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Vol. 33, No. 21 www.cmnewsletter.com November 1, 2011

Ceftaroline: a Cephalosporin with Anti-MRSA Activity

Cheung Yee, M.Sc., Ph.D.,1 Donald Biek, Ph.D.,2 Kevin Krause, B.S.,2 Gregory Williams, Ph.D.,2 1Forest Laboratories, Inc.,
New York, New York, 2Cerexa, Inc. (a wholly owned subsidiary of Forest Laboratories, Inc.), Oakland, California
Abstract
Ceftaroline is a cephalosporin antibiotic with broad-spectrum activity against gram-positive and gram-negative bacteria,
including contemporary resistant gram-positive phenotypes, such as methicillin-resistant Staphylococcus aureus (MRSA), multi-
drug-resistant Streptococcus pneumoniae, and penicillin-resistant S. pneumoniae. Ceftaroline is administered as the prodrug cef-
taroline fosamil, which is rapidly converted via plasma phosphatases to its bioactive metabolite, ceftaroline. Ceftaroline fosamil
was approved in October 2010 by the U.S. Food and Drug Administration (FDA) and launched in March 2011 for the treatment
of acute bacterial skin and skin structure infections and for the treatment of community-acquired bacterial pneumonia caused by
designated susceptible isolates. The Clinical and Laboratory Standards Institute (CLSI) designated ceftaroline a member of a new
subclass of β-lactam antimicrobials, cephalosporins with anti-MRSA activity, based on its unique spectrum of activity. At this
time, no ceftaroline surrogate is recommended for in vitro susceptibility testing because no other FDA-approved β-lactam has a
similar spectrum of activity, although studies to identify potential surrogates are in progress. Ceftaroline susceptibility testing can
be performed using CLSI standardized dilution or diffusion techniques, and FDA susceptibility interpretive criteria for broth dilu-
tion MIC values and disk diffusion zone diameters are available. Commercial broth-based antimicrobial susceptibility tests for
ceftaroline are in development. A ceftaroline Etest for MIC testing is also in development. Ceftaroline Kirby-Bauer disks for
diffusion were recently approved by the FDA and have been validated against the reference broth microdilution method.

Introduction
Ceftaroline is a cephalosporin anti-
biotic with broad-spectrum activity
against gram-positive and gram-nega-
tive bacteria, including contemporary
resistant gram-positive phenotypes,
such as methicillin-resistant Staphy-
lococcus aureus (MRSA), multidrug-
resistant Streptococcus pneumoniae
(MDRSP), and penicillin-resistant
S. pneumoniae (PRSP). Like other
β-lactams, ceftaroline inhibits
penicillin-binding proteins (PBPs),
which are cytoplasmic-membrane-
bound enzymes involved in the bio-
synthesis of the bacterial cell wall.
Ceftaroline exhibits properties that
Corresponding Author: Cheung Yee,
M.Sc., Ph.D., Forest Laboratories, Inc.,
909 Third Ave, New York, NY 10022.
Tel.: 212-224-7185. Fax: 212-750-9152.
E-mail: cheung.yee@frx.com
distinguish it from other β-lactams, in
that it has potent bactericidal activity
against resistant gram-positive organ-
isms as a result of its high affinity for
PBPs (e.g., PBP2a in MRSA and PBP2x
in PRSP). Ceftaroline is administered
as the N-phosphonoamino water-soluble
prodrug ceftaroline fosamil (Fig. 1),
which is rapidly converted via plasma
phosphatases to its bioactive metabolite,
ceftaroline (1,2). In this article, “cefta-
roline fosamil” is used when necessary
to clearly differentiate the prodrug from
the bioactive form and when specifically
referring to the form of the drug admin-
istered to patients (i.e., when describing
dosages or proposed labeling). For brev-
ity, however, the name “ceftaroline” is
used in table headers and footnotes and
in general discussions.
Teflaro (ceftaroline fosamil) for
injection was approved for intravenous
(i.v.) use in October 2010 by the FDA.
The approved indications and usage
of Teflaro are for the treatment of acute
bacterial skin and skin structure infec-
tions (ABSSSI) (which include celluli-
tis, deep abscesses, and wounds) caused
by susceptible isolates of S. aureus
(including methicillin-susceptible
and -resistant isolates), Streptococcus
pyogenes, Streptococcus agalactiae,
Escherichia coli, Klebsiella pneumo-
niae, and Klebsiella oxytoca and for
the treatment of community-acquired
bacterial pneumonia (CABP) caused by
susceptible isolates of S. pneumoniae
(including cases of concurrent bacter-
emia), S. aureus (methicillin-susceptible

Clinical Microbiology Newsletter 33:21,2011 © 2011 Elsevier 0196-4399/00 (see frontmatter) 161
 Prodrug: Active Metabolite:
Ceftaroline fosamil Ceftaroline
CH3 CH3

N+ N+
O O

O N N
H H H
N N N S
HO P N N S
N H 2N N
OH S N O N O
N S N
S S S S
O O

O O- • CH3COOH • H2O O O-

Figure 1. The prodrug ceftaroline fosamil, which contains a phosphono group (circled) to increase solubility, is rapidly converted in plasma to
the bioactive ceftaroline.

