vancomycin mrsa

S184 CID 2007:45 (Suppl 3) Micek

S U P P L E M E N T A R T I C L E

Alternatives to Vancomycin for the Treatment ofMethicillin-Resistant Staphylococcus aureus Infections

Scott T. MicekDepartment of Pharmacy, Barnes-Jewish Hospital, St. Louis, Missouri

Vancomycin remains the reference standard for the treatment of systemic infection caused by methicillin-

resistant Staphylococcus aureus (MRSA). However, as a result of limited tissue distribution, as well as the

emergence of isolates with reduced susceptibility and in vitro resistance to vancomycin, the need for alternative

therapies that target MRSA has become apparent. New treatment options for invasive MRSA infections include

linezolid, daptomycin, tigecycline, and quinupristin/dalfopristin. Additionally, a number of new anti-MRSA

compounds are in development, including novel glycopeptides (dalbavancin, telavancin, and oritavancin),

ceftobiprole, and iclaprim. The present article will review clinical issues surrounding the newly marketed and

investigational agents with activity against MRSA.

Vancomycin has been considered to be the reference

standard for the treatment of invasive methicillin-re-

sistant Staphylococcus aureus (MRSA) infections, as a

result of its relatively clean safety profile, its durability

against the development of resistance, and, for many

years, the lack of other approved alternatives. However,

the advent and testing of new compounds with anti-

MRSA activity, for comparison with vancomycin, have

rendered results that call into question the efficacy of

vancomycin in the treatment of many serious infec-

tions. The reasons for clinical failure of vancomycin are

many and have been hypothesized to include poor pen-

etration of the drug to certain tissues [13], loss of

accessory generegulator function in MRSA [4], and

potential escalation of vancomycin MICs for MRSA [5].

Additionally, an increasing number of reports of van-

comycin-intermediate S. aureus (VISA) and vanco-

mycin-resistant S. aureus (VRSA) have populated the

literature dating back to 1999. Many alternatives for

the treatment of MRSA infections, including linezolid,

daptomycin, tigecycline, and quinupristin/dalfopristin,

Reprints or correspondence: Dr. Scott T. Micek, Dept. of Pharmacy, Barnes-Jewish Hospital, Mailstop 90-52-411, 216 S. Kingshighway Blvd., St. Louis, MO([email protected]).

Clinical Infectious Diseases 2007; 45:S18490 2007 by the Infectious Diseases Society of America. All rights reserved.1058-4838/2007/4506S3-0005$15.00DOI: 10.1086/519471

are currently approved by the US Food and Drug Ad-

ministration (FDA). Additionally, there are several in-

vestigational compounds with demonstrated in vitro

activity against MRSA. The chemical structures of these

agents are shown in figure 1.

LINEZOLID

Linezolid is a synthetic oxazolidinone that inhibits the

initiation of protein synthesis at the 50S ribosome [6].

It is currently approved by the FDA for the treatment

of complicated skin and skin-structure infections

(SSSIs) and nosocomial pneumonia caused by suscep-

tible pathogens, including MRSA. Several retrospective

analyses of pooled data from randomized trials have

compared linezolid with vancomycin in patients with

proven MRSA infection. An analysis of 2 double-blind

studies of patients with MRSA nosocomial pneumonia

found that 75 patients treated with linezolid had sur-

vival rates that were significantly higher than those of

85 patients treated with vancomycin (80% vs. 64%;

) [7]. The authors hypothesized that a possiblePp .03

explanation for the finding was vancomycins poor pen-

etration of the lung, particularly when the standard

dosage is 1 g administered every 12 h. However, ag-

gressive dosing strategies for vancomycin (goal trough

concentrations of 115 mg/mL, or 45 the MIC value)

may not offer an advantage over traditional dosing

strategies [8, 9]. A follow-up, randomized, double-blind

by guest on February 25, 2015http://cid.oxfordjournals.org/

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Novel Antibiotics for MRSA CID 2007:45 (Suppl 3) S185

