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An Update for Community-Acquired Bacterial Pneumonia Pharmacotherapy : What's New and Where
Does It Fit?
Heather F. DeBellis, Melissa C. Jones and Scott E. Kincaid
Journal of Pharmacy Practice 2012 25: 569 originally published online 11 October 2012
DOI: 10.1177/0897190012460829
The online version of this article can be found at:
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Abstract
In 2007, 1.2 million people in the United States were hospitalized with pneumonia, and more than 52 000 died from the disease.
Community-acquired bacterial pneumonia (CABP) can be caused by a variety of organisms as a result of patient factors such as
comorbidities, epidemiologic conditions, or the setting in which the infection was contracted. Treatment of CABP differs depending on the types of bacteria that are suspected. In the last several years, due to the concern regarding multidrug-resistant organisms (MDROs), 2 new antibiotics have been developed and approved for use in CABP. Ceftaroline fosamil (Teflaro) was approved
by the US Food and Drug Administration (FDA) in October 2010 and tigecycline (Tygacil) in March 2009. In clinical trials, both
agents have been shown to be efficacious and are generally well tolerated. Although these agents have received approval as therapy for CABP, it is the responsibility of physicians and pharmacists to prudently use these antimicrobials where they are truly
needed. Until these agents show superiority over conventional therapy for selected patient populations, given the wide variety
of pharmacotherapy that can prove efficacious for pneumonia, the new agents should be reserved for patients who have known
risk factors for MDROs. Further studies are warranted for these agents in the setting of CABP.
Keywords
pneumonia, tigecycline, ceftaroline fosamil
Introduction
In 2007, 1.2 million people in the United States were
hospitalized with pneumonia and more than 52 000 died from
the disease. Community-acquired bacterial pneumonia (CABP)
in the outpatient setting is caused mainly by Streptococcus
pneumoniae but can also be attributed to such organisms as
Mycoplasma pneumoniae, Haemophilus influenza, Chlamydophila pneumoniae, and certain respiratory viruses. The cause
of hospital-acquired pneumonia is similar; however,
Legionella, Staphylococcus aureus, and other bacteria could
be the culprit. The causative organisms can vary due to comorbid or epidemiologic conditions, such as diabetes, alcoholism,
chronic lung or renal disease, or the recent use of antibiotics.1
According to the current Infectious Disease Society of
America/American Thoracic Society (IDSA/ATS) treatment
guidelines for CABP, there are several empiric treatment
options for CABP in the outpatient setting. Outpatients who are
otherwise healthy should receive monotherapy with a macrolide or doxycyline. In those with comorbid conditions, a
respiratory fluoroquinolone (levofloxacin, moxifloxacin, or
gemifloxacin) or a beta-lactam plus a macrolide are recommended. If a patient is admitted to the hospital, a respiratory
fluoroquinolone or a macrolide plus a beta-lactam are
Corresponding Author:
Heather F. DeBellis, PharmD, CDE, South University School of Pharmacy,
709 Mall Boulevard, Savannah, GA 31406, USA
Email: hdebellis@southuniversity.edu
570
Ceftaroline Fosamil
The FOCUS 1 and FOCUS 2 clinical trials are randomized,
double-blind, multicenter phase III studies evaluating the
safety and efficacy of ceftaroline fosamil when compared to
ceftriaxone for the treatment of hospitalized patients with
CABP. Study participants were randomized (1:1) to receive
treatment for 5 to 7 days of either ceftaroline fosamil 600 mg
