LSU Journal Club
Effect of Procalcitonin-Based Guidelines vs Standard
Guidelines on Antibiotic Use in Lower Respiratory
Tract Infections: the ProHOSP Randomized
Controlled Trial
P. Schuetz, M. Christ- Crain, R. Thomann, C. Falconnier, M. Wolbers, I. Widmer, S. Neidert, T.
Fricker, C. Blum, U. Schild, K. Regez, R. Schoenenberger, C. Hensen, T. Bregenzer, C. Hoess,
M. Krause, H. Bucher, W. Zimmerli, B. Mueller
Allison Leonard, PGY-1
September 18, 2014
Background
Why use procalcitonin as a marker?
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Unreliable “gold standard” for diagnosis and assessment of severity
of bacterial infections, distinguishing symptoms of viral from
bacterial
Other markers include CRP, WBC count, Blood Cx which all have
drawbacks
Procalcitonin- precursor peptide which increases several thousand
fold secondary to microbial infection, inflammation.
Level and duration of elevation correlates with severity of
condition and mortality
Levels increase via transcriptional upregulation of CT- mRNA which
in sepsis bypasses normal enzymatic processing
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Pros of Using PCT as a marker:
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Levels unaffected by steroid use, not a product of WBCs,
levels increase earlier in infection, can differentiate
between bacterial and viral infections [exception malaria]
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Shows promise in studies involving PNA, acute endocarditis,
UTIs, ?Catheter related infections, febrile neutropenia
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Cons of using PCT as a marker:
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FP reported in trauma, systemic fungal infections, ARDS,
patients with cancers [medullary thyroid, small cell in lung,
carcinoid, paraneoplastic syndromes]
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FN reported in early infections, localized infections,
subacute endocarditis
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More expensive than CRP, CBC
Research question
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Is an algorithm using procalcitonin levels to guide antibiotic therapy in LRTI “noninferior” in
comparison to standard guidelines for LRTI?
Does the procalcitonin algorithm reduce antibiotic use or duration of hospitalization in
patients admitted for LRTI?
Study panel initially set a number of 7.5% difference in failure rate to be considered “non
inferior”
Primary outcome measure: “Noninferior”
– Adverse outcomes at thirty days following admission: death from any cause, ICU
admission for any reason, disease specific complications- lung abscess, empyema, ARDS,
reoccurrence of LRTI needing antibiotics
Secondary outcome measures:
– time of antibiotic treatment, duration of antibiotic therapy, side effects of antibiotics,
length of hospitalization
Study Subjects
What they were looking for in ER patients to
potentially include in the study
Who they excluded
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Primary diagnosis of Lower RTI
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Classification of LRTI:
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presence of one respiratory symptom [cough, sputum,
dyspnea, tachypnea, pleuritic pain] + at least 1 finding
during auscultation [rales, crepitus] OR 1 sign of infection
[Temp over 38 C, shivering, WBC over 10 or under 4]
CAP [new infiltrates on CXR]
acute exacerbation of COPD [Post Bronchodilator
spirometry criteria according to GOLD guidelines],
Acute bronchitis [LRTI with absence of underlying lung dx or
infiltrates on CXR
18 years or older, symptoms less than 28 days
Cannot speak German
Cannot give written informed consent
Active IV drug users
Severe immunosuppression other than steroid use
Life threatening comorbidities
Immediate need for ICU care
Hospital acquired pneumonia patients
Patients with chronic infection requiring long term
antibiotics
Study Design
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What type of study is this? Randomized Controlled Trial
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Interventional type
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Randomized allocation
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Endpoint: Safety/efficacy
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Parallel assignment
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Single Blinded
Assessed for eligibility– then excluded ineligible– then
randomized into procalcitonin group or guidelines only
group
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Guidelines only group- followed ATS guidelines for CAP
and European guidelines for adult lower RTI
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Patient safety concerns allowed for preset criteria for
physician overruling of PCT algorithm
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Severe CAP based on PSI or severe COPD based on GOLD score with
Procalcitonin levels indicating no treatment
Immediate need for ICU admission, respiratory/hemodynamic instability,
positive urine antigen for Legionella, or after consulting with the study
center
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Study Protocol
for Procalcitonin
Group
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Antibiotic use discouraged in levels (< 0.1 or < 0.25 ug/L)
Antibiotic use encouraged in levels (> 0.5 or > 0.25 ug/L)
Reevaluation with repeat PCT levels after 6 to 24 hours in
those who had antibiotics withheld (with Procalcitonin < 0.1
or < 0.25 ug/L) who have worsening or non-improvement of
vital signs
Those given antibiotics based on algorithm were reassessed
at day 3, 5 and 7 with repeat procalcitonin levels and
antibiotics stopped based on the same cutoff values
Those who initially had high procalcitonin levels >10 ug/L at
admit had antibiotics stopped if levels decreased by 80%
In those given antibiotics at discharge the recommended
duration of therapy was based on the last procalcitonin level
in the hospital :
0.5 ug/L, 5 days
> 0.25 ug/L, 3 days
< 0.25 ug/L, none
Antibiotic choices left up to MD
Adherence
• In procalcitonin groupalgorithm used correctly to
initiate or hold antibiotics in
90% of those enrolled in trial
• Algorithm overruled or
stopped based on physician’s
judgment in the other 10%
• In control group- guidelines
were overruled in 20% based
on physician judgment
Study Results
Primary End Point [Adverse
outcomes]
• Risk difference in
overall outcomes was
3.5% [less than goal of
“noninferiority”] with
less adverse outcomes
in PCT group
• Overall deaths lower
but not significantly
different in PCT group
Secondary End Point [Antibiotic
exposure]
• Mean duration of
antibiotic exposure was
decreased overall as a
whole and in all
subgroups of
procalcitonin patients
Conclusions
Procalcitonin algorithm WAS noninferior
to algorithm based on guidelines for LRTI
and at the same time was effective at
reducing antibiotic exposure and
associated adverse events
Physicians can use procalcitonin values to
guide therapy for LRTI without risking
more adverse events than if they used
standard guidelines
PCT values are especially helpful when the
etiology and severity of infection are
unclear
Algorithm has substantial impact on
clinical management of patients and also
impacts public health by reducing
antibiotic exposure/resistance/selection
of resistant infections/risks of prolonged
antibiotic therapy
Other conclusions to note:
Patients with proven bacteremia had
higher procalcitonin levels and
therefore longer duration of
treatment
Procalcitonin had higher peak levels
and took longer to normalize when
infection was more severe/systemic
No significant differences in hospital
stay between PCT and standard
guidelines groups
Discussion
Strengths
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Limitations
Multiple hospital study
• “Hawthorne effect”
Large group of patients with ranging
• “Spillover effect”
comorbidities, infection severity
Even distribution of patient
• Large cohort of excluded
characteristics [age, sex, prior AB use,
patients
comborbidities, vitals on admit, PSI
• Physician discretion to “pull
severity, initial PCT value]
Ease of algorithm instructions with
patients” out of study
computer based guidelines based on
lab results
Blinded follow up