Figure 1. Molecular structures of novel antibiotics for methicillin-resistant Staphylococcus aureus infections

trial is under way that compares these 2 agents in hospitalized

patients with nosocomial pneumonia due to MRSA. Similarly,

retrospective evaluations of complicated skin and soft-tissue

infections (SSTIs) caused by MRSA have found that, compared

with vancomycin, linezolid is associated with significantly

higher clinical cure rates and reduced lengths of hospitalization

[6, 10]. A retrospective analysis of pooled data from 5 ran-

domized studies did not find linezolid to be superior to van-

comycin in patients with secondary MRSA bacteremia [11].

Linezolid should also be considered for necrotizing infec-

tions, including skin lesions [12], fasciitis [13], and pneumonia

[14] caused by community-associated MRSA, particularly the

USA300 strain. The severity of these infections may be asso-

ciated with allotypes of mobile genetic elements found in

USA300 that code for pathogenic toxins, including Panton-

Valentine leukocidin, enterotoxin Q, and enterotoxin K [15].

It has been hypothesized that antibiotics with the ability to

inhibit protein synthesis may demonstrate efficacy against sus-

ceptible toxin-producing strains. Linezolid, along with clin-

damycin, has recently been found to reduce production of

Panton-Valentine leukocidin, a-hemolysin, and toxic-shock

syndrome toxin1, whereas vancomycin and nafcillin have been

found to increase such production in an in vitro model [16].

Despite the apparent advantages of linezolid in the treat-

ment of MRSA infections, concerns about safety often limit

its use. Of particular concern is the association of linezolid

with serotonin toxicity and thrombocytopenia [17, 18]. Li-

nezolid exhibits weak reversible inhibition of monoamine

oxidase and can induce toxicity when used in combination

with agents that have serotonergic activity, most commonly

selective serotonin reuptake inhibitors. Twenty-nine cases of

linezolid-associated serotonin toxicity were recently reported.

Postmarketing information submitted to the FDA regarding

29 patients with serotonin toxicity showed that 61% had re-

ceived concomitant treatment with a selective serotonin reup-

take inhibitor [17]. Three patients died, possibly because of

serotonin toxicity, and another 13 patients required medical

treatment [13]. Linezolid used concomitantly with selective

serotonin reuptake inhibitors in hospitalized patients has also

been evaluated in a retrospective study [19]. This study found

a high probability of serotonin toxicity in association with 2

of 72 concomitant uses. The authors suggest that linezolid


Dow

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S186

Tabl

e1.

Ove

rvie

wof

nove

lan

timic

robi

alag

ents

avai

labl

eto

trea

tm

ethi

cilli

n-re

sist

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taph

yloc

occu

sau

reus

(MRS

A).

Dru

g,au

thor

s[r

efer

ence

]In

fect

ion

trea

ted

(no.

ofpa

tient

sin

stud

y)R

egim

enE

ffica

cyS

afet

y

LZD W

unde

rink

etal

.[7

]N

osoc

omia

lpne

umon

ia(1

60pa

tient

sw

ithM

RS

A)

LZD

(600

mg

q12h

)or

VM

(1g

q12h

);bo

thpl

usAT

Nfo

r7

12da

ysC

linic

alcu

rera

te:

LZD

,59

%(3

6of

61pa

tient

s);

VM

,36

%(2

2of

62pa

tient

s)(P

!.0

1).S

urvi

val

rate

:LZ

D,

80%

(60

of75

patie

nts)

;VM

,64

%(5

4of

85pa

tient

s)(Pp

.03)

.

Not

repo

rted

Wie

gelt

etal

.[6

]S

STI

s(2

85pa

tient

sw

ithM

RS

A)

LZD

(600

mg

ivor

poq1

2h)o

rV

M(1

gq1

2h)

Clin

ical

cure

rate

:LZ

D,

89%

(124

of14

0pa

-tie

nts)

;VM

,67

%(9

7of

145

patie

nts)

(P!

