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Should

we go All In with Procalcitonin?


Examining the Utility of the New Biomarker


http://www.amctv.com/shows/breaking-bad/


Residency Rounds
Justin Gonzalez, PharmD
PGY1 Pharmacy Resident
Department of Pharmacy, North Austin Medical Center, Austin, TX
The University of Texas at Austin College of Pharmacy

November 1, 2013










Learning Objectives:

1. Describe the implications of inappropriate antibiotic use
2. Discuss procalcitonin, sepsis, and ventilator associated pneumonia
3. Interpret the literature examining the use of procalcitonin in clinical practice
4. Recommend a strategy for procalcitonins utility in guiding antibiotic therapy

I. Inappropriate Antibiotic Use and its Implications 1-3
a. Up to 50% of all antibiotics (abx) prescribed for people are not needed or are not optimally
effective as prescribed
i. Acute bronchitis (usually viral) antibiotics prescribed 80% of the time
ii. Length of treatment for some infections has been poorly studied and it is likely that
treatment durations are inappropriately long
b. Implications
i. Adverse events due to antibiotics
1. Estimated 142,505 emergency department visits annually
ii. Multi-drug resistant organisms (Appendix A)
1. Methicillin Resistant Staph Aureus (MRSA), S. pneumoniae, Extended
Spectrum -Lactamases (ESBLs), Vancomycin-resistant Enterococcus (VRE),
Carbapenem-resistant Enterobacteriaceae (CRE), etc.
2. Annual cases 2,049,442
3. Annual deaths 23,488
iii. Clostridium difficile infections
1. Annual cases 250,000
2. Annual deaths 14,000
iv. Cost
1. Estimated $20 billion a year in excess direct healthcare cost
2. Estimated $35 billion a year (2008 dollars)
c. Four Core Actions to Prevent Antibiotic Resistance as Recommended by CDC
i. Preventing infections and preventing spread of resistance
ii. Tracking resistant bacteria
iii. Improving antibiotic stewardship
iv. Promoting the development of new antibiotics
d. Challenges of curbing antibiotic use
i. Patient expectations
ii. Differentiating a true infection from an inflammatory non-infectious cause
iii. Differentiating bacterial vs viral infective sources
iv. Physician hesitation to discontinue antibiotics earlier than guideline
recommendations, especially in critically ill patients

II. Procalcitonin 3-8
a. What is procalcitonin (PCT)?
i. A 116 amino acid polypeptide precursor to the calcium regulatory hormone
calcitonin
ii. Synthesis regulated by the Calc-1 gene located on chromosome 11
1. Stimulus for gene transcription and subsequent PCT secretion
a. Directly microbial toxins
b. Indirectly pro-inflammatory cytokines [interleukin (IL)-1, IL-6, and
tumor necrosis factor- (TNF-)]
2. Induction attenuation
a. Interferon- cytokine released during a viral infection
iii. Production
1. Healthy individuals- restricted to neuroendocrine thyroid C-cells
a. Concentration <0.05 mcg/L
2. Infection- ubiquitously from extra-thyroidal tissues throughout the body
(liver, kidney, pancreas, adipose, and white blood cells)
a. Concentration up to 1000 mcg/L
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b. Levels correlate with severity of bacterial infection (Figure 1)


Figure 1: Procalcitonin levels associated with degree of bacterial infection7

iv. Kinetics
1. Detectable in the blood within 2-4 hrs and peaks within 6-24 hrs
2. Half life of 25-30hrs
v. Other factors that affect PCT levels
1. Significant elevations
a. Neonates (aged less than 48hrs)
b. First day(s) after a major trauma/surgery, severe burns/heat stroke,
treatment w/ mono/polyclonal antibodies
c. Patients w/ prolonged or severe cardiogenic shock and prolonged
severe organ perfusion abnormalities
d. Patients w/ small-cell lung cancer and/or medullary C-cell carcinoma
of the thyroid
e. Patients w/ acute malaria and certain types of invasive fungal
infections
2. Levels remain low during:
a. Early course of infections
b. Localized infections
c. Subacute endocarditis
3. Levels are NOT attenuated by NSAIDS or steroids (unlike CRP)
vi. Assays
1. Older LUMI test, Brahms Diagnostics (Berlin, Germany)
a. Detection limit 0.5 mcg/L
b. Not approved for clinical use
2. Newer Kryptor, Brahms Diagnostics (Berlin, Germany)
a. Detection limit 0.06 mcg/L








