Antimicrobial Reports

A Multicenter, Randomized, Observer-blinded,

Active-controlled Study Evaluating the Safety and Effectiveness
of Ceftaroline Compared With Ceftriaxone Plus Vancomycin
in Pediatric Patients With Complicated Community-acquired
Bacterial Pneumonia
Jeffrey L. Blumer, PhD, MD,* Tina Ghonghadze, PhD, MD,† Christopher Cannavino, MD,‡ Tanya O’Neal, MD,§
Alena Jandourek, MD,§ Hillel David Friedland, MD, MBA,§ and John S. Bradley, MD‡

Key Words: community-acquired bacterial pneumonia, CABP, ceftaroline

Background: The broad-spectrum cephalosporin ceftaroline, a metabolite
fosamil, complicated CABP, pediatric
of the prodrug ceftaroline fosamil, has shown in vitro activity against clini-
cal isolates from pediatric patients. (Pediatr Infect Dis J 2016;35:760–766)
Methods: This multicenter, randomized, observer-blinded, active-controlled
study (NCT01669980) assessed the safety and effectiveness of ceftaroline
fosamil compared with ceftriaxone plus vancomycin in patients between 2
months and 17 years of age with complicated community-acquired bacterial
pneumonia. Patients were randomized 3:1 (stratified by age cohort) to receive
either ceftaroline fosamil or ceftriaxone plus vancomycin (comparator) as
D ata on death rates in the United States during 2011 listed pneu-
monia as the sixth leading cause of death in children 1–4 years
of age and the eighth highest cause of death among those 5–14 years
intravenous therapy for ≥3 days. Patients who met specific study criteria on of age.1 Community-acquired pneumonia is defined as “the pres-
or after Study Day 4 were permitted to switch to an oral study drug. Safety ence of signs and symptoms of pneumonia in a previously healthy
assessments were treatment-emergent adverse events, and the effectiveness of child caused by an infection that has been acquired outside of the
treatment was assessed by clinical and microbiologic outcomes. hospital.”2 Lower age, asthma and previous upper respiratory tract
Results: The median duration of intravenous treatment was 9.0 (range, 3.0– infections have been shown as risk factors for children with commu-
19.0) days in the ceftaroline fosamil group (N=30) and 7.5 (5.0–13.0) days in nity-acquired bacterial pneumonia (CABP) <15 years of age.3 Strep-
the comparator group (N=10). At least one treatment-emergent adverse event tococcus pneumoniae is the most commonly identified organism
was experienced by 12/30 patients (40%) in the ceftaroline fosamil group causing CABP in children,2,4 while Staphylococcus aureus, includ-
and 8/10 (80%) in the comparator group; most treatment-emergent adverse ing methicillin-resistant strains (MRSA), have recently emerged as
events in both groups were mild to moderate in intensity. Clinical response increasingly clinically important pathogens responsible for CABP.5,6
rates in the modified intent-to-treat population were 52% (15/29 patients) in The introduction of pneumococcal conjugate vaccines (PCV7 and
the ceftaroline fosamil group and 67% in the comparator group (6/9); clinical PCV13)7,8 has reduced the prevalence of CABP caused by S. pneu-
stability at Study Day 4 was 21% (6/29) and 22% (2/9), respectively. moniae;2 however, it remains an important consideration in popula-
Conclusions: Ceftaroline fosamil was well tolerated and showed similar tions where there is an increased prevalence of invasive pneumococ-
clinical response rates to ceftriaxone plus vancomycin in pediatric patients cal disease caused by serotypes not covered by the vaccines.9,10
with complicated community-acquired bacterial pneumonia. The Pediatric Infectious Diseases Society and the Infectious
Diseases Society of America have published joint guidelines on
the treatment and management of CABP in infants and children
Accepted for publication December 21, 2015. >3 months of age.2 In these guidelines, complicated pneumonia
From the *Toledo Children’s Hospital, Toledo, Ohio; †Children’s New Clinic, is defined as “a pulmonary parenchymal infection complicated by
Tbilisi, Georgia; ‡University of California at San Diego and Rady Children’s parapneumonic effusions, multilobar disease, abscesses or cavities,
Hospital, San Diego, California; and §Cerexa, Inc., Oakland, California. necrotizing pneumonia, empyema, pneumothorax or bronchop-
This study was funded by Cerexa, Inc. a wholly owned subsidiary of Forest Lab-
oratories, which was acquired by Actavis plc, an Allergan affiliate, in July leural fistula, or pneumonia that is a complication of bacteremic
2014. Editorial and writing assistance was provided by Micron Research Ltd, disease that includes other sites of infection.”
Ely, UK, and funded by Forest Laboratories. J.L. Blumer, T. Ghonghadze, Ceftaroline, which is the active metabolite of the prod-
J.S. Bradley, and C.R. Cannavino are study investigators for this ceftaroline rug ceftaroline fosamil, is a broad-spectrum cephalosporin and
fosamil study funded by Cerexa, Inc., a wholly owned subsidiary of Forest
Laboratories. Actavis plc, an Allergan affiliate, acquired Forest Laboratories possesses in vitro activity against bacterial strains isolated from
in July 2014. The employer of Drs. Cannavino and Bradley, the University patients with CABP, including S. pneumoniae, S. aureus (including
of California, San Diego, has contracts with Cerexa/Forest for both consult- MRSA), Haemophilus influenzae and Moraxella catarrhalis.11,12 In
ing and clinical investigation. T. O’Neal, A. Jandourek, and H. David Fried-
land are former employees of Cerexa, Inc., a wholly owned subsidiary of
vitro activity of ceftaroline has been demonstrated against clinical
Forest Laboratories, and have received stock and stock options from Forest isolates from pediatric patients ≤5 years of age and 6–17 years of
Laboratories. As a result of the acquisition, Dr. O’Neal, Dr. Jandourek, and age,13,14 and ceftaroline has shown greater in vitro activity than cef-
Dr. Friedland are shareholders of Actavis, plc. Dr. Friedland and Dr. Jan- triaxone against clinical isolates of S. pneumoniae from pediatric14
dourek are also consultants for Actavis, plc. All authors confirm they
received no payment for the preparation of this manuscript. and adult patients with CABP.11
Address for correspondence: Jeffrey L. Blumer PhD, MD, Toledo Children’s Ceftaroline possesses a bactericidal mechanism of action
Hospital, 2142 North Cove Boulevard, Conrad Jobst Tower, Suite 980, similar to other cephalosporins, binding to penicillin-binding
Toledo, OH 43606. E-mail: Jeffrey.Blumer@UToledo.edu. proteins to disrupt bacterial cell wall biosynthesis and cause cell
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0891-3668/16/3507-0760 death.15 Unlike most other cephalosporins, however, ceftaroline is
DOI: 10.1097/INF.0000000000001160 able to bind to organisms expressing penicillin-binding protein2a