.001

)

Dru

g-re

late

dad

vers

eev

ents

wer

ere

port

edin

sim

ilar

num

bers

ofpa

tient

sin

both

trea

tmen

tar

msa

Sho

rret

al.

[11]

Bac

tere

mia

b(5

3pa

tient

sw

ithM

RS

A)

LZD

(600

mg)

orV

M(1

gea

chq1

2h);

ATN

isad

ded

inst

udie

sof

pneu

mon

ia

Clin

ical

cure

rate

:LZ

D,

56%

(14

of25

patie

nts)

;V

M,

46%

(13

of28

patie

nts)

;OR

,1.

47(9

5%C

I,0.

504

.34)

The

rate

ofad

vers

eev

ents

was

sim

ilar

betw

een

trea

tmen

tgr

oups

(LZD

,80%

;V

M,

70%

),as

wer

eth

era

teof

serio

usad

vers

eev

ents

c(L

ZD,

47%

;V

M,

39%

)an

dth

era

teof

trea

tmen

tdi

s-co

ntin

uatio

n(L

ZD,3

7%;

VM

,39

%);

alld

iffer

-en

ces

wer

eN

S

TIG B

reed

tet

al.

[25]

SS

TIs

(546

patie

nts

[0w

ithdo

cu-

men

ted

MR

SA

and

8w

ithpr

e-su

med

MR

SA

])

TIG

(100

mg/

day,

with

anin

itial

100-

mg

load

ing

dose

);V

M(1

gq1

2h)

plus

ATN

(2g

q12h

)

Clin

ical

resp

onse

rate

:TI

G,

84%

;V

M/A

TN,8

7%(Pp

NS

).P

atho

gen

erad

icat

ion

rate

:TI

G,

85%

;V

M/A

TN,9

3%(Pp

.02)

.

Adv

erse

even

tssi

mila

rbe

twee

n2

grou

ps,b

utth

ere

wer

ein

crea

sed

rate

sof

naus

eaan

dvo

miti

ngin

the

TIG

grou

pan

dhi

gher

rate

sof

rash

and

incr

ease

sin

LFT

resu

ltsin

the

VM

/AT

Ngr

oup

DP

T Arb

eit

etal

.[2

8]S

STI

s(8

99pa

tient

s[8

7pa

tient

sw

ithM

RS

A])

DP

T(4

mg/

kgiv

q24h

for

714

days

);co

mpa

rato

rs(r

esul

tspo

oled

)in-

clud

edP

RP

sd(4

12

g/da

yiv

)or

VM

(1g

ivq1

2h)

Clin

ical

succ

ess

rate

(all

eval

uabl

epa

tient

s):D

PT,

83%

;co

mpa

rato

rs,8

4%.

Clin

ical

succ

ess

rate

(pat

ient

sw

ithM

RS

A):

DP

T,75

%;

com

para

tors

,68

%.

Freq

uenc

yan

ddi

strib

utio

nof

adve

rse

even

tsw

ere

sim

ilar

betw

een

trea

tmen

tgr

oups

Fow

ler

etal

.[2

9]B

acte

rem

iaan

den

doca

rditi

s(2

46pa

-tie

nts

[89

patie

nts

with

MR

SA

])D

PT

(6m

g/kg

ivq2

4h);

OR

VM

(1g

q12h

)or

PR

Psd

(2g

q4h)

plus

GM

(1m

g/kg

ivq8

h)

Clin

ical

succ

ess

rate

atda

y42

oftr

eatm

ent:

DP

T,44

%;

com

para

tors

,42%

.C

linic

alsu

cces

sra

te(p

atie

nts

with

MR

SA

):D

PT,

44%

;co

mpa

rato

rs,

32%

.

Ove

rall

inci

denc

eof

adve

rse

even

tsw

assi

mila

rbe

twee

ntr

eatm

ent

grou

ps.R

ate

ofse

rious

ad-

vers

eev

ents

:eD

PT,

52%

;co

mpa

rato

rs,4

5%.