isolates only), Haemophilus influenzae,
K. pneumoniae, K. oxytoca, and E. coli
(3). Ceftaroline fosamil (brand name
Teflaro) was launched in the United
States in March 2011. This article pro-
vides an overview of ceftaroline micro-
biology in terms of the mechanism of
action (and resistance), pharmacokinet-
ics, susceptibility profile compared with
other agents, and in vitro susceptibility
testing methods.
Mechanism of Action
Ceftaroline is an oximino-cephalo-
sporin similar to third-generation cepha-
losporins; however, ceftaroline differs
from these agents in that it has a spec-
trum of activity that includes methicillin-
resistant isolates of S. aureus and
penicillin-resistant isolates of
S. pneumoniae.
Similar to other β-lactam antimicro-
bials, ceftaroline is a substrate analog of
PBPs present in bacterial cell walls (4).
The antimicrobial effect of ceftaroline
results from its binding to essential PBPs,
which in turn leads to inhibition of cell
wall biosynthesis, lysis, and cell death.
Increased β-lactam MICs in gram-
positive bacteria are largely mediated
by altered PBPs, including PBP2a in
S. aureus and PBP2x in S. pneumoniae.
Ceftaroline facilitates a conformational
change in these altered PBPs allowing
access to the closed active site and
essentially irreversible inactivation (4).
The high affinity of ceftaroline for
MRSA PBP2a, methicillin-susceptible
S. aureus (MSSA) PBPs 1 to 3, and
S. pneumoniae PBP2x/2a/2b correlates
well with its low MICs and bactericidal
activity against these resistant organisms
(5-7).
The Clinical and Laboratory
Standards Institute (CLSI) designated
ceftaroline a member of a new subclass
of β-lactam antimicrobials, cephalo-
sporins with anti-MRSA activity (8),
which is based on its unique spectrum
of activity. Ceftaroline is the only anti-
microbial in this cephalosporin subclass
that is approved by the FDA for use in
the U.S. It is important for microbiol-
ogy laboratory personnel to understand
the distinction between ceftaroline and
other cephalosporins with respect to
reporting MRSA susceptibility. Accord-
ing to CLSI M100, cephalosporins other
than ceftaroline are to be reported as
resistant for isolates of MRSA. How-
ever, isolates of MRSA with ceftaroline
MICs ≤1 μg/ml are reported as ceftar-
oline susceptible. No surrogate should
be used for in vitro susceptibility test-
ing for ceftaroline because no other
FDA-approved β-lactam has a similar
spectrum of activity that includes gram-
positive organisms, including MRSA
and penicillin-resistant strains of
S. pneumoniae, as well as common
gram-negative organisms.
Pharmacokinetics
Pharmacokinetic (PK) studies
determined that systemic exposure to
ceftaroline increases approximately in
proportion to increases in dose within
the dose range of 50 to 1,000 mg. The
terminal elimination half-life (t ½ ) of
ceftaroline is approximately 2.66 hours
in adults with normal renal function, and
no appreciable accumulation is observed
following multiple q12h (every 12 h)
doses. Ceftaroline is predominantly
eliminated by the kidneys, and dosage
adjustment is recommended for patients
with creatinine clearance of ≤50 ml/min.
Ceftaroline does not appear to be meta-
bolized by the liver and does not inhibit
or induce the cytochrome P450 system,
nor is ceftaroline a P450 substrate (3).
Monte Carlo simulations based on
population PK modeling demonstrated
that adults with normal renal function
dosed with ceftaroline fosamil 600 mg

