SUPPLEMENT ARTICLE
Ceftaroline Potency Among 9 US Census
Regions: Report From the 2010 AWARE
Program
Robert K. Flamm,1 Helio S. Sader,1 David J. Farrell,1 and Ronald N. Jones1,2
1
JMI Laboratories, North Liberty, Iowa, and 2 Tufts University School of Medicine, Boston, Massachusetts
Ceftaroline is a new antibacterial agent that is active against the major bacterial pathogens found in acute
bacterial skin and skin structure infections and community-acquired bacterial pneumonia. The 2010 Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) Surveillance Program in the United States collected a total of 8434 bacterial isolates from 65 US medical centers across 9 US regions. The isolates were
cultured and tested for susceptibility to ceftaroline and comparator agents by reference minimum inhibitory
concentration (MIC) methods. An analysis by US Census Bureau region demonstrated that Staphylococcus
aureus, including methicillin-resistant S. aureus (MRSA), and coagulase-negative staphylococci (CoNS),
including methicillin-resistant CoNS, were particularly susceptible to ceftaroline (MIC90, 1 and 0.5 µg/mL
respectively). The MRSA rate was 50.0% overall, which varied from a low of 44.6% in the South Atlantic
region to a high of 53.1% in the Mountain region. Susceptibility among MRSA for ceftaroline ranged from
96.7% in the West South Central region to 100% in the West North Central region. All MRSA isolates were
inhibited at a ceftaroline MIC of ≤2 μg/mL, and 98.4% were inhibited at a ceftaroline MIC of ≤1 μg/mL. In
general, regional differences in activity among staphylococci, streptococci, Haemophilus spp., and Moraxella
catarrhalis were minimal due to the high potency of ceftaroline. Greater differences in activity were observed
among the Enterobacteriaceae due to the greater diversity of organism types and resistance mechanisms,
including those producing extended-spectrum β-lactamase enzymes.
Infections due to multidrug-resistant (MDR) bacteria
cause significant morbidity and mortality [1–7]. Especially problematic has been the increase in methicillinresistant Staphylococcus aureus (MRSA), which may
represent >50% of S. aureus in severe infections [8–11].
Also concerning has been the increase in penicillinresistant and MDR Streptococcus pneumoniae, which
has led to the increased use of non-β-lactams [12, 13].
Further, the spread of newer β-lactamases to
include extended-spectrum β-lactamases (ESBLs),
carbapenemases such as Klebsiella pneumoniae carbapenemases, and metallo-β-lactamases representing a
Correspondence: Robert K. Flamm, PhD, JMI Laboratories, 345 Beaver Kreek
Centre, Ste A, North Liberty, Iowa 52317 (robert-fl[email protected]).
Clinical Infectious Diseases 2012;55(S3):S194–205
© The Author 2012. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
[email protected].
DOI: 10.1093/cid/cis562
S194
•
CID 2012:55 (Suppl 3)
•
Flamm et al
variety of families, such as IMP, VIM, and NDM, have
severely limited therapeutic options for many infection
types where Gram-negative bacteria may be present
[14–17].
Acute bacterial skin and skin structure infections
(ABSSSIs) are primarily caused by Gram-positive bacteria that are usually S. aureus or less frequently β-haemolytic Streptococcus species [18–22]. Methicillin-resistant
S. aureus are commonly encountered in ABSSSIs [19–23].
Community-acquired bacterial pneumonia (CABP) is
most often caused by the bacterial pathogens S. pneumoniae, Haemophilus spp., S. aureus, and Moraxella
catarrhalis [24–26]. There are serious concerns over
emerging antimicrobial resistance in S. pneumoniae
and its deleterious effect on patient outcomes [24–26].
Ceftaroline fosamil is a new antibacterial cephalosporin agent with bactericidal activity against the
major pathogens in ABSSSIs and CABP [27]. It is an
N-phosphonoamino water-soluble prodrug cephem
8434
893
598
896
722
1008
971
1396
1130
Total
820
200
21
13
18
13
21
22
40
24
28
68
CID 2012:55 (Suppl 3)
Moraxella catarrhalis
770
67
7
3
55
89
4
6
66
97
6
9
98
130
17
8
94
74
Haemophilus influenzae
8
16
Morganella morganii
•
Haemophilus parainfluenzae
250
116
12
5
13
5
16
14
22
653
24
13
30
18
20
25
25
30
46
657
Klebsiella oxytoca
32
60
60
45
41
88
91
59
55
77
75
77
75
104
100
66
Klebsiella pneumoniae
87
65
Escherichia coli
85
492
195
21
15
21
18
24
21
30
18
Enterococcus faecalis
27
50
31
36
41
54
56
90
90
44
1201
Ceftaroline Regional Activity
Viridans group streptococci
1200
136
141
86
83
112
113
101
79
161
125
150
147
207
210
158
117
β-Haemolytic streptococci
150
125
Streptococcus pneumoniae
486
2146
247
41
41
162
230
61
45
209
276
51
56
216
318
82
59
303
185
50
Coagulase-negative
staphylococci
Staphylococcus aureus
East S. Central
(6)
South
Atlantic (8)
West
N. Central (7)
East N. Central
(10)
Mid Atlantic
(9)
Isolates were tested for susceptibility to ceftaroline and multiple comparator agents by reference broth microdilution
methods as described by the Clinical and Laboratory Standards Institute (CLSI) M07-A9 [30]. The CLSI interpretations
were based on M100-S21 and M45-A2 breakpoints [31, 32].
Ceftaroline and tigecycline breakpoints in the product package
insert were applied [29, 33]. Streptococci were tested in
Mueller–Hinton broth supplemented with 3%–5% lysed horse
blood, and Haemophilus spp. were tested in Haemophilus test
media. Staphylococcus aureus, E. faecalis, and Enterobacteriaceae isolates were tested in cation-adjusted Mueller–Hinton
broth. The quality control strains S. aureus ATCC 29213, S.
pneumoniae ATCC 49619, and H. influenzae ATCC 49247
and 49766 were tested concurrently. The ESBL phenotype was
defined as a minimum inhibitory concentration (MIC) ≥2 µg/
mL for ceftazidime or ceftriaxone or aztreonam [31].
New England
(6)
Susceptibility Testing
Table 1.
During January through December of 2010, 65 medical
centers distributed over the 9 US Census regions (5–10
medical centers per region) (Table 1) contributed consecutively collected clinical isolates (1 strain per patient infection
episode). Isolates were from various anatomic sites of infection
to include respiratory tract, skin and skin structure, bloodstream, urinary tract, and other infections. Each site was
requested to target 30 S. aureus, 8 coagulase-negative staphylococci (CoNS), 20 β-haemolytic streptococci, 20 S. pneumoniae, 8 viridans group streptococci, 3 Enterococcus faecalis, 10
Escherichia coli, 10 K. pneumoniae, 5 Klebsiella oxytoca, 3
Morganella morganii, 10 H. influenzae, 3 Haemophilus parainfluenzae, and 3 M. catarrhalis. Isolates were sent to JMI Laboratories (North Liberty, Iowa) for reference susceptibility
testing [30–32].
