Download What are the properties that make an antibiotic

J Antimicrob Chemother 2011; 66 Suppl 3: iii61 – iii67
doi:10.1093/jac/dkr100
What are the properties that make an antibiotic acceptable
for therapy of community-acquired pneumonia?
George L. Drusano *
Ordway Research Institute, New Scotland Avenue, Albany, NY 12208, USA
*Tel: +1-518-641-6410; Fax: +1-518-641-6304; E-mail: [email protected]
The factors associated with identifying an appropriate dose and schedule of an antimicrobial agent for treatment of hospitalized, seriously ill patients with pneumonia are straightforward. Information is required about
the potency of the agent for typical pathogens likely to be encountered with pneumonia. It is helpful to understand the utility of the agent against pathogens that express resistance to older antimicrobial agents. The
agent must be able to gain access to the site of infection at the dose and schedule chosen and at concentrations high enough to attain microbiologically effective targets [e.g. 1 or 2 log10 (cfu/g) bacterial cell kill,
accounting for between-patient variability]. Finally, therapeutic concentrations should be attained quickly at
the primary site of infection to optimize clinical outcomes. When considering all of these factors, it is expected
that ceftaroline fosamil will be a valuable addition to the therapeutic armamentarium for management of
community-acquired pneumonia.
Keywords: antimicrobial therapy, microbiological target attainment, therapeutic concentrations
Introduction
Serious community-acquired pneumonia (CAP) continues to be a
major source of morbidity and mortality around the world.1,2
Treatment of Streptococcus pneumoniae, called the ‘Captain of
the Men of Death’ by Osler,3 was revolutionized with the introduction of penicillin, but still remains the leading pathogen
associated with CAP.4 – 6 Since then, numerous other pathogens
have been recognized as causative agents for CAP, both typical
(Haemophilus influenzae and Staphylococcus aureus) and atypical (Mycoplasma pneumoniae, Chlamydophila pneumoniae and
Legionella pneumophila).6 In this manuscript, the emphasis will
be on typical pathogens and factors that influence the adequacy
of a drug for treatment of these infectious pathogens in CAP.
Four major factors influence the adequacy of an agent for use
in CAP: (i) potency (i.e. low MIC values); (ii) the related issue
of binding to mutated b-lactam-binding proteins; (iii) adequacy
of penetration at the primary infection site; and (iv) rapidity of
penetration.
Potency
Currently, third-generation cephalosporins such as ceftriaxone
and cefotaxime are employed as parenteral agents of choice for
patients with serious (hospitalized) CAP caused by standard pathogens.6 Ceftaroline fosamil (TAK-599 or PPI-0903; subsequently
referred to as ceftaroline), is the prodrug form of ceftaroline.7
Ceftaroline is a novel, broad-spectrum cephalosporin exhibiting
bactericidal activity against resistant Gram-positive organisms,
including S. pneumoniae and methicillin-resistant S. aureus
(MRSA), as well as common Gram-negative pathogens.8 – 13
Ceftaroline represents a potential new addition to the physician’s
therapeutic armamentarium for management of CAP.
Table 110 – 12,14,15 shows the MIC values of ceftaroline and comparators for S. aureus, S. pneumoniae and H. influenzae. Ceftaroline
exhibits potent in vitro activity against S. pneumoniae with MIC90
values for penicillin-susceptible, penicillin-intermediate and
penicillin-resistant strains of 0.015 mg/L, 0.06 mg/L and
0.12 mg/L, respectively; MIC values of ceftaroline remain consistently lower for S. pneumoniae than those of ceftriaxone. Similarly,
ceftaroline has exceptional activity against S. aureus, including
resistant isolates, with MIC90 values 16- to 32-fold lower than
those of ceftriaxone. The spectrum of activity of ceftaroline
against Gram-negative pathogens is consistent with other
extended-spectrum b-lactams. Ceftaroline demonstrates potent
activity against H. influenzae, including b-lactamase-positive strains
(MIC90 ,0.03). Clearly, if the pathogen is wild-type, the older
agents continue to have adequate potency, as does ceftaroline.