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The Pediatric Infectious Disease Journal  •  Volume 35, Number 7, July 2016 Ceftaroline in Pediatric Complicated CABP

or penicillin-binding protein2x, such as MRSA or S. pneumoniae, organisms or linezolid for clindamycin-resistant MRSA. Combined
respectively.15,16 IV plus oral drug or IV study drug was required for 5–21 days.
Ceftaroline fosamil has been approved in the United States Prior therapy was defined as any medication taken within
and many other countries for the treatment of adults with acute bac- 14 days before the first day of dosing with IV study drug, and con-
terial skin and skin structure infections and CABP. It is well toler- comitant therapy was defined as any medication taken on or after
ated in adults, with a safety profile comparable with other cepha- the first day of dosing with IV study drug through to the late follow-
losporins.17,18 up visit.
This article describes the study (registration number An end-of-IV assessment was conducted within 24 hours of
NCT01669980; http://clinicaltrials.gov/ct2/show/NCT01669980) the last dose of IV study drug. The end-of-therapy (EOT) visit took
assessing the safety, tolerability and efficacy of ceftaroline fosamil place within 48 hours after the last dose of oral study drug or within
in pediatric patients between 2 months and 17 years of age with 24 hours if the patient had continued to receive IV study drug. If
complicated CABP (cCABP). a patient had continued receiving IV study drug, then end-of-IV
assessments were conducted at the EOT. The test-of-cure (TOC)
visit was at 8–15 days after the last dose of IV or oral study drug
METHODS (whichever was given last). The late follow-up visit occurred at
Study Design and Treatment 21–35 days after the last dose of any IV or oral study drug. Assess-
This was a multicenter, randomized, observer-blinded, ments for safety were conducted at each study visit.
active-controlled study. The objectives were to assess the safety, The study was approved by the institutional review board
tolerability and effectiveness of ceftaroline fosamil or ceftriaxone or independent ethics committee for each study center and was
plus vancomycin (referred to as “comparator” hereafter) in pediat- conducted in full compliance with the International Conference on
ric patients with cCABP. Harmonisation E6 guidelines.19 Informed consent from patients’
Patients were enrolled in 4 cohorts of descending age: parents or legally acceptable representative, and assent from
cohort 1, 12 years to <18 years; cohort 2, 6 years to <12 years; patients who were old enough to provide it, was obtained before
cohort 3, 24 months to <6 years; and cohort 4, 2 months to initiation of any study procedures.
<24 months. Block randomization using an interactive voice Inclusion Criteria
response system was used to assign patients (3:1) to the ceftaroline Male or female patients with CABP between 2 months and
fosamil or comparator group stratified by age cohort. The study was 18 years of age and requiring 3 days of initial hospitalization were
observer-blinded, and each center had at least one blinded investi- eligible for enrollment into the study. A diagnosis of CABP required
gator who did not know each patient’s assigned treatment and con- presence of fever (temperature >38°C) or hypothermia (tempera-
ducted the clinical assessments. Ceftaroline fosamil or comparator ture <35°C), new pulmonary infiltrate(s) compatible with bacterial
was administered as an intravenous (IV) infusion to patients for a pneumonia based on diagnostic testing (eg, radiographic imaging),
minimum of 3 days. Patients randomized to the ceftaroline fosa- and one of the following: a typical respiratory pathogen isolated
mil group received IV ceftaroline fosamil infused over 120 (±10) from a respiratory (eg, sputum, pleural fluid, deep bronchial or deep
min every 8 (±1) hours at a dose of 15 mg/kg (or 600 mg if weight tracheal culture) or blood culture; leukocytosis (>15,000 white
>40 kg) if ≥6 months or at 10 mg/kg for patients <6 months of age. blood cells/mm3, >15% immature neutrophils [bands], regardless
Ceftriaxone was administered to patients randomized to the com- of total white blood cell count); leucopenia (<4500 white blood
parator group as an IV infusion over 30 (±10) min every 12 (±2) cells/mm3); or hypoxemia (oxygen saturation <92% on room air).
hours at a total daily dose of 75 mg/kg/day (up to 4 g/day) in equally The presence of cCABP was confirmed using protocol
divided doses. Initial empiric therapy with IV vancomycin was also criteria that were developed with Food and Drug Administration
administered to patients in the comparator group at 15 mg/kg every guidance.20 To distinguish cCABP as a clinical entity distinct from
6 (±1) hours, infused over ≥60 min (or at a maximum of 10 mg/min, community-acquired pneumonia, at least one of the following indi-
whichever was longer). cators had to be present: empyema, pulmonary abscess, necrotiz-
Patients could have continued to receive IV study drug for ing pneumonia, pneumatocele, pleural effusion needing chest tube
the entire duration of study drug therapy at the discretion of the drainage, Gram-positive cocci in clusters on Gram stain from a
investigator. Vancomycin could be discontinued on or after Study respiratory specimen, requirement for positive pressure-assisted
Day 4 (after at least 72 hours of IV study drug) if MRSA, or peni- ventilation, previous influenza-like illness (within 28 days before
cillin-resistant or -intermediate S. pneumoniae, was not confirmed enrollment) or treatment in an intensive care unit. In addition, an
or suspected. A switch from IV study drug to open-label oral study acute onset or worsening (within the previous 5 days) of at least two
drug (amoxicillin–clavulanate, clindamycin or linezolid) was of the following clinical signs and symptoms were required: cough,
allowed on or after Study Day 4. Patients considered for switch- tachypnea, dyspnea, grunting, sputum production, chest pain, cya-
ing to oral study drug must have fulfilled the following criteria: nosis, evidence of pneumonia with parenchymal consolidation and
received >72 hours of IV study drug therapy; had their clinical increased work of breathing.
signs and symptoms assessed on Study Day 4; able to maintain oral
intake; afebrile (temperature ≤38°C) for ≥24 hours; oxygen satura- Exclusion Criteria
tion ≥92% on room air; had a white blood cell count within normal A history of hypersensitivity or allergic reaction to vancomy-
range for age or ≥20% improvement from baseline; and an absence cin or any β-lactam antibiotic resulted in exclusion from the study.
or improvement and no worsening of any of the signs and symp- Confirmed or suspected infection caused by a pathogen resistant to
toms among cough, dyspnea, sputum production or chest pain. any of the IV study drugs, infection caused by a sole atypical organ-
An appropriate oral study drug was given at the discretion of the ism at baseline or infection caused by bacteria other than CABP
investigator depending on the results of pathogen cultures and sus- pathogens (eg, organisms associated with ventilator-associated or
ceptibility testing whenever it was available. Preferred oral study hospital-acquired pneumonia) also resulted in exclusion, as did
drug was amoxicillin clavulanate for the treatment of infections non-infectious pulmonary infiltrations on chest radiography. A
because of susceptible organisms, clindamycin for proven methicil- patient was ineligible if they had received more than 24 hours of
lin-susceptible S. aureus (MSSA) or MRSA because of susceptible any systemic antimicrobial therapy for CABP within 96 hours of

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Blumer et al The Pediatric Infectious Disease Journal  •  Volume 35, Number 7, July 2016