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Table 1: Comparison of procalcitonin and C-reactive protein 7,8
Procalcitonin (PCT) C-Reactive Protein (CRP)
Normal physiologic levels < 0.05 mcg/L < 10 mg/L
Type of infection that cause levels Bacterial All types
to significantly increase
Detectable within 2-4 hrs 12-24 hrs
Peaks 6-24 hrs 48 hrs
Time it takes for levels to fall once 24hr (50% reduction per day) 3-7 days
infection has been controlled

III. Sepsis9,10
a. American College of Chest Physicians (ACCP)/Society of Critical Care Medicine (SCCM)
Definitions
i. Systemic inflammatory response syndrome (SIRS) a clinical response arising from
a nonspecific insult manifested by 2 of the following:
1. Temp 38C (100.4F) or 36C (96.8F)
2. HR 90 beats/min
3. Respirations 20/min or PaCO2< 32mmHg
4. WBC count 12K/mL or 4K/mL or >10% bands
ii. Sepsis- 2 SIRS criteria + suspected or proven infection
iii. Severe sepsis- sepsis + organ dysfunction, sepsis induced tissue hypoperfusion or
organ dysfunction
iv. Septic shock- severe sepsis with persistent hypotension despite adequate fluid
resuscitation
b. Microbiology
i. Gram (+) most common
1. S. aureus, S. pneumoniae, Coagulase (-) Staph, Enterococcus, Group A Strep
Viridans
ii. Gram (-) common, higher mortality
1. E. coli, P. aeruginosa, Klebsiella, Serratia, Proteus, and Enterobacter
iii. Fungal on the rise
1. Candida albicans > non-albicans Candida >> other fungi
iv. Other less common
1. Viruses, anaerobes
c. Most Common Infection Sources of Sepsis
i. Respiratory
ii. Intra-abdominal
iii. Urinary tract
iv. Bloodstream infections (catheter-related)
d. Society Critical Care Medicine Surviving Sepsis Campaign 2012:
Antibiotic Recommendations
i. Use of low procalcitonin or similar biomarkers to assist the clinician in the
discontinuation of empiric abx in patients who initially appeared infected but has no
subsequent evidence of infection (grade 2C)
ii. Empiric antibiotic should not be administered for more than 3-5 days. De-escalation
to the most appropriate single therapy should be performed as soon as
susceptibilities are known (grade 2B)
iii. Duration of therapy typically 7-10 days; longer courses for pt. with a slow clinical
response, undrainable foci of infection, bacteremia with S. aureus; some fungal and
viral infections or immunologic deficiencies, including neutropenia (grade 2C).
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e. Potential uses of procalcitonin in sepsis
i. Diagnosis
1. Difficult due to nonspecific signs and symptoms that often overlap with other
non-infectious causes of systemic inflammation
ii. Prognosis
1. Trending of levels has shown correlation with severity and mortality
iii. Decreasing duration of antibiotic therapy
1. Physician hesitation to discontinue antibiotics due to fragile state of patient