Organisms Included in the 2010 Ceftaroline Surveillance Report Stratified by US Census Regions
Organism Collection
Organism
MATERIALS AND METHODS
US Census Region (No. of Medical Centers)
West
S. Central (7)
Mountain
(5)
Pacific
(7)
Overall
(65)
possessing broad-spectrum antimicrobial activity [28]. Its bioactive form, ceftaroline, is rapidly released in vivo upon hydrolysis of the phosphonate group. Ceftaroline fosamil was
recently approved by the US Food and Drug Administration
for treatment of ABSSSIs and CABP [29].
The Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) Surveillance Program provides contemporary
and longitudinal data covering the activity of ceftaroline and
comparators for relevant pathogens. In this report of the US
AWARE 2010 program, an analysis by US Census Bureau
regions of the activity of ceftaroline and comparator agents for
key pathogens is presented.
•
S195
RESULTS
Numbers of Target Organisms by Census Region and Overall
There were 8434 total isolates collected. These organisms were
from documented infections, including 3055 (36.2%) from
bloodstream infections (bacteremia), 2282 (27.1%) from respiratory tract infections (including CABP), 1965 (23.3%) from
ABSSSIs, 665 (7.9%) from urinary tract infections, and 467
(5.5%) from other miscellaneous infection sites. The numbers
of isolates, by Census region and overall, of each species/organism group tested are listed in Table 1. The East North
Central region provided the greatest number of organisms at
1396 from 10 sites, whereas the Mountain region had the
fewest (598 from 5 sites). The largest number of organisms
collected were S. aureus (2146), which ranged from162 in the
Mountain region to 318 in the East North Central region. This
was followed by 1201 β-haemolytic streptococci (range, 86–
210) and 1200 S. pneumoniae (range, 79–207). Haemophilus
parainfluenzae (68) and M. morganii (116) were the least frequently collected organisms.
In Vitro Activity of Ceftaroline and Comparator Agents for Key
Groups and Subsets of Organisms
The in vitro activity of ceftaroline in comparison with select
antimicrobial agents tested against isolates from each of the
US Census regions is summarized in Tables 2–4.
In Vitro Activity Against S. aureus
The MRSA rate was 50.0% overall and varied from a low of
44.6% in the South Atlantic region to a high of 53.1% in the
Mountain region. Only two regions, the South Atlantic
(44.6%) and Pacific (48.6%), had MRSA rates <50.0%. Staphylococcus aureus was very susceptible to ceftaroline (MIC90,
1 μg/mL; data not shown) overall. When tested against methicillin-susceptible S. aureus (MSSA), ceftaroline was >16-fold
more active (MIC90, 0.25 μg/mL) than ceftriaxone (MIC90,
4 μg/mL) and 4-fold more active than linezolid (1 μg/mL; data
not shown). Ceftaroline and ceftriaxone MIC90 values for
MSSA (0.25 μg/mL and 4 μg/mL, respectively) were identical
in all 9 Census regions (Table 2). Linezolid (100.0% susceptible) exhibited MIC90 values for MSSA that were also 1 μg/mL
in 6 of the Census regions but were 2 μg/mL in the West
North Central, East South Central, and the Mountain regions.
Tigecycline and vancomycin both exhibited 100.0% susceptibility with MIC90 values ranging 0.12–0.25 μg/mL and 1 μg/
mL, respectively. Macrolide resistance was elevated in MSSA
(Table 2). Erythromycin MIC90 values were >4 μg/mL across
all regions, with susceptibility ranging from 56.9% in the
South Atlantic region to 77.6% in the Mountain region. Clindamycin was more active than erythromycin, with MIC90
values ≤0.25 μg/mL in all regions except the East South
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Flamm et al
Central region, where it was >2 μg/mL. Levofloxacin MIC90
values ranged 0.5–≥4 μg/mL, with 6 regions at ≥4 μg/mL; susceptibility ranged 83.8%–92.9%.The highest ceftaroline MIC
value among MSSA strains was only 0.5 μg/mL. Methicillinsusceptible S. aureus isolates with a MIC value of 0.5 μg/mL
were identified in 7 regions; in New England and the South
Atlantic regions, the highest MIC value for MSSA was
0.25 μg/mL (data not shown). Overall 97.5% of MSSA strains
were inhibited at a ceftaroline MIC of only ≤0.25 μg/mL (data
not shown). The overall susceptibility for MSSA was 100.0%.
Ceftaroline susceptibility for MRSA for all regions was high
at 98.4%. It ranged from 96.7% in the West South Central
region to 100% in the West North Central region (Table 2).
All MRSA isolates were inhibited at a ceftaroline MIC of ≤2
µg/mL (data not shown). Although ceftaroline MIC90 values
in each region were higher (4-fold) among MRSA than among
MSSA (0.25 μg/mL compared with 1 µg/mL), its activity was
considerably greater than other cephalosporins tested against
MRSA. Furthermore, ceftaroline was slightly more potent
overall than linezolid (MIC50 and MIC90, 1 μg/mL) and vancomycin (MIC50 and MIC90, 1 μg/mL) (data not shown). In
contrast, ceftaroline was less active than tigecycline (MIC90
ranging 0.12–0.25 μg/mL) when tested against MRSA strains
(Table 2). Methicillin-resistant S. aureus strains exhibited high
rates of resistance to erythromycin, ranging from 83.6% in the
East South Central region to 91.9% in the Mountain region.
High rates of levofloxacin resistance were noted, ranging from
49.1% in the East South Central region to 84.9% in the Mountain region (data not shown).
