Review of ceftaroline fosamil microbiology: Integrated FOCUS studies

Article · April 2011with179 Reads
DOI: 10.1093/jac/dkr098 · Source: PubMed
Ceftaroline fosamil, the prodrug form of ceftaroline, is a novel broad-spectrum parenteral cephalosporin that exhibits antibacterial activity against typical respiratory pathogens such as Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus and common Gram-negative pathogens. In particular, ceftaroline has activity against resistant Gram-positive cocci, including penicillin- and multidrug-resistant S. pneumoniae, as well as methicillin-resistant S. aureus. The activity of ceftaroline against these phenotypes is attributed to its ability to bind to modified penicillin-binding proteins with high affinity when compared with other β-lactams. The activity of ceftaroline is not compromised by the ability of H. influenzae to produce β-lactamase. Ceftaroline fosamil was compared with ceftriaxone for safety and efficacy in two randomized, double-blinded, controlled Phase III clinical trials for the treatment of community-acquired pneumonia (CAP). Microbiological assessments at baseline included respiratory specimen cultures, blood cultures, urinary antigen testing and atypical pathogen serology testing. By-subject and by-pathogen microbiological outcomes were assessed in the microbiologically evaluable population at the test-of-cure visit. The favourable microbiological response rates by subject for ceftaroline were 87.0% compared with 81.0% for ceftriaxone. The by-pathogen microbiological response rates of ceftaroline and ceftriaxone were 87.3% and 72.9% for S. pneumoniae, 83.3% and 85.0% for H. influenzae and 76.0% and 70.4% for S. aureus, respectively. Key baseline pathogens such as S. pneumoniae, H. influenzae and methicillin-susceptible S. aureus were susceptible to ceftaroline, with MIC90s of 0.03, 0.03 and 0.25 mg/L, respectively, supporting its utility as a promising new agent for treatment of CAP.
Ceftaroline Efficacy in cSSSI CID 2010:51 (15 September) 000
Integrated Analysis of CANVAS 1 and 2: Phase 3,
Multicenter, Randomized, Double-Blind Studies
to Evaluate the Safety and Efficacy of Ceftaroline
versus Vancomycin plus Aztreonam in Complicated
Skin and Skin-Structure Infection
G. Ralph Corey,
Mark Wilcox,
George H. Talbot,
H. David Friedland,
Tanya Baculik,
Gary W. Witherell,
Ian Critchley,
Anita F. Das,
and Dirk Thye
Duke Clinical Research Institute, Durham, North Carolina;
Cerexa, Inc,
Oakland, and
AxiStat, Inc, San Francisco, California;
Leeds Teaching
Hospitals and University of Leeds, Leeds, United Kingdom
Background. Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of complicated skin and
skin-structure infection (cSSSI). Increasing antimicrobial resistance in cSSSI has led to a need for new safe and
effective therapies. Ceftaroline was evaluated as treatment for cSSSI in 2 identical phase 3 clinical trials, the pooled
analysis of which is presented here. The primary objective of each trial was to determine the noninferiority of the
clinical cure rate achieved with ceftaroline monotherapy, compared with that achieved with vancomycin plus
aztreonam combination therapy, in the clinically evaluable (CE) and modified intent-to-treat (MITT) patient
Methods. Adult patients with cSSSI requiring intravenous therapy received ceftaroline (600 mg every 12 h)
or vancomycin plus aztreonam (1 g each every 12 h) for 5–14 days.
Results. Of 1378 patients enrolled in both trials, 693 received ceftaroline and 685 received vancomycin plus
aztreonam. Baseline characteristics of the treatment groups were comparable. Clinical cure rates were similar for
ceftaroline and vancomycin plus aztreonam in the CE (91.6% vs 92.7%) and MITT (85.9% vs 85.5%) populations,
respectively, as well as in patients infected with MRSA (93.4% vs 94.3%). The rates of adverse events, discontin-
uations because of an adverse event, serious adverse events, and death also were similar between treatment groups.
Conclusions. Ceftaroline achieved high clinical cure rates, was efficacious against cSSSI caused by MRSA and
other common cSSSI pathogens, and was well tolerated, with a safety profile consistent with the cephalosporin
class. Ceftaroline has the potential to provide a monotherapy alternative for the treatment of cSSSI.
Trial registration. identifiers: NCT00424190 for CANVAS 1 and NCT00423657 for CAN-
VA S 2 .
Complicated skin and skin-structure infections (cSSSIs)
are predominantly caused by Staphylococcus aureus or
Streptococcus pyogenes [1–5] and various other gram-
Received 9 February 2010; accepted 6 June 2010; electronically published 9 August
Present affiliation: Talbot Advisors, LLC, Wayne, Pennsylvania.
A wholly owned subsidiary of Forest Laboratories, Inc, New York, New York.
Reprints or correspondence: Dr G. Ralph Corey, Gary Hock Professor of Global
Health, Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715 (corey001@
Clinical Infectious Diseases 2010;51(6):000–000
2010 by the Infectious Diseases Society of America. All rights reserved.
DOI: 10.1086/655827
positive and gram-negative bacteria [4, 6], depending
on infection etiology, host characteristics, and anatom-
ical location. The increasing frequency of methicillin-
resistant S. aureus (MRSA) presents difficulties in the
prevention and treatment of hospital- and community-
acquired infections [7, 8]. The prevalence of methicillin
resistance among community-associated S. aureus iso-
lates from surveillance studies and patients in emer-
gency departments in the United States is nearly 60%
[9, 10]. First-line treatment of cSSSI caused by MRSA
includes vancomycin, linezolid, or daptomycin; oral
options for outpatients include clindamycin, doxycy-
cline, or sulfamethoxazole-trimethoprim. The utility of
000 CID 2010:51 (15 September) Corey et al
these drugs can be limited by a narrow spectrum of activity,
resistance, the need for monitoring of serum concentration,
and/or adverse effects [11–13].
Pathogenic streptococci are also showing signs of increasing
resistance. Although S. pyogenes remains susceptible to most
b-lactams, macrolide resistance has increased; recent global es-
timates range from 6.8% in the United States to 195% in China
[14–17]. In addition, 7.5% of isolates in Belgium were reported
to be resistant to fluoroquinolones [18]. Non–group A and
non–group B b-hemolytic streptococci have demonstrated re-
sistance to erythromycin, fluoroquinolones, tetracycline, and
clindamycin [19]. These factors suggest a need for additional
safe and efficacious therapies with a spectrum consistent with
commonly encountered cSSSI pathogens.
Ceftaroline fosamil (hereafter, ceftaroline) is a novel, broad-
spectrum cephalosporin prodrug, the active metabolite of
which exhibits bactericidal activity against gram-positive or-
ganisms (including MRSA), vancomycin-intermediate S. aureus
strains, and macrolide-resistant S. pyogenes, as well as poten-
tial gram-negative pathogens, including non–extended-spec-
trum b-lactamase (ESBL)–producing Klebsiella pneumoniae
and Escherichia coli [20–24]. Ceftaroline is in development for
treatment of hospitalized patients with cSSSI. A phase 2 trial
initially investigated the efficacy and safety of ceftaroline in the
treatment of cSSSI [25].