IV. Ventilator Associated Pneumonia (VAP)12,13
a. Clinical Diagnosis [American Thoracic Society (ATS)]
i. After 48hrs of intubation New or persistent infiltrate on chest radiography
associated with at least two of the following:
1. Purulent tracheal secretions
2. Temp >38C
3. Leukocyte count >11,000mcL or <3,000mcL
ii. Clinical pulmonary infection score (CPIS) [Appendix B]
1. Used to increase sensitivity and specificity of VAP diagnostic criteria
b. Microbiology
i. Early-Onset VAP (4 days)
1. S. pneumoniae, H. influenzae, MSSA, Enterobacteriaceae (E.coli, Klebsiella,
Enterobacter spp.)
ii. Late-Onset VAP (5 days) +/- MDR Risk Factors
1. Early-onset pathogens + MDR pathogens
a. P. aeruginosa, Klebsiella (ESBL+), Acinetobacter spp., MRSA
c. ATS Guidelines Antibiotic Duration Recommendation
i. If patients receive an initially appropriate antibiotic regimen, efforts should be made
to shorten the duration of therapy from the traditional 14 to 21 days to periods as
short as 7 days, provided that the etiologic pathogen is not P. aeruginosa, and that
the patient has a good clinical response with resolution of clinical features of
infection (Level I)
ii. Procalcitonin not mentioned
d. Potential uses of procalcitonin in VAP
i. Diagnosis
1. No gold standard, optimal approach remains to be defined
ii. Decreasing duration of antibiotic therapy
1. ProVAP study15













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V. Literature Evaluation 14-19
a. Four studies examining procalcitonins utility in the intensive care unit (ICU) setting and 1
meta-analysis
i. Nobre et al. 2008 (ProSEP) trial duration of antibiotic therapy in 79 patients w/
sepsis and septic shock
ii. Hochreiter et al. 2009 (ProSICU) duration of antibiotic therapy in 110 surgical
ICU patients
iii. Stolz et al. 2009 (ProVAP) duration of antibiotic therapy in 101 patients w/
ventilator associated pneumonia (VAP)
iv. Bouadma et al. 2010 (ProRATA) initiation and cessation of antibiotics in a mixed
medical/surgical cohort of 630 patients
v. Heyland et al. 2011 meta-analysis, aggregated results of all 4 trials plus one small
separate trial (Schroeder et al. [n=27]); includes an economic evaluation

Appendix C offers explanations of the intensive care unit (ICU) assessment scores used in these trials
- Simplified Acute Physiology Score (SAPS)
- Sepsis-related Organ Failure Assessment (SOFA) Score
- Organ Dysfunction and/or Infection (ODIN) Score

Table 3: Nobre et al. Use of procalcitonin to shorten antibiotic treatment duration in septic patients (ProSEP trial): a
randomized trial. Am J Respir Crit Care Med. 2008;177(5):498-505.
Objective To test if an algorithm based on serial measurements of procalcitonin (PCT) allows reduction in the duration of
antibiotic therapy compared with empirical rules, and does not result in more adverse outcomes in patients
with severe sepsis and septic shock.
Design Single center, randomized, controlled, open interventional trial
Inclusion Patients w/ suspected severe sepsis or septic shock admitted to the ICU
Exclusion Microbiologically documented infections caused by Pseudomonas aeruginosa, Acinetobacter baumanni,
Listeria spp., Legionella pneumophila, Pneumocystitis jiroveci, or Mycobacterium tuberculosis
Severe infections due to viruses or parasites (e.g. hemorrhagic fever, malaria)
Infectious conditions requiring prolonged antibiotic therapy (e.g. bacterial endocarditis, brain abscess,
deep abscesses)
Antibiotic therapy started 48hrs or more before enrollment
Chronic, localized infections (e.g. chronic osteomyelitis)
Severely immunocompromised patients (e.g. HIV pt. CD4<200, neutropenic patients, and patients on
immunosuppressive therapy after solid organ transplant)
Withholding of life support
Absence of antimicrobial treatment despite clinical suspicion of sepsis
Methods/ Randomization performed by computer-based random number generation
Intervention All patients received abx therapy according to guidelines and susceptibility patterns, according to the
treating physician who was unaware of the patients initial PCT levels
Patients w/ positive blood cultures received at least 5 full days of abx therapy
PCT group (PCT daily for 7 days, then at 5 day intervals) used predefined stopping rules based on
circulating PCT levels
o Baseline PCT 1 mcg/L reevaluated at day 5; discontinue abx when:
PCT dropped more than 90% from baseline peak level
Absolute value <0.25 mcg/L
o Baseline PCT 1 mcg/L reevaluated at day 3; discontinue abx when:
PCT < 0.1 mcg/L, and clinical evaluation rules out severe infection
Control
o Treated according to standard practice
Final decision concerning duration of antibiotic therapy was left to the discretion of the physician in charge