In Vitro Activity Against β-Haemolytic Streptococci
Ceftaroline and other β-lactams were very potent against βhaemolytic streptococci, with the highest ceftaroline MIC
value at 0.12 μg/mL (data not shown). Group A streptococci had
MIC90 values of ≤0.008 μg/mL in 8 regions and 0.015 μg/mL
in the East North Central region for ceftaroline. The MIC90
values in each of the 9 regions for ceftriaxone and for penicillin were at ≤0.06 and ≤0.03 μg/mL, respectively. Erythromycin regional MIC90 values ranged ≤0.25–>4 μg/mL, with
susceptibility ranging 83.5%–92.1%. Clindamycin regional
MIC90 values were ≤0.25 μg/mL, with susceptibility ranging
92.2%–97.9%. Levofloxacin MIC90 values ranged 1–2 μg/mL,
with susceptibility ranging 97.8%–100.0%. Linezolid and vancomycin MIC90 values were at 1 and 0.5 μg/mL, respectively,
with 100.0% susceptibility for both group A and group B
streptococci. Group B streptococci had MIC90 values that were
slightly higher for ceftaroline (0.015 μg/mL in 5 regions;
0.03 μg/mL in 4 regions), ceftriaxone (0.12 μg/mL, all
regions), and penicillin (0.06 μg/mL, all regions). Erythromycin and clindamycin MIC90 values were >4 and >2 μg/mL,
respectively. The levofloxacin MIC90 was 1 μg/mL in each
Table 2. Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) 2010 Regional Analysis of In Vitro Activity of Ceftaroline Against Select Gram-Positive Bacteria in
Comparison With Select Antimicrobial Agents
New England
Organism/Antimicrobial
Agent (No. Tested)
%Sb
MICa90
0.25
4
100.0
98.0
0.5
>4
≤0.25
MICa90
MSSA (1074)
Ceftarolinec
Ceftriaxone
Oxacillin
Erythromycin
Clindamycin
Mid-Atlantic
%Sb
MICa90
0.25
4
100.0
97.3
100.0
0.5
68.4
91.8
>4
≤0.25
98
Levofloxacin
4
Linezolid
Tigecyclined
1
0.25
Vancomycin
1
East N. Central
%Sb
MICa90
0.25
4
100.0
97.4
100.0
0.5
59.3
92.7
>4
≤0.25
85.3
≤0.5
150
84.7
4
West
N. Central
South Atlantic
%Sb
MICa90
0.25
4
100.0
100.0
100.0
0.5
68.8
95.5
>4
≤0.25
154
%Sb
MICa90
0.25
4
100.0
97.4
100.0
0.5
100.0
67.6
92.6
>4
≤0.25
56.9
94.8
>4
>2
86.9
>4
108
92.9
4
%Sb
MICa90
0.25
4
100.0
98.0
0.5
153
88.9
4
West
S. Central
East S. Central
Mountain
%Sb
MICa90
0.25
4
100.0
96.3
100.0
0.5
59.6
89.9
>4
≤0.25
99
%Sb
MICa90
0.25
4
100.0
100.0
0.25
4
100.0
98.4
100.0
0.5
100.0
0.5
100.0
60.6
93.6
>4
≤0.25
77.6
98.7
>4
≤0.25
74.8
97.6
86.8
≤0.5
109
83.8
1
76
90.8
4
100.0
100.0
1
0.25
100.0
100.0
1
0.25
100.0
100.0
2
0.25
100.0
100.0
1
0.12
100.0
100.0
2
0.25
100.0
100.0
1
0.12
100.0
100.0
2
0.25
100.0
1
100.0
1
100.0
1
100.0
1
100.0
1
100.0
1
100.0
1
108
123
110
121
92.9
100.0
100.0
1
0.12
100.0
100.0
100.0
1
100.0
Ceftaroline Regional Activity
1
98.9
1
99.3
1
98.8
1
100.0
1
97.6
1
97.3
1
96.7
1
98.8
1
>8
0.0
>8
0.0
>8
0.0
>8
0.0
>8
0.0
>8
0.0
>8
0.0
>8
0.0
>8
0.0
Oxacillin
Erythromycin
>2
>4
0.0
10.3
>2
>4
0.0
8.5
>2
>4
0.0
9.1
>2
>4
0.0
14.8
>2
>4
0.0
11.4
>2
>4
0.0
14.5
>2
>4
0.0
9.9
>2
>4
0.0
7.0
>2
>4
0.0
12.5
Clindamycin
>2
66.7
>2
64.1
>2
78.0
>2
70.4
>2
75.6
>2
75.5
>2
76.9
>2
62.8
>2
68.3
Levofloxacin
Linezolid
>4
1
27.6
100.0
>4
1
24.8
100.0
>4
1
43.9
100.0
>4
1
40.7
100.0
>4
1
30.1
100.0
>4
1
50.9
100.0
>4
1
31.4
100.0
>4
1
14.0
100.0
>4
1
21.7
100.0
Group A (422)
Ceftarolinec
164
127
Ceftriaxone
Vancomycin
β-Haemolytic
streptococci
153
%Sb
MRSA (1072)
Ceftarolinec
Tigecyclined
87
Pacific
86
120
98.3
0.25
100.0
0.25
100.0
0.25
100.0
0.25
100.0
0.25
100.0
0.25
100.0
0.25
100.0
0.25
100.0
0.12
100.0
1
100.0
1
100.0
1
100.0
1
100.0
1
100.0
1
100.0
1
100.0
1
100.0
1
100.0
40
≤0.008 100.0
45
≤0.008
97.8
79
0.015
98.7
38
≤0.008 100.0
40
≤0.008 100.0
31
≤0.008 100.0
38
≤0.008 100.0
47
≤0.008 100.0
64
≤0.008 100.0
•
CID 2012:55 (Suppl 3)
Ceftriaxone
≤0.06
100.0
≤0.06
100.0
≤0.06
100.0
≤0.06
100.0
≤0.06
100.0
≤0.06
100.0
≤0.06
100.0
≤0.06
100.0
≤0.06
100.0
Penicillin
Erythromycin
≤0.03
2
100.0
85.0
≤0.03
2
100.0
86.7
≤0.03
>4
100.0
83.5
≤0.03
≤0.25
100.0
92.1
≤0.03
>4
100.0
85.0
≤0.03
≤0.25
100.0
90.3
≤0.03
≤0.25
100.0
92.1
≤0.03
2
100.0
87.2
≤0.03
≤0.25
100.0
90.6
Clindamycin
≤0.25
95.0
≤0.25
95.6
≤0.25
94.9
≤0.25
97.4
≤0.25
92.5
≤0.25
96.8
≤0.25
97.4
≤0.25
97.9
≤0.25
Levofloxacin
Linezolid
1
1
Vancomycin
0.5
100.0
100.0
2
1
97.8
100.0
1
1
100.0
100.0
1
1
100.0
0.5
100.0
0.5
100.0
0.5
•
S197
Group B (576)
Ceftarolinec
55
0.03
85.5
Ceftriaxone
0.12
100.0
100.0
100.0
2
1
100.0
0.5
1
1
100.0
0.5
1
1
100.0
100.0
2
1
97.9
100.0
1
1
100.0
100.0
100.0
0.5
100.0
0.5
100.0
0.5
100.0
101
0.015
93.1
0.03
88.2
0.03
87.3
0.03
80.9
0.12
0.12
0.12
100.0
0.12
100.0
0.12
100.0
100.0
71
92.2
100.0
100.0
84
0.015
91.7
100.0
76
100.0
100.0
47
59
0.015
91.5
31
0.015
90.3
52
0.015
92.3
0.12
0.12
0.12
100.0
100.0
100.0
Flamm et al
Food and Drug Administration breakpoints were applied when available [33].
d
Criteria as published by Clinical and Laboratory Standards Institute [31] except where noted.
Food and Drug Administration breakpoints were applied when available [29].
c
b
MIC90 in µg/mL.
In Vitro Activity Against Coagulase-Negative Staphylococci,
Viridans Streptococci, and E. faecalis
a
Abbreviations: MIC90, 90% median inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible St aureus; %S, percent susceptible.
1
0.5
100.0
100.0
100.0
1
96.8
1
0.5
100.0
100.0
100.0
100.0
100.0
1
0.5
1
100.0
100.0
100.0
1
0.5
1
100.0
100.0
100.0
1
0.5
1
97.4
100.0
100.0
1
0.5
1
99.0
100.0
100.0
1
0.5
1
1
0.5
100.0
100.0
100.0
1
1
0.5
98.2
1
Linezolid
Vancomycin
100.0
100.0
•
Levofloxacin
CID 2012:55 (Suppl 3)
Erythromycin
Clindamycin
•
Penicillin
1
65.4
76.9
100.0
0.06
>4
>2
54.8
67.7
100.0
0.06
>4
>2
52.5
79.7
100.0
0.06
>4
>2
46.8
63.8
100.0
0.06
>4
>2
54.9
73.2
100.0
0.06
>4
>2
55.3
68.4
100.0
0.06
>4
>2
41.6
71.3
100.0
0.06
>4
>2
45.2
72.6
100.0
0.06
100.0
0.06
>4
>2
%S
%S
%S
63.6
83.6
%S
%S
%S
%S
MICa90
b
MICa90
b
MICa90
b
MICa90
Organism/Antimicrobial
Agent (No. Tested)
>4
>2
%Sb
MICa90
%S
Pacific
b
MICa90
Mountain
b
MICa90
b
MICa90
b
b
MICa90
West
S. Central
East S. Central
South Atlantic
West
N. Central
East N. Central
Mid-Atlantic
New England
Table 2 continued.