One new development has been the recent emergence of
community-associated MRSA (CA-MRSA).16 Although it remains
to be seen whether this pathogen will become a frequent
cause of CAP,17 ceftaroline has a spectrum of activity that
includes MRSA (MIC90¼ 1 mg/L), along with other typical pathogens associated with CAP8,11,12,18 (Table 1). As will be explored
below, MRSA displays b-lactam resistance because of the acquisition of the mecA gene, which encodes a modified penicillinbinding protein (PBP) 2A (alternatively, PBP 2′ ).19 PBP 2A binds
standard b-lactams with markedly diminished affinity. The 3′
side chain of ceftaroline allows high-affinity binding to PBP 2A,
with resultant potent activity against MRSA.20,21
# The Author 2011. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
For Permissions, please e-mail: [email protected]
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Drusano
Table 1. In vitro activity of ceftaroline and comparators against S. aureus, S. pneumoniae and H. influenzae 10 – 12,14,15
Ceftaroline
Bacteria, number of isolates
S. aureus (MS), 1554
S. aureus (MR), 1237
S. aureus (VISA and hVISA), 100
CA-MRSA, 152
S. pneumoniae (PS), 202
S. pneumoniae (PI), 103
S. pneumoniae (PR), 296
H. influenzae (BL-neg), 305
H. influenzae (BL-pos), 101
Ceftazidime
Ceftriaxone
MIC50 (mg/L)
MIC90 (mg/L)
range (mg/L)
MIC50 (mg/L)
MIC90 (mg/L)
MIC50 (mg/L)
MIC90 (mg/L)
0.25
1
1
0.5
≤0.008
0.015
0.12
≤0.008
0.015
0.25
1
2
0.5
0.015
0.06
0.12
0.015
0.03
≤0.008 –1
0.25 – 2
0.25 – 4
0.25 – 1
≤0.008 –0.12
≤0.008 –0.5
≤0.008 –0.5
≤0.008 –0.25
≤0.008 –2
NA
NA
NA
NA
≤1
2
16
NA
0.06
NA
NA
NA
NA
≤1
8
32
NA
0.12
4
32
.32
32
0.03
0.12
1
≤0.25
≤0.06
4
.32
.32
.32
0.06
0.5
2
≤0.25
,0.06
MS, methicillin susceptible; MR, methicillin resistant; VISA, vancomycin-intermediate S. aureus; hVISA, heteroresistant VISA; PS, penicillin susceptible;
PI, penicillin intermediate; PR, penicillin resistant; BL-neg, b-lactamase negative; BL-pos, b-lactamase positive; NA, not available/assessed in study
from which data for this pathogen are reported.
6
25
5
20
4
15
3
10
2
5
1
0
1984
1985
1986
1987
1988 1989
Year
1990
1991
1992
1993
0
Ratio of aminopenicillins:cephalosporins ( )
Percentage of resistant strains ( )
Resistance trends of respiratory pathogens
30
Figure 1. Prescription ratio of aminopenicillins:cephalosporins per 1000 French inhabitants (white bars) and comparison with the evolution of penicillin
resistance in S. pneumoniae (black bars) (reproduced from Baquero,23 with permission).
Binding to PBPs
Over the past two decades, there has been a continual loss
of activity of b-lactam agents against S. pneumoniae.22 Part of
the reason for the decrease in activity has been associated
with overuse of oral b-lactams, particularly oral cephalosporins.
Baquero23 studied antibiotic prescription data from five countries
in Europe (France, Germany, Italy, Spain and the UK) and the
USA, linking prescription rates to resistance emergence.
Figure 123 shows the ratio of aminopenicillin:cephalosporin
use over time in France plotted next to the rate of emergence
of resistance to b-lactams in S. pneumoniae. There is a clear
association between increasing cephalosporin use relative to
aminopenicillins and the emergence of pneumococcal resistance. This pattern was widely recapitulated, with the single
exception of Italy, where there was extensive cephalosporin
use, but quite low pneumococcal resistance at the time.
Baquero23 hypothesized that this occurred because
iii62
approximately two-thirds of cephalosporin use was parenteral
in Italy. This study suggests that antimicrobial pressure plays
an important role in resistance emergence. This relationship
has also been shown by the Emerging Infections Pharmacodynamics Laboratory at Ordway Research Institute in a study
evaluating quinolone exposure and resistance amplification.24
Ironically, resistance emergence in pneumococcus may not
be as simple as direct selection.25 Resistant pneumococcal
isolates mainly have mutations identified in PBP 1A, 2B and 2X.