randomization, with the exception of patients who were considered visit. Any AE was considered a treatment-emergent adverse
to have failed prior treatment, defined as failing nonstudy antimi- event (TEAE) if it was not present before the start of study drug
crobial therapy for more than 48 hours. Moderate or severe renal administration or if it was present before study drug administra-
insufficiency (creatinine clearance <50 mL/min/1.73 m2, as calcu- tion but increased in severity after the start of dosing with IV
lated using the updated Schwartz “bedside” formula),21 a history of study drug.
seizures or suspected bacterial meningitis, each meant a patient was
ineligible. Evidence of any of the following categories of conditions Assessment of Clinical Outcomes
also resulted in exclusion: hepatic (defined as acute viral hepatitis, Clinical Response and Clinical Stability at Study Day 4
aspartate or alanine aminotransferase [AST or ALT] concentration Clinical response was defined as an improvement in at least
greater than 5-fold the upper limit of normal or total bilirubin greater 2 and worsening in none of the following 7 symptoms: cough, dysp-
than 2-fold the upper limit of normal), hematologic (neutropenia nea, chest pain, sputum production, chills or rigors, feeling feverish
[<500 neutrophils/mm3], thrombocytopenia [<60,000 platelets/ and exercise intolerance or lethargy. Symptoms were assessed by a
mm3]), or immunocompromising (human immunodeficiency virus questionnaire in which patients, parents or caregivers were asked
and a CD4 count <250 cells/mm3 or a history of another acquired if each symptom was mild, moderate or severe. Patients who did
immune deficiency syndrome-defining illness). not meet the criteria for clinical response were defined as clinical
nonresponders. Patients with insufficient information for deriving
Study Populations an outcome were identified separately under an “incomplete data”
The intent-to-treat (ITT) population consisted of all rand- category and were treated as nonresponders for analysis purposes.
omized patients (Fig. 1). The safety population was a subset of the Clinical stability was defined as afebrile (temperature
ITT population and included all patients who received any amount ≤38°C), age-appropriate normal pulse and respiratory rates, oxy-
of IV study drug. The modified ITT (MITT) population consisted gen saturation ≥92% on room air and worsening of none of the
of all patients in the ITT population who had a confirmed diagnosis 7 symptoms described above for clinical response, relative to
of cCABP in accordance with the study protocol criteria. Patients baseline. If patients failed to meet any of the criteria for clinical
with a sole atypical pathogen based on IgM baseline or IgG (paired stability, they were defined as not clinically stable. Patients with
baseline and post-baseline) serology samples were excluded from insufficient information for deriving an outcome were identified
the MITT population. The clinically evaluable population consisted separately under an “incomplete data” category and were treated as
of patients who met minimal cCABP disease criteria and all evalua- not clinically stable for analysis purposes.
bility criteria, which included receiving at least 80% of study drug,
receiving permitted concomitant medications and performance of Clinical Outcome at EOT and TOC Visits
study visits within the Study Days specified in the protocol. Clinical cure at the EOT and TOC visits was defined as a
resolution of all acute signs and symptoms of CABP or improve-
Safety Assessments ment to such an extent that no further antimicrobial therapy was
The primary outcome measures were safety and tolerabil- required. Clinical failure at the EOT visit was defined as con-
ity and included assessment of adverse events (AEs; graded as tinuation of study drug beyond the 21 days specified in the treat-
“mild,” “moderate” or “severe” by the blinded observer), serious ment period based on an investigator’s wish to continue treatment;
adverse events (defined as any medical occurrence that resulted discontinuation of study drug because of insufficient therapeu-
in death, resulted in permanent disability/incapacity, was life- tic effect, discontinuation of study drug because of an AE and