S198
region, with susceptibility ranging 96.8%–100.0%. Susceptibility for ceftaroline for group A steptococci was 100.0% in 7
regions, 97.8% in the Mid-Atlantic region, and 98.7% in the
East North Central region. For group B streptococci, susceptibility varied from 85.5% in the New England region to 93.1%
in the East North Central region.
Ceftaroline was highly active against CoNS, with MIC90 values
in all regions of 0.5 μg/mL. The highest MIC value of 2 μg/mL
occurred in the Pacific region (data not shown). As for
S. aureus, the MIC values for methicillin-resistant CoNS were
2–4-fold higher than for methicillin-susceptible CoNS. Also,
ceftaroline activity was significantly greater for methicillinresistant CoNS than other cephalosporins. Tigecycline was
active, with regional MIC values ranging 0.06–0.12 μg/mL.
Linezolid susceptibility for CoNS ranged 95.1%–100% across
the 9 Census regions, with an overall rate of 97.9%. Vancomycin susceptibility was at 100.0%. High levels of resistance
occurred for levofloxacin (range, 37.3%–68.3% susceptible),
erythromycin (range, 26.7%–56.1% susceptible), and clindamycin (range, 59.0%–80.0% susceptible). For the viridans
group streptococci, MIC90 values varied 0.03–0.5 μg/mL (data
not shown), with the highest MIC90 value of 0.5 μg/mL occurring in the West South Central region. The highest MIC value
for viridans group streptococci (1 μg/mL) occurred in the
Pacific, East North Central, and Mid-Atlantic regions. Ceftaroline was generally 8–16-fold more active than ceftriaxone. Susceptibility for linezolid and vancomycin was 100.0%. Regional
susceptibility to erythromycin, levofloxacin, and penicillin
ranged 37.0%–61.3%, 83.3%–98.9%, and 58.3%–83.3%, respectively. Ceftaroline was moderately active against E. faecalis,
with MIC90 values ranging 2–8 μg/mL (data not shown). The
highest MIC value of 16 μg/mL occurred in the Mountain
region. Susceptiblity to ampicillin was 100.0%. Regional vancomycin susceptibility ranged 90.5%–100.0%. Linezolid susceptibility was 100.0% in 8 regions, with susceptibility in 1
region at 95.8%.
In Vitro Activity Against Enterobacteriaceae
Escherichia coli isolates were generally susceptible to ceftaroline, with MIC50 regional values ranging 0.06–0.12 μg/mL and
susceptibility rates from 70.3% in the West South Central
region to 92.3% in New England (Table 3). Ceftazidime regional MIC50 values ranged 0.12–0.25 μg/mL, with susceptibility ranging from 83.1% in the East South Central to 96.7% in
the Pacific region. Levofloxacin susceptibility ranged 53.8%–
85.0%, and gentamicin susceptibility ranged 83.1%–97.8%.
Meropenem susceptibility was at 100.0% for all regions, and
piperacillin/tazobactam susceptibility ranged 88.9%–100.0%.
Table 3. Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) 2010 Regional Analysis of In Vitro Activity of Ceftaroline Against Select Gram-Negative Bacteria in
Comparison With Select Antimicrobial Agents
New England
Organism/Antimicrobial Agent
(No. Tested)
MICa50
Escherichia coli (657)
Mid-Atlantic
%Sb
MICa50
65
East
N. Central
%Sb
MICa50
85
West
N. Central
%Sb
MICa50
100
South Atlantic
%Sb
MICa50
77
East
S. Central
%Sb
MICa50
75
West
S. Central
%Sb
MICa50
59
Mountain
%Sb
MICa50
91
Pacific
%Sb
MICa50
45
%Sb
60
Ceftarolinec
0.12
92.3
0.12
85.9
0.06
88.0
0.06
87.0
0.12
89.3
0.12
78.0
0.12
70.3
0.06
82.2
0.06
Ceftazidime
0.12
95.4
0.12
94.1
0.12
94.0
0.12
90.9
0.25
93.3
0.12
83.1
0.25
90.1
0.12
93.3
0.12
96.7
Ceftriaxone
≤0.06
90.8
≤0.06
90.6
≤0.06
92.0
≤0.06
89.6
≤0.06
92.0
≤0.06
79.7
≤0.06
85.7
≤0.06
86.7
≤0.06
93.3
91.7
Ampicillin/sulbactam
4
58.5
4
56.5
4
67.0
4
58.4
8
56.0
16
49.2
16
49.5
8
60.0
4
63.3
Piperacillin/tazobactam
2
100.0
2
94.1
2
96.0
2
94.8
2
96.0
2
96.6
2
92.3
2
88.9
2
98.3
Meropenem
≤0.12
Gentamicin
≤1
89.2
≤1
88.2
≤1
90.0
≤1
92.2
≤1
90.7
≤1
83.1
≤1
83.5
≤1
97.8
≤1
93.3
Levofloxacin
≤0.5
64.6
≤0.5
74.1
≤0.5
84.0
≤0.5
76.6
≤0.5
65.3
≤0.5
57.6
≤0.5
53.8
≤0.5
77.8
≤0.5
85.0
Non-ESBL phenotype (579)
100.0
≤0.12
59
100.0
≤0.12
76
100.0
≤0.12
92
100.0
≤0.12
67
100.0
≤0.12
67
100.0
≤0.12
46
100.0
≤0.12
78
100.0
≤0.12
39
100.0
55
Ceftarolinec
0.06
100.0
0.06
96.1
0.06
95.7
0.06
98.5
0.12
97.0
0.12
100.0
0.12
82.1
0.06
94.9
0.06
Ceftazidime
0.12
100.0
0.12
100.0
0.12
100.0
0.12
100.0
0.12
100.0
0.12
100.0
0.12
100.0
0.12
100.0
0.12
100.0
Ceftriaxone
≤0.06
100.0
≤0.06
100.0
