St udent , Phar mD candi dat e

2015

Uni ver si t y of Sai nt Joseph School of Phar macy

August 27, 2014

Procalcitonin Guided
Antimicrobial Therapy
Procalcitonin Guided Antimicrobial Therapy
Early initiation of antimicrobials in certain infections, like sepsis in the
critically ill, is crucial for reducing mortality
As a consequence, inappropriate use of antimicrobials can occur in patients
with suspected infections
Guidelines do not have strong recommendations for stopping therapy

Inappropriate antimicrobial use can lead to adverse events and
bacterial resistance

Procalcitonin is a biomarker that can be used to assist physicians in
making clinical decisions
Identify patients where antimicrobial therapy would be appropriate
Discontinue antimicrobials when no longer necessary






Soni NJ, et al. J Hosp Med. 2013 Sep;8(9):530-40.

Procalcitonin (PCT)
Elevated in the presence of a bacterial infection
PCT levels are detectable within 2-4 hours and peak within 6-24
hours
Higher levels correlate with a more severe infection
Normal value: < 0.05 ng/mL
Levels start decreasing steadily by ~50% daily during infection
resolution
False-Positive False-Negative
Newborns
Acute respiratory distress syndrome
Trauma
Surgery
Systemic fungal infections
Monoclonal or polyclonal anti-thymocyte globulin

Localized infections
Early course of infection
Subacute endocarditis
Becker KL. J Clin Endocrinol Metab 2004, 89:1512-1525.
Christ-crain M, et al. Swiss Med Wkly. 2005;135(31-32):451-60.
PCT Guided Therapy In ICU
Patients With Sepsis or Septic Shock
Systematic review and meta-analysis
Seven randomized clinical trials performed in Europe
Included a total of 1,075 patients

Comparator: standard of care for sepsis and septic shock

Primary outcome
Hospital mortality and 28-day mortality

Secondary outcomes
Duration of antimicrobial therapy
Length of stay (LOS) in the intensive care unit (ICU) and hospital
Prkno A, et al. Crit Care. 2013 Dec 11;17(6):R291.
PCT Guided Therapy In ICU
Patients With Sepsis or Septic Shock



Outcome Hazard Ratio/Relative Risk
Confidence
Interval
Random-effects model Fixed-effects model
Hospital Mortality 0.91 0.91 [0.60; 1.36]
28-day mortality 1.02 1.02 [0.85; 1.23]
Duration of therapy 1.27 1.27 [1.01; 1.53]
ICU length of stay 1.05 0.93 [0.82; 1.29]
Hospital length of
stay
1.03 1.00 [0.82; 1.24]
Prkno A, et al. Crit Care. 2013 Dec 11;17(6):R291.
PCT Guided Therapy In ICU
Patients With Sepsis or Septic Shock
Limitations
Different PCT algorithms were used between studies

Exclusion criteria of included trials may not represent a general ICU
population
Immunocompromised patients
Infections that require long term therapy
Endocarditis, osteomyelitis, tuberculosis, Pseudomonas aeruginosa,
Acinetobacter baumannii

Patients were in different settings
Medical ICU versus surgical ICU

Standard of therapy group had higher mean Sequential Organ Failure
Assessment (SOFA) scores
Prkno A, et al. Crit Care. 2013 Dec 11;17(6):R291.
PCT Guided Therapy In ICU
Patients With Sepsis and/or Pneumonia
Single center observational case-control study
Included 100 patients with pneumonia, sepsis, or both
Enrolled between September 2012 to January 2013
Mostly patients with pneumonia (74/100)


Comparator: historical control group
Enrolled between January 2011 and December 2011




Bishop BM, et al. Ann Pharmacother. 2014 May;48(5):577-83.

PCT Guided Therapy In ICU
Patients With Sepsis and/or Pneumonia
Primary outcome
Duration of antimicrobial therapy


Secondary outcomes
Length of stay in the hospital and ICU
Readmission to the ICU during index admission
30-day readmission for any reason
30-day mortality
Relapse of infection
30-day incidence of Clostridium difficle infection
Positive culture result data

Bishop BM, et al. Ann Pharmacother. 2014 May;48(5):577-83.

PCT Guided Therapy In ICU
Patients With Sepsis and/or Pneumonia
Outcome PCT (n=50) Control (n=50) P value
Duration of initial
antimicrobial therapy (days)
10.0 (4.9) 13.3(7.2) 0.0238
LOS in Hospital (days) 13.5 (6.6) 17.8 (11) 0.0299
30-day readmission for
infection to hospital
6 (12%) 11 (22%) 0.0010
Positive culture 29 (58%) 38 (76%) 0.0440
Relapse of infection 3 (6%) 11 (22%) 0.0200
Bishop BM, et al. Ann Pharmacother. 2014 May;48(5):577-83.