Outcomes Primary duration of antibiotics
Secondary Clinical cure, 28-day mortality, in-hospital mortality, sepsis-related death, primary infection
relapse rate, length of stay (LOS) in the ICU and hospital

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Statistics Intention to treat (ITT) analysis for primary endpoints
Power analysis needed 66 patients to meet 90% power to detect a 33% (4 day) difference in duration of
antibiotic therapy
Comparability of the two groups was analyzed by the 2 test, two-sample t test, and Mann-Whitney U test
Cox proportional hazards regression analysis used to estimate the rate of abx treatment discontinuation
Results Randomized 39 to PCT group and 40 to control group
Excluded 72%
Similar demographic, clinical, and laboratory baseline characteristics
o Sepsis of pulmonary origin predominated both groups (68% control, 71% PCT [p=0.96])
o Septic shock (42% control, 43.6% PCT group [p=0.89])
o Mechanical ventilation (81% control, 84% PCT group [p=0.50])
o Vasopressors (62% control, 52% PCT group [p=0.52])
o Positive blood culture (30% control, 36% PCT group [p=0.80])
o Baseline PCT level mcg/L, median (5.4 control, 7.3 PCT group [p=0.76])
Algorithm overruling by physicians occurred w/ 19% of the patients in PCT group
Outcomes Control PCT Group RR or Mean P Value
Group (n=39) Difference (95%)
(n=40)
Primary outcomes
ITT, Duration of abx 9.5 (2-33) 6 (3-34) Mean difference: NS
therapy, median days 2.6 (-0.3 to 5.5)
(range)
ITT, Total abx exposure 644 541 1.1 (0.9 to 1.3) NS
days/1000
Per Protocol, Duration of 10 (3-33) 6 (4-16) Mean difference: 0.003
abx therapy, median days [n=37] [n=31] 3.2 (1.1 to 5.4)
(range)
Secondary Outcomes
No statistically significant difference between groups for any secondary outcome, except for
ICU length of stay, median 7 (1-91) 4 (1-21) Mean difference: 0.02

days (range) 4.6 (1.0 to 8.2)
Authors Observed a significant reduction in antibiotic use, without apparent harm in patients with severe sepsis
Conclusions and septic shock when PCT algorithm was followed
These patients also happened to have a shorter ICU stay
Strengths ITT analysis used for primary outcomes
Attrition described
Compliance to PCT algorithm stated
Weaknesses Single center
Small study
Algorithm overruled in 19% of PCT group
High exclusion rate [72%] (difficult to treat microorganisms, chronic localized infections, severely
immunocompromised, and neutropenic patients)














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Table 4: Hochreiter M, Kohler T, Schweiger AM, et al. Procalcitonin to guide duration of antibiotic therapy in intensive care
patients (ProSICU): a randomized prospective controlled trial. Crit Care 2009;13:R83.
Objective To investigate the clinical usefulness of PCT for guiding antibiotic therapy in surgical intensive care patients.
Design Single center, randomized prospective controlled, open label trial
Inclusion All patients admitted to the surgical intensive care unit (SICU) requiring antibiotic therapy based on
confirmed or highly suspected bacterial infections and at least two concomitant SIRS criteria
Exclusion Refused consent
Antibiotic treatment initiated before intensive care admission
Had therapy limitations (did not specify)
Methods/ Randomization method not defined
Interventions PCT group (assay measured daily)
o Antibiotic therapy was discontinued if:
Clinical signs and symptoms of infection improved AND
PCT decreased to < 1 mcg/L OR
Initial PCT value was > 1 mcg/L, but had dropped to 25-35% of the initial value over
three days
Control group
o Antibiotic treatment was applied as standard regimen over eight days
Irrespective of study group and at any time point, the physician in charge had the option to proceed
with or adjust the abx treatment
Outcomes Primary - duration of antibiotics
Secondary - intensive care days, mortality
Statistics Mann-Whitney-Wilcoxon U test for comparative statistics
Chi-squared test for comparison of proportions (gender, diagnosis, antibiotic substance classes,
survival/death)
Results Randomized 57 to PCT group and 53 to control group
Exclusion rate 72%
Both groups were comparable in terms of age, gender distribution, diagnoses, disease severity, and
outcome
o Peritonitis 54%
o Pneumonia 39%
Outcomes PCT Group Control Group P Value
(n=57) (n=53)
Primary Outcomes
Length of abx therapy 5.9 (+/- 1.7) 7.9 (+/- 0.5) <0.001
(days)
Secondary Outcomes
Intensive care (days) 15.5 (+/- 12.5) 17.7 (+/- 10.1) 0.046