This article describes the integrated findings of CANVAS 1
and CANVAS 2 (Ceftarolineversus Vancomycin in Skin and
Skin-Structure Infection), 2 phase 3 clinical trials that compared
ceftaroline monotherapy with vancomycin plus aztreonam
combination therapy for the treatment of adults with cSSSI.
Study design and treatment. CANVAS 1 (NCT00424190) and
CANVAS 2 (NCT00423657) are phase 3, international, mul-
ticenter, randomized, double-blind, comparative efficacy and
safety studies, with identical designs and protocols, of intra-
venous ceftaroline versus intravenous vancomycin plus az-
treonam for 5–14 days in adults with cSSSI. The studies were
designed to allow pooling of results for a larger database of
pathogens and safety information. A total of 111 study centers
in Europe, Latin America, and the United States participated.
Study participants were randomized to receive 600 mg of
ceftaroline followed by normal saline placebo or 1 g of van-
comycin followed by 1 g of aztreonam. All doses were masked
within a yellow bag to maintain blinding. The ceftaroline dose
was adjusted by unblinded pharmacy or study staff to 400 mg
for patients with creatinine clearance 130 and 50 mL/min.
The vancomycin dose was adjusted according to institutional
guidelines or local prescribing practices. Treatments were ad-
ministered intravenously in 250 mL of sodium chloride (0.9%)
over 60 min every 12 h for 5–14 days. Therapy was deemed
to be complete on the basis of investigator determination that
all signs and symptoms of infection had resolved or improved
such that no further antimicrobial therapy was necessary. If a
gram-negative pathogen was neither identified nor suspected,
the blinded investigator could decide to discontinue aztreonam
(or placebo in the ceftaroline group). It was not mandatory for
culture results to be obtained before randomization. Test-of-
cure and late follow-up visits occurred 8–15 and 21–35 days,
respectively, after the last dose of study drug.
Study populations. Inclusion and exclusion criteria are
listed in Table 1. The modified intent-to-treat (MITT) popu-
lation included all randomized patients who received any treat-
ment. The microbiological modified intent-to-treat (mMITT)
population included MITT patients who met clinical disease
criteria for cSSSI and had 1 bacterial pathogen isolated from
blood or the cSSSI site at baseline. The clinically evaluable (CE)
population included MITT patients who met clinical disease
criteria for cSSSI, received a prespecified minimum amount of
study drug, and for whom outcome information was available.
The microbiologically evaluable (ME) population included CE
patients with 1 bacterial pathogen isolated from blood or the
cSSSI site at baseline. Patients were excluded from the ME
population if baseline culture revealed monomicrobial Pseu-
domonas aeruginosa or anaerobic infection.
Efficacy assessments. At the test-of-cure visit, clinical cure
was defined as total resolution of all signs and symptoms of
the baseline infection or improvement such that no further
antimicrobial therapy was necessary. Microbiological eradica-
tion was defined as absence of the baseline pathogen. Eradi-
cation was presumed if an adequate source specimen was not
available for culture and the patient was assessed to have
achieved clinical cure. At the late follow-up visit, relapse was
noted if a patient considered to be clinically cured at the test-
of-cure visit exhibited a return of symptoms and/or signs of
infection. Microbiological recurrence or reinfection was defined
as isolation of a baseline or new pathogen from the original
cSSSI site in patients who had clinical evidence of relapse.
Safety assessments. Safety assessments (MITT population)
included physical examination, electrocardiogram, clinical chem-
istry and hematology parameters, coagulation tests, and reporting
of adverse events (AEs) and serious AEs (SAEs). One patient
randomized to ceftaroline received vancomycin plus aztreonam
for the full course of therapy and thus was analyzed in the com-
parator group. Treatment-emergent AEs were defined as AEs with
onset or worsening severity at or after the first dose of study
drug through the test-of-cure visit (for all AEs) or the late follow-
up visit (for SAEs only).
Statistical methods. Sample size was calculated using the
Farrington-Manning method [26]. Assuming a point estimate
for the primary outcome measure of a clinical cure rate of 85%
in both treatment groups, a noninferiority margin of 10%, power
Table 1. Inclusion and Exclusion Criteria
Inclusion criteria Exclusion criteria
Age 18 years Received 124 h of antimicrobial treatment within 96 h before randomization, unless there was
evidence of clinical and microbiological failure after 48 h of therapy
cSSSI of severity substantial enough to require initial hospitalization or treatment in an emer-
gency department and 5 days of intravenous antimicrobial therapy; hospitalization was not
required if the patient was suitable for outpatient parenteral antimicrobial therapy
Current pathogen was known or suspected to be resistant to vancomycin or aztreonam
3 clinical signs of infection (purulent or seropurulent drainage or discharge, erythema, fluctu-
ance, heat or localized warmth, pain or tenderness to palpation, temperature 138Corhy-
pothermia, WBC count 110,000 cells/mL, or 110% immature neutrophils irrespective of
WBC count)
Creatinine clearance 30 mL/min
cSSSI that met either of the following criteria: (1) involved deep soft tissue or required signifi-
cant surgical intervention, such as wound infection with purulent or seropurulent drainage
or 5 cm of surrounding cellulitis, major abscess surrounded by 2 cm of cellulitis, in-
fected ulcer, or cellulitis with surface area of 10 cm
; (2) cellulitis or abscess of a lower
extremity in patients with diabetes mellitus (requiring insulin, insulin analogues, or oral hy-
poglycemic agents) or well-documented peripheral vascular disease
cSSSI known or suspected to be caused by Pseudomonas aeruginosa or an anaerobic, fungal,
parasitic, or viral pathogen
Patients had to provide written informed consent Decubitus ulcer, diabetic foot ulcer, or ulcer associated with peripheral vascular disease ac-
companied by osteomyelitis or likely to require amputation or revascularization within 60
Required surgical intervention that could not be performed within 48 h
Third-degree burn or burn covering 15% of the body
Human or animal bite (arthropod bites were allowed)
Necrotizing fasciitis or gangrene
Endocarditis, osteomyelitis, or septic arthritis
Required concomitant antimicrobial therapy or high-dose corticosteroid therapy
NOTE. cSSSI, complicated skin and skin-structure infection; WBC, white blood cell.
000 CID 2010:51 (15 September) Corey et al
Figure 1. Disposition of patients in studies of ceftaroline versus vancomycin plus aztreonam (Vanco/Az) for the treatment of complicated skin and skin-
structure infections. Eighteen patients were excluded from the modified intent-to-treat (MITT) population because they did not receive study drug; 334
patients were excluded from the microbiological MITT population because a baseline pathogen was not isolated, the minimal disease definition was not
met, or they did not receive study drug; 194 patients were excluded from the clinically evaluable (CE) population, the most common reasons for which
were indeterminate assessment at the test-of-cure visit ( ), breaking of the blind ( ), and receipt of a potentially effective concomitantnp112 np20
antimicrobial ( ). Patients from the CE population were included in the microbiologically evaluable (ME) population if they met the assessmentnp14
criteria, a baseline pathogen was isolated, and they did not have only anaerobic infection or monomicrobial Pseudomonas aeruginosa isolated from the
infection site (482 patients were excluded from the ME population).
of 90%, and a 20% nonevaluable rate, a sample size of 690
patients (345 per treatment group) was required for each study.