Incr

ease

sin

crea

tine

kina

sele

vels

wer

em

ore

com

mon

inth

eD

PT

grou

p(7

%vs

.1%

)(Pp

.04)

.


Dow

nloaded from

S187

DB

V Jaur

egui

etal

.[3

0]S

STI

s(6

60pa

tient

s[2

87pa

tient

sw

ithM

RS

A])

DB

V(1

000

mg

onda

y1,

follo

wed

by50

0m

giv

onda

y8)

;LZ

D(6

00m

giv

orpo

q12h

for

14da

ys)

Clin

ical

effic

acy

atte

st-o

f-cu

re:D

BV,

89%

;LZ

D,

91%

Adv

erse

even

tsin

volv

ing

the

GI

trac

tw

ere

the

mos

tco

mm

onad

vers

eev

ents

inbo

thtr

eat-

men

tgr

oups

;ahi

gher

prop

ortio

nof

patie

nts

rece

ivin

gLZ

Dha

dad

vers

eev

ents

that

wer

eju

dged

byin

vest

igat

ors

tobe

trea

tmen

tre

late

d

Raa

det

al.

[31]

CR

-BS

Is(7

5pa

tient

s[1

4pa

tient

sw

ithM

RS

A])

DB

V(1

000

mg

onda

y1,

follo

wed

by50

0m

giv

onda

y8)

;V

M(1

gq1

2hfo

r14

days

)

Ove

rall

succ

ess

rate

:D

BV,

87%

;V

M,

73%

Adv

erse

even

tsw

ere

gene

rally

mild

and

wer

eco

mpa

rabl

ein

the

2tr

eatm

ent

grou

ps

TLV S

tryj

ewsk

iet

al.

[32]

SS

TIsf

(167

patie

nts

[48

patie

nts

with

MR

SA

])TL

V(7

.5m

g/kg

/day

iv);

stan

dard

ther

-ap

y:V

M(1

gq1

2h),

NA

For

OX

(2g

q6h)

,and

Clo

x(0

.51

gq6

h)

Ove

rall

test

-of-

cure

rate

:TL

V,80

%;

stan

dard

ther

-ap

y,77

%.

MR

SA

test

-of-

cure

rate

:TL

V,82

%;

stan

dard

ther

apy,

69%

.M

RS

Am

icro

biol

ogic

aler

adic

atio

nra

te:

TLV,

84%

;st

anda

rdth

erap

y,74

%

Few

erse

rious

adve

rse

even

tsw

ere

note

dw

ithTL

V;

the

mos

tco

mm

onad

vers

eev

ents

wer

esi

mila

rbe

twee

ntr

eatm

ent

grou

psan

din

clud

edna

usea

,ps

ychi

atric

diso

rder

,hea

dach

e,vo

mit-

ing,

and

dysp

nea

CTB B

asile

aP

harm

aceu

tica

[33]

SS

TIs

due

togr

am-p

ositi

vepa

thog

ens

(784

patie

nts

[125

%w

ithM

RS

A])

CTB

(500

mg

q12h

);V

M(1

gq1

2h)

Clin

ical

cure

rate

:C

TB,

93%

;V

M,

93%

.M

RS

Acl

inic

alre

spon

sera

te:

CTB

,92

%;

VM

,90

%.

Ther

ew

ere

few

serio

ustr

eatm

ent-

rela

ted

ad-

vers

eev

ents

,the

inci

denc

esof

whi

chw

ere

sim

ilar

betw

een

trea

tmen

tgr

oups

NO

TE

.AT

N;

aztr

eona

m;

Clo

x,cl

oxac

illin

;C

R-B

SIs

,ca

thet

er-r

elat

edbl

oods

trea

min

fect

ions

;C

TB,

ceft

obip

role

;D

BV,

dalb

avan

cin;

DP

T,da

ptom

ycin

;G

I,ga

stro

inte

stin

al;

GM

,ge

ntam

icin

;iv

,in

trav

enou

sly;