Deceased 14 (25%) 15 (28%) NS
Authors Procalcitonin assessment is a helpful tool to decide on the duration of antibiotic treatment in surgical
Conclusions ICU patients.
Also had a favorable effect on the length of the intensive care stay.
This may contribute to an optimized antibiotic regimen with beneficial effects on microbial resistance
and costs in intensive care medicine.
Strengths Did not exclude immunosuppressed or difficult to treat microorganisms
Encouraged 8 day antibiotic therapy in control group
Weaknesses Small study
Used less sensitive LUMI test assay
High exclusion rate
Type of surgery performed not reported
Randomization method not described
Attrition not reported
Did not report if any patients were immunosuppressed
Did not report microorganism culture data
Adherence to PCT guidance not reported
Obscure exclusion criteria had therapy limitations


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Table 5: Stolz D, Smyrnios N, Eggimann P, et al. Procalcitonin for reduced antibiotic exposure in ventilator-associated
pneumonia (ProVAP): a randomized study. Eur Respir J. 2009;34:1364-1375.
Objective To determine if procalcitonin serum evaluation reduces antibiotic exposure in patients with clinically
diagnosed ventilator-associated pneumonia (VAP) with a similar clinical and laboratory outcome.
Design Multinational, randomized, controlled open interventional trial
Inclusion Patients intubated for mechanical ventilation for 48hrs if they:
o >18yrs
o Clinically diagnosed VAP (American Thoracic Society criteria)
Exclusion Pregnant
Enrolled in another trial
Received immunosuppressants or corticosteroid therapy (0.5 mg/kg/day for > 1 month)
Were severely immunosuppressed (including AIDS)
Coexisting extrapulmonary infection diagnosed between day 1 and 3 requiring abx therapy for >3 days
Methods/ Randomization through arbitrary allocation to one of the groups based on sealed envelopes
Interventions In both groups, physician was unaware of PCT levels on initiation
Educational sessions provided to physicians emphasizing current standard antibiotic de-escalation
strategy according to American Thoracic Society guidelines
PCT group (after 72hr)
o Daily procalcitonin levels were notified to the physicians for 10 days
o Level < 0.25 mcg/L discontinuation of antibiotics strongly encouraged
o Level 0.25-0.5 mcg/L or a decrease of 80% compared with day 0 discontinuation of
antibiotics encouraged
o Level 0.5 mcg/L or decrease by <80% compared with day 0 discontinuation of antibiotics
discouraged
o Level >1 mcg/L discontinuation of antibiotics strongly discouraged
Control group
o Standard antibiotic duration w/ an emphasis on ATS guideline recommendations
Irrespective of study group and at any time point, the physician in charge had the option to proceed
with or adjust the abx treatment
Outcomes Primary - Number of antibiotic-free days alive assessed 28 days after enrollment in the study
Secondary - Number of mechanical ventilation-free days, the number of ICU-free days, the evolution of
disease severity scores, length of hospital stay, the VAP-related clinical deterioration rate, and overall
mortality at 28 days
Statistics Power analysis: 84 patients (42 per group) needed to detect a significant difference in antibiotic-free
days alive between groups with a power of 90% and error of 0.05 using a two-tailed test
Intention to treat analysis
Categorical variables Chi-squared or Fishers exact test
Continuous variables Non-parametric Mann-Whitney U-test or unpaired t-test
Cumulative events curves Kaplan-Meier
Time to discontinuation of abx Log-rank test
Occurrence of events on day 28 Cox proportional hazards regression analysis
Results 101 patients randomized, PCT= 50, Control=51
Exclusion rate of 38%
Clinical characteristics similar between groups except for ODIN score, which was slightly higher for the
control group (p=0.042)
Algorithm overruling in 16% of PCT group
Appropriate initial empiric antibiotic therapy in 86% of cases (no differences between groups)