The primary outcome measure in each study, as well as the
integrated analysis, was the per-patient clinical cure rate at the
test-of-cure visit in the CE and MITT populations (coprimary
analysis). Secondary efficacy analyses included per-patient mi-
crobiological response and per-pathogen clinical and micro-
biological response at the test-of-cure visit and relapse and
reinfection/recurrence rates at the late follow-up visit.
A 2-sided 95% confidence interval (CI) for the observed
difference in the primary outcome measure between treatment
groups was calculated using the Miettinen-Nurminen method
[27], stratified by study. Noninferiority was concluded if the
lower limit of the 95% CI was above 10%. For per-patient
microbiological response and clinical cure within subgroups of
patients, 95% CIs were calculated using the same method and
are provided for descriptive purposes.
Patient disposition and analysis populations. Of the 1396
randomized patients in the ITT population, 1378 received study
drug (for ceftaroline, ; for vancomycin plus aztreonam,np693
) (Figure 1).np685
Patient demographics and baseline medical characteristics.
The patient population was predominantly white and male (Ta-
ble 2), and 78.2% were hospitalized at study entry. The median
patient age was 48 years; 18.1% and 7.5% were aged 65 and
75 years or older, respectively. Both treatment groups had sim-
ilar demographic characteristics, type and site of cSSSI, and
relevant medical or surgical history. Moderate renal impairment
(creatinine clearance 130 and 50 mL/min) was present in
3.6% of patients. In 54.5% of cases, patients had 2 signs or
symptoms (erythema, swelling, tenderness, or warmth) clas-
sified as severe; 36.3% had leukocytosis, and 29.9% were febrile.
Bacteremia was present in 4.0% of patients. Infection types
occurred at similar frequencies in the ceftaroline and vanco-
mycin plus aztreonam groups, with cellulitis, major abscess,
and infected wound accounting for the majority (Figure 2).
The median infection area was 156 cm
for the ceftaroline group
and 150 cm
for the vancomycin plus aztreonam group. All
abscesses were required to contain loculated fluid and be sur-
rounded by 2 cm of erythema. In addition, 188% had 1
dimension 15 cm. The mean treatment duration in the CE
population was 8 days for both groups. A pathogen was iso-
lated from 76.1% of patients; the most common pathogen iso-
lated from the primary infection site was S. aureus, with MRSA
accounting for 40% in the ceftaroline group and 34% in the
vancomycin plus aztreonam group (Table 3). Gram-negative
potential pathogens were isolated from the primary infection
site in 16.3% of patients; gram-negative bacteria alone were
recovered from 5.9% of patients. Polymicrobial infections that
included a gram-positive potential pathogen occurred in 20.6%
of patients.
Clinical outcomes. In the integrated analysis, the efficacy
of ceftaroline was similar to that of vancomycin plus aztreonam
in the CE and MITT populations (Table 4). The lower limit of
the 95% CI was above 10%, which was the predefined re-
quirement for noninferiority in each trial. Similarly, each of the
2 trials met the primary objective of noninferiority in the clin-
ical cure rate for ceftaroline versus vancomycin plus aztreonam
Ceftaroline Efficacy in cSSSI CID 2010:51 (15 September) 000
Table 2. Demographic and Baseline Characteristics (Modified Intent-to-Treat Population)
plus aztreonam
Age, median years (range) 48.0 (18–93) 48.0 (18–96)
Male sex, no. (%) 444 (64.1) 419 (61.2)
Race, no. (%)
White 506 (73.0) 512 (74.7)
Nonwhite 62 (8.9) 52 (7.6)
Other/unknown 125 (18.0) 121 (17.7)
Region of enrollment, no. (%)
EU 147 (21.2) 145 (21.2)
Non-EU Europe 187 (27.0) 188 (27.4)
Latin America 56 (8.1) 53 (7.7)
United States 303 (43.7) 299 (43.6)
Median (range) 26.9 (14.1–74.1) 27.4 (16.6–66.5)
130, no. (%) 222 (32.0) 227 (33.1)
Duration of therapy, mean days SD 8.3 3.2 8.4 3.3
Comorbid conditions, no. (%)
Diabetes mellitus 122 (17.6) 120 (17.5)
Peripheral vascular disease 93 (13.4) 93 (13.6)
Injection drug use 46 (6.6) 59 (8.6)
Bacteremia, no. (%) 29 (4.2) 26 (3.8)
Site of primary infection, no. (%)
Lower limb 338 (48.8) 339 (49.5)
Head/neck 45 (6.5) 33 (4.8)
Other 310 (44.7) 313 (45.7)
Prior antimicrobial therapy, no. (%) 276 (39.8) 260 (38.0)
Infection measurements
Length, median cm (range) 15.00 (0.4–65.0) 15.00 (0.2–99.0)
Width, median cm (range) 10.00 (0.5–55.0) 10.00 (0.2–61.3)
Surgical procedures on primary infection site 48 h after enrollment,
no. (%)
1 procedure 97 (14.0) 108 (15.8)
Incision and drainage 46 (6.6) 51 (7.4)
Debridement 31 (4.5) 29 (4.2)
NOTE. BMI, body mass index (calculated as the weight in kilograms divided by the square of height in meters); EU, European Union;
SD, standard deviation.
Includes patients with surgical procedures performed !24 h before first dose or randomization and !48 h after first dose.
(95% CIs in CANVAS 1, 6.6 to 2.1 for CE and 4.1 to 6.2
for MITT; 95% CIs in CANVAS 2, 4.4 to 4.5 for CE and
5.8 to 5.0 for MITT). The efficacy of ceftaroline and of van-
comycin plus aztreonam against polymicrobial and monomi-
crobial infections was similar (Table 4). Clinical cure rates by
baseline pathogen are presented in Table 5.
Clinical cure rates in subgroups of patients (CE) were similar
between treatment groups (Table 6). Infection type did not affect
clinical cure rates between treatment groups. Of note, clinical
cure was reported in 91.1% and 94.1% of patients with a major
abscess in the ceftaroline and vancomycin plus aztreonam groups,
respectively. When major abscesses were excluded from analysis
(CE), the clinical cure rate remained similar both overall and
between treatment groups (for ceftaroline, 91.9%; for vanco-
mycin plus aztreonam, 92.1%). Clinical cure rates were similar
between treatment groups for subgroups of patients with diabetes
mellitus (for ceftaroline, 87.3%; for vancomycin plus aztreonam,
90.9%) or peripheral vascular disease (for ceftaroline, 88.9%; for
vancomycin plus aztreonam, 89.3%).
Clinical cure rates among the 47 patients with bacteremia
(CE) were 84.6% (22 of 26) for ceftaroline versus 100% (21
of 21) for vancomycin plus aztreonam (Table 6). Of note, more
patients in the ceftaroline group than the comparator group
experienced staphylococcal bacteremia (18 vs 9, respectively),
whether caused by methicillin-susceptible S. aureus (11 vs 7)
or MRSA (7 vs 2). The remaining bacteremias were predom-
inantly caused by S. pyogenes (2 vs 3), gram-negative bacilli (2
vs 5), and other streptococci. Among patients with S. aureus
bacteremia, the ceftaroline group had an 88.9% clinical cure
rate. Similar cure rates were found among patients infected
with MRSA. Four of the 26 patients in the ceftaroline-treated
bacteremia group were classified as having experienced clinical
000 CID 2010:51 (15 September) Corey et al
Figure 2. Infection type at baseline (modified intent-to-treat population). DM, diabetes mellitus; LE, lower extremity; PVD, peripheral vascular disease.