≤0.06
100.0
≤0.06
100.0
≤0.06
100.0
≤0.06
100.0
≤0.06
100.0
≤0.06
100.0
≤0.06
100.0
100.0
Ampicillin/sulbactam
4
61.0
4
61.8
4
72.8
4
67.2
4
62.7
8
52.2
8
53.8
4
69.2
2
65.5
Piperacillin/tazobactam
2
100.0
2
98.7
2
98.9
2
98.5
2
98.5
2
100.0
2
94.9
2
92.3
2
100.0
Meropenem
≤0.12
≤0.12
100.0
≤0.12
Gentamicin
≤1
89.8
≤1
92.1
≤1
93.5
≤1
94.0
≤1
91.0
≤1
87.0
≤1
85.9
≤1
100.0
≤1
92.7
Levofloxacin
≤0.5
69.5
≤0.5
80.3
≤0.5
90.2
≤0.5
82.1
≤0.5
70.1
≤0.5
69.6
≤0.5
62.8
≤0.5
≤0.5
87.3
Ceftaroline Regional Activity
Klebsiella spp. (903)
100.0
≤0.12
90
100.0
≤0.12
119
100.0
≤0.12
150
100.0
≤0.12
105
100.0
≤0.12
102
100.0
≤0.12
80
100.0
108
87.2
59
100.0
90
Ceftarolinec
0.12
88.9
0.12
73.1
0.12
90.7
0.12
90.5
0.06
90.2
0.12
75.0
0.12
81.5
0.12
96.6
0.06
88.9
Ceftazidime
0.12
93.3
0.12
83.2
0.12
96.0
0.12
97.1
0.12
91.2
0.12
85.0
0.12
86.1
0.12
98.3
0.12
100.0
Ceftriaxone
≤0.06
90.0
≤0.06
78.2
≤0.06
93.3
≤0.06
93.3
≤0.06
90.2
≤0.06
77.5
≤0.06
85.2
≤0.06
98.3
≤0.06
94.4
Ampicillin/sulbactam
4
83.3
8
62.2
4
78.7
8
83.8
4
79.4
8
71.3
8
69.4
8
84.7
4
72.2
Piperacillin/tazobactam
2
93.3
2
80.7
2
93.3
2
94.3
2
95.1
2
88.8
2
87.0
2
100.0
2
94.4
Meropenem
≤0.12
98.9
≤0.12
89.9
≤0.12
98.7
≤0.12
98.1
≤0.12
96.1
≤0.12
98.8
≤0.12
93.5
≤0.12
100.0
≤0.12
Gentamicin
≤1
96.7
≤1
90.8
≤1
96.7
≤1
96.2
≤1
94.1
≤1
95.0
≤1
93.5
≤1
100.0
≤1
95.6
Levofloxacin
≤0.5
94.4
≤0.5
86.6
≤0.5
94.7
≤0.5
93.3
≤0.5
93.1
≤0.5
90.0
≤0.5
86.1
≤0.5
100.0
≤0.5
94.4
•
CID 2012:55 (Suppl 3)
Non-ESBL phenotype (791)
80
90
139
97
92
61
91
57
100.0
84
Ceftarolinec
0.06
98.8
0.12
96.7
0.12
97.8
0.12
96.9
0.06
100.0
0.12
98.4
0.12
96.7
0.12
100.0
0.06
95.2
Ceftazidime
0.12
100.0
0.12
100.0
0.12
100.0
0.12
100.0
0.12
100.0
0.12
100.0
0.12
100.0
0.12
100.0
0.12
100.0
Ceftriaxone
≤0.06
100.0
≤0.06
100.0
≤0.06
100.0
≤0.06
100.0
≤0.06
100.0
≤0.06
100.0
≤0.06
100.0
≤0.06
100.0
≤0.06
100.0
Ampicillin/sulbactam
4
93.8
4
81.1
4
84.2
4
89.7
4
88.0
4
86.9
4
81.3
4
86.0
4
Piperacillin/tazobactam
2
98.8
2
98.9
2
97.8
2
99.0
2
100.0
2
100.0
2
96.7
2
100.0
2
Meropenem
≤0.12
100.0
≤0.12
100.0
≤0.12
100.0
≤0.12
100.0
≤0.12
100.0
100.0
•
S199
Gentamicin
≤1
97.5
≤1
98.9
≤1
99.3
≤1
99.0
≤1
Levofloxacin
≤0.5
98.8
≤0.5
97.8
≤0.5
98.6
≤0.5
97.9
≤0.5
98.9
≤0.12
100.0
≤0.12
≤1
100.0
≤1
≤0.5
100.0
≤0.5
100.0
98.9
100.0
≤0.12
100.0
≤0.12
77.4
98.8
100.0
≤1
100.0
≤1
97.6
≤0.5
100.0
≤0.5
96.4
83.3
91.7
100.0
8.3
91.7
75.0
58.3
83.3
≤0.5
100.0
≤1
≤0.12
100.0
100.0
≤0.5
32
40.0
100.0
0.12
80.0
0.25
80.0
0.12
80.0
≤0.5
69.2
≤0.12
≤1
92.3
100.0
≤0.5
32
15.4
100.0
≤0.06
92.3
84.6
0.12
5
0.12
76.9
≤0.5
80.0
≤1
≤0.12
100.0
100.0
≤0.5
32
0.0
100.0
≤0.06
80.0
80.0
0.25
13
0.12
80.0
≤0.5
≤0.5
92.9
≤0.12
≤1
85.7
100.0
≤0.5
16
14.3
100.0
≤0.06
85.7
0.12
85.7
≤0.5
72.7
≤0.12
≤1
86.4
100.0
≤0.5
16
27.3
90.9
≤0.06
81.8
0.12
81.8
≤0.5
69.2
≤0.12
≤1
61.5
100.0
≤0.5
16
23.1
92.3
≤0.06
84.6
0.12
76.9
1
81.3
≤0.5
Levofloxacin
≤0.12
≤1
87.5
100.0
≤0.12
≤1
Meropenem
Gentamicin
32
Piperacillin/tazobactam
≤0.5
12.5
93.8
32
≤0.5
Ampicillin/sulbactam
≤0.06
75.0
0.12
75.0
0.12
≤0.06
Ceftazidime
Ceftriaxone
Flamm et al
Abbreviations: ESBL, extended-spectrum β-lactamase; MIC50, 50% minimum inhibitory concentration; %S, percent susceptible.
a
MIC90 in µg/mL.
b
Criteria as published by Clinical and Laboratory Standards Institute [31] except where noted.
c
Food and Drug Administration breakpoints were applied when available [29].
81.3
≤0.12
≤1
93.8
100.0
≤0.5
16
18.8
100.0
≤0.06
87.5
87.5
0.25
5
0.5
81.3
16
0.12
78.6
14
0.06
68.2
22
0.12
69.2
13
0.12
62.5
16
0.12
Ceftarolinec
•
Morganella morganii (116)
CID 2012:55 (Suppl 3)
Organism/Antimicrobial Agent
(No. Tested)
•
12
%Sb
MICa50
%Sb
MICa50
%Sb
MICa50
%Sb
MICa50
%Sb
MICa50
%Sb
MICa50
%Sb
MICa50
%Sb
MICa50
%Sb
MICa50
Pacific
Mountain
West
S. Central
East
S. Central
South Atlantic
West
N. Central
East
N. Central
Mid-Atlantic
New England
Table 3 continued.
S200
Among non-ESBL phenotype strains of E. coli, regional MIC50
values ranged 0.06–0.12 μg/mL, and susceptibility ranged
from 82.1% in the West South Central region to 100% in New
England, the Pacific, and East South Central regions (Table 3).
Eight of the 9 regions had susceptibility for non-ESBL phenotype E. coli >90% (Table 3). The ESBL phenotype strains were
not susceptible to ceftaroline (MIC50 and MIC90, >32 μg/mL
overall) and other cephalosporins tested (data not shown).