162 0196-4399/00 (see frontmatter) © 2011 Elsevier Clinical Microbiology Newsletter 33:21,2011
q12h as a 1-hour infusion achieved
sufficient plasma exposure to provide
at least 90% probability of target attain-
ment for a percentage of time that
plasma free-drug concentrations
exceeded the MIC target of up to 44%
for pathogens with an MIC up to and
including 1 μg/ml (9,10). The target
attainment analyses also supported
doses of 600 mg q12h in patients with
mild renal impairment and 400 mg
q12h in those with moderate renal
impairment.
Susceptibility Interpretive
Criteria for Ceftaroline
Interpretive criteria or breakpoints
are set based on a variety of factors,
including, but not limited to, MIC dis-
tribution of the bacterial population of
interest, PK, and clinical trial outcome
data. FDA breakpoints for ceftaroline
for S. aureus (including methicillin-
resistant isolates), S. agalactiae, S. pyo-
genes, S. pneumoniae, H. influenzae, and
Enterobacteriaceae (E. coli, K. pneu-
moniae, and K. oxytoca) are listed in
Table 1 (3). MIC values derived from
standardized broth microdilution tech-
niques and zone diameters determined
from disk diffusion methods should be
interpreted according to these criteria
for ceftaroline. Currently, only Entero-
bacteriaceae have intermediate or resis-
tant breakpoints (3). The paucity of
patients having bacterial isolates with
higher ceftaroline MICs in clinical trials
prevented the setting of a category other
than susceptible for S. aureus, S. aga-
lactiae, S. pyogenes, S. pneumoniae,
and H. influenzae. No intermediate or
resistant interpretive categories have
been set for these organisms. Isolates
with MICs above or with zone diame-
ters smaller than the susceptible break-
point are deemed “non-susceptible.”
These non-susceptible isolates are
neither susceptible nor resistant to cef-
taroline until additional clinical data
become available and an intermediate
or resistant category can be defined.
Isolates with MIC results above the
susceptible breakpoint should be sub-
mitted to a reference laboratory for fur-
ther testing. It should be noted that the
clinical efficacy of ceftaroline for treat-
ment of CABP caused by MRSA has
not been studied in adequate, well-
controlled trials. Thus, the interpretive
criteria for S. aureus include MSSA
Clinical Microbiology Newsletter 33:21,2011
for both skin and CABP isolates and
MRSA for skin isolates only.
Ceftaroline exhibits in vitro MICs
of 1 μg/ml or less against most isolates
(>90%) of the following bacteria:
• Gram-positive: Streptococcus
dysgalactiae
• Gram-negative: Citrobacter koseri,
Citrobacter freundii, Enterobacter
cloacae, Enterobacter aerogenes,
Moraxella catarrhalis, Morganella
morganii, Proteus mirabilis, and
Haemophilus parainfluenzae.
The clinical significance of these
in vitro data is unknown (3); the safety
and effectiveness of ceftaroline in treat-
ing clinical infections caused by these
bacteria have not been established in
adequate and well-controlled clinical
trials.
Susceptibilities to Ceftaroline and
Other Commonly Used Agents
The susceptibilities of commonly
tested bacterial pathogens to ceftaroline
and other agents can provide a baseline
for the reader who wishes to compare
ceftaroline with their local susceptibil-
ity rates. FDA breakpoints for ceftaro-
line and other antimicrobials indicated
for the treatment of skin infections
and/or CABP are provided in Table 2
(3,11-17). Currently, neither CLSI nor
the European Committee on Antimicro-
bial Susceptibility Testing provides
Table 1. Susceptibility interpretive criteria for ceftarolinea
Pathogen and isolate source
Staphylococcus aureus
(includes methicillin-resistant
isolates – skin isolates only)
Streptococcus agalactiaeb
(skin isolates only)
Streptococcus pyogenesb
(skin isolates only)
Streptococcus pneumoniaeb
(CABP c isolates only)
Haemophilus influenzae
(CABP isolates only)
Enterobacteriaceaed
(CABP and skin isolates)
a
b
Adapted from reference 3.
The current absence of resistant isolates precludes defining any results other than “susceptible.” Isolates yielding MIC
results other than “susceptible” should be submitted to a reference laboratory for further testing.
c
CABP, community-acquired bacterial pneumonia; I, intermediate; MIC, minimum inhibitory concentration; R, resistant;
S, susceptible.
d
Clinical efficacy was shown for the following Enterobacteriaceae: Escherichia coli, Klebsiella pneumoniae, and
Klebsiella oxytoca.
© 2011 Elsevier
breakpoints for ceftaroline. National
susceptibility data for ceftaroline and
comparators are available from a 2009
U.S. surveillance study (Table 3).
Current Susceptibility Test
Methods for Ceftaroline
The current recommended methods
of performing ceftaroline susceptibility
testing are by broth or agar dilution MIC
testing and disk diffusion testing, with
interpretation according to the suscepti-
bility interpretive criteria listed in the
Teflaro label. In vitro susceptibility test
methods use bioactive ceftaroline rather
than the prodrug, ceftaroline fosamil.
Broth Microdilution
Diagnostic-grade ceftaroline powder
is soluble at approximately 1 to 2
mg/ml in 0.85% physiological saline.
To increase solubility and facilitate
preparation of the stock solution, the
procedure recommended by the CLSI
M100-S21 (18) for ceftaroline specifies
that the stock solution be prepared by
first suspending ceftaroline in 100%
dimethyl sulfoxide (DMSO) and then
diluting it with 0.85% physiological
saline to a final concentration of 30%
DMSO by volume. Stock solutions
should be made immediately prior to
use (never frozen) and discarded after
use. MICs should be determined using
the CLSI standardized test methods
(broth and/or agar). Broth dilution
Disk diffusion zone
MIC (μg/ml) diameter (mm)
S I R S I R
≤1b ≥24
≤0.03 ≥26
≤0.015 ≥24
≤0.25 ≥27
≤0.12 ≥33
≤0.5 1 ≥2 ≥23 20-22 ≤19
0196-4399/00 (see frontmatter) 163
MICs must be read within 18 hours
because ceftaroline activity degrades
to 70% potency by 24 hours in Mueller-
Hinton broth (MHB) (3; data on file,
study P0903-BDM-01, Forest Labo-
ratories, Inc., 2009).
Ceftaroline MIC testing by broth
microdilution (BMD) is minimally
affected by modest changes in in vitro
test conditions relative to CLSI-recom-
mended conditions for clinical and
control strains of gram-positive and
gram-negative pathogens, including
MSSA, MRSA, Enterococcus faecalis,
S. pyogenes, S. pneumoniae, H. influen-
zae, M. catarrhalis, K. pneumoniae,
E. coli, E. cloacae, Pseudomonas aeru-
ginosa, and Acinetobacter baumannii
(19,20). In vitro testing variables, such
as inoculum size, increased calcium con-
centration, addition of serum or laked
horse blood, and altered broth pH, had
impacts on ceftaroline MICs that were
similar to those of other cephalosporins
across a variety of test conditions (19,20).
The MICs were minimally affected by
the use of Haemophilus test media or 5%
carbon dioxide incubation. The presence
of 5% sodium chloride completely
inhibited growth of M. catarrhalis,
H. influenzae, and all streptococci.
Ceftaroline is minimally bound to human
serum proteins (protein binding, approxi-
mately 20%) (3). In vitro testing revealed
that ceftaroline MICs were not affected
by the presence of 5%, 10%, or 50%
serum or 45 mg/ml albumin, as would
be predicted by its low affinity for
serum proteins (19-21).
Commercial antimicrobial
susceptibility tests
Broth-based methodologies are used
in many of the commercial antimicrobial
susceptibility tests. Although ceftaroline
is not yet available in commercial MIC
tests, several are in development. Trek
Diagnostics Systems (Cleveland, OH)
has submitted an application to the
FDA to add ceftaroline to its Sensititre
Autoreader and Vizion susceptibility
systems based on a series of studies.
The accuracy and reproducibility of the
Sensititre systems with ceftaroline were
compared with those of the CLSI M7
reference BMD method (22,23) for
gram-positive and gram-negative iso-
lates (24,25). The Sensititre 18- to 24-
hour dried susceptibility plate yielded
highly reproducible results, equivalent to
those of the CLSI M7 reference BMD
method (23) for susceptibility testing
of ceftaroline over the range of 0.004 to
64 μg/ml. The overall essential agree-
ment for ceftaroline with a ±1 log2 dilu-
tion range was 100% for the Sensititre
plate and the CLSI M7 BMD method
(24). Intra-laboratory reproducibility
was 100%, and susceptibility data for
quality control (QC) strains were in
agreement with the QC limits approved
by CLSI for ceftaroline. In a second
study, the ceftaroline Sensititre systems
were evaluated using both automated
(Autoreader) and manual (Vizion) read-
ing methodologies against an expanded
panel of challenge organisms and clini-
cal isolates (25). Essential agreement
using the ±1 log2 dilution standard was
97.8% and 98.3% for the automated and
manual read methods, respectively. For
gram-positive isolates, overall essential
agreement was 99.4% for both the auto-
mated and manual methods. For gram-
negative isolates, agreement was 99.6%