Table 3. Minimum Inhibitory Concentration (MIC) Ranges and MIC
Values for Selected Baseline Isolates from the Primary
Infection Site (Microbiologically Evaluable Population)
No. of
No. of
mg/mL mg/mL
MIC range MIC
MIC range MIC
Gram-positive organisms Vancomycin
Staphylococcus aureus 377 0.06 to 2 0.5 357 0.25 to 2 1
MRSA 150 0.25 to 2 1 121 0.5 to 2 1
MSSA 227 0.06 to 0.5 0.25 236 0.25 to 2 1
Streptococcus pyogenes 55 0.004 to 0.008 0.004 58 0.25 to 1 0.5
Streptococcus agalactiae 20 0.008 to 0.015 0.015 18 0.25 to 0.5 0.5
Enterococcus faecalis 25 0.25 to 16 4 24 0.5 to 2 2
Gram-negative organisms Aztreonam
Pseudomonas aeruginosa 16 4 to 116 116 18 1 to 132 132
Escherichia coli 21 0.015 to 116 1 21 0.03 to 0.5 0.12
Klebsiella pneumoniae 18 0.03 to 116 116 14 0.03 to 132 132
Proteus mirabilis 15 0.008 to 116 116 21 0.03 to 16 0.06
, MIC value for which 90% of isolates are susceptible; MRSA, methicillin-resistant S. aureus; MSSA, methicillin-susceptible S. aureus.
failure: 2 due to a treatment-limiting AE leading to withdrawal
of study drug (1 episode of Clostridium difficile–associated di-
arrhea and 1 allergic rash), 1 because of the need for surgical
intervention on study day 7, and 1 due to a resistant copathogen
(P. aeruginosa) and failure to timely perform surgical interven-
tion. The organisms isolated from these patients were S. aureus
(2 patients), an organism from the Streptococcus anginosus
group (1 patient), and P. aeruginosa and Morganella morganii
as copathogens (1 patient). Follow-up blood cultures indicated
clearance in all 4 patients; for the 3 patients with staphylococcal
or streptococcal bacteremia, sterilization of blood cultures was
achieved during continued ceftaroline therapy.
Clinical relapse at the late follow-up visit was noted in 1.1%
(6 of 559) of patients in the ceftaroline group, compared with
0.9% (5 of 549) of patients in the vancomycin plus aztreonam
group (CE).
Microbiological efficacy. Favorable microbiological response
(ME) was observed in 92.3% (432 of 468) of patients in the
ceftaroline group, compared with 93.7% (418 of 446) of patients
in the vancomycin plus aztreonam group (difference, 1.4%;
95% CI, 4.8% to 2.0%). For patients with infection caused by
1 gram-positive pathogen, a favorable microbiological response
was achieved in 93.5% (403 of 431) of patients in the ceftaroline
group, compared with 93.8% (396 of 422) of patients in the
vancomycin plus aztreonam group (difference, 0.3%; 95% CI,
3.7% to 3.1%). For infections in which 1 potential gram-
negative pathogen was present, a favorable per-pathogen micro-
biological response was achieved in 86.3% (82 of 95) of patients
Ceftaroline Efficacy in cSSSI CID 2010:51 (15 September) 000
Table 4. Clinical Cure Rates by Analysis Population at the Test-of-Cure Visit
Population, type of infection
Cure rate, no. of patients cured/total no. of patients (%)
plus aztreonam
% (95% CI)
Clinically evaluable 559/610 (91.6) 549/592 (92.7) 1.1 (4.2to2.0)
MITT 595/693 (85.9) 586/685 (85.5) 0.3 (3.4 to 4.0)
Microbiologically evaluable 434/468 (92.7) 421/446 (94.4) 1.7 (4.9to1.6)
Gram positive only 348/371 (93.8) 330/350 (94.3) 0.5 (4.1to3.1)
Gram negative only 29/34 (85.3) 24/24 (100) 15.6 (31.6 to 1.2)
Mixed gram positive and negative 57/63 (90.5) 67/72 (93.1) 2.6 (13.4 to 7.2)
Polymicrobial infection 125/136 (91.9) 134/139 (96.4) 4.2 (10.5 to 1.5)
NOTE. CI, confidence interval; MITT, modified intent-to-treat.
Ceftaroline monotherapy minus vancomycin plus aztreonam combination therapy.
Table 5. Clinical Cure Rates for Selected Baseline Isolates at the Test-of-Cure Visit
Cure rate, no. of patients cured/total no. of patients (%)
Isolates identified
in ME population
Isolates identified
in mMITT population
plus aztreonam Ceftaroline
plus aztreonam
Staphylococcus aureus 352/378 (93.1) 336/356 (94.4) 377/425 (88.7) 356/409 (87.0)
MRSA 142/152 (93.4) 115/122 (94.3) 155/179 (86.6) 124/151 (82.1)
MSSA 212/228 (93.0) 225/238 (94.5) 221/245 (90.2) 233/258 (90.3)
Streptococcus pyogenes 56/56 (100) 56/58 (96.6) 56/63 (88.9) 57/62 (91.9)
Streptococcus agalactiae 21/22 (95.5) 18/18 (100) 25/27 (92.6) 19/21 (90.5)
Enterococcus faecalis 20/25 (80.0) 22/24 (91.7) 20/28 (71.4) 23/28 (82.1)
Escherichia coli 20/21 (95.2) 19/21 (90.5) 21/23 (91.3) 19/21 (90.5)
Pseudomonas aeruginosa NA NA 20/25 (80.0) 22/25 (88.0)
Proteus mirabilis 10/15 (66.7) 20/21 (95.2) 11/16 (68.8) 20/23 (87.0)
Klebsiella pneumoniae 17/18 (94.4) 13/14 (92.9) 17/18 (94.4) 14/19 (73.7)
NOTE. ME, microbiologically evaluable; mMITT, microbiological modified intent-to-treat; MRSA, methicillin-re-
sistant S. aureus; MSSA, methicillin-susceptible S. aureus; NA, not applicable.
in the ceftaroline group, compared with 93.6% (88 of 94) of
patients in the vancomycin plus aztreonam group (difference,
7.4%; 95% CI, 16.6% to 1.3%).
Safety and tolerability. Incidences of treatment-emergent
AEs, regardless of relationship to study drug, were similar be-
tween study groups (Table 7). Diarrhea occurred in 4.9% of
patients in the ceftaroline group and in 3.8% of patients in the
vancomycin plus aztreonam group (MITT population). C. dif-
ficile infection occurred in 2 patients in the ceftaroline group
and in 1 patient in the vancomycin plus aztreonam group.
These infections were successfully managed. AEs considered to
be related to study drug in 3% of patients were pruritus,
nausea, and diarrhea. Pruritus occurred more often with van-
comycin plus aztreonam than with ceftaroline (8.2% vs 3.5%).