threatening, or required hospitalization), deaths and discontinu- requirement for alternative nonstudy antimicrobial therapy for
ations because of AEs. Laboratory values were also assessed. CABP, or death in which CABP was contributory. Clinical failure
All information on AEs was collected from the time that writ- at the TOC visit was defined as an incomplete resolution or wors-
ten informed consent was given through to the late follow-up ening of CABP signs or symptoms or the development of new

Intent-to-treat (ITT), N = 40 Safety population, N = 40

All randomized Received any amount of study drug

Ceftaroline fosamil = 30 Ceftaroline fosamil = 30

Comparator = 10 Comparator = 10

Unconfirmed diagnosis of complicated

CABP or presence of atypical pathogen

Ceftaroline fosamil = 1
Comparator = 1

Modified-intent-to-treat (MITT), N = 38
Any amount of IV study drug and
confirmed diagnosis of complicated CABP

Ceftaroline fosamil = 29
Comparator = 9
Did not meet specific conditions

Ceftaroline fosamil = 3
Comparator = 0
(concomitant antibiotic violation [1];
received <80% of study drug [1]; TOC
visit outside specified window [1]
Clinically evaluable (CE), N = 35
Met minimal disease criteria for CABP and
evaluability criteria

Ceftaroline fosamil = 26
Comparator = 9
FIGURE 1.  Study populations.

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The Pediatric Infectious Disease Journal  •  Volume 35, Number 7, July 2016 Ceftaroline in Pediatric Complicated CABP

signs or symptoms requiring alternative nonstudy antimicrobial

TABLE 1.  Demographic and Baseline Characteristics
therapy or death in which CABP was contributory. An indeter-
minate outcome at either visit was recorded because of missing (MITT Population)
study data on the evaluation of efficacy.
Ceftaroline
Comparator*
Characteristic Fosamil
Microbiologic Outcomes at TOC Visit (N = 29)
(N = 9)
Among patients with one or more pathogens identified at
baseline, evidence of eradication or persistence for each pathogen Age (years)
 Median (range) 4.0 (0.3–17.0) 4.0 (0.3–16.0)
was based on comparison of culture results from microbiologi- Age cohort, n (%)
cal respiratory specimen or blood collected at the TOC visit. If no  12 to <18 years 4 (13.8) 2 (22.2)
valid respiratory specimen or blood was obtained at the TOC visit,  6 to <12 years 7 (24.1) 1 (11.1)
the microbiological outcome was based on the clinical outcome at  2 to <6 years 12 (41.4) 4 (44.4)
TOC. A favorable microbiological outcome was defined as eradi-  2 months to <2 years 6 (20.7) 2 (22.2)
Male, n (%) 21 (72.4) 5 (55.6)
cation or presumed eradication of the baseline pathogen, and an
Country of enrolment, n (%)
unfavorable microbiological outcome was defined as persistence or  United States 13 (44.8) 5 (55.6)
presumed persistence of the baseline pathogen.  Georgia 11 (37.9) 4 (44.4)
 Ukraine 5 (17.2) 0
Statistical Methods Pleural effusion present, n (%)
Prior and concomitant therapy data were summarized  Unilateral 11 (37.9) 4 (44.4)
 Bilateral 3 (10.3) 1 (11.1)
for subjects in the MITT population receiving any prior sys- Lobes involved in disease, n (%)
temic antimicrobial therapy within 96 hours of the first dose  One lobe 12 (41.4) 4 (44.4)
of IV study drug and those receiving concomitant therapy. AE  Multiple lobes 17 (58.6) 5 (55.6)
were coded using MedDRA Version 17.0,22 and safety analysis Medical conditions occurring in
was performed on the study population, with the incidence of >30% of patients in either
treatment group, n (%)
AEs, TEAEs, serious adverse events, deaths and discontinua-  Pyrexia 11 (37.9) 5 (55.6)
tions summarized by treatment group. Efficacy was assessed by  Anemia 3 (10.3) 3 (33.3)
the proportion of patients with a favorable efficacy response in  Hypoxia 3 (10.3) 3 (33.3)
each treatment group. Between-group comparisons were made *Ceftriaxone + vancomycin.
with confidence intervals (CIs) calculated using the method of n indicates number of patients in each category; and SD, standard deviation.
Miettinen and Nurminen without stratification for descriptive
purposes.23
blood cultures (2/29 patients [7%] in the ceftaroline fosamil group),
RESULTS both of which were S. pneumoniae.