Ceftaroline was active against Klebsiella spp. with regional
MIC50 values of 0.06–0.12 μg/mL, and susceptibility ranged
from 73.1% in the Mid-Atlantic region to 96.6% in the Mountain region (Table 3). Ceftazidime regional MIC50 values were
0.12 μg/mL, with susceptibility ranging from 83.2% in the
Mid-Atlantic region to 100.0% in the Pacific region. Levofloxacin susceptibility ranged 86.1%–100.0%, and gentamicin susceptibility ranged 93.5%–100.0%. Meropenem susceptibility
ranged from 89.9% in the Mid-Atlantic region to 100.0% in
the Mountain and Pacific regions. Piperacillin/tazobactam susceptibility ranged 80.7%–100.0%. For the non-ESBL phenotype strains, MIC50 values ranged 0.06–0.12 μg/mL, and
susceptibility ranged from 95.2% in the Pacific region to
100.0% in the South Atlantic and Mountain regions (Table 3).
Susceptibility to ceftaroline >95% in each of the 9 regions
(Table 3). In contrast, the majority of ESBL phenotype strains
showed elevated ceftaroline MIC values (MIC50 and MIC90,
>32 μg/mL; data not shown) and high resistance rates to other
third- and fourth-generation cephalosporins (data not shown).
Klebsiella pneumoniae and K. oxytoca exhibited similar susceptibility to ceftaroline (data not shown). Among non-ESBL
strains, MIC50 results were 0.06 µg/mL and 0.25 µg/mL and
MIC90 results were 0.12 µg/mL and 0.25 µg/mL for K. pneumoniae and K. oxytoca, respectively (data not shown). Decreased
susceptibility in Klebsiella spp. to meropenem (MIC, ≥2 µg/mL)
ranged from 0% in the Mountain and Pacific regions to 10.1%
in the Mid-Atlantic region (Table 3). Ceftaroline showed variable activity against M. morganii, with MIC50 values ranging
0.06–0.12 μg/mL and susceptibility rates ranging from 58.3% in
the Pacific region to 81.3% in the South Atlantic region (Table 3).
Overall, 71.6% of strains were inhibited at ≤0.5 µg/mL of ceftaroline, and 81.0% of strains were susceptible to ceftazidime
(data not shown). Ceftazidime regional MIC50 values were
0.12–0.25 μg/mL, with susceptibility ranging 75.0%–87.5%.
Levofloxacin susceptibility ranged 69.2%–100.0%, and gentamicin susceptibility ranged 61.5%–100.0%. Meropenem susceptibility was 100.0% for all regions, and piperacillin/
tazobactam susceptibility ranged 90.9%–100.0%.
In Vitro Activity Against the Fastidious Respiratory Tract
Pathogens
A total of 1200 pneumococcal isolates were evaluated
(Table 1). The number of isolates ranged from 79 in the East
Table 4. Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) 2010 Regional Analysis of In Vitro Activity of Ceftaroline Against Select Respiratory Tract Pathogens
in Comparison With Select Antimicrobial Agents
New England
Organism/Antimicrobial
Agent (No. Tested)
MICa90
Streptococcus pneumoniae
(1200)
%Sb
Mid-Atlantic
%Sb
MICa90
125
East
N. Central
%Sb
MICa90
150
West
N. Central
MICa90
207
%Sb
South Atlantic
%Sb
MICa90
147
East
S. Central
MICa90
161
%Sb
West
S. Central
79
Ceftarolinec
0.12
99.2
0.12
98.7
0.25
97.1
0.12
99.3
0.12
98.8
0.12
Ceftriaxone
Cefuroxime
1
8
92.8
80.0
1
4
94.0
77.3
2
8
86.0
68.6
2
8
88.4
74.1
2
8
85.1
62.1
2
8
%Sb
MICa90
Mountain
MICa90
112
100.0
88.6
68.4
%Sb
Pacific
%Sb
MICa90
83
136
0.12
99.1
0.06
100.0
2
8
85.7
65.2
0.5
4
96.4
84.3
0.12
99.3
1
4
95.6
82.4
Amoxicillin/clavulanate
8
87.2
4
88.7
8
78.3
8
82.3
8
76.9
8
78.5
8
80.4
2
91.6
4
88.9
Penicillind
Penicilline
4
4
88.8
62.4
2
2
90.7
62.0
4
4
80.2
50.7
4
4
83.7
56.5
4
4
79.5
47.8
4
4
83.5
49.4
4
4
80.4
51.8
2
2
96.4
65.1
2
2
91.9
66.9
Tetracycline
>8
72.8
>8
82.6
>8
66.2
>8
72.8
>8
72.7
>8
77.2
>8
69.6
>8
84.3
>8
80.9
4
77.6
>4
77.3
>4
59.9
4
66.7
>4
61.5
>4
62.0
>4
58.9
4
67.5
4
69.9
Erythromycin
>8
60.0
>8
67.3
>8
51.7
>8
55.1
>8
57.1
>8
51.9
>8
50.0
>8
66.3
>8
67.6
Clindamycin
Levofloxacin
>1
1
75.2
99.2
>1
1
85.3
99.3
>1
1
69.1
99.0
>1
1
79.6
98.6
>1
1
75.8
98.1
>1
1
75.9
100.0
>1
1
73.2
100.0
>1
1
86.7
98.8
>1
1
81.6
98.5
100.0
100.0
0.03
≤0.06
100.0
100.0
0.015
≤0.06
Trimethoprim/
Sulfamethoxazole
Haemophilus influenzae (770)
Ceftaroline Regional Activity
Ceftarolinec
Ceftriaxone
Cefuroxime
Ampicillin
Amoxicillin/clavulanate
Azithromycin
74
0.015
≤0.06
94
100.0
100.0
0.03
≤0.06
130
100.0
100.0
0.03
≤0.06
98
98.5
100.0
0.015
≤0.06
97
100.0
100.0
0.03
≤0.06
66
100.0
100.0
0.03
≤0.06
89
55
67
100.0
100.0
0.03
≤0.06
100.0
100.0
2
100.0
2
98.9
2
100.0
2
100.0
2
100.0
2
97.0
2
98.9
2
100.0
2
100.0
>8
≤1
74.3
100.0
>8
≤1
68.1
100.0
>8
2
73.8
100.0
>8
≤1
80.6
100.0
>8
2
58.8
100.0
>8
≤1
78.8
100.0
>8
2
76.4
100.0
>8
≤1
69.1
100.0
>8
≤1
71.6
100.0
•
CID 2012:55 (Suppl 3)
2
100.0
2
96.8
2
99.2
2
98.0
2
95.8
2
98.5
2
100.0
2
100.0
2
100.0
Clarithromycin
Tetracycline
16
1
86.5
98.6
16
1
77.7
100.0
16
1
74.6
99.2
16
1
81.6
100.0
16
1
75.0
96.9
16
1
69.7
98.5
16
0.5
80.9
98.9
16
1
81.8
98.2
16
1
83.6
97.0
Trimethoprim/
Sulfamethoxazole
Levofloxacin
>4
74.3
>4
81.9
>4
76.9
>4
78.6
>4
79.4
>4
69.7
>4
73.0
>4
72.7
>4
74.6
≤0.5
Moraxella catarrhalis (200)
Ceftaroline
Ceftriaxone
Cefuroxime
Amoxicillin/clavulanate
Erythromycin
100.0
≤0.5
28
0.12
0.5
100.0
≤0.5
24
…
100.0
2
100.0
≤1
0.5
100.0
100.0
0.12
0.5
2
≤1
0.25
100.0
≤0.5
40
…
100.0
100.0
100.0
95.8
0.12
0.5
2
≤1
0.25
100.0
≤0.5
22
…
100.0
100.0
100.0
100.0
0.25
0.5
2
≤1
0.25
100.0
≤0.5
21
…
100.0
100.0
100.0
100.0
0.12
0.5
2
≤1
0.25
100.0
≤0.5
13
…
100.0
95.2
100.0
100.0
0.12
0.5
2
≤1
0.25
100.0
≤0.5
18
…
100.0
100.0
100.0
100.0
0.12
1
2
≤1
0.25
100.0
≤0.5
13
…
100.0
100.0
100.0
100.0
0.25
1
2
≤1
0.25
100.0
21
…
100.0
100.0
100.0
100.0
0.12
0.5
2
≤1
0.25
…
100.0
100.0
100.0
100.0
•
S201
CID 2012:55 (Suppl 3)
≤0.5
100.0
≤0.5
100.0
≤0.5
100.0
≤0.5
100.0
≤0.5
Criteria as published by the CLSI (2011) for penicillin parenteral (non-meningitis).