Table 2. FDA susceptible breakpoints for ceftaroline fosamil and comparators indicated for treatment of pneumonia
and/or skin infections
Breakpoint (μg/ml)
Zosyn
Teflaro Rocephin (piperacillin
(ceftaroline Tygacil Zyvox (ceftriaxone vancomycin Levaquin sodium/ Cubicin
fosamil) (tigecycline) (linezolid) sodium) HCl (levofloxacin) tazobactam (daptomycin)
Organism (3) (11)a (12)b (13)c (14)d (15)e sodium) (16) f (17) g
Staphylococcus aureus ≤1h,i,j ≤0.5h,i ≤4h ≤4k ≤4 ≤2k ≤8 ≤1h,i,l
h,j h h,m h,m
Streptococcus agalactiae ≤0.03 ≤0.25 ≤2 ≤0.5 ≤1 ≤1h,n
Streptococcus pyogenes ≤0.015h,j ≤0.25h ≤2h,m ≤0.5 ≤1h,m ≤2 ≤1h,n
h,o h h,m m m
Streptococcus pneumoniae ≤0.25 ≤0.06 ≤2 ≤0.5 0.12 - 0.5 ≤2
o h h
Haemophilus influenzae ≤0.12 ≤0.25 ≤2 ≤2p ≤1q
r,s t
Enterobacteriaceae ≤0.5 ≤2 ≤1 ≤2 ≤16
a
FDA susceptible breakpoints are also available for Enterococcus faecalis (vancomycin-susceptible isolates) and anaerobes.
b
FDA susceptible breakpoint is also available for Enterococcus spp.
c
FDA susceptible breakpoints are also available for Neisseria gonorrhoeae, Neisseria meningitidis, and anaerobes.
d
FDA susceptible breakpoints are also available for diphtheroids and enterococci.
e
FDA susceptible breakpoints are also available for Haemophilus parainfluenzae, Enterococcus faecalis, and Pseudomonas aeruginosa.
f
FDA susceptible breakpoints are also available for Acinetobacter baumannii, Pseudomonas aeruginosa, and Bacteroides fragilis group.
g
FDA susceptible breakpoints are also available for Streptococcus dysgalactiae subsp. equisimilis and Enterococcus faecalis (vancomycin susceptible only).
h
The current absence of resistant isolates precludes defining any results other than “susceptible.”
i
Includes methicillin-resistant S. aureus (MRSA) isolates.
j
Skin isolates only.
k
Methicillin-susceptible S. aureus (MSSA) isolates only.
l
Interpretive criteria applicable only to tests performed by broth dilution using Mueller-Hinton broth adjusted to a calcium content of 50 mg/L.
m
Interpretive criteria applicable only to tests performed by broth microdilution using cation-adjusted Mueller-Hinton broth with 2% to 5% lysed horse blood.
n
Interpretive criteria applicable only to tests performed by broth dilution using Mueller-Hinton broth adjusted to a calcium content of 50 mg/L, supplemented with 2% to 5% lysed
horse blood, inoculated with a direct colony suspension, and incubated in ambient air at 35ºC for 20 to 24 hours.
o
Community-acquired bacterial-pneumonia isolates only.
p
Interpretive criteria applicable only to tests performed by broth dilution using a haemophilus test medium.
q
Interpretive criteria applicable only to tests performed using a haemophilus test medium inoculated with a direct colony suspension and incubated at 35ºC in ambient air for 20 to
24 hours.
r
Clinical efficacy was shown for the following Enterobacteriaceae: Escherichia coli, Klebsiella pneumoniae, and Klebsiella oxytoca.
s
CABP and skin isolates.
t
Tigecycline has decreased in vitro activity against Morganella spp., Proteus spp., and Providencia spp.