When examined in detail, resistant pneumococcal isolates
tended to contain mosaic genes that encoded these low-affinity
PBPs. S. pneumoniae has an exceptional ability to take up DNA
from other organisms, sometimes from other resistant
pneumococci, particularly those that are capsule deficient. But
a much more likely possibility is that the DNA originates from
oral streptococci (e.g. Streptococcus mitis).25
The improved activity of ceftaroline against both S. aureus and
S. pneumoniae is a function of the 3′ side chain mediating
JAC
Acceptable antibiotic therapy for CAP
Table 2. MIC values of ceftaroline and comparators for S. pneumoniae and S. aureus (reproduced from Kosowska-Shick et al.,26 with permission)
MIC (mg/L)
Strain
Species
Country of origin
Year isolated
1564a
2688a
1394a
24
3413
2527
1076
Phenotype
PEN
CRO
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pneumoniae
Romania
Poland
Slovakia
South Africa
Slovakia
Croatia
Austria
1996
2000
1999
before 1998
2000
2000
1996
PEN resistantb
PEN resistantb
PEN resistantb
PEN resistantb
PEN resistantb
PEN resistantb
PEN susceptibleb
16
8
4
4
4
2
0.03
ATCC 29213
873
510 (VRS2)
2149A
S. aureus
S. aureus
S. aureus
S. aureus
reference strain
USA
USA
USA
1981
2006
2002
2006
1
8
32
64
2
.64
.64
64
2
.64
.64
32
0.5
0.5
1
0.5
1287
25
S. aureus
S. aureus
USA
USA
2007
2005
MSSA, VSSA
MRSA, hVISA, b-lactamase negative
MRSA, VRSA, b-lactamase positive
MRSA, VISA, linezolid resistant,
b-lactamase positive
MRSA, VISA, b-lactamase positive
MRSA, VISA, daptomycin resistant,
b-lactamase positive
32
64
8
.64
4
.64
0.5
0.5
32
8
2
2
2
0.03
0.03
CTX
32
16
4
1
2
0.015
0.03
CPT
2
0.5
0.25
0.25
0.125
0.015
0.015
PEN, penicillin G; CRO, ceftriaxone; CTX, cefotaxime; CPT, ceftaroline; MSSA, methicillin-susceptible S. aureus; VISA, vancomycin-intermediate S. aureus;
hVISA, heteroresistant VISA; VSSA, vancomycin-susceptible S. aureus.
a
No demonstrable PBP binding affinity observed, with the exception of PBP 3.
b
Classified according to 2006 CLSI M100-S17 interpretive data.
improved binding to PBPs that exhibit decreased binding affinity
for standard b-lactams, which gives ceftaroline potent activity
against even MRSA and penicillin-resistant pneumococci.20,21
Kosowska-Shick et al.26 compared the affinity of ceftaroline for
all PBPs with those of ceftriaxone and cefotaxime in six isolates
of S. aureus and seven isolates of S. pneumoniae. The MICs of ceftaroline and comparators for the MRSA and penicillin-resistant
pneumococci pathogens are shown in Table 2;26 binding affinity
for PBPs is the determinant that drives MIC values for both of
these pathogens. In this study, ceftaroline exhibited the lowest
MICs for all seven S. pneumoniae strains evaluated, ranging
from 0.015 to 2 mg/L. Against the six S. aureus isolates, ceftaroline had the lowest MICs [MIC¼ 0.5 mg/L for all isolates except
one vancomycin-resistant S. aureus (VRSA) isolate for which the
MIC was 1 mg/L] compared with cefotaxime, ceftriaxone and
penicillin G. PBP affinities for ceftaroline and comparators for
S. aureus and S. pneumoniae are shown in Table 3.26 Although
mutations in PBP 2B are likely to be important, PBP 2X may be
the dominant factor in increasing b-lactam MIC values (Table 4
and Figure 2).26 The ability of ceftaroline to bind to these
altered PBPs explains its potent activity against resistant isolates
and makes it a potentially valuable addition in the treatment of
CAP. An important study to perform would be to determine the
likelihood of an isolate already bearing a mosaic chromosome
with a mutated PBP acquiring further mutations mediating
higher resistance to ceftaroline.
Adequacy of penetration
For an antimicrobial to affect key pathogens, provide clinical efficacy and minimize resistance, it is critical that antimicrobial
agents reach the primary site of infection. This is often taken
for granted in such circumstances as complicated skin and skin
structure infections. Infections such as meningitis, endophthalmitis (involving places with tight junctions between cells) and
endocarditis (penetration into a fibrin– platelet complex) are
examples where penetration should not be taken for granted.