Criteria as published by Clinical and Laboratory Standards Institute (CLSI) [31] except where noted.
MIC90 in µg/mL.
Criteria as published by the CLSI (2011) for penicillin (oral penicillin V).
e
d
c
b
a
Abbreviations: MIC90, 90% minimum inhibitory concentration; %S, percent susceptible.
Flamm et al
Food and Drug Administration breakpoints were applied when available [29].
100.0
≤0.5
100.0
≤0.5
100.0
≤0.5
100.0
≤0.5
•
Levofloxacin
100.0
100.0
≤0.25
≤0.5
0.5
≤0.5
100.0
89.3
0.5
2
Tetracycline
Trimethoprim/
Sulfamethoxazole
%S
100.0
95.8
%S
%S
MICa90
b
MICa90
Organism/Antimicrobial
Agent (No. Tested)
100.0
100.0
95.2
0.5
≤0.5
100.0
84.6
0.5
2
100.0
100.0
0.5
≤0.5
100.0
100.0
≤0.25
≤0.5
100.0
100.0
≤0.25
≤0.5
%S
%S
100.0
95.5
%S
%S
%S
MICa90
b
MICa90
b
MICa90
MICa90
b
b
•
0.5
≤0.5
%Sb
MICa90
Pacific
b
MICa90
Mountain
b
MICa90
b
West
S. Central
East
S. Central
South Atlantic
West
N. Central
East
N. Central
Mid-Atlantic
New England
Table 4 continued.
S202
South Central region (6 sites) to 207 in the East North Central
(10 sites). The in vitro activity of ceftaroline and other βlactams varied according to the susceptibility to penicillin.
The MIC values of β-lactams increased with penicillin MIC.
However, ceftaroline was the most potent of all β-lactams
tested, with regional MIC90 values ranging 0.06–0.25 μg/mL
(Table 4). For tigecycline, vancomycin, and linezolid, regional
MIC90 values were ≤0.03, 0.5, and 1 μg/mL, respectively, with
susceptibility >99% (data not shown). Regional MIC90 values
for erythromycin were all >8 μg/mL, with susceptibility
ranging 50.0%–67.6%. Clindamycin MIC90 values were all
>1 μg/mL, with susceptibility ranging 69.1%–86.7%. Regional
levofloxacin MIC90 values were 1 μg/mL, with susceptibility
ranging
98.1%–100.0%.
Trimethoprim-sulfamethoxazole
(MIC90, ≥4) susceptibility ranged 58.9%–77.6%. Tetracycline
regional MIC90 values were >8 μg/mL, with susceptibility
ranging 66.2%–84.3%. For S. pneumoniae strains that were
penicillin intermediate, ceftaroline MIC90 values ranged 0.06–
0.12 μg/mL (New England, South Atlantic regions); for penicillin-resistant strains, MIC90 values were 0.25 μg/mL in 7
regions and 0.5 μg/mL in the East North Central region, and
the MIC range was 0.06–0.12 μg/mL for 9 isolates in the
Mountain region. All penicillin-intermediate strains were susceptible to ceftaroline in each of the 9 regions; for penicillinresistant strains, ceftaroline susceptibility ranged from 88.9%
in the East North Central region to 100.0% in the East South
Central region (data not shown). The highest ceftaroline MIC
value observed was 0.5 μg/mL. Ceftriaxone, amoxicillin/clavulanic acid, vancomycin, linezolid, tigecycline, and levofloxacin
all exhibited high levels of susceptibility (>98%) to penicillinintermediate strains. Against penicillin-resistant (MIC, ≥2 μg/
mL) pneumococci, ceftaroline regional MIC90 values (MIC90,
0.25–0.5 μg/mL) were 8–16-fold more active than ceftriaxone
(MIC90, 2–8 μg/mL) and 32–64-fold more potent than cefuroxime and amoxicillin/clavulanic acid (MIC90, 8–>8 μg/mL;
data not shown). Regional MIC90 values for erythromycin
were all >8 μg/mL, with susceptibility ranging 0.0%–17.2%.
Clindamycin MIC90 values were all >1 μg/mL, with susceptibility ranging 27.3%–55.2%. Regional levofloxacin
MIC90 values were 1 μg/mL, with susceptibility ranging
88.9%–100.0%. Trimethoprim-sulfamethoxazole (MIC90, >4)
susceptibility ranged 5.3%–33.3%. Tetracycline regional MIC90
values were >8 μg/mL, with susceptibility ranging 18.5%–
47.4%.
Ceftaroline was highly active against H. influenzae, with
MIC90 values ranging 0.015–0.03 μg/mL across the 9 Census
regions (Table 4). Nearly all (99.7%) strains were inhibited at a
ceftaroline MIC of ≤0.25 μg/mL. There was only 1 isolate with
a ceftaroline MIC value of 0.5 μg/mL (East North Central
region; data not shown). Ceftriaxone and cefuroxime were also
highly active. Regional ceftriaxone MIC90 values were
≤0.06 μg/mL (100.0% susceptible). Regional cefuroxime
MIC90 values were 2 μg/mL, with susceptibility ranging
97.0%–100.0%. All isolates were susceptible to levofloxacin
(regional MIC90, ≤0.5 μg/mL) and amoxicillin/clavulanic acid
(regional MIC90, ≤1–2 μg/mL). Tetracycline susceptibility
ranged 96.9%–100.0%, and trimethoprim-sulfamethoxazole
susceptibility ranged 69.7%–81.9%. Regional susceptibility
ranged 69.7%–86.5% for clarithromycin and 95.8%–100.0%
for azithromycin. β-Lactamase–producing strains showed ceftaroline MIC values slightly higher (regional MIC90 values of
0.03–0.12 μg/mL) than non-β-lactamase–producing ampicillin-susceptible strains (regional MIC90 values of 0.015–
0.03 μg/mL) but were still highly susceptible to ceftaroline.