Outcomes PCT Group Control Group P Value
(n=51) (n=50)
Primary Outcomes
Antibiotic-free days alive (range) 13 (2-21) 9.5 (1.5-17) 0.049
Antibiotic duration days (range) 10 (6-16) 15 (10-23) 0.038
Antibiotic duration in pt w/ 7 (0-13.5) 14 (1-21) 0.017
microbiologically diagnosed VAP
Secondary Outcomes

No statistically significant difference between groups for any secondary outcome

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Authors We observed a benefit of incorporating procalcitonin into the antibiotic reduction strategy suggested by
Conclusions current ATS/IDSA guidelines.
The absence of differences in secondary outcomes suggests procalcitonin-guided antibiotic reduction is
not associated with a worse outcome in VAP.
Serum procalcitonin reduces antibiotic exposure in critically ill patients treated for VAP.
Strengths Similar baseline characteristics (including taking into account causative microorganisms)
No attrition
Met 90% power to detect a significant difference between the groups for the primary outcome
Measured and took into account appropriate empiric antibiotics between groups
Weaknesses Small study
Focused only on critically ill VAP patients
Excluded immunocompromised patients and patients on large amounts of corticosteroids
Algorithm overruling in 16%
High rate of exclusion (38%)






































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Table 6: Bouadma L, Luyt CE, Tubach F, et al. Use of procalcitonin to reduce patients exposure to antibiotics in intensive care
units (ProRATA trial): a multicenter randomized controlled trial. Lancet. 2010;375(9713):463-474.
Objective To establish the effectiveness of an algorithm based on the biomarker procalcitonin to reduce antibiotic
exposure in intensive care units.
Design Multicenter, randomized prospective, parallel-group, open-label trial
Setting - eight ICUs at university-affiliated hospitals in France (five medical, three surgical)
Inclusion Admitted to the ICU with suspected infections
Not receiving antibiotics before inclusion
Patients who developed sepsis during their ICU stay
Exclusion Under 18 years of age
Known pregnancy
Expected stay in ICU of < 3 days
Bone-marrow transplant or chemotherapy-induced neutropenia (<500 neutrophils/mL)
Infections for which long-term antibiotic treatment is recommended (i.e. infective endocarditis,
osteoarticular infections, anterior mediastinitis after cardiac surgery, hepatic or cerebral abscesses,
chronic prostatitis, or infection with Mycobacterium tuberculosis, Pneumocystis jirovecii, or Toxoplasma
gondii), poor chance of survival (SAPS II score of more than 65 points), do not resuscitate (DNR) orders
Methods/ Computer generated randomization
Interventions PCT group (blood samples at inclusion, at each infectious episode until day 28, every day while on abx)
o Guidelines for starting antibiotics*
Conc. <0.25 mcg/L abx strongly discouraged
Conc. 0.25 and <0.5 mcg/L abx discouraged
Conc. 0.5 and <1 mcg/L abx encouraged
Conc. 1 mcg/L abx strongly encouraged
o Guidelines for continuing or stopping of antibiotics
Conc. <0.25 mcg/L stopping abx strongly encouraged
Decrease by 80% from peak conc. or conc. 0.25 and <0.5 mcg/L stopping abx
encouraged
Decrease by <80% from peak conc., and conc. 0.5 mcg/L continuing of abx
encouraged
Increase of conc. compared w/ peak conc. and conc. 0.5 mcg/L changing of abx
strongly encouraged
o Final decision was at the discretion of the patients physician
Control group
o Antibiotics given for standard duration
*Excludes situations requiring immediate abx treatment (e.g. septic shock, purulent meningitis)
Outcomes Primary
o Death from any cause by days 28 and 60 (non-inferiority)
o Number of days without antibiotics at 28 days after inclusion
Secondary percentage of patients with relapse or superinfection, number of days without mechanical