Because distribution into tissues is dependent on the pharmacokinetic/pharmacodynamic parameters of each agent, one way to
evaluate adequacy of penetration is to measure concentrations
at the site of infection. Little research has been conducted to
evaluate antimicrobial penetration for pneumonia (including
the linkage of lung penetration to clinical outcome). Indeed,
there is some debate regarding the most appropriate method
for determining antimicrobial concentration at the site of infection for pneumonia.27 For pulmonary infections, penetration
into epithelial lining fluid (ELF) is considered one of the better
methods currently available for quantification of drug penetration into the lung for extracellular pathogens, although
studies have also evaluated concentrations in lung tissue or
sputum. One reason ELF concentrations are assessed is
because bronchoalveolar lavage is quantitatively cultured, particularly for intensive care unit (ICU) patients with pneumonia.28
Antimicrobial agents that readily diffuse across the alveolar
capillary wall, interstitial fluid and alveolar epithelial cells are
likely to achieve sufficient concentrations in ELF that will
exceed the MIC for typical respiratory pathogens.
Unfortunately, there is no reliable theory to explain the difference in ELF penetration between drugs, even within the same
class. As an example, cefepime concentration in ELF has been
shown to exceed 100% in patients with pneumonia in the
ICU.29,30 In contrast, ceftazidime was also studied in ICU patients
and demonstrated to have an ELF penetration of 20%.31 Both
iii63
Drusano
Table 3. PBP binding affinities of ceftaroline and comparators for S. aureus
and S. pneumoniae (adapted from Kosowska-Shick et al.,26 with permission)
CPT
CTX
CRO
PEN
ATCC 29213
873
510
2149A
1287
25
0.5
8
0.5
1
0.125
0.5
0.5
4
2
0.5
4
1
0.25
2
0.5
4
1
16
4
0.5
128
2
4
0.5
ATCC 29213
873
510
2149A
1287
25
0.25
0.5
0.125
1
4
0.25
1
0.5
0.5
2
1
0.5
0.25
0.5
0.25
1
1
2
8
0.5
64
.128
4
1
ATCC 29213
873
510
2149A
1287
25
NP
0.5
0.25
1
1
0.01
PBP 3
ATCC 29213
873
510
2149A
1287
25
0.125
0.125
0.125
0.5
0.1
0.25
PBP 4
ATCC 29213
873
510
2149A
1287
25
S. aureus
PBP 1
PBP 2
PBP 2A
S. pneumoniae
PBP 1A
1076 (S)
24 (R)
3413 (R)
2527 (R)
.8
.128
.128
.128
64
ND
1
0.125
0.25
4
1
0.25
.8
.128
.128
.128
.128
ND
NP
.128
1
.128
2
0.25
NP
64
64
2
4
4
1
0.25
0.25
2
1
1
1
0.03
4
2
0.25
0.5
.8
.128
.128
.128
.128
ND
.8
.128
64
.128
4
ND
0.25
0.125
0.25
0.25
0.1
0.125
0.25
0.25
0.1
0.25
0.25
0.25
PBP 1B
1076 (S)
24 (R)
3413 (R)
2527 (R)
0.25
0.1
0.25
0.25
0.25
8
4
0.25
0.1
1
4
0.125
PBP 2X
1076 (S)
24 (R)
3413 (R)
2527 (R)
0.1
1
0.25
0.1
0.25
1
4
0.1
0.1
1
4
0.1
PBP 2A
1076 (S)
24 (R)
3413 (R)
2527 (R)
0.25
0.5
0.25
0.25
0.25
0.5
0.25
0.25
0.25
1
1
0.25
Continued
iii64
CPT
PBP 2B
1076 (S)
24 (R)
3413 (R)
2527 (R)
4
0.5
2
4
PBP 3
1076 (S)
24 (R)
3413 (R)
2527 (R)
0.1
0.1
0.1
0.25
PBP
NP
.128
.128
.128
4
0.5
IC50 (mg/L)
Strain (penicillin
susceptibility)
IC50 (mg/L)
Strain (penicillin
susceptibility)
PBP
Table 3. Continued
CTX
.32
16
16
4
0.1
0.1
0.1
0.1
CRO
PEN
.32
16
16
4
0.1
0.25
0.25
0.25
CPT, ceftaroline; CTX, cefotaxime; CRO, ceftriaxone; PEN, penicillin G; NP,
ATCC 29213, as a methicillin-susceptible strain, lacks PBP 2A; ND, no
demonstrable binding of Bocillin FL to PBP 4 was observed; S,
susceptible; R, resistant.