Patient Disposition and Study Populations Antibiotic Use (Safety or MITT Population)
A total of 11 study centers in 3 countries (United States, Among the safety population, the median number of days
Georgia and Ukraine) enrolled 40 patients in the study. The first that the ceftaroline fosamil group received IV study drug was 9.0
patient was enrolled in January 2013, and the last study visit (range, 3.0, 19.0), and 7.5 days (5.0, 13.0) in the comparator group.
occurred in May 2014. Study populations and exclusions from There was a switch to oral treatment in 22/30 patients (73%) in the
the MITT and clinically evaluable populations are summarized in ceftaroline fosamil group and all patients in the comparator group,
Fig. 1. and oral study drug was received by patients for a median of 7.5
days in each group. Patients in the ceftaroline fosamil group were
Baseline Patient Characteristics (MITT Population) switched to clindamycin (13/30 patients [59%]), amoxicillin clavu-
Among the MITT population, median ages of patients were lanate (8/30 [36%]) or linezolid (2/30 [9%]), and in the compara-
similar in both treatment groups; the majority of patients were tor group, patients were switched to clindamycin (6/10 [60%]) or
male, and the largest proportion of patients were enrolled in the amoxicillin clavulanate (4/10 [40%]).
United States (Table 1). The most common relevant medical con- Among the MITT population, 18/29 patients (62%) in the
dition among patients in each treatment group was a history of ceftaroline fosamil group and 5/9 patients (56%) in the comparator
pyrexia/fever. group received prior antibiotics within 96 hours of the first dose of
IV study drug. The most commonly administered prior antibiot-
Baseline Pathogenic Organisms (MITT Population) ics in the ceftaroline fosamil group were ceftriaxone (7/29 patients
Respiratory specimens were obtained at baseline from [24%]) and vancomycin and azithromycin (both 5/29 patients
11/29 patients (38%) in the ceftaroline fosamil group and 6/9 [17%]), and in the comparator group were ceftriaxone and clin-
patients (67%) in the comparator group. The most commonly iden- damycin (both 3/9 patients [33%]) and cefotaxime (2/9 patients
tified organism in the ceftaroline fosamil group was S. aureus, [22%]). Prior antibiotics were administered less than 24 hours
(4/29 patients [14%]), including one case of MRSA. Other patho- before the first dose of IV study drug in 12/29 patients (41%) in the
gens in the ceftaroline fosamil group included S. pneumoniae in ceftaroline fosamil group and 4/9 patients (44%) in the comparator
one patient (deep tracheal specimen), S. pneumoniae together group. The proportion of patients entering the study who were con-
with Pseudomonas aeruginosa in one patient (deep tracheal speci- firmed to have been treatment failures after >48 hours of prior ther-
men), Streptococcus pyogenes from pleural fluid in one patient and apy was 6/29 (21%) in the ceftaroline fosamil group and 1/9 (11%)
H. influenzae in one patient (deep tracheal specimen). In the compar- in the comparator group. Concomitant antibiotics were given to
ator group, one organism (MSSA) was identified in a single patient. 4/29 patients (14%) in the ceftaroline fosamil group for conditions
Blood samples for culture were obtained at baseline from that developed during the study; azithromycin was administered to
28/29 patients (97%) in the ceftaroline fosamil group and all 1 patient; 3 other patients were clinical failures and one of these
patients in the comparator group. In total, there were 2 positive received clindamycin, while another first received vancomycin,