Susceptibility across all regions was 100.0% for either β-lactamase–producing or non-β-lactamase–producing H. influenzae
(data not shown). Against H. parainfluenzae, 98.5% of strains
were inhibited at a ceftaroline MIC of ≤0.12 μg/mL (MIC50,
≤0.008 μg/mL; MIC90, 0.03 μg/mL) (data not shown). The
MIC50 values were ≤0.008 μg/mL for 7 of the regions and
0.015 μg/mL for the Pacific and Mid-Atlantic regions. There
was 100.0% susceptibility to amoxicillin/clavulanic acid, ceftriaxone, cefuroxime, and meropenem, and there was 1 isolate in
the Mid-Atlantic and 1 in the South Atlantic that was not susceptible to levofloxacin. For M. catarrhalis, ceftaroline was
also very active, with MIC90 values across the regions ranging
0.12–0.25 μg/mL, with the highest MIC at 0.25 μg/mL
(Table 4). Moraxella catarrhalis was susceptible (100.0%) to
ceftriaxone, amoxicillin/clavulanic acid, tetracycline, and levofloxacin. Trimethoprim-sulfamethoxazole susceptibility ranged
84.6%–100.0%, and cefuroxime susceptiblity was 100.0% in
each region except the South Atlantic (95.2%).
DISCUSSION
Bacterial resistance to antimicrobial agents is a serious public
health problem. Numerous efforts have been undertaken by
government and professional societies to address this issue. In
2004, the Infectious Diseases Society of America (IDSA)
launched the Bad Bugs Need Drugs campaign as part of an
effort to combat bacterial resistance [1]. In that effort, the
IDSA identified 7 key pathogens in which development of resistance has become a major problem (ESKAPE pathogens;
Enterococcus faecium, Staphylococcus aureus, Klebsiella spp.,
Acinetobacter spp., Pseudomonas spp., and Enterobacter spp.)
and stated that there was an immediate need for new agents to
treat these organisms. Further, in 2010, IDSA launched their
10 × ‘20 initiative in an effort to encourage the development of
10 new antimicrobials by 2020 [34] as one of the approaches
to assist in controlling emerging untreatable pathogens.
Methicillin-resistant S. aureus, listed among the ESKAPE
pathogens, has been increasing in prevalence, causing
increased morbidity and mortality [5, 6, 8–10]. It is an important pathogen in a variety of infections, including ABSSSIs
[18–22]. The incidence of MRSA has increased to the extent
that it may exceed one-half of the S. aureus strains in certain
infections and geographies [18].
Although not an ESKAPE pathogen, the emergence of MDR
S. pneumoniae has also caused great concern. S. pneumoniae
is the major bacterial pathogen in CABP [24–26]. Increasing
rates of resistance to macrolides, tetracyclines, and penicillins/
cephalosporins have limited the therapeutic options available
for this respiratory tract pathogen [24–26].
In the 2010 US AWARE Program, ceftaroline was demonstrated to be the most potent β-lactam agent tested against staphylococci. It exhibited consistent activity across the United States, as
evidenced by susceptibility rates of 100% for MSSA and rates
ranging 96.7%–100% for MRSA across all 9 Census Bureau
regions. Ceftaroline also showed consistent and potent activity
against CoNS. For both S. aureus and CoNS, the MIC values
were 2–4-fold higher for methicillin-resistant than for methicillin-susceptible isolates. Other non-β-lactam agents that demonstrated potent activity against staphylococci included linezolid,
vancomycin, and tigecycline. For the β-haemolytic streptococci,
there was some variation in MIC90 values across the regions for
ceftaroline; however, MIC90 values varied only ≤0.008–0.03 μg/
mL due to the extremely potent activity. Other β-lactam agents,
as well as linezolid, tigecycline, and vancomycin, demonstrated
high levels of susceptibility for the β-haemolytic streptococci.
Macrolide resistance was the most common resistance observed,
with limited fluoroquinolone resistance noted.
Ceftaroline demonstrated potent activity against the
respiratory pathogens S. pneumoniae, Haemophilus spp., and
M. catarrhalis. Against S. pneumoniae, the activity of ceftaroline
and other β-lactams varied according to the susceptibility to
penicillin, and ceftaroline was the most potent β-lactam tested,
with the highest MIC value observed at only 0.5 μg/mL. For
H. influenzae, there was only 1 isolate (MIC, 0.5 µg/mL) with
a ceftaroline MIC value >0.25 µg/mL, and regional MIC90
values for H. influenzae were ≤0.03 μg/mL. Other agents that
demonstrated potent activity against the respiratory pathogens
included the Gram-positive agents linezolid and vancomycin
and broader-spectrum agents including fluoroquinolones, tigecycline, amoxicillin/clavulanic acid, and ceftriaxone.
Ceftaroline also demonstrated potent activity against commonly encountered Gram-negative bacteria. For Enterobacteriaceae that do not express broad-spectrum β-lactamase activity
(ESBL or AmpC-derepressed), ceftaroline was generally active
at the breakpoint concentration [29]. Isolates with decreased
susceptibility to ceftriaxone and/or ceftazidime usually exhibited elevated ceftaroline MIC values.
The results of the 2010 US AWARE Program confirmed
that ceftaroline is a promising new agent with a spectrum of
Ceftaroline Regional Activity
•
CID 2012:55 (Suppl 3)
•
S203
activity that provides expanded coverage for key pathogens
found in ABSSSIs and CABP. Regional differences in activity
in the United States among staphylococci, streptococci, Haemophilus spp., and M. catarrhalis were minimal due to the
extreme potency of ceftaroline. Greater differences in activity
were noted among the Enterobacteriaceae due to the greater
diversity of organism types and resistance mechanisms,
usually mediated by β-lactamases. Continued resistance surveillance along with longitudinal analysis will provide a valuable assessment of the activity of ceftaroline as this agent is
used more broadly over time. Such data will provide clinicians
with up-to-date information to assist them in their therapeutic
decision making.
Notes
Acknowledgments. We wish to express our appreciation to S. Benning
and M. Stillwell in the preparation of this manuscript and to the following
JMI staff members for scientific assistance in performing this study:
D. J. Biedenbach, P. R. Rhomberg, and G. Moet. This study was supported
by Cerexa, Inc, a wholly owned subsidiary of Forest Laboratories, Inc.
Cerexa, Inc was involved in the study design and decision to present these
results. Cerexa, Inc was not involved in the collection, analysis, or interpretation of data. Scientific Therapeutics Information, Inc provided editorial
coordination, which was funded by Forest Research Institute, Inc.
Financial support. This study was funded by educational/research
grants from Cerexa, Inc (Oakland, CA), a wholly owned subsidiary of
Forest Laboratories, Inc (New York, NY).
Supplement sponsorship. This article was published as part of a supplement entitled “Ceftaroline Applications for Therapy in the United
States,” sponsored by Forest Laboratories, Inc (New York, NY).
Potential conflicts of interest. All authors: JMI Laboratories, Inc. has
received research and educational grants in 2009–2011 from Achaogen,
American Proficiency Institute (API), Anacor, Astellas, AstraZeneca,
Bayer, bioMerieux, Cempra, Cerexa, Contrafect, Cubist, Daiichi,
Dipexium, Enanta, Furiex, GlaxoSmithKline, Johnson & Johnson (Ortho
McNeil), LegoChem Biosciences Inc, Meiji Seika Kaisha, Merck, Nabriva,
Novartis, Paratek, Pfizer (Wyeth), PPD Therapeutics, Premier Research
Group, Rempex, Rib-X Pharmaceuticals, Seachaid, Shionogi, The Medicines Co, Theravance, ThermoFisher, TREK Diagnostics, and some other
corporations.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the
content of the manuscript have been disclosed.
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