164 0196-4399/00 (see frontmatter) © 2011 Elsevier Clinical Microbiology Newsletter 33:21,2011
Table 3. National susceptibility data for ceftaroline and comparators: 2009 U.S. surveillance studya
MIC (μg/ml) Susceptibility (%)
Organism Agent Range 50% 90% S I R
Gram-positive Ceftaroline 0.03 - 2 0.5 1 98.4
Staphylococcus aureus – Oxacillin ≤0.25 - >2 1 >2 52.3 47.7
all (n = 2,363) Ceftriaxone 0.5 - >32 4 >32 50.4 1.9 47.7
Piperacillin/tazobactam ≤0.5 - >64 2 64 52.3 47.7
Vancomycin ≤0.12 - 2 1 1 100 0 0
Daptomycin ≤0.06 - 1 0.25 0.5 100
Linezolid ≤0.12 - >8 2 2 99.8 0.2
Clindamycin ≤0.25 - >2 ≤0.25 >2 80.4 0.4 19.2
Levofloxacin ≤0.5 - >4 ≤0.5 >4 59.2 0.9 39.9
Co-trimoxazole ≤0.5 - >2 ≤0.5 ≤0.5 98.5 1.5
Tigecycline ≤0.03 - 1 0.12 0.25 >99.9
MRSA Ceftaroline 0.25 - 2 0.5 1 96.6
(n = 1,127) Oxacillin >2 >2 >2 0 100
Ceftriaxone 2 - >32 >32 >32 0 100
Piperacillin/tazobactam 1 - >64 32 >64 0 100
Vancomycin 0.25 - 2 1 1 100 0 0
Daptomycin ≤0.06 - 1 0.5 0.5 100
Clindamycin ≤0.25 - >2 ≤0.25 >2 64.7 0.6 34.7
Linezolid 0.5 - 8 2 2 99.6 0.4
Levofloxacin ≤0.5 - >4 >4 >4 26.5 1 72.5
Co-trimoxazole ≤0.5 - >2 ≤0.5 ≤0.5 98.2 1.8
Tigecycline ≤0.03 - 1 0.12 0.25 99.9
MSSA Ceftaroline 0.03 - 1 0.25 0.25 100
(n = 1,236) Oxacillin ≤0.25 - 2 0.5 1 100 0
Ceftriaxone 0.5 - 16 4 4 95.3 4.4 0.3
Piperacillin/tazobactam ≤0.5 - 16 1 2 99.8 0.2
Vancomycin ≤0.12 - 2 1 1 100 0 0
Daptomycin ≤0.06 - 1 0.25 0.5 100
Clindamycin ≤0.25 - >2 ≤0.25 ≤0.25 94.7 0.2 5.1
Linezolid ≤0.12 - 2 2 2 100 0
Levofloxacin ≤0.5 - >4 ≤0.5 4 89 0.9 10.1
Co-trimoxazole ≤0.5 - >2 ≤0.5 ≤0.5 98.7 1.3
Tigecycline ≤0.03 - 0.5 0.12 0.25 100
CoNS Ceftaroline ≤0.008 - 2 0.25 0.5
(n = 549) Oxacillin ≤0.25 - >2 >2 >2 25.5 74.5
Ceftriaxone ≤0.25 - >32 8 32 25.5 74.5
Piperacillin/tazobactam ≤0.5 - >64 1 8 25.5 74.5
Vancomycin ≤0.12 - 4 1 2 100 0 0
Daptomycin ≤0.06 - 1 0.25 0.5 100 0
Linezolid 0.12 - >8 1 1 98.5 1.5
Levofloxacin ≤0.5 - >4 4 >4 46.8 1.7 51.5
Co-trimoxazole ≤0.5 - >2 ≤0.5 >2 58.6 41.4
Streptococcus Ceftaroline ≤0.008 - 0.5 0.015 0.25 98.5
pneumoniae - all Ceftriaxone ≤0.25 - 8 ≤0.25 2 87.2 10.4 2.4
(n = 1,235) Penicillinb ≤0.03 - >4 ≤0.03 4 84 13.2 2.8
Levofloxacin ≤0.5 - >4 1 1 99.3 0 0.7
Erythromycin ≤0.25 - >2 ≤0.25 >2 61.1 0.7 38.2
Co-trimoxazole ≤0.5 - >2 ≤0.5 >2 65.6 7.6 26.8
MDRSP c Ceftaroline ≤0.008 - 0.5 0.12 0.25 96.2
(n = 368) Ceftriaxone 0.25 - 8 1 2 61.1 32.6 6.3
Penicillinb ≤0.03 - >8 2 4 50 43.7 6.3
Levofloxacin ≤0.5 - >4 1 1 98.1 1.9
Erythromycin ≤0.25 - >2 >2 >2 2.7 0.3 97
Co-trimoxazole ≤0.5 - >2 >2 >2 13.9 8.9 77.2
Streptococcus pyogenes Ceftaroline ≤0.008 - 0.06 ≤0.008 ≤0.008 99.1
(n = 318) Ceftriaxone ≤0.25 - 0.5 ≤0.25 ≤0.25 100
Penicillin ≤0.015 - 0.12 ≤0.015 ≤0.015 100
Erythromycin ≤0.25 - >2 ≤0.25 2 84.6 0.6 14.8
Clindamycin ≤0.25 - >2 ≤0.25 ≤0.25 95.9 0.3 3.8
Levofloxacin ≤0.5 - >4 ≤0.5 1 99.4 0 0.6
Daptomycin ≤0.06 - 0.25 ≤0.06 ≤0.06 100
Linezolid ≤0.12 - 2 1 1 100
Tigecycline ≤0.03 - 0.12 ≤0.03 0.06 100