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Blumer et al The Pediatric Infectious Disease Journal  •  Volume 35, Number 7, July 2016

then ceftriaxone, and was then given amoxicillin, and a final patient tract viral infection experienced by a patient in the comparator
received meropenem, vancomycin and azithromycin. No patients in group 28 days after ceasing treatment. This improved after hospital
the comparator group received concomitant antibiotics. treatment and was considered to be unrelated to study drug.
Direct Coombs test seroconversion at the TOC visit occurred
Safety and Tolerability (Safety Population) in 6/23 (26%) patients in the ceftaroline fosamil group who were
A summary of AEs in each study group is presented in negative at baseline and no patients in the comparator group. There
Table 2. Overall, 50% of patients in the safety population experi- was no evidence of hemolytic anemia or hemolysis in these patients
enced at least one TEAE; a lower proportion of patients in the cef- or any other patients in the study.
taroline fosamil group experienced at least one TEAE than in the
comparator group. Most patients in the study experienced TEAEs Clinical Outcomes
of mild or moderate intensity, and only one patient, who was in the Clinical cure rates at the EOT and TOC visits in the MITT
ceftaroline fosamil group, experienced TEAEs that were of severe population were similar in the 2 groups and are presented in Table 3.
intensity (increases in AST and ALT). After discontinuation of the In the clinically evaluable population, clinical cure rates at the EOT
study drug, the patient’s AST level returned to the normal range visit were 81% (21/26) in the ceftaroline fosamil group and 78%
after 6 days and ALT after a further 4 days. Both TEAEs were (7/9) in the comparator group (difference 3.0, 95% CI −23.1, 38.8).
resolved by the time of the TOC visit; these events were considered Corresponding values at the TOC visit were 89% (23/26) and 100%
related to IV ceftaroline fosamil. (9/9), respectively (difference −11.5, 95% CI −29.3, 20.1). Clinical
The most common TEAEs in the ceftaroline fosamil group response and clinical stability rates at Study Day 4 in the MITT
were anemia, pruritus and vomiting. Seven patients (23%) in the population are shown in Table 3. Clinical failure was reported in
ceftaroline fosamil group experienced a TEAE that was suspected to 3 patients in the ceftaroline fosamil group. Two of these patients
be related to oral or IV study drug (eosinophilia, vomiting, diarrhea, had study treatment discontinued because of AEs (one with elevated
infusion site extravasation, ALT increased, AST increased, transami- AST and ALT and another with pruritus and rash), and the third
nases increased, pruritus, dermatitis diaper, rash, rash macular), and patient experienced a worsening of pneumonia on Study Day 5.
none of these occurred in more than one patient. In the comparator Respiratory specimens or blood culture were obtained from
group, none of the most common TEAEs (vomiting and upper res- 10 patients at the TOC visit in the ceftaroline fosamil group and one
piratory tract viral infection) were suspected to be related to IV or patient in the comparator group, and a favorable microbiological
oral study drug. Of the TEAEs that were related to study drug (ALT response was reported in 10 of these patients. Ceftaroline fosamil
increased, transaminases increased, rash erythematous, red man syn- was discontinued in one patient because of increased AST and ALT,
drome), each occurred in no more than one patient. who also had the pathogen S. pneumoniae detected in blood. The
Of the 2 discontinuations of IV study drug because of AEs infection was treated with nonstudy antimicrobial medication (IV
in the ceftaroline fosamil group, one was the patient with increased vancomycin), so this patient was considered to be a clinical failure,
ALT and AST and the other patient had rash and pruritus, which and an unfavorable microbiologic response was presumed as speci-
resolved 6 days after discontinuation of IV study drug. Both patients fied by the study protocol. The 5 patients with S. aureus detected in
completed the study. No patients in the comparator group discontin- respiratory specimens at baseline all had a favorable microbiologi-
ued IV study drug because of AEs. The sole serious adverse event cal response at the TOC visit.
that occurred during the study was a lower and an upper respiratory

TABLE 3.  Clinical Outcome and Clinical Response in

TABLE 2.  Incidence and Severity of Adverse Events the MITT Population
(Safety Population)
Ceftaroline
Comparator
Ceftaroline Comparator* Fosamil
(N = 9), n (%)
Fosamil (N = 10), (N = 29), n (%)
(N = 30), n (%) n (%)
Clinical outcome EOT
Patients with ≥1 TEAE 12 (40.0) 8 (80.0)  Clinical cure 24 (82.8) 7 (77.8)
Incidence of TEAEs†‡  Difference, % (95% CI) 5.0 (−19.9, 40.3)
 Anemia 3 (10.0) 0  Clinical failure 3 (10.3) 0
 Pruritus 3 (10.0) 0  Indeterminate 2 (6.9) 2 (22.2)
 Vomiting 2 (6.7) 2 (20.0) Clinical outcome TOC
 URI 0 2 (20.0)  Clinical cure 26 (89.7) 9 (100)
Patients with ≥1 TEAE by  Difference, % (95% CI) −10.3 (−26.7, 21.0)
severity  Clinical failure 3 (10.3) 0
 Mild 5 (16.7) 4 (40.0)  Indeterminate 0 0
 Moderate 6 (20.0) 4 (40.0) Clinical response at study day 4
 Severe 1 (3.3) 0  Responder 15 (51.7) 6 (66.7)
Patients with ≥1 TEAE related 7 (23.3) 3 (30.0)  Difference, % (95%, CI) −14.9 (−44.6, 22.0)
to IV or oral study drug  Nonresponder 11 (37.9) 3 (33.3)
Patients with ≥1 SAE 0 1 (10.0)  Incomplete data 3 (10.3) 0
Discontinuation of IV or oral 3 (10.0) 0 Clinical stability at study day 4
study drug caused by AE  Stability 6 (20.7) 2 (22.2)
Discontinuation of IV study drug 2 (6.7) 0  Difference, % (95% CI) −1.5 (−37.2, 23.8)
caused by AE  No stability 22 (75.9) 7 (77.8)
 Incomplete data 1 (3.4) 0
*Ceftriaxone + vancomycin.
†MedDRA Version 17.0 was used to code TEAEs. Patients were counted once within Confidence intervals for the difference between groups are calculated using the
each preferred term. method of Miettinen and Nurminen without stratification.23
‡TEAEs reported for ≥3 patients in the ceftaroline group or ≥2 patients in the n is number of patients classified as achieving clinical cure; N is number of patients
comparator group. in the study population.
SAE indicates serious adverse events; URI, upper respiratory tract infection. CI indicates confidence interval.