The most common reason for premature discontinuation of
study drug was possible allergic reactions (for ceftaroline, 1.9%;
for vancomycin plus aztreonam, 2.9%).
An SAE occurred in 4.3% of patients in the ceftaroline group
and in 4.1% of patients in the vancomycin plus aztreonam
group. Important medical events related to ceftaroline therapy,
such as neutropenia, thrombocytopenia, and liver failure, were
not observed in these studies. Possible allergic reaction occurred
in 2.0% and 4.1% of patients in the ceftaroline and vancomycin
plus aztreonam groups, respectively. Three patients in the cef-
taroline group died during the 2 studies. The causes of death
were respiratory failure, neck cancer, and cardiopulmonary in-
sufficiency; none of the deaths was assessed by an investigator
as related to either study drug or the cSSSI.
As observed with cephalosporins, a higher incidence of
Coombs test positivity was recorded in the ceftaroline group
than in the comparator group; however, no laboratory or clin-
ical manifestations of hemolytic anemia were identified. Fewer
than 2% of patients in each group had a clinically significant
electrocardiogram abnormality; the majority of these patients
entered the study with an underlying condition that may have
been associated with cardiac irregularities. No difference in
abnormal physical findings or vital signs was identified between
treatment groups.
000 CID 2010:51 (15 September) Corey et al
Table 6. Clinical Cure Rates by Type of Infection, Underlying Comorbidity, or Bacteremia
Status (Clinically Evaluable Population) at the Test-of-Cure Visit
Clinical diagnosis
Cure rate, no. of patients cured/total no. of patients (%)
plus aztreonam
% (95% CI)
Cellulitis 213/229 (93.0) 222/243 (91.4) 1.7 (3.4 to 6.7)
Major abscess 184/202 (91.1) 177/188 (94.1) 3.0 (8.5to2.3)
Infected wound 73/84 (86.9) 65/73 (89.0) 2.2 (12.8 to 8.7)
Infected ulcer 48/53 (90.6) 47/50 (94.0) 3.5 (15.7 to 8.3)
Infected burn 25/25 (100) 18/18 (100) 0.0 (13.6 to 17.9)
Infected bite 9/9 (100) 9/9 (100) 0.0
Other 4/5 (80.0) 9/9 (100) 20.0
Underlying comorbidity
Diabetes mellitus 96/110 (87.3) 100/110 (90.9) 3.5 (12.2 to 5.0)
Peripheral vascular disease 80/90 (88.9) 75/84 (89.3) 0.2 (10.0 to 9.7)
Bacteremia 22/26 (84.6) 21/21 (100) 15.4 (33.8 to 1.5)
Staphylococcus aureus 16/18 (88.9) 9/9 (100) 11.1 (33.2 to 5.7)
MRSA 6/7 (85.7) 2/2 (100) 14.3 (53.5 to 58.4)
NOTE. CI, confidence interval; MRSA, methicillin-resistant S. aureus.
Ceftaroline monotherapy minus vancomycin plus aztreonam combination therapy.
Table 7. Summary of Treatment-Emergent Adverse Events in the Safety
plus aztreonam
Adverse event
Nausea 41 (5.9) 35 (5.1)
Headache 36 (5.2) 31 (4.5)
Diarrhea 34 (4.9) 26 (3.8)
Pruritus 24 (3.5) 56 (8.2)
Rash 22 (3.2) 17 (2.5)
Vomiting 20 (2.9) 18 (2.6)
Constipation 18 (2.6) 18 (2.6)
Insomnia 17 (2.5) 17 (2.5)
Generalized pruritus 15 (2.2) 19 (2.8)
Dizziness 14 (2.0) 8 (1.2)
Transaminases increased 15 (2.2) 25 (3.6)
Hypokalemia 10 (1.4) 15 (2.2)
Pyrexia 9 (1.3) 16 (2.3)
Any 309 (44.7) 326 (47.5)
Discontinuation because of an adverse event 21 (3.0) 33 (4.8)
NOTE. Shown are treatment-emergent adverse events occurring in 2% of patients.
The data from this integrated analysis demonstrate that cef-
taroline monotherapy is efficacious for the treatment of cSSSI,
with a clinical cure rate comparable to that of vancomycin plus
aztreonam. The cure rates consistently exceeded 93% in the
ME population. The overall cure rate for ceftaroline-treated
patients with staphylococcal infection was 93.1% (93.4% for
patients with cSSSI caused by MRSA). The efficacy of ceftar-
oline monotherapy was consistently demonstrated in the rel-
evant populations (CE, MITT, ME, and mMITT). In addition,
clinical cure rates were similar between patients infected with
single or multiple pathogens, across infection types (including
cellulitis, major abscess, and infected wound), and between
patients with common comorbidities, such as diabetes mellitus
and peripheral vascular disease.
The proportions of causative pathogens isolated in these
studies are consistent with the broader epidemiologic picture
of cSSSI. The majority of cSSSIs are caused by gram-positive
pathogens [4], as reflected in these studies. Additionally, 40%
of S. aureus isolates in the ceftaroline group and 34% in the
Ceftaroline Efficacy in cSSSI CID 2010:51 (15 September) 000
vancomycin plus aztreonam group were methicillin resistant,
which is representative of the rate seen across countries with
varying MRSA epidemiology [9, 10, 28–32]. As such, the CAN-
VAS studies provide efficacy data in the context of the current
endemicity of this important cSSSI pathogen.
The combination of vancomycin plus aztreonam demon-
strated higher favorable microbiological response rates than did
ceftaroline monotherapy against gram-negative infection. The
efficacy of ceftaroline against non–ESBL-producing E. coli and
K. pneumoniae infection was comparable to that of aztreonam;
however, the efficacy of aztreonam against P. aeruginosa and
Proteus mirabilis infection was better than that of ceftaroline.
These results are not surprising, given in vitro data previously
reported for ceftaroline [33]. Interestingly, despite the reported
low in vitro activity against P. aeruginosa, ceftaroline therapy
in the CANVAS trials demonstrated a high cure rate for this
organism when found in combination with another pathogen.
Given the difficulty of differentiating causative from coloniz-
ing pathogens in polymicrobial infections, it is not surprising
that ceftaroline appears to be effective against infections from
which ceftaroline-resistant organisms such as P. aeruginosa are
There was a trend toward a higher clinical cure rate among
patients with bacteremia treated with vancomycin plus aztre-
onam; because of the small numbers of such cases (with greater
numbers and more staphylococci in the ceftaroline group), this
observation is of unknown significance. Of note, sterilization of
blood cultures was achieved during continued therapy in the 3
ceftaroline-treated patients with staphylococcal or streptococcal
bacteremia who were assessed as experiencing clinical failure. This
finding confirms the designation of clinical failure as a result of
reasons other than a lack of microbiological efficacy.
Safety and tolerability of new antibiotics are of primary con-
cern, especially in light of the limitations demonstrated by sev-
eral currently available anti-MRSA agents. Data from 11300
patients in this analysis demonstrated that ceftaroline mono-
therapy was generally safe and well tolerated, consistent with
the safety profile of the cephalosporin class. The incidence of
treatment-emergent AEs was similar between treatment groups.
No cardiac, hepatic, or renal toxicity signal was identified.