LFT,

liver

func

tion

test

;LZD

,lin

ezol

id;M

RS

A,m

ethi

cilli

n-re

sist

ant

Sta

phyl

ococ

cus

aure

us;N

AF,

nafc

illin

;NS

,not

sign

ifica

nt;O

X,o

xaci

llin;

po,b

ym

outh

;PR

Ps,

peni

cilli

nase

-res

ista

ntpe

nici

llins

;q4h

,eve

ry4

h;q6

h,ev

ery

6h;

q8h,

ever

y8

h;q1

2h,e

very

12h;

q24h

,eve

ry24

h;S

STI

s,sk

inan

dso

ft-t

issu

ein

fect

ions

;TIG

,tig

ecyc

line;

TLV,

tela

vanc

in;V

M,

vanc

omyc

in.

aD

iarr

hea,

naus

ea,

and

thro

mbo

cyto

peni

aw

ere

mos

tco

mm

only

asso

ciat

edw

ithLZ

D,

and

anem

ia,

naus

ea,

and

prur

itus

wer

em

ost

com

mon

lyas

soci

ated

with

VM

.b

Poo

led

anal

ysis

ofre

sults

from

5st

udie

s.c

Det

ails

rega

rdin

gth

ena

ture

ofth

ese

rious

adve

rse

even

tsar

eno

tav

aila

ble.

Inve

stig

ator

sas

sess

edea

chev

ent

asse

rious

orno

tse

rious

.d

Clo

x,flu

clox

acill

in,N

AF,

and

OX

.e

Ser

ious

adve

rse

even

tsin

clud

edin

fect

ions

and

infe

stat

ions

,car

diac

diso

rder

s,re

spira

tory

,tho

raci

c,an

dm

edia

stin

aldi

sord

ers,

nerv

ous

syst

emdi

sord

ers,

psyc

hiat

ricdi

sord

ers,

and

labo

rato

ryab

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aliti

es.

fP

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2st

udy.


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may be used concomitantly with selective serotonin reuptake

inhibitors, with careful monitoring, and they recommend

prompt discontinuation of the serotonergic agent if serotonin

syndrome is suspected [19]. The occurrence of thrombocy-

topenia has proven to be not significantly different than that

encountered in patients with nosocomial pneumonia or or-

thopedic infections. Of note, patients with renal insufficiency

may be at higher risk of developing this toxicity [20, 21].

Finally, there have been sporadic reports of peripheral neu-

ropathy, typically in patients with osteomyelitis or other un-

derlying diseases, and lactic acidosis [22, 23].

TIGECYCLINE

Tigecycline is the first drug approved in the class of glycylcyc-

lines, a derivative of minocycline. A modified side chain on

tigecycline enhances binding to the 30S ribosomal subunit, in-

hibiting protein synthesis and bacterial growth across a broad

spectrum of pathogens, including MRSA [24]. In addition, this

structural modification circumvents resistance mechanisms that

plague tetracycline and other antibiotics in this class. Tigecyc-

line is approved in the United States for the treatment of com-

plicated SSSIs due to MRSA. The drug is also approved for the

treatment of complicated intra-abdominal infections but only

for those caused by methicillin-susceptible S. aureus. At this

time, the published experience with tigecycline for the treat-

ment of MRSA infections is limited to 2 double-blind com-

parison studies of vancomycin and aztreonam in patients with

complicated SSSIs and case reports [25, 26]. Tigecycline has a

large volume of distribution and produces high concentrations

in tissues outside of the bloodstream, including bile, the colon,

and the lung. Conversely, serum concentrations of tigecycline

rapidly decrease after infusion, and the area under the con-

centration-time curve (AUC) after administration of multiple

50-mg doses every 12 h is 3 mg7h/mL [27]. On the basis ofstudies of the pharmacodynamic properties of tetracycline, the

target AUC for tigecycline should be 24 times the MIC, in an

effort to optimize efficacy in the treatment of MRSA infections.