Table 4. Comparison of binding affinities and MIC values of ceftaroline
for selected S. pneumoniae strains26
Strain
Ceftaroline/penicillin G
MIC (mg/L)
Ceftaroline IC50
PBP 2B (mg/L)
Ceftaroline IC50
PBP 2X (mg/L)
1076
24
3413
2527
0.015/0.03
0.25/4.0
0.125/4.0
0.015/2.0
4.0
0.5
2.0
4.0
0.1
1.0
0.25
0.1
of these drugs have protein binding in the area of 20%. Another
b-lactam (albeit of a different type), ertapenem, has protein
binding exceeding 90%, yet exhibits ELF penetration of 30%.32
No overall theory is able to predict ELF penetration, at least for
b-lactams. To choose the correct dose and schedule of an antimicrobial for use in pneumonia, a number of pieces of data may
be evaluated: (i) penetration of the agent into ELF in an animal
model of infection; (ii) linkage of ELF penetration in the animal
model to microbiological effect observed in the animal model;
and (iii) penetration of the drug into ELF in humans to allow bridging between animal and human data.33
Although one may assume adequate ELF penetration of ceftaroline based on the findings from the FOCUS trials,34,35 lung penetration data are not yet available. Evaluation of ELF and lung
penetration data for other b-lactam antibiotics may provide
some insight into the penetration of this class of agents in pulmonary infections. Studies evaluating pulmonary penetration (ELF) of
cefepime, ceftazidime, ceftobiprole, ertapenem and piperacillin/
tazobactam have been conducted (Table 5).30 – 33,36 As noted
earlier, cefepime penetration into ELF approximates 100% in
patients with severe nosocomial bacterial pneumonia on mechanical ventilation,29 whereas piperacillin/tazobactam (4 g/0.5 g
every 8 h) showed a mean percentage penetration into ELF of
56.8% for piperacillin and 91.3% for tazobactam (somewhat
inadequate penetration methodology), suggesting that higher
JAC
Acceptable antibiotic therapy for CAP
0
1A
1B
2X
2A
2B
0.008
0.03
0.125
0.5
2
8
32
Ceftaroline concentration (mg/L)
1076
3
0
1A
1B
2X
2A
2B
0.008 0.03 0.125
0.5
2
8
32
M
Ceftaroline concentration (mg/L)
24
3
1A
1B
2X
2A
2B
0
0.008 0.03 0.125
0.5
2
8
32
M
Ceftaroline concentration (mg/L)
3413
3
0
1A
1B
2X
2A
2B
0.008
0.03
0.125
0.5
2
8
32
Ceftaroline concentration (mg/L)
2527
3
Figure 2. Competition assays for ceftaroline binding to PBPs from S. pneumoniae strains (reproduced from Kosowska-Shick et al.,26 with permission).
Table 5. Penetration of different b-lactam antibiotics into ELF
Agent
Protein
Reference binding (%) Penetration (%)
Comment
Cefepime
30
20
104
—
Ceftazidime
31
20
20
—
Ertapenem
32
90
30
% of free drug in
plasma
Ceftobiprole
33
18
15 – 26
—
Piperacillin
36
20
57
poor penetration
methods
Tazobactam
36
25
91
poor penetration
methods
doses of this agent may be needed to exceed the MIC for causative
pathogens in pulmonary infections.37
If ceftaroline penetrates at least as well as other b-lactam
antibiotics, then it would be expected to provide microbiological
effect in the primary effect site for the target CAP pathogens. In
an experimental pneumonia model caused by MRSA, treatment
with ceftaroline (20 mg/kg) significantly reduced bacterial
counts in murine lung tissue.36 A study investigating the efficacy
of ceftaroline (human equivalent dosage of 600 mg every 12 h)
compared with ceftriaxone (human equivalent dosage of 1 g
every 24 h) in a rabbit pneumonia model showed that ceftaroline
effectively treated pulmonary infections caused by penicillin-
susceptible, -intermediate and -resistant strains of S. pneumoniae. Ceftaroline demonstrated excellent bactericidal activity
against penicillin-resistant S. pneumoniae, reducing bacterial
counts in lungs by 8 log (P,0.001), effectively eradicating
the infection, compared with a 2 log reduction in the ceftriaxone
treatment group.38
Rapidity of penetration
The time it takes for an antimicrobial to reach therapeutic concentrations at the site of infection also should be taken into
consideration. Fleishaker and McNamara39 calculated that the
amount of protein binding for an antimicrobial had a significant
impact on time to attainment of therapeutic concentrations
at the site of infection. This is an important distinction. The
Emerging Infections Pharmacodynamics Laboratory at Ordway
Research Institute recently demonstrated that granulocyte
killing of pathogens is a saturable process.40 Delay of the
arrival of the therapeutic agent at the site of infection increases
the probability that the pathogen can achieve a bacterial burden
in excess of the saturation point for granulocyte killing. Higher
bacterial burden may translate to an increased reliance on the
antimicrobial agent to drive bacterial clearance to a level
below granulocyte saturation, possibly increasing dosing requirements and prolonging the necessary time required for clearing
the infection. Assuming permeability of unbound drug into vascular capillaries, therapeutic efficacy may be more quickly
achieved by agents with low protein binding. Ceftaroline has relatively low protein binding (,20%) and would be predicted on the
basis of the Fleishaker and McNamara39 study to attain rapid
penetration to the primary infection site.
