Reduction of antibiotic therapy by biomarkers in patients with CAP episodes

Community-acquired pneumonia (CAP) is a common and serious illness. In
developed countries it is the most important cause of death due to an
infectious disease and in the Netherlands it is the fourth leading cause of
death overall. 1-3
In CAP caused by bacteria prompt initiation of antibiotic therapy is
recommended, since a delay might be associated with increased mortality.4;5 The
optimal duration of antibiotic therapy in bacterial CAP remains unknown.6 Most
likely, it varies from patient to patient.
Current guidelines recommend treatment duration of 7-21 days, depending on
illness severity and type of pathogen.2;7-9 However, adherence to guidelines is
variable and physicians tend to treat longer, especially in patients with
comorbidities and patients with severe CAP.10;11 Duration of treatment can be
guided by clinical signs, but interpretation of the clinical response lacks
standardization and is prone to interobserver variability.12
A new approach to estimate the presence of an infection and response to
treatment is the use of biomarkers.13;14 Circulating levels of calcitonin
precursors, including procalcitonin are elevated in bacterial infections.15;16
Procalcitonin can follow either a classic hormonal expression pathway or in the
presence of an infection, a cytokine-like expression pathway.16;17
The release of procalcitonin during infection can be induced either directly by
microbial toxins such as endotoxin and indirectly by humoral factors such as
IL-1*, TNF-* and IL-6 or the cell-mediated host response. 16;17
Several studies have shown procalcitonin can be used as a marker for bacterial
lower respiratory infections and CAP. 18-20 Some studies demonstrate
procalcitonin can be used effectively and safely as a marker to initiate or
discontinue treatment with antibiotics.11;21-23 However only one of these
trials focuses on patients with CAP admitted to hospital. One of our objectives
is to validate the procalcitonin based treatment strategy mentioned by Christ
Crain et al. and Long et al. 23;24
A different way to assess the presence of (bacterial) infection is measuring
the blood level of C-Reactive Protein (CRP). An elevated CRP correlates only
with (systemic) inflammation and not per se infection. Several studies have
attempted to use CRP as a marker in lower respiratory tract infections and CAP
in a primary care setting. 25-29 Over the years several reviews have questioned
the use of CRP in patients with community acquired pneumonia/lower respiratory
tract infections as a marker to initiate or withhold antibiotic treatment.
27;30 There is however evidence that supports the use of consecutive
measurements of CRP in follow up of antibiotic treatment in CAP. Several
studies showed that a delayed normalisation of CRP within the first 3*7 days of
follow-up is suggestive of inappropriate antibiotic therapy and eventually
treatment failure. 31-34
Using the database from the CAPISCE study35 we retrospectively derived a CRP
based treatment strategy which we believe can be used just as effectively as
the PCT based strategy to discontinue antibiotic treatment in patients with CAP
admitted to hospital.
Our main goal is to determine whether the CRP and PCT guided strategies can be
used to safely and effectively reduce the duration of antibiotic treatment in
patients with CAP admitted to hospital.

2.1 Primary objective(s)
The primary objective of this study is to determine whether a CRP guided and
PCT guided treatment strategy (strategies mentioned below) can be used to
safely and effectively reduce the duration of antibiotic treatment as compared
to common clinical practice in patients with CAP requiring hospitalisation.

The diagnosis CAP will be made if a non-hospitalized person presents with one
or more symptoms associated with a lower respiratory tract infection and a new
infiltrate on the chest radiograph. These symptoms are: temperature greater
than 38°C (100.4°F); cough with or without sputum; hemoptysis; pleuritic chest
pain; dyspnea; malaise or fatigue; myalgia; gastro-intestinal symptoms; rales,
rhonchi or wheezing; egophony or bronchial breath sounds.

2.2 Secondary objective(s)
The secondary objectives of this study are to assess the length of hospital
stay, clinical response, 30-day mortality, time to clinical stability and
relapse rate within 30 days. A relapse is defined as new or worsening symptoms
indicative of pneumonia after initial improvement on therapy. Furthermore
several biomarkers and genetic polymorfisms for corticosteroid-receptors will
be assessed at the end of the study.

This study will be set up as a Randomised Controlled Trial with a parallel
design, patients will be randomly allocated to one of 3 treatment groups. No
blinding will be performed, since treating physicians will have to make a
decision to continue or withhold treatment based on laboratory evaluations. In
order to make the right decision they will have to know whether or not the
patient is receiving antibiotics.
Patients will be included at hospital admission and the follow up period is 1
month. The control group will consist of patients getting treated according to
common clinical practice.
Patients will be admitted to hospital and receive therapy according to the
study protocol. They will be discharged from the hospital when their medical
condition and social situation is stable. If patients are discharged and still
using antibiotics, blood tests will be performed daily in the participating
centre and the researcher will contact the patients by phone to inform them
whether or not antibiotic treatment can be discontinued. After discharge the
patient will be evaluated at an outpatient visit on day 30. In case of any
event an interim visit will be scheduled. If for some reason a patient fails to
perform an outpatient blood test, antibiotics will be continued until the next
blood test or for a total of 7 days and the reason for failure will be
documented.
This study will be conducted in the Medical Centre Alkmaar and the Slotervaart
hospital in Amsterdam.

The 3 different treatment strategies are as follows:
1. Treatment according to common practice: often a 7 day course of antibiotics.
2. Treatment with antibiotics for at least 3 days according to current
guidelines, with extension of antibiotic treatment according to procalcitonin
levels. Antibiotic treatment will be discontinued if the procalcitonin level is
below 0.25 mcg/L or shows a reduction to 10% of the initial value.
3. Treatment for 3 days according to current guidelines, with extension of
antibiotic treatment according to CRP levels. Antibiotic treatment will be
discontinued if the value is below 100 mg/L and shows a reduction to 50% of the
initial value.

Low risk study according to the risk-classification as designed by the Dutch
Foundation of University Medical Centres.
Risks include those associated with obtaining a blood sample and possibly
worsening of the patients condition if the antibiotics happened to be stopped
early, in which case antibiotic therapy can be resumed.