PCT Guided Therapy In ICU
Patients With Sepsis and/or Pneumonia
Limitations
Single center observational study may have potential for prescribing
bias

Historical control group
Significantly more positive cultures

Included trauma and renal failure patients

Exclusion criteria
Immunosuppressed patients
Infections with long duration of therapy
Acute Physiology and Chronic Health Evaluation II score >25





Bishop BM, et al. Ann Pharmacother. 2014 May;48(5):577-83.

PCT Guided Therapy In Febrile Patients In the ED
Randomized controlled trial
Performed in the Netherlands between May 2010 and March 2012

First study to assess PCT guided antimicrobial therapy in febrile adult
patients in the emergency department (ED)

Patient population: 107 patients
Randomized into two groups
PCT guided antimicrobial therapy and standard of care


Study Aim
Reduce unnecessary prescribed antimicrobials by using a PCT guided
algorithm


Limper M, et al. J Infect. 2014

PCT Guided Therapy In Febrile Patients In the ED









Multivariate logistic regression analysis showed a trend toward a
lower rate of antibiotic use in the PCT guided group

Outcome PCT Control P value
Antibiotics prescribed 80% 92% 0.08
ICU admittance 24% 8% 0.03
Mean length of hospital stay (days) 8 8 -
Mortality 0 2 0.12
Limper M, et al. J Infect. 2014

Outcome Odds Ratio 95% Confidence Interval
Number of patients who
received antibiotics
0.47 [0.13; 1.66]
PCT Guided Therapy In Febrile Patients In the ED
Limitations
Small sample size
Protocol adherence


Strengths
Randomized clinical trial
Inclusion criteria
Fever irrelevant of underlying cause
Patient population had varied diagnoses


Limper M, et al. J Infect. 2014

Future Research Needs
Larger, multi-centered, prospective clinical trials
o Previous studies have exclusion criteria that makes it difficult to
extrapolate results to general ICU populations
o Need to use a standardized comparator and PCT algorithm

Unstudied patient populations
o Immunocompromised and pregnant patients
o Certain infections

Assessment of cost-effectiveness in the ICU or ED setting

Antibiotic stewardship programs compared with and without PCT
guided therapy




Soni NJ, et al. J Hosp Med. 2013 Sep;8(9):530-40.

Discussion Questions
At your institution, you are given the task to decide whether to
implement a PCT guided antimicrobial therapy protocol or not.
Would you implement it? Why or why not?
Which patient populations? Setting?
What type of protocol would you use?
Escalation
Discontinuation
Combination of both



Key Points
PCT guided therapy results in a decreased duration of antibiotic
therapy without an increase in mortality
However, these studies excluded important patient populations that
represent an ICU population

PCT guided therapy should be used in conjunction with clinical
judgment

A consensus still needs to be made for the best PCT algorithm
and for which patient populations to use it in. An algorithm
focused on discontinuing antimicrobials appears to be the best
option












Soni NJ, et al. J Hosp Med. 2013 Sep;8(9):530-40.

References

Soni NJ, Samson DJ, Galaydick JL, et al. Procalcitonin-guided antibiotic therapy: a
systematic review and meta-analysis. J Hosp Med. 2013 Sep;8(9):530-40.
Becker KL: Procalcitonin and the Calcitonin Gene Family of Peptides in
Inflammation, Infection, and Sepsis: A Journey from Calcitonin Back to Its
Precursors. J Clin Endocrinol Metab 2004, 89:1512-1525.
Christ-crain M, Mller B. Procalcitonin in bacterial infections--hype, hope, more or
less?. Swiss Med Wkly. 2005;135(31-32):451-60.
Prkno A, Wacker C, Brunkhorst FM, Schlattmann P. Procalcitonin-guided therapy in
intensive care unit patients with severe sepsis and septic shock - a systematic
review and meta-analysis. Crit Care. 2013 Dec 11;17(6):R291.
Bishop BM, Bon JJ, Trienski TL, Pasquale TR, Martin BR, File TM. Effect of
introducing procalcitonin on antimicrobial therapy duration in patients with sepsis
and/or pneumonia in the intensive care unit. Ann Pharmacother. 2014
May;48(5):577-83.
Limper M, Van der does Y, Brandjes DP, De kruif MD, Rood PP, Van gorp EC.
Procalcitonin guided antibiotic therapy in patients presenting with fever in the
emergency department. J Infect. 2014