every 12 hours or ceftriaxone 1 g every 24 hours if hospitalized
with CABP, requiring iv therapy, and having a Pneumonia Outcomes Research Team (PORT) risk class score of III or IV. The
FOCUS 1 and FOCUS 2 studies were intended as parallel,
methodologically alike (with the exception of 2 doses of
clarithromycin given on day 1 in FOCUS 1 only), comparative
analyses that did not allow switching to oral medications for
treatment completion.8,9
DeBellis et al
571
FOCUS 1
FOCUS 2
Integrated efficacy analysis
Ceftaroline
fosamil group
Ceftriaxone
group
Difference
86.6%
82.1%
84.3%
78.2%
77.2%
77.7%
8.4%
4.9%
6.7%
1.4%-15.4%
2.5%-12.5%
1.6%-11.8%
FOCUS 1
FOCUS 2
Integrated efficacy analysis
Ceftaroline
fosamil group
Ceftriaxone
group
Difference
83.8%
81.3%
82.6%
77.7%
75.5%
76.6%
6.2%
5.9%
6.0%
0.2%-12.6%
1.0%-12.7%
1.4%-10.7%
Clinical Efficacy
The primary end point of the FOCUS program was to determine noninferiority of ceftaroline fosamil in clinical cure rates
when compared with ceftriaxone in the clinically evaluable
(CE) and modified intent-to-treat efficacy (MITTE) populations at the TOC visit (Tables 1 and 2). A clinical cure was
defined as resolution of all signs and symptoms of pneumonia
or improvement to that point that no further antimicrobial treatment was needed. Patients had to demonstrate total resolution
of CABP signs and symptoms in addition to being afebrile for
24 consecutive hours for clinical cure to be established. If a
patient previously established a clinical cure at the TOC visit,
but later displayed returning symptoms involving additional
antimicrobial treatment during the LFU visit then relapse was
confirmed. The TOC visit occurred 8 to 15 days from the last
dose of study drug administered, and the LFU occurred 21 to
35 days from the last dose of study drug.12
FOCUS 1 clinical cure rates in CE patients were 86.6% in
the ceftaroline fosamil group versus 78.2% in the ceftriaxone
group (difference, 8.4%; 95% confidence interval [CI], 1.4%15.4%). During FOCUS 2, the clinical cure rates in the CE population were 82.1% in the ceftaroline fosamil group versus
77.2% in the ceftriaxone group (difference, 4.9%; 95% CI,
2.5%-12.5%). In the integrated efficacy analysis of the 2
Tigecycline
Currently, there are results from 2 phase III, multicenter,
double-blind, randomized clinical trials evaluating the safety
and efficacy of tigecycline for the treatment of CABP when
compared to levofloxacin in hospitalized patients requiring iv
therapy.1315 Bergallo et al investigated a comparison study
featuring an initial dose of tigecycline 100 mg administered
iv followed by 50 mg every 12 hours versus levofloxacin 500
mg administered iv every 24 hours for creatinine clearance
rates 50 mL/min. Patients in the levofloxacin group with
creatinine clearance rates <50 mL/min received a dose appropriate for their degree of renal impairment per the approved
package insert. Patients were randomized (1:1) to receive either
572
study drug for a minimum of 3 days. The total duration of therapy was 7 to 14 days. After receiving 6 or more doses of study
drug iv, patients could be changed to oral levofloxacin for the
remaining treatment duration.13
Tanaseanu et al conducted a prospective, noninferiority
study testing an initial dose of tigecycline 100 mg administered
iv over 1 hour followed by 50 mg every 12 hours versus levofloxacin 500 mg administered iv over 1 hour every 12 or 24
hours for creatinine clearance rates 50 mL/min. Patients in
the levofloxacin group with creatinine clearance rates of 20
to 49 mL/min received an initial dose of levofloxacin 500 mg
followed by 250 mg every 12 or 24 hours administered iv.