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The Pediatric Infectious Disease Journal  •  Volume 35, Number 7, July 2016 Ceftaroline in Pediatric Complicated CABP

DISCUSSION In this study, a baseline respiratory specimen was obtained

This study was the first to compare ceftaroline fosamil from 11/29 patients in the ceftaroline group and 6/9 in the com-
with standard of care for the treatment of cCABP in pediatric parator group. Although a respiratory specimen affords the
patients. Ceftaroline fosamil was well tolerated when compared opportunity to identify pathogenic organisms, in clinical prac-
with the comparator; the incidence of TEAEs in the ceftaroline tice, not every child or infant can produce a respiratory specimen,
fosamil group was 40% (12/30 patients), and in the comparator induced sputum is not high yield and the routine use of invasive
group, it was 80% (8/10 patients). These TEAE rates may be partly procedures in a pediatric population is not ethically acceptable.28
attributed to the complicated infections in these patients such as The stringent signs/symptoms of cCABP in the study protocol
pneumonia-related pleural effusions, which require intervention. inclusion/exclusion criteria were intended to reduce the chances
Similar proportions of patients in the ceftaroline fosamil and com- of a patient with a viral cause of pneumonia being enrolled into
parator groups reported a TEAE related to IV or oral study drug the study. Of the 5 patients with S. aureus infections enrolled
(23% and 30%, respectively). Two patients in the ceftaroline fosa- into the study, 4 were randomized to receive ceftaroline fosa-
mil group discontinued IV study drug because of an AE, and these mil (including a patient with a MRSA infection), and one (who
events resolved after withdrawal of study drug. Direct Coombs’ test had a MSSA infection) received comparator treatment. Notably,
seroconversion, which is a known effect of ceftaroline, occurred in all 5 patients had a favorable microbiological outcome, suggest-
26% of patients in the ceftaroline fosamil group who were negative ing an efficacious response to treatments in both groups. The
at baseline. This is a higher frequency than has been reported in patient from the ceftaroline fosamil group with a MRSA infec-
adult patients with CABP (8%–12%).17,18 However, no patients in tion was classified as a responder and showed clinical stability
the study showed evidence of hemolytic anemia or hemolysis, and at Study Day 4 and achieved clinical cure at the TOC visit. The
so seroconversion may represent red blood cell membrane changes patient from the comparator group with an MSSA infection also
and nonspecific binding of IgG to the red blood cell membrane that achieved clinical cure at the TOC visit, despite being considered
have been described with other cephalosporins and β-lactamase not clinically stable at Study Day 4. Together, these findings war-
inhibitors.24 rant the instigation of further randomized controlled trials with
Published safety data from clinical studies involving pedi- larger numbers of patients to increase the evidence for treatment
atric patients have reported a similar overall tolerability with other options in pediatric patients with cCABP, including infections
cephalosporins. A review of the clinical trials that have assessed the suspected to be caused by MRSA.
safety of cefepime in patients <19 years of age reported AE rates The majority (73%) of patients who were randomized to the
of 38% (224/597patients) for cefepime and 37% (227/618 patients) ceftaroline fosamil group in the current study were switched to oral
for comparator groups across all studies.25 therapy, and IV study drug was continued at the discretion of the
In our current study, concomitant antibiotics were used only investigator in 8 patients. All patients in the comparator group were
in the ceftaroline fosamil group (14% of patients). A higher propor- switched to oral therapy, and the median time on IV study drug
tion of patients who were confirmed to have been treatment fail- (7.5 days) was less compared with the ceftaroline fosamil group (9
ures after >48 hours of antibiotic therapy before recruitment were days). The similar clinical response rates between groups at Study
recruited into the ceftaroline fosamil group (6/29 [21%]) than the Day 4 suggest that most patients improved on IV therapy, and the
comparator group (1/9 [11%]), perhaps increasing the likelihood of majority were placed on oral treatment before being discharged
an imbalance in concomitant medications in this small study popu- from hospital. In a study of pediatric patients (3 months to 18 years
lation. of age) with a variety of severe infections, patients switched from
The effectiveness of ceftaroline fosamil in the current study IV to oral antibiotics had a shorter median duration of treatment
was similar to that in the comparator group, with clinical cure (4 days, compared with 5 days in the control group), and an esti-
rates of 90% and 100%, respectively, at the TOC visit for patients mated reduction in healthcare costs of 230 international dollars per
in the MITT population. Clinical response and clinical stability episode of pneumonia.29 These results are consistent with 2 fur-
rates in the MITT population were largely similar between the ther studies that reported shortened median duration of treatment,
2 treatment groups, although at Study Day 4, a lower proportion length of hospital stay and decreased healthcare costs in hospi-
of patients achieved clinical stability (21%) than a positive clinical talized children with lower respiratory tract infections who were
response (52% in the ceftaroline group and 67% in the comparator switched from parenteral to oral antibiotics.30,31
group). This apparent discrepancy is likely to have arisen because This study was relatively small in size and was not powered
of the differences in definitions applied to the 2 assessments. Many for comparative inferential analysis, restricting any comparative
patients who fulfilled the criteria for clinical response, defined as conclusions between treatment groups. No efficacy end point was
no worsening of clinical symptoms and improvement of at least 2 identified as primary; however, several end points were examined
symptoms, did not satisfy the afebrile (temperature ≤38°C), age- across multiple populations, with CIs provided for between-group
appropriate pulse or respiratory criteria for clinical stability. point estimates for descriptive purposes. Ceftaroline has been
The published guidelines on the management of CABP shown to be well tolerated and effective in 2 large, Phase III trials
advise treatment with a third-generation parenteral cephalosporin of adults with community-acquired pneumonia,17,18 and future trials
for pediatric patients with severe CABP.2 The clinical cure rates investigating treatments for pediatric patients with cCABP would
presented in our study are similar to published cure rates from clini- benefit from randomization of larger numbers of patients into treat-
cal trials for the treatment of CABP with third-generation cephalo- ment groups, stratified by age.
sporins. One double-blind randomized trial of ceftriaxone (IV at Despite the limitations of this study, ceftaroline fosamil was
50 mg/kg q12h for 10 days) in the empirical treatment of severe well tolerated; furthermore, the clinical cure rates presented here
CABP in 51 children 2–24 months of age showed a cure rate of for patients receiving ceftaroline fosamil are similar to those for the
80%.26 In a second randomized controlled trial that was unblinded, comparator group (ceftriaxone plus vancomycin). In summary, the
the combination of oxacillin (IV at 200 mg/kg/day q6h) with ceftri- results from this multicenter study indicate that ceftaroline fosamil
axone (IV at 100 mg/kg/day q12h) for 10 days achieved a clinical may be a useful treatment option for pediatric patients with cCABP,
success rate of 85% in 48 patients between 2 months and 5 years of and additional clinical studies are needed to evaluate its safety and
age with very severe CABP.27 effectiveness in this patient group.