Given a tigecycline MIC90 range of 0.250.5 mg/mL for MRSA,

caution should be used when using tigecycline for the treatment

of patients with suspected or proven bacteremia [27]. The re-

sults of further clinical evaluation should be cumulated and

assessed to determine whether to accept or refute this potential

limitation. The approved dose is a 100-mg intravenous loading

dose followed by 50 mg given every 12 h. Nausea and vomiting

are the predominant adverse events, and they increase in fre-

quency with dose escalation.

DAPTOMYCIN

Daptomycin is a cyclic lipopeptide that causes depolarization

of the bacterial cell membrane. The indicated dose for MRSA-

associated complicated SSTIs is 4 mg/kg once daily, and that

for bloodstream infections, including right-side endocarditis, is

6 mg/kg once daily [28]. Of note, daptomycin should not be

used in the treatment of MRSA pneumonia, because the activity

of the drug is inhibited by pulmonary surfactant. The results

of daptomycin trials in patients with complicated SSTIs and

bacteremia/endocarditis are shown in table 1 [28, 29]. In brief,

of the patients who had MRSA isolated, 20 (44%) of 45 were

successfully treated with daptomycin, and, of the patients in

the bacteremia/endocarditis trial, 14 (32%) of 44 patients were

successfully treated with vancomycin. The difference between

daptomycin and standard therapy in the treatment of MRSA

infections was not statistically significant. Significantly, for 6

patients who experienced microbiological failure while receiv-

ing daptomycin, it was reported that, during therapy, the MICs

for the isolated pathogen increased from 0.25 or 0.5 mg/mL to

2 or 4 mg/mL [29]. The mechanism for resistance development

while receiving therapy is, at present, not understood, but it is

likely to be a consequence and a concern in patients who require

prolonged courses of daptomycin therapy.

GLYCOPEPTIDES

Dalbavancin. Dalbavancin is a semisynthetic lipoglycopep-

tide that inhibits cell wall synthesis and has in vitro activity

against MRSA [34]. The unique feature of this investigational

agent is its long half-life (610 days), which allows for once-

weekly dosing. In a randomized, double-blind trial, dalbavancin

(1000 mg given intravenously on day 1 and 500 mg given

intravenously on day 8) has been compared with linezolid in

the treatment of SSSIs [30]. Overall clinical success rates are

presented in table 1. In this trial, 51% of the isolates were found

to be MRSA. In a phase 2, open-label study of the treatment

of catheter-related bloodstream infections, once-weekly treat-

ment with dalbavancin was compared with treatment with van-

comycin [31]. MRSA was identified at baseline in 5 patients

who received dalbavancin, and, in the overall intention-to-treat

analysis, dalbavancin was found to result in a success rate sig-

nificantly higher than that noted with vancomycin (87% vs.

50%; ). The most common adverse events included nau-P ! .05

sea and diarrhea or constipation; however, dalbavancin may

also be associated with hypotension, hypokalemia, and increases

in alanine aminotransferase and aspartate aminotransferase lev-

els measured in liver function tests, although, to date, the re-

ports of these adverse events are conflicting [34].

Telavancin. Telavancin is another semisynthetic lipogly-

copeptide that has a dual mechanism of action, including in-

hibition of cell wall synthesis and disruption of membrane

barrier function [35]. It has a half-life of 79 h, which allows

once-daily dosing (7.510 mg/kg/day). The disruption of

membrane barrier function translates to rapid bactericidal ac-


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Novel Antibiotics for MRSA CID 2007:45 (Suppl 3) S189

tivity against pathogens, including MRSA. It is currently under

investigation for the treatment of SSTIs, nosocomial pneu-

monia, and uncomplicated bacteremia due to S. aureus [35].

As shown in table 1, the efficacy of telavancin was similar to

that of standard therapy in early trials [32, 36]. Preliminary,

unpublished phase 3 results indicate that the clinical cure and

eradication rates associated with telavancin were higher than

those associated with vancomycin, particularly in patients in-

fected with MRSA [37]. Adverse events reported to date include

nausea, taste disturbance, and insomnia.