Clinical Microbiology Newsletter 33:21,2011 © 2011 Elsevier 0196-4399/00 (see frontmatter) 165
Table 3. National susceptibility data for ceftaroline and comparators: 2009 U.S. surveillance studya (continued)
MIC (μg/ml) Susceptibility (%)
Organism Agent Range 50% 90% S I R
Enterococcus faecalis Ceftaroline 0.25 - >16 2 8
(n = 252) Ampicillin ≤1 - 8 ≤1 2 100 0
Piperacillin/tazobactam 2 - 32 4 8 99.6
Erythromycin ≤0.25 - >2 >2 >2 9.2 29.6 61.2
Levofloxacin ≤0.5 - >4 1 >4 68.3 0 31.7
Daptomycin ≤0.06 - 8 1 2 99.6
Linezolid 0.5 - 2 1 2 100 0 0
Tigecycline ≤0.03 - 1 0.12 0.25 98.4
Vancomycin 0.25 - >16 1 2 96.8 0 3.2
Gram-negative
Haemophilus influenzae Ceftaroline ≤0.008 - 0.06 ≤0.008 0.015 100
(n = 394) Ceftriaxone ≤0.25 - 0.5 ≤0.25 ≤0.25 100
Amoxicillin/clavulanate ≤1 - 8 ≤1 ≤1 99.7 0.3
Piperacillin/tazobactam ≤0.5 ≤0.5 ≤0.5 100
Ampicillin ≤1 - >16 ≤1 >16 75.9 1 23.1
Azithromycin ≤0.5 - >4 1 2 98.5
Levofloxacin ≤0.5 ≤0.5 ≤0.5 100
Co-trimoxazole ≤0.5 - >2 ≤0.5 >2 75.6 3.1 21.3
Escherichia coli Ceftaroline 0.015 - >16 0.12 4 84.9 4.7 10.4
(n = 1,136) Ceftriaxone ≤0.25 - >32 ≤0.25 0.5 91.1 0.3 8.6
Ceftazidime ≤1 - >16 ≤1 ≤1 93.9 1 5.1
Piperacillin/tazobactam ≤0.5 - >64 2 8 93.7 3.4 2.9
Meropenem ≤0.12 - 4 ≤0.12 ≤0.12 99.9 0 0.1
Levofloxacin ≤0.5 - >4 ≤0.5 >4 68.3 0.8 30.9
Gentamicin ≤2 - >8 ≤2 >8 86.9 0.6 12.5
Tigecycline ≤0.03 - 2 0.12 0.25 100 0 0
Klebsiella pneumoniae Ceftaroline ≤0.008 - >16 0.12 >16 79.3 6.2 14.5
(n = 759) Ceftriaxone ≤0.25 - >32 ≤0.25 32 86.8 0.3 12.9
Ceftazidime ≤1 - >16 ≤1 >16 87.1 1.2 11.7
Piperacillin/tazobactam ≤0.5 - >64 4 64 87.9 2.7 9.4
Meropenem ≤0.12 - 8 ≤0.12 ≤0.12 94.6 0.1 5.3
Levofloxacin ≤0.5 - >4 ≤0.5 >4 86.3 1.3 12.4
Gentamicin ≤2 - >8 ≤2 ≤2 92.2 1.1 6.7
Tigecycline 0.06 - >4 0.5 1 97.4 2.3 0.3
a
CoNS, coagulase-negative staphylococci; I, intermediate; MDRSP, multidrug-resistant S. pneumoniae; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant S. aureus;
MSSA, methicillin-susceptible S. aureus; R, resistant; S, susceptible.
b
Penicillin parenteral (nonmeningitis) breakpoints (8).
c
Defined as resistance to 2 or more of the following agents: penicillin (MIC ≥8 μg/ml), cefuroxime, erythromycin, tetracycline, co-trimoxazole, and levofloxacin.

for the manual and 99% for the auto-
mated methods. Reproducibility testing
for gram-positive and gram-negative
isolates was 100% for both the
automated and manual read methods.
BioMérieux, Inc. (Durham, NC) is
completing clinical trials that evaluate
VITEK 2 antimicrobial susceptibility
testing with ceftaroline. Both Siemens
Medical Solutions Diagnostics (West
Sacramento, CA) and Becton Dickinson
(Sparks, MD) are initiating development
to add ceftaroline to their automated
susceptibility testing products.
It is important to note that the soft-
ware used in reporting susceptibility
data is developed after FDA approval,
requiring additional time before it
can be released commercially.
Agar dilution
The MICs of ceftaroline can be
determined by the CLSI dilution method
on Mueller-Hinton agar using bioactive
ceftaroline. Ceftaroline MICs produced
by BMD methods were compared with
those produced using Mueller-Hinton
agar plates according to CLSI standards
(data on file, study P903-M-075, Forest
Laboratories, Inc., 2009). A total of 528
isolates were tested, including staphy-
lococci, streptococci, H. influenzae,
nonfermentative species, and Entero-
bacteriaceae. There was a satisfactory
correlation between MICs obtained by
BMD and those obtained with agar
dilution. In another in vitro study, the
activity of ceftaroline was determined
by CLSI agar dilution against clinical
isolates, including some with defined
resistance mechanisms and phenotypes
(26). The agar dilution MIC tests showed
the ceftaroline MIC for MSSA was 0.12
to 0.25 μg/ml; the corresponding value
for MRSA was 0.5 to 2 μg/ml. Geometric
mean MICs were 0.005, 0.05, and 0.09
μg/ml for penicillin-susceptible, -inter-
mediate, and -resistant S. pneumoniae
strains, respectively. MICs were con-
sistently ≤0.06 μg/ml for H. influenzae
and ≤1 μg/ml for M. catarrhalis. MICs
ranged from 1 to 2 μg/ml for many
Enterobacteriaceae with classic TEM
β-lactamases. These agar dilution MIC
ranges are similar to those typically
observed using BMD.

