococcus aecalis, in-
cluding be a-lac amase-p oducing and ancomycin- esis an iso-
la es. An imic ob. Agen s Chemo he ., 2007,51, 2043-7.
[148] Laue, H.; Weiss, L.; Be na di, A.; Hawse , S.; Lociu o, S.; Islam,
K. In i o ac i i y o he no el diaminopy imidine, iclap im, in
combina ion wi h ola e inhibi o s and o he an imic obials wi h
di e en mechanisms o ac ion. J. An imic ob. Chemo he ., 2007,
60, 1391-4.
[149] Schneide , P.; Hawse , S.; Islam, K. Iclap im, a no el diamino-
py imidine wi h po en ac i i y on ime hop im sensi i e and esis-
an bac e ia. Bioo g. Med. Chem. Le ., 2003,13, 4217-21.
[150] Zhanel, G.G.; Ka lowsky, J.A. In i o ac i i y o iclap im agains
espi a o y and bac e emic isola es o S ep ococcus pneumoniae.
An imic ob. Agen s Chemo he ., 2009,53, 1690-2.
[151] Kohlho , S.A.; Roblin, P.M.; Reznik, T.; Hawse , S.; Islam, K.;
Hamme schlag, M.R. In i o ac i i y o a no el diamino-
py imidine compound, iclap im, agains Chlamydia achoma is
and Chlamydia pneumoniae.An imic ob. Agen s Chemo he ., 2004,
48, 1885-6.
[152] Bozdogan, B.; Esel, D.; Whi ene , C.; B owne, F.A.; Appelbaum,
P.C. An ibac e ial suscep ibili y o a ancomycin- esis an S aphy-
lococcus au eus s ain isola ed a he He shey Medical Cen e . J.
An imic ob. Chemo he ., 2003,52, 864-8.
[153] Kohlho , S.A.; Sha ma, R. Iclap im. Expe . Opin. In es ig. D ugs,
2007,16, 1441-8.
[154] Mo issey, I.; Mahe , K.; Hawse , S. Ac i i y o iclap im agains
clinical isola es o S ep ococcus pyogenes and S ep ococcus aga-
lac iae. J. An imic ob. Chemo he ., 2009,63, 413-4.
[155] Mo issey, I.; Hawse , S. Ac i i y o iclap im agains Legionella
pneumophila.J. An imic ob. Chemo he ., 2007,60, 905-6.
[156] And ews, J.; Honeybou ne, D.; Ashby, J.; Je ons, G.; F aise, A.;
F y, P.; Wa ing on, S.; Hawse , S.; Wise, R. Concen a ions in
plasma, epi helial lining luid, al eola mac ophages and b onchial
mucosa a e a single in a enous dose o 1.6 mg/kg o iclap im
(AR-100) in heal hy men. J. An imic ob. Chemo he ., 2007,60,
677-80.
[157] F ench, G.L. Wha 's new and no so new on he an imic obial ho i-
zon? Clin. Mic obiol. In ec ., 2008,14(Suppl 6), 19-29.
[158] Peppa d, W.J.; Schuenke, D.C. Iclap im, a diaminopy imidine
dihyd o ola e educ ase inhibi o o he po en ial ea men o an i-
bio ic- esis an s aphylococcal in ec ions. Cu . Opin. In es ig.
D ugs,2008,9, 210-25.
Recei ed: 12 Feb ua y, 2009 Re ised: 09 Ap il, 2009 Accep ed: 09 Ap il, 2009
