Effect of procalcitonin-based
guidelines vs standard
guidelines on antibiotic use in
lower respiratory tract
infections: the ProHOSP
randomized controlled trial.
JAMA. 302(10):1059-66. (Sept 2009)
Ria Dancel, MD
11/13/2009
Question: In adults with lower respiratory
tract infection (LRTI), is antibiotic
treatment based on a procalcitonin driven
algorithm inferior to treatment based on
current guidelines, in terms of adverse
events?
Rationale
• Antibiotic overuse – we all know the pitfalls: resistance,
cost, adverse events, C. Diff
• 75% of patients with LRTI are prescribed antibiotics
despite predominantly viral etiology
• Procalcitonin (PCT) is the precursor of calcitonin.
– Low or undetectable in healthy subjects
– Increases in proportion to severity of bacterial disease (infection,
septicemia, meningitis)
– Falls quickly in response to appropriate antibiotic therapy
– Most importantly, PCT remains low in viral illness, making it a
unique acute phase reactant that can potentially distinguish
bacterial from viral infections
Prior studies have suggested that algorithms using PCT
cutoffs have decreased antibiotic use but these studies
were small and insufficiently powered to show whether
they caused more complications
Study Design
• Investigator initiated, multicenter, noninferiority
RCT
• 6 tertiary care centers in Switzerland
• Duration from 10/2006-3/2008
• Power:
– Based on previous intervention trials, authors
assumed overall adverse outcome risk of at most 20%
– Planning committee agreed that cut-off for inferiority
would be risk greater than 27.5%
– Minimum sample size calculated to be 1002 patients
to achieve 90% power
• Randomized concealed via centralized website
Inclusion criteria
• 18 years or older, from community or
nursing home
• LRTI < 28 days in duration
– 1 respiratory symptom (cough, sputum
production, dyspnea, tachypnea, pleuritic
pain)
– PLUS 1 auscultory finding (rales, crepitation)
– OR 1 sign of infection (fever > 38, shivering,
WBC > 10K or < 4K)
Definitions
• CAP = LRTI with new infiltrate on CXR
• COPD defined by postbronchodilator
spirometric criteria set by the Global
Initiative for Chronic Obstructive Lung
Disease (GOLD)
• Acute bronchitis = LRTI in the absence of
an underlying lung disease or focal chest
signs and infiltrates on chest radiograph
Exclusion criteria
• Inability to give written consent due to language
restriction or dementia
• Active IVDA
• Severe immunosuppression other than
corticosteroid use
• Life threatening comorbidities leading to
possible imminent death
• HAP (development of PNA > 48 hrs after
admission or within 14 days of recent
hospitalization)
• Chronic infection necessitating antibiotic use
Study protocol for intervention
group (PCT group)
• PCT levels were communicated to physicians caring for
patients allocated to PCT group along with treatment
recommendations based on following protocol
– PCT < 0.1
 Abx strongly discouraged, remeasure PCT in 6-24 hrs
– PCT 0.1 – 0.25
 Abx discouraged, remeasure PCT in 6-24 hrs
– PCT 0.25 – 0.5
 Abx encouraged, remeasure PCT on days 3, 5, 7
– PCT > 0.5
Abx strongly encouraged, remeasure PCT on days 3, 5, 7
– If abx were started, they were discontinued according to the
same cutoffs
Study protocol for intervention
group (PCT group)
Study protocol for control
group
• For CAP:
– Abx encouraged for 5-10 days
– Abx for 14 days for Legionella CAP
– Abx for at least 10 days in necrotizing CAP
• For COPD:
– Abx encouraged for 5-10 days if pt had severe COPD
– Abx encouraged for 5-10 days if pt had purulent sputum + either
increased dyspnea OR increased sputum volume
• For acute bronchitis (no focal signs, no underlying lung
dz):
– Abx discouraged UNLESS
– Purulent sputum + increased risk (age > 75 and fever, CHF,
insulin dependent DM, serious neurological disorder)
• Abx for 3-5 days
Primary non-inferiority
endpoint
Composite of adverse outcomes within 30
days of ED admission of:
• Death
• ICU admission
• Persistence or development of PNA
• Disease specific complications (abscess,
empyema, ARDS)
• Recurrence of LRTI in need of antibiotics
Secondary superiority
endpoints
• Duration of IV or PO abx
• Adverse effects of abx
• LOS
Assessment of outcomes
• Outcomes during the hospital stay
assessed by unblinded physicians
• At 30 days, outcomes assessed by
blinded medical students via telephone
interviews
Patient flowchart
Retained
92.6%
Retained
94.4%
Patient demographics
Primary outcome
OR 0.76 (95%
CI 0.57-1.01),
favoring PCT
group
Kaplan Meier Curves for
Primary outcome
Secondary outcomes
Validity
1. Randomized? Yes, concealed by website
2. Were the groups similar at start of trial?
Yes
3. Blinded? Pts were blinded. BUT outcomes
assessed during the hospitalization by
unblinded physicians  Introduces bias!
(Detection bias of subjective outcomes,
Hawthorne effect)
4. Adequate follow-up? Yes
5. Large dropout? No. >90% of pts
randomized were assessed at 30 days
6. Intention to treat analysis? Yes
Validity
7. Was the noninferiority margin defined a
priori on the basis of statistical reasoning
and clinical judgment? Yes. Based on
previous intervention trials, authors assumed
overall adverse outcome rate of 20% (in this
trial overall adverse outcome of control group
was 18.9%, so this was a good assumption).
Inferiority was defined a priori as overall
adverse outcome of >27.5%.
8. Was the noninferiority assessment
adequately powered? Sample size of 1002
was calculated to give power of 90%. 1381 pts
were randomized
Conclusions
This study showed that patients treated by
a procalcitonin based algorithm did no
worse than control patients with regard
to the composite of adverse events
The PCT algorithm decreased antibiotic
prescribing, duration of exposure to
antibiotics and adverse reactions to
antibiotics
Further thoughts
• Could we come to the same conclusion if
we used a CRP guided algorithm?
• What if we ignored biomarkers altogether
and just treated LRTI with 3-5 days of
antibiotics instead of 5-10 days?
References
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