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Blumer et al The Pediatric Infectious Disease Journal  •  Volume 35, Number 7, July 2016

ACKNOWLEDGMENTS 14. Sader HS, Mendes RE, Farrell DJ, et al. Ceftaroline activity tested against
bacterial isolates from pediatric patients: results from the assessing world-
We thank the following investigators and study sites for their wide antimicrobial resistance and evaluation program for the United States
participation in this study. United States: Antonio Arrieta, Chil- (2011-2012). Pediatr Infect Dis J. 2014;33:837–842.
dren’s Hospital of Orange County; Jeffrey L. Blumer, Toledo Chil- 15. Moisan H, Pruneau M, Malouin F. Binding of ceftaroline to penicillin-
dren’s Hospital; Christopher Cannavino, Rady Children’s Hospi- binding proteins of Staphylococcus aureus and Streptococcus pneumoniae.
tal San Diego; Kenji M. Cunnion, Children’s Hospital of the King’s J Antimicrob Chemother. 2010;65:713–716.
Daughters, Norfolk; Marian G Michaels, Children’s Hospital of 16. Kosowska-Shick K, McGhee PL, Appelbaum PC. Affinity of ceftaroline
Pittsburgh. Georgia: Eka Uberi, Tbilisi State Medical University and other beta-lactams for penicillin-binding proteins from Staphylococcus
G. Zhvania Pediatric Academic Clinic; Tina Ghonghadze, Chil- aureus and Streptococcus pneumoniae. Antimicrob Agents Chemother.
2010;54:1670–1677.
dren’s New Clinic; Rusudan Gujabidze, Department of Pediatrics
17. File TM Jr, Low DE, Eckburg PB, et al. FOCUS 1: a randomized, double-
Amtel Hospital First Clinical, LLC. Ukraine: Tetiana V Litvinova, blinded, multicentre, Phase III trial of the efficacy and safety of ceftaroline
Department of Pediatric Pulmonology and Thoracic Surgery, Kry- fosamil versus ceftriaxone in community-acquired pneumonia. J Antimicrob
vyi Rih City Clinical Hospital No 8; Olena D Shustakevych, Ivano- Chemother. 2011;66(suppl 3):iii19–iii32.
Frankivsk Regional Children’s Clinical Hospital, Department of 1 8. Low DE, File TM Jr, Eckburg PB, et al. FOCUS 2 investigators. FOCUS
Pulmonology; Ivan P Zhurylo, Department of Septicopyemic Sur- 2: a randomized, double-blinded, multicentre, Phase III trial of the
gery with Thoracic Wards Regional Children’s Clinical Hospital. efficacy and safety of ceftaroline fosamil versus ceftriaxone in com-
munity-acquired pneumonia. J Antimicrob Chemother. 2011;66(suppl
3):iii33–iii44.
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