166 0196-4399/00 (see frontmatter) © 2011 Elsevier Clinical Microbiology Newsletter 33:21,2011
Etest
The Etest for ceftaroline has com-
pleted initial development and is cur-
rently in clinical trials. It has not yet
been submitted to the FDA. The Etest
ceftaroline (bioMérieux SA, La Balme,
France) provides predefined gradient
MIC testing on agar across 15 dilutions.
Etest ceftaroline was validated against
the reference CLSI BMD method using
a collection of clinical and ATCC iso-
lates, including S. aureus (MSSA,
MRSA, vancomycin-intermediate
S. aureus [VISA], and heteroresistant
VISA [hVISA]; 14 strains), Staphylo-
coccus epidermidis (2), Staphylococcus
haemolyticus (1), S. pneumoniae (1),
E. faecalis (3), E. coli (7), H. influenzae
(1), K. pneumoniae (6), P. aeruginosa
(2), P. mirabilis (2), Enterobacter
species (7), and C. freundii (1) (27).
Etest was used according to the manu-
facturer’s instructions, and BMD was
performed using CLSI recommenda-
tions for water-insoluble agents. The
MIC was read as the complete inhi-
bition of growth.
Disk diffusion tests
Quantitative methods that use zone
diameter measurements also provide
reproducible estimates of the suscep-
tibility of bacteria to ceftaroline. To
determine the optimal ceftaroline disk
content for in vitro testing, 7 reference
strains were tested with 5 ceftaroline
disk concentrations (5, 10, 30, 50, and
100 μg) (20). The strains included
S. aureus ATCC 25923 and 29213,
E. faecalis ATCC 29212, S. pneumoniae
ATCC 49619, E. coli ATCC 25922, P.
aeruginosa ATCC 27853, and Entero-
coccus faecium 89-736D. Disk diffu-
sion tests were performed according to
CLSI methods, with ceftriaxone and
cefepime as control agents.
Susceptible gram-positive QC strains
all had ceftaroline zone diameters of
>20 mm for disk concentrations ranging
from 10 to 100 μg and a corresponding
MIC of ≤0.5 μg/ml. With ceftaroline
disk concentrations of 10 or 30 μg,
maximum zone diameter differences
were apparent between susceptible
strains and possible ceftaroline-resistant
strains (e.g., E. faecium). The 30-μg
disk was selected for use in diffusion
techniques (3) because it was shown
to be ideal for making determinations
between susceptible and resistant
isolates (20).
Clinical Microbiology Newsletter 33:21,2011
Table 4. Acceptable quality control ranges for susceptibility testinga
Quality control organism
Staphylococcus aureus ATCC 25923b
Staphylococcus aureus ATCC 29213
Escherichia coli ATCC 25922
Haemophilus influenzae ATCC 49247
Streptococcus pneumoniae ATCC 49619
a
b
Adapted from reference 3.
ATCC = American Type Culture Collection; MIC = minimum inhibitory concentration.
The Hardy Diagnostics (Santa
Maria, CA) Kirby-Bauer paper disk
has received FDA approval for anti-
microbial susceptibility testing (28).
Results from the FDA-cleared disk
may be used in patient care. The disk is
impregnated with 30 μg of ceftaroline
and should be kept frozen and stored
away from direct light. A 1-week sup-
ply could be stored at 2 to 8°C. It is
recommended that the disks be stored
in a sealed container with a desiccant.
A Kirby-Bauer disk for ceftaroline
susceptibility testing is currently in
development by Becton Dickinson.
Quality controls
Standardized susceptibility test pro-
cedures require the use of laboratory con-
trols to monitor and ensure the accuracy
and precision of supplies and reagents
used in the assay and the techniques
of the individuals performing the test
(8,22,29). The MIC and disk diffusion
QC ranges for ceftaroline were deter-
mined for 5 standard ATCC reference
strains (30). Eight testing laboratories
in the U.S. participated, including both
hospital and commercial microbiology
laboratories. The QC organisms were
those recommended by CLSI: S. aureus
ATCC 29213 and ATCC 25923, S.
pneumoniae ATCC 49619, E. coli
ATCC 25922, and H. influenzae ATCC
49247. Replicate tests were performed
on 3 lots of MHB or agar and 2 lots of
30-μg ceftaroline disks. QC ranges for
MIC testing and disk diffusion zone
diameter were accepted by the Anti-
microbial Susceptibility Testing Sub-
committee of the CLSI. Standard
bioactive ceftaroline powder should
provide the range of MIC values listed
in Table 4 (3). The diffusion technique
using the 30-μg ceftaroline disk should
achieve the criteria in Table 4. There
© 2011 Elsevier
Disk diffusion zone
MIC (μg/ml) diameter (mm)
Not applicable 26 - 35
0.12 - 0.5 Not applicable
0.03 - 0.12 26 - 34
0.03 - 0.12 29 - 39
0.008 - 0.03 31 - 41
have been some reports of double zone
sizes for S. aureus 25923. If this occurs,
only the inner zone should be read; the
QC results are acceptable if the inner
zone is within the accepted QC range