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Drusano
proof that a new agent has comparable or superior efficacy and
lack of toxicity when compared with available agents. Emergence
of resistance in the primary pathogens seen in CAP was not seen in
the FOCUS trials.
Another important aspect of placing a new drug into perspective are the adverse events seen with its use. Generally, even
Phase III clinical trials are not large enough to provide accurate
point estimates of rates of adverse events for such issues as Clostridium difficile-associated diarrhoea. This important information
will be available only with broader utilization. To date there is no
substantive hint of any unusual rate of toxicity attendant on the
use of ceftaroline. Ceftaroline is, therefore likely to be a welcome
addition to the physician’s therapeutic armamentarium for CAP.
12
Simulated ELF concentration (mg/L)
Mice
Human
10
8
6
4
2
Funding
0
0
24
48
72
Time (h)
96
120
Figure 3. ELF concentration–time profiles in mice and man. Arrows
demonstrate the time to achievement of therapeutic ELF
concentrations between species (reproduced from Ambrose et al.41).
One last issue is to be aware that animal models may not
provide a good guide to the rapidity of penetration to the
primary site of infection. An example is seen with the drug oritavancin,41 an agent that is heavily protein bound. As shown in
Figure 3,41 first-order rate constants of penetration differ significantly between mice and men, indicating that a much longer
period is required to achieve optimal ELF levels in man versus
mouse. In such a circumstance, it is likely that a loading dose
would be required to attain optimal concentrations early in the
infection course in clinical practice. Again, it is unlikely that
such a scenario would be required for an agent like ceftaroline.
Summary
In summary, potent antimicrobial activity against both wild-type
and defined mutant pathogens likely to be encountered in CAP,
along with adequate and rapid penetration to the primary infection site of pneumonia, are the main factors that determine
whether an antimicrobial agent will provide excellent activity
against the target pathogens in seriously ill patients with pneumonia. Ceftaroline provides potent antimicrobial activity against
wild-type and mutant target pathogens typically present in CAP,
exhibiting significantly lower in vitro MICs for S. aureus and S. pneumoniae, including resistant strains, compared with ceftriaxone and
other cephalosporins. The improved activity of ceftaroline against
both S. aureus and S. pneumoniae is a function of the 3′ side chain
mediating improved binding to PBPs that exhibit decreased binding
affinity for standard b-lactams. Although no data are currently
available to evaluate the extent and rate of penetration of ceftaroline into the primary infection site for pneumonia, rapid and
adequate penetration is expected so as to drive high target attainment rates. As reported elsewhere in this Supplement, the FOCUS
clinical trials have established the bacteriological and clinical
effectiveness of ceftaroline in the management of CAP,34,35
suggesting that this agent has the potential to be a valuable therapeutic addition in the armamentarium for CAP. Indeed, it is the
outcome of controlled clinical trials that provides the ultimate
iii66
Funding for editorial assistance was provided by Forest Laboratories, Inc.
Transparency declarations
This article was developed from a scientific panel of FOCUS investigators
and experts in community-acquired bacterial pneumonia, held on 1 –2
May 2010 in New York, NY, USA. This article is part of a Supplement sponsored by Forest Laboratories, Inc.
G. L. D. has served as a consultant to both Cerexa, Inc. and Forest Laboratories, Inc. and has received grant funding support from Cerexa, Inc.
Scientific Therapeutics Information, Inc. (Springfield, NJ, USA) provided editorial assistance on this manuscript.
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