Patients were randomized (1:1) to receive either study drug for
a minimum of 7 days. The total duration of therapy was 7 to 14
days.14
Clinical Efficacy
The primary efficacy end points analyzed by Bergallo et al
were clinical responses (categorized as cure, failure, or indeterminate) in the CE and clinical mITT (c-mITT) populations at
the TOC visit (Tables 3 and 4). A clinical cure response means
all signs and symptoms of CABP improved or resolved, chest
radiographs were improved or not worse, no further antibiotic
therapy was required, and there were no new signs and symptoms of CABP at the TOC visit. Noninferiority was confirmed
since the lower limit of the 2-sided 95% CI was greater than or
equal to 15%. The clinical cure rates in CE patients were
90.6% in the tigecycline group versus 87.2% in the levofloxacin group (difference, 3.4%; 95% CI, 4.4%-11.2%). Clinical
cure rates were also consistent with the c-mITT patients, 78%
in the tigecycline group versus 77.8% in the levofloxacin group
(difference, 0.2%; 95% CI, 8.5%-8.9%). Since there were no
statistically significant differences found at TOC, the efficacy
of tigecycline was determined to be statistically noninferior
to levofloxacin. This comparison study confirmed tigecycline
to be efficacious and noninferior to levofloxacin for the
DeBellis et al
573
Bergallo et al13
Tanaseanu et al14
Tigecycline
group
Levofloxacin
group
Adjusted
difference
90.6%
88.9%
87.2%
85.3%
3.4%
3.6%
4.4%-11.2%
4.5%-11.8%
Bergallo et al13
Tanaseanu et al14
Tigecycline
group
Levofloxacin
group
Adjusted
difference
78.0%
83.7%
77.8%
81.5%
0.2%
2.0%
8.5%-8.9%
5.5%-9.6%
Discussion
As the identification of resistant organisms continues to rise
and the lack of new antimicrobials with novel mechanisms
of action persists, it becomes more evident every day that
antimicrobial stewardship and judicious use of antimicrobials
is the new necessity. Antimicrobials such as ceftaroline fosamil and tigecycline are some new options that have gained an
indication in the treatment of CABP. The data show that these
agents are considered noninferior but there have yet to be
adequate studies to support the preferred use of these antimicrobials. As bacteria adapt to the selective pressure that we
place on them, it is unknown what will be the next reaction
after significant use of these antimicrobials. The approach
to antimicrobial research and practice has shifted more toward
preservation than development due to the lack of novel agents
in the pipeline. This is one reason why antimicrobial
stewardship programs are becoming increasingly important
in all hospital settings and the use of new agents should be
subjected to educated skepticism.
When we step back and take a look at the niche that has been
created for these medications we must consider the relevance
of each individual patients history and their risk for MDROs.
These agents were specifically designed to cover MDROs and
according to the current guidelines the patients at risk for
MDROs would not necessarily meet the criteria for a simple
CABP. Many, if not all of these patients, would be classified
as a health careassociated pneumonia (HCAP). According to
the IDSA guidelines, this classification would justify a more
broad therapy than the currently recommended therapy for
CABP.18 Thus, the utility of these agents in patients who are
actual CABP patients becomes greatly reduced. Empiric
therapy should be driven by evidence-based medicine
(ie, guidelines) and the resistance patterns seen in the community where they reside. Local antibiograms should provide an
appropriate source of guidance when choosing empiric therapy
574
Recommendations
Ceftaroline fosamil and tigecycline are both agents with
great potential for use in selected patient populations. Nonetheless, true CABP patients who do not exhibit the appropriate risk factors should receive more intensive evaluation by
trained infectious disease practitioners prior to initiating
therapy, whether it is empiric or targeted, with ceftaroline
or tigecycline. There may be a greater utility for deescalation therapy to one of these agents when Pseudomonas aeruginosa, which neither agent has efficacy against,
has been ruled out.
Novel antimicrobials agents are of a dying breed and
MDROs are continuing to adapt to the selective pressure
of the antimicrobial era. Agents such as ceftaroline fosamil
and tigecycline should be used judiciously. Practitioners
should be reserving these antimicrobials for patients who
have risk factors that justify their use or for identified
pathogens with specific resistance to other antimicrobials
that are more cost effective. Given their noninferiority,
more research is warranted to determine whether there is
a significant clinical and pharmacoeconomic benefit to supplant other traditional less-expensive antimicrobials.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
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