(data on file, Forest Laboratories, Inc.,
2011).
MBC method
The bactericidal activity of an anti-
microbial can be determined using the
minimum bactericidal concentration
(MBC) method. The MBC is defined
as the concentration of antimicrobial
needed to reduce the number of viable
organisms by 99.9% (3-log10 reduction).
Ceftaroline demonstrated bactericidal
activity against a wide range of gram-
positive and -negative species, including
isolates of resistant S. aureus (MRSA,
VISA, hVISA, vancomycin-resistant
S. aureus, and daptomycin-nonsuscepti-
ble S. aureus) and penicillin-nonsuscep-
tible S. pneumoniae (20,31,32).
Interaction with Other
Antimicrobials
The in vitro activity of ceftaroline
with other antimicrobial agents has been
evaluated in several studies. Ceftaroline
was tested in time-kill studies in com-
bination with other antimicrobials to
determine synergistic or antagonistic
effects against P. aeruginosa, extended-
spectrum β-lactamase (ESBL)-producing
E. coli, ESBL-producing K. pneumo-
niae, and AmpC-derepressed E. cloacae
(33). The combination of ceftaroline
plus amikacin was synergistic against
9 of 10 isolates tested; no synergy was
observed against 1 P. aeruginosa isolate.
Synergy was also observed for ceftaro-
line plus meropenem against both E. coli
isolates tested. In another study, synergy
was observed with ceftaroline and tobra-
mycin against 2 MRSA strains and
0196-4399/00 (see frontmatter) 167
1 hVISA strain (34). Using a checker-
board approach, ceftaroline in combi-
nation with meropenem demonstrated
synergy against 1 ESBL-producing
K. pneumoniae isolate and 1 of 2
community-associated-MRSA isolates
(no interaction was noted for the other
isolate), and ceftaroline with amikacin
showed synergy against 1 ESBL-pro-
ducing E. coli isolate and 1 of 2 isolates
of P. aeruginosa (no interaction was
noted for the other isolate) (35). In vitro
studies have not demonstrated any anta-
gonism between ceftaroline and other
commonly used antibacterial agents,
including amikacin, azithromycin, aztre-
onam, cefepime, daptomycin, linezolid,
meropenem, tazobactam, tigecycline,
tobramycin, and vancomycin (33-35).
Emergence of Resistance
Multistep resistance selection studies
have demonstrated a low probability of
development of resistance to ceftaroline
(36,37). After 50 daily serial passages,
ceftaroline MICs were maintained and
no clones with increased MICs (>4-fold)
were observed for S. pneumoniae, S. pyo-
genes, MRSA, MSSA, M. catarrhalis,
or K. pneumoniae (36). The only iso-
lates that gave rise to clones with MICs
increased >4-fold were 1 of 5 tested
H. influenzae isolates (a quinolone-
resistant isolate, after 20 days) and
2 of 2 tested E. faecalis isolates (after
38 and 41 days, respectively) (36).
The broad-spectrum activity of
ceftaroline includes many wild-type
gram-negative pathogens. Like many
cephalosporins, however, ceftaroline is
not active against gram-negative bacte-
ria that produce ESBLs from the TEM,
SHV, or CTX-M families; serine carba-
penemases (such as KPC); class B met-
allo-β-lactamases; or class C (AmpC)
cephalosporinases, which are known
to hydrolyze later-generation oximino-
cephalosporins (3,26).
Summary
• Ceftaroline fosamil is a broad-
spectrum, bactericidal, parenteral
cephalosporin and is approved for
the treatment of ABSSSI and CABP
in the U.S.
• Ceftaroline exhibits antimicrobial
activity against gram-positive
organisms, including MRSA and
S. pneumoniae, as well as common
gram-negative organisms in the
168 0196-4399/00 (see frontmatter)
approved indications.
• CLSI designates ceftaroline as a
member of a new subclass of anti-
microbials: cephalosporins with
anti-MRSA activity.
• Ceftaroline susceptibility testing can
be performed using CLSI standard-
ized dilution or diffusion techniques,
and FDA susceptibility interpretive
criteria for broth dilution MIC values
and disk diffusion zone diameters are
available.
• Commercial broth-based antimicro-
bial susceptibility tests are in develop-
ment.
• Ceftaroline Kirby-Bauer disks for
diffusion were recently approved by
the FDA and have been validated
against the reference BMD method.
• Development of the Etest is nearing
completion.
• Ceftaroline MBC values demonstrate
bactericidal activity against many
common gram-positive and gram-
negative pathogens, including MRSA
and penicillin-nonsusceptible S. pneu-
moniae.
• In vitro studies have not demonstrated
any antagonism between ceftaroline
and other commonly used antibacter-
ial agents.
Acknowledgments
Scientific Therapeutics Information,
Inc. provided editorial assistance, which
was funded by Forest Research Institute,
Inc.
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