Oritavancin. Oritavancin is also a semisynthetic glycopep-

tide that is in development. The mechanism of action of this

drug involves disruption of transmembrane potential, and it

has demonstrated activity against vancomycin-resistant strains

of staphylococci and enterococci [38]. Oritavancin has a very

long half-life of 100 h, and dosing once daily or every otherday is likely to be recommended. The percentage of time above

the MIC of the free drug was found to be the determinant of

microbiological and clinical response in bacteremia [39]. Stud-

ies of oritavancin are being conducted in patients with com-

plicated SSTIs, catheter-related bloodstream infections, and

nosocomial pneumonia [38]. Preliminary results of studies of

SSTIs showed noninferiority of oritavancin to vancomycin and

cephalexin. Adverse events associated with oritavantin include

headache, nausea, and sleep disorders.

CEFTOBIPROLE AND CEFTAROLINE

Ceftobiprole is an investigational cephalosporin engineered to

bind tightly to penicillin-binding protein 2a, a peptidoglycan

transpeptidase that confers b-lactam resistance in S. aureus iso-

lates harboring the mecA gene [40, 41]. This compound is the

first of the b-lactam antibiotics to have activity against MRSA

as well as penicillin-resistant streptococci. Importantly, in pre-

clinical, multipassage resistance-selection studies, ceftobiprole

demonstrated a low potential to select for resistance; the highest

MIC found in the presence of prolonged serial passages with

ceftobiprole at subinhibitory concentrations was 8 mg/mL in 1

of 10 strains after 50 passages [42]. Ceftobiprole is administered

twice daily by the intravenous route and has been granted fast-

track status by the FDA for the indications of complicated SSSIs

and health careassociated pneumonia [41]. Two phase 3 trials

for complicated SSSIs have been completed (STRAUSS and

STRAUSS II), with preliminary results reportedly demonstrat-

ing noninferiority of ceftobiprole to comparators overall and

in patients with MRSA [40, 33]. The most common adverse

effects were nausea and taste disturbances.

Ceftaroline is another broad-spectrum cephalosporin with

gram-positive and gram-negative bactericidal activity. Early

testing indicates that MRSA and vancomycin-resistant staph-

ylococci are susceptible to ceftaroline [43]. Phase 2 studies of

this agent in patients with SSTIs are under way.

ICLAPRIM

Iclaprim is a diaminopyrimidine that inhibits the enzyme di-

hydrofolate reductase. Data on iclaprim are limited. However,

it has activity against MRSA, and preliminary results from a

phase 3 trial in patients with complicated SSTIs showed non-

inferiority of iclaprim to linezolid at the test of cure [44]. In

this study, 25% of the infections were due to MRSA.

CONCLUSIONS

Several antibiotics with anti-MRSA activity, including linezolid,

tigecycline, and daptomycin, have been approved by the FDA.

Additionally, there are a number of compounds in development

that will likely provide a broader armamentarium for clinicians

in the management of infections due to MRSA. The emergence

of vancomycin-intermediate and vancomycin-resistant strains

of S. aureus has also created a need for agents with expanded

coverage. The in vitro activity of new and investigational agents

against VISA and VRSA has recently been reviewed elsewhere

[45]. In brief, linezolid, daptomycin, tigecycline, and quinu-

pristin/dalfopristin, as well as the new investigational com-

pounds dalbavancin, telavancin, oritavancin, ceftobiprole, and

iclaprim, have demonstrated in vitro activity against VISA and

VRSA.

Acknowledgments

Supplement sponsorship. This article was published as part of a sup-plement entitled Bugging the Bugs: Novel Approaches in the StrategicManagement of Resistant Staphylococcus aureus Infections, jointly spon-sored by the Dannemiller Memorial Educational Foundation and EmeritusEducational Sciences and supported by an educational grant from Ortho-McNeil, Inc., administered by Ortho-McNeil Janssen Scientific Affairs, LLC.

Potential conflicts of interest. S.T.M. has received research/grant sup-port from Ortho-McNeil.

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