The inclusion of a significant number of cutaneous abscesses
in cSSSI trials is controversial. It is recognized that many small,
uncomplicated cutaneous abscesses can be treated with incision
and drainage alone [34]. Antimicrobial therapy is recommended
when abscesses are large, surrounded by extensive cellulitis, or
accompanied by systemic symptoms [35]. By design, abscesses
in these studies fulfilled several or all of these criteria.In addition,
the CANVAS trials were similar to other recent studies of anti-
microbial treatment of cSSSI [36, 37], which also included a high
proportion of abscesses. Most importantly, significant efficacy
was maintained in both groups when abscesses were excluded
from analyses, with ceftaroline being comparable to vancomycin
plus aztreonam.
Potential limitations of these analyses include small numbers
of black, Asian, and elderly (175 years old) patients and the
exclusion of patients !18 years old; these are typical of regis-
trational trials of new antimicrobials. Future studies involving
such important populations as patients with diabetic foot in-
fection will be needed to supplement the current understanding
of the safety and efficacy profile of ceftaroline.
In conclusion, ceftaroline administered intravenously to
adults at a dosage of 600 mg every 12 h for 5–14 days was
efficacious and well tolerated for the treatment of cSSSI. In
light of these analyses, ceftaroline has the potential to provide
a monotherapy alternative for the treatment of cSSSI.
Statistical and other analyses were performed by Cerexa, Inc (Oakland,
California), a wholly owned subsidiary of Forest Laboratories, Inc (New
York, New York). Scientific Therapeutics Information, Inc (Springfield, New
Jersey), provided assistance in preparing and editing the manuscript, for
which funding was provided by Forest Laboratories, Inc.
Financial support. Forest Laboratories, Inc.
Potential conflicts of interest. G.H.T. was an employee of Cerexa, Inc,
at the time the work was performed; his company, Talbot Advisors, LLC,
is currently a consultant to Cerexa, but it was not paid for the time he
spent on manuscript preparation (travel expenses were reimbursed), and
he has an equity interest in Cerexa. H.D.F., T.B., G.W.W., I.C., and D.T.
are employees of Cerexa, a wholly owned subsidiary of Forest Laboratories,
Inc. G.R.C., M.W., and A.F.D.: no conflicts.
1. Ho RC, Ho EC, Mak A. Cutaneous complications among i.v. buprenor-
phine users. J Dermatol 2009; 36:22–29.
2. Lamagni TL, Darenberg J, Luca-Harari B, et al. Epidemiology of severe
Streptococcus pyogenes disease in Europe. J Clin Microbiol 2008;46:
3. Lamagni TL, Neal S, Keshishian C, et al. Severe Streptococcus pyogenes
infections, United Kingdom, 2003–2004. Emerg Infect Dis 2008;14:
4. Moet GJ, Jones RN, Biedenbach DJ, et al. Contemporary causes of
skin and soft tissue infections in North America, Latin America, and
Europe: report from the SENTRY Antimicrobial Surveillance Program
(1998–2004). Diagn Microbiol Infect Dis 2007; 57:7–13.
5. Rennie RP, Jones RN, Mutnick AH; SENTRY Program Study Group
(North America). Occurrence and antimicrobial susceptibility patterns
of pathogens isolated from skin and soft tissue infections: report from
the SENTRY Antimicrobial Surveillance Program (United States and
Canada, 2000). Diagn Microbiol Infect Dis 2003; 45:287–2 93.
6. Chang CM, Lee HC, Lee NY, et al. Community-acquired Klebsiella
pneumoniae complicated skin and soft-tissue infections of extremities:
emphasis on cirrhotic patients and gas formation. Infection 2008;36:
7. Grundmann H, Aires-de-Sousa M, Boyce J, et al. Emergence and re-
surgence of methicillin-resistant Staphylococcus aureus as a public-
health threat. Lancet 2006; 368:874–885.
8. Nubel U, Roumagnac P, Feldkamp M, et al. Frequent emergence and
limited geographic dispersal of methicillin-resistant Staphylococcus au-
reus. Proc Natl Acad Sci U S A 2008; 105:14130–14135.
9. Moran GJ, Krishnadasan A, Gorwitz RJ, et al; EMERGEncy ID Net
Study Group. Methicillin-resistant S. aureus infections among patients
in the emergency department. N Engl J Med 2006; 355:666–674.
000 CID 2010:51 (15 September) Corey et al
10. Tillotson GS, Draghi DC, Sahm DF, et al. Susceptibility of Staphylo-
coccus aureus isolated from skin and wound infections in the United
States 2005–07: laboratory-based surveillance study. J Antimicrob Che-
mother 2008; 62:109–115.
11. LoVecchio F, Perera N, Casanova L, et al. Board-certified emergency
physicians’ treatment of skin and soft tissue infections in the com-
munity-acquired methicillin-resistant Staphylococcus aureus era. Am J
Emerg Med 2009; 27:68–70.
12. Napolitano LM. Early appropriate parenteral antimicrobial treatment
of complicated skin and soft tissue infections caused by methicillin-
resistant Staphylococcus aureus. Surg Infect (Larchmt) 2008; 9(suppl 1):
13. Sievert DM, Rudrik JT, Patel JB, et al. Vancomycin-resistant Staphy-
lococcus aureus in the United States, 2002–2006. Clin Infect Dis 2008;46:
14. Gracia M, Diaz C, Coronel P, et al. Antimicrobial susceptibility of
Streptococcus pyogenes in Central, Eastern, and Baltic European Coun-
tries, 2005 to 2006: the cefditoren surveillance program. Diagn Mi-
crobiol Infect Dis 2009; 64:52–56.
15. Liu X, Shen X, Chang H, et al. High macrolide resistance in Strepto-
coccus pyogenes strains isolated from children with pharyngitis in China.
Pediatr Pulmonol 2009; 44:436–441.
16. Montagnani F, Stolzuoli L, Croci L, et al. Erythromycin resistance in
Streptococcus pyogenes and macrolide consumption in a central Italian
region. Infection 2009; 37:353–357.
17. Richter SS, Heilmann KP, Beekmann SE, et al. Macrolide-resistant
Streptococcus pyogenes in the United States, 2002–2003. Clin Infect Dis
2005; 41:599–608.
18. Malhotra-Kumar S, Van Heirstraeten L, Lammens C, et al. Emergence
of high-level fluoroquinolone resistant in emm6 Streptococcus pyogenes
and in vitro resistance selection with ciprofloxacin, levofloxacin and
moxifloxacin. J Antimicrob Chemother 2009; 63:886–894.
19. Broyles LN, van Beneden C, Beall B, et al. Population-based study of
invasive disease due to b-hemolytic streptococci of groups other than
A and B. Clin Infect Dis 2009; 48:706–712.
20. Ge Y, Biek D, Talbot GH, Sahm DF. In vitro profiling of ceftaroline
against a collection of recent bacterial clinical isolates from across the
United States. Antimicrob Agents Chemother 2008; 52:3398–3407.
21. Iizawa Y, Nagai J, Ishikawa T, et al. In vitro antimicrobial activity of
T-91825, a novel anti-MRSA cephalosporin, and in vivo anti-MRSA
activity of its prodrug, TAK-599. J Infect Chemother 2004; 10:146–156.
22. Jacqueline CJ, Caillon V, Le Mabecque AF, et al. In vivo efficacy of
ceftaroline (PPI-0903), a new broad-spectrum cephalosporin, com-
pared with linezolid and vancomycin against methicillin-resistant and
vancomycin-intermediate Staphylococcus aureus in a rabbit endocarditis
model. Antimicrob Agents Chemother 2007;51:3397–3 400.
23. Mushtaq S, Warner M, Ge Y, et al. In vitro activity of ceftaroline (PPI-
0903M, T-91825) against bacteria with defined resistance mechanisms
and phenotypes. J Antimicrob Chemother 2007; 60:300–311.
24. Sader HS, Fritsche TR, Jones RN. Antimicrobial activities of ceftaroline
and ME1036 tested against clinical strains of community-acquired
methicillin-resistant Staphylococcus aureus. Antimicrob Agents Che-
mother 2008; 52:1153–1155.
25. Talbot GH, Thye D, Das A, et al. Phase 2 study of ceftaroline versus
standard therapy in treatment of complicated skin and skin structure
infections. Antimicrob Agents Chemother 2007; 51:3612–3616.
26. Farrington CP, Manning G. Test statistics and sample size formulae for
comparative binomial trials with null hypothesis of non-zero risk dif-
ference of non-unity relative risk. Stat Med 1990; 9:1447–1454.
27. Miettinen O, Nurminen M. Comparative analysis of two rates. Stat
Med 1985; 4:213–226.
28. Frazee BW, Lynn J, Charlebois ED, et al. Highprevalence of methicillin-
resistant Staphylococcus aureus in emergency department skin and soft
tissue infections. Ann Emerg Med 2005;45: 311–320.
29. Kaplan SL, Hulten KG, Gonzalez BE, et al. Three-year surveillance of
community-acquired Staphylococcus aureus infections in children. Clin
Infect Dis 2005; 40:1785–1791.
30. Miller LG, Perdreau-Remington F, Bayer AS, et al. Clinical and epi-
demiologic characteristics cannot distinguish community-associated
methicillin-resistant Staphylococcus aureus infection from methicillin-
susceptible S. aureus infection: a prospective investigation. Clin Infect
Dis 2007; 44:471–482.
31. Moran GJ, Amii RN, Abrahamian FM, et al. Methicillin-resistant Staph-
ylococcus aureus in community-acquired skin infections. Emerg Infect
Dis 2005; 11:928–930.
32. Young DM, Harris HW, Charlebois ED, et al. An epidemic of meth-
icillin-resistant Staphylococcus aureus soft tissue infections among med-
ically underserved patients. Arch Surg 2004;1 39:947–951.
33. Sader HS, Fritsche TR, Kaniga K, et al. Antimicrobial activity and
spectrum of PPI-0903M (T-91825), a novel cephalosporin, tested
against a worldwide collection of clinical strains. Antimicrob Agents
Chemother 2005; 49:3501–3512.
34. Hankin A, Everett WW. Are antibiotics necessary after incision and
drainage of a cutaneous abscess? Ann Emerg Med 2007; 50:49–51.
35. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the
diagnosis and management of skin and soft-tissue infections. Clin In-
fect Dis 2005; 41:1373–1406.
36. Noel GJ, Strauss RS, Amsler K, et al. Results of a double-blind, ran-
domized trial of ceftobiprole treatment of complicated skin and skin
structure infections caused by gram-positive bacteria. Antimicrob
Agents Chemother 2008; 52:37–44.
37. Stryjewski ME, Graham DR, Wilson SE, et al; Assessment of Telavancin
in Complicated Skin and Skin-Structure Infections Study. Telavancin
versus vancomycin for the treatment of complicated skin and skin-
structure infections caused by gram-positive organisms. Clin Infect Dis
2008; 46:1683–1693.
    • Although it is generally well tolerated, minor adverse events have included rash, nausea, vomiting, diarrhea, headache, and tendon pain [32]. The favorable features of ceftaroline include avid binding to penicillin-binding protein 2a and 2 × ( penicillin-binding proteins ) of MRSA and MDRSP, respectively [1, 8] , minimal disruption of normal bowel flora [32], lack of antagonism with other agents used in combination [33] , and an in vitro postantibiotic effect against Gram-positive pathogens of 1–2 hours' duration [34]. These features, coupled with documented efficacy of ceftaroline fosamil in the treatment of serious CABP [2, 13], make this agent particularly attractive in the initial management of CABP patients requiring hospitalization and infected with potentially refractory pathogens such as MDRSP [35].
    [Show abstract] [Hide abstract] ABSTRACT: Ceftaroline fosamil, the prodrug form of the active metabolite ceftaroline, is a new broad-spectrum parenteral cephalosporin with antibacterial activity against the prevalent respiratory pathogens Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus. Bacterial resistance surveillance (5330 isolates) was conducted in the United States between 2008 and 2010 to assess the in vitro activity of ceftaroline and comparator antibacterial agents against invasive respiratory isolates of S. pneumoniae (3329 isolates), H. influenzae (1545 isolates), and M. catarrhalis (456 isolates). All organisms were cultured from patient infections in 71 US hospital laboratories and were submitted to a central reference monitor for broth microdilution testing by Clinical and Laboratory Standards Institute reference methods. Against S. pneumoniae, ceftaroline inhibited 98.7% of strains at the susceptible breakpoint of ≤0.25 µg/mL (50% minimum inhibitory concentration [MIC50], 0.01 µg/mL; 90% MIC [MIC90], 0.12 µg/mL) and was 16-fold more active than ceftriaxone (MIC90, 2 µg/mL). Among 70 ceftriaxone-resistant pneumococcal isolates, all were inhibited by ≤0.5 µg/mL of ceftaroline. Haemophilus influenzae (MIC50, ≤0.008 µg/mL; MIC90, 0.015 µg/mL) and M. catarrhalis (MIC50, 0.06 µg/mL; MIC90, 0.12 µg/mL) were very susceptible to ceftaroline regardless of β-lactamase production. Whereas the high-level of activity of ceftaroline was maintained against S. pneumoniae and H. influenzae from 2008 through 2010, increased rates of nonsusceptibility were observed for amoxicillin/clavulanate, erythromycin, and levofloxacin among S. pneumoniae and for trimethoprim/sulfamethoxazole and azithromycin among H. influenzae. In summary, ceftaroline resistance surveillance (Assessing Worldwide Antimicrobial Resistance Evaluation [AWARE] Program) in the United States (2008–2010) documented in vitro sustained potency and spectrum against Gram-positive and Gram-negative pathogens known to cause community-acquired bacterial pneumonia.
    Full-text · Article · Sep 2012
    • Because of the expanded ceftaroline activity against grampositive organisms, including MRSA and MDRSP, this parenteral cephalosporin is considered by some to represent a newgeneration of cephalosporins [23, 45]. The ceftaroline MIC 90 of 0.12 µg/mL against S. pneumoniae, with all isolates inhibited at an MIC of ≤0.5 µg/mL, found in this study is in agreement with numerous other studies throughout the world, including the United States, that reported an MIC 90 of 0.12– 0.25 µg/mL, with the highest MIC rarely exceeding 0.5 µg/mL [19][20][21][46][47][48][49][50][51][52]. The results presented in this study further document the excellent in vitro potency of ceftaroline against contemporary US pneumococcal isolates.
    [Show abstract] [Hide abstract] ABSTRACT: Ceftaroline is a new broad-spectrum parenteral cephalosporin with antibacterial activity against the prevalent pathogens causing both acute bacterial skin and skin structure infections (ABSSSIs) and community-acquired bacterial pneumonia (CABP). The Assessing Worldwide Antimicrobial Resistance Evaluation Surveillance Program was conducted in the United States between 2008 and 2010 to assess the in vitro activity of ceftaroline and comparator antibacterial agents against ABSSSI and CABP pathogens. A total of 8469 Staphylococcus aureus isolates and 3593 Streptococcus pneumoniae isolates collected from 72 medical centers representing all US Census regions were submitted to a central reference laboratory (JMI Laboratories, North Liberty, IA) for broth microdilution testing by reference methods. The overall prevalence of methicillin resistance among S. aureus isolates was 52.6%, and although ceftaroline showed more potent activity against methicillin-susceptible S. aureus (minimum inhibitory concentration for 50% [MIC50] and 90% [MIC90] of organisms, both 0.25 µg/mL) than against methicillin-resistant S. aureus (MIC50 and MIC90, both 1 µg/mL), it showed good activity against all 8469 S. aureus isolates (MIC50 and MIC90, 0.5 and 1 µg/mL, respectively), with 8296 isolates (98.0%) testing susceptible at the US Food and Drug Administration (FDA) break point of ≤1 µg/mL and no isolates having MICs of >2 µg/mL. Against S. pneumoniae, ceftaroline inhibited 98.7% of tested isolates at the FDA susceptible break point of ≤0.25 µg/mL (MIC50 and MIC90, 0.015 and 0.12 µg/mL, respectively) and was 16-fold more active than ceftriaxone (MIC90, 2 µg/mL). The prevalence of multidrug resistance among S. pneumoniae isolates was 30.1% overall and remained stable over each of the 3 monitored years. Ceftaroline demonstrated high activity (MIC50 and MIC90, 0.12 and 0.25 µg/mL, respectively) against multidrug-resistant S. pneumoniae, with only 44 of 1001 strains (4.4%) testing nonsusceptible and all 44 nonsusceptible strains having a ceftaroline MIC of only 0.5 µg/mL. Ceftriaxone resistance among S. pneumoniae was 2.1% (10.9% were nonsusceptible), with an intermediate susceptibility rate of 8.8%, resulting in an overall susceptibility rate of only 89.1%. Ceftaroline surveillance in the United States during 2008–2010 documented sustained potency and spectrum against multidrug-resistant S. aureus and multidrug-resistant S. pneumoniae known to cause ABSSSI and CABP.
    Full-text · Article · Sep 2012
  • [Show abstract] [Hide abstract] ABSTRACT: Community-acquired pneumonia (CAP) is a serious condition associated with significant morbidity and potential long-term mortality. Although the majority of patients with CAP are treated as outpatients, the greatest proportion of pneumonia-related mortality and healthcare expenditure occurs among the patients who are hospitalized. There has been considerable interest in determining risk factors and severity criteria assessments to assist with site-of-care decisions. For both inpatients and outpatients, the most common pathogens associated with CAP include Streptococcus pneumoniae, Haemophilus influenzae, group A streptococci and Moraxella catarrhalis. Atypical pathogens, Gram-negative bacilli, methicillin-resistant Staphylococcus aureus (MRSA) and viruses are also recognized aetiological agents of CAP. Despite the availability of antimicrobial therapies, the recent emergence of drug-resistant pneumococcal and staphylococcal isolates has limited the effectiveness of currently available agents. Because early and rapid initiation of empirical antimicrobial treatment is critical for achieving a favourable outcome in CAP, newer agents with activity against drug-resistant strains of S. pneumoniae and MRSA are needed for the management of patients with CAP.
    Article · Apr 2011
  • Article · Jan 2012
  • [Show abstract] [Hide abstract] ABSTRACT: Ceftaroline fosamil (ceftaroline) was recently approved for the treatment of community- acquired pneumonia (CAP) and complicated skin infections. This newly developed cephalosporin possesses a broad spectrum of activity against gram-positive and gram-negative bacteria. Most importantly, ceftaroline demonstrates potent in vitro antimicrobial activity against multi-drug resistant Streptococcus pneumoniae and methicillin-resistant strains of Staphylococcus aureus. In two Phase III, double-blinded, randomized, prospective trials (FOCUS 1 and FOCUS 2), ceftaroline was shown to be non-inferior to ceftriaxone for the treatment of CAP in hospitalized patients. Ceftaroline exhibits low resistance rates and a safety profile similar to that of other cephalosporins. In this review, we will evaluate the pharmacological characteristics, safety, antimicrobial properties, and efficacy of ceftaroline and its applications in the treatment of CAP.
    Full-text · Article · Feb 2012
  • [Show abstract] [Hide abstract] ABSTRACT: Drug resistance in Streptococcus pneumoniae, a frequent pathogen in community-acquired pneumonia, is increasing. Ceftaroline (active metabolite of ceftaroline fosamil) is a broad-spectrum intravenous cephalosporin with activity in vitro against drug-resistant Gram-positive organisms. We investigated ceftaroline at 600 mg every 12 h (q12h) (maximum concentration of the free, unbound drug in serum [fCmax] is 15.2 μg/ml, and half-life [T1/2] is 2.5 h) versus ceftriaxone at 1 g q24h (fCmax = 23 μg/ml, T1/2 = 8 h) against six clinical S. pneumoniae isolates in a one-compartment in vitro pharmacokinetic/pharmacodynamic 96-h model (starting inoculum of 107 CFU/ml). Differences in CFU/ml (at 24 to 96 h) were evaluated by analysis of variance with a Tukey's post hoc test. Bactericidal activity was defined as a ≥3 log10 CFU/ml decrease from the initial inoculum. Ceftaroline MICs were 0.06, 0.015, ≤0.008, 0.25, 0.25, and 0.5 μg/ml, and ceftriaxone MICs were 0.5, 0.25, 0.25, 4, 4, and 8 μg/ml for SP 1477, SP 669, SP 132, SP 211, SP 90, and SP 1466, respectively. Against the ceftaroline- and ceftriaxone-susceptible strain SP 1477, ceftaroline displayed sustained bactericidal activity (3 to 96 h, −5.49 log10 CFU/ml) and was significantly (P ≤ 0.012) better than ceftriaxone (72 to 96 h, −2.03 log10 CFU/ml). Against the ceftriaxone-resistant strains, ceftaroline displayed sustained bactericidal activity at 96 h and was significantly better than ceftriaxone (SP211 [−5.91 log10 CFU/ml, P ≤ 0.002], SP 90 [−5.26 log10 CFU/ml, P ≤ 0.008], and SP1466 [−5.14 log10 CFU/ml, P ≤ 0.042]). Ceftaroline was the more effective drug and displayed sustained bactericidal activity. Ceftaroline fosamil may provide a therapeutic option to treat ceftriaxone-resistant S. pneumoniae infections.
    Full-text · Article · Feb 2012
Show more