ventilation, Sepsis related organ failure assessment (SOFA) score, length of stay in the ICU and hospital,
days of antibiotic exposure per 1000 inpatient days
Statistics Power analysis: 133 patients per group to detect a 3 day increase in days without antibiotics w/ 90%
power, p<0.05 (assumed mean 12 days without antibiotics)
Non-inferiority mortality comparison: 300 patients per group to exclude a 10% difference in mortality
w/ 80% power
Comparisons chi squared, students t test, Kaplan Meier
Results Randomized 307 to PCT group and 314 to control group (52% rate of exclusion)
Similar demographic, clinical, and laboratory baseline characteristics
Medical admission 90% PCT group, 89% control group
Surgical admission 10% PCT group, 11% control group
Infection site
o Pulmonary PCT- 71%, Control- 74%
o Urinary tract PCT- 9%, Control- 6%
o Skin and soft tissue PCT- 2%, Control- 2%
o Intra-abdominal PCT- 5%, Control- 7%
o CNS PCT- 3%, Control- 2%
o Catheter related PCT- 2%, Control- 1%
o Primary blood stream PCT 3%, Control- 4%
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Non-adherence to algorithm 53% PCT group
For initiation of abx 93 (30%) had initial PCT levels <0.5 mcg/L (the cutoff point for discouraging
antimicrobial initiation) Antibiotics only withheld for 28 pts. (9%)
Outcomes PCT Group Control Group Between group P Value
(n=307) (n=314) absolute difference
Primary Outcomes
28-day mortality* 65 (21.2%) 64 (20.4%) 0.8% (-4.6 to 6.2) NA
60-day mortality* 92 (30%) 82 (26.1%) 3.8% (-2.1 to 9.7) NA
Number of days without 14.3 (9.1) 11.6 (8.2) 2.7 (1.4 to 4.1) <0.0001
antibiotics
Secondary Outcomes
No differences between groups for any of the safety parameters
Duration of antibiotics 6.1 (6.0) 9.9 (7.1) -3.8 (-4.8 to -2.7) <0.0001
(days [SD])
Data are number (%), difference (95% CI), or mean (SD).
*Non-inferiority outcomes - Difference (90% CI)
Authors Procalcitonin guided antibiotic therapy substantially lowers antibiotic exposure and is non-inferior to
Conclusion standard care with respect to outcomes
Strengths Largest RCT to date
Powered to compare mortality differences
Intention to treat analysis
Did not exclude immunocompromised (except for bone marrow transplant and neutropenic pts.)
Explored using PCT for starting antibiotic therapy as well
Weaknesses Surgical patients represented only 10% of the study population
Excluded difficult to treat microorganisms and neutropenic patients
Algorithm overruled in 53% of patients in PCT group




























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Table 7: Heyland DK, Johnson AP, Reynolds SC, et al. Procalcitonin for reduced antibiotic exposure in the critical care setting: A
systematic review and an economic evaluation. Crit Care Med. 2011;(9)37:1792-1799.
Objective To evaluate the effect of a procalcitonin-guided antibiotic strategy on clinical and economic outcomes.
Design Included randomized controlled trials conducted in the ICU that compared procalcitonin-guided
strategy to usual care and reported on antibiotic utilization and clinically important outcomes.
Results were qualitatively and quantitatively summarized.
On the basis of no effect in hospital mortality or hospital length of stay, a cost minimization analysis was
conducted using the costs of procalcitonin testing and antibiotic administration and acquisition. Costs
were determined from the literature and are reported in 2009 Canadian dollars.
Five articles met the inclusion criteria
o Nobre et al. (2008)
o Hochreiter et al. (2009)
o Schroeder et al. (2009)
o Stolz et al. (2009)
o Bouadma et al. (2010)
Aggregated Effect on Antibiotic Duration
Results o Weighted mean difference -2.14 (95% CI, -2.51 to -1.78) [p<0.00001]
Mortality
o No effect was seen of a PCT guided strategy on hospital mortality (risk ratio 1.06, 95% CI
0.86-1.30, p=0.59; risk difference 0.01, 95% CI -0.04 to +0.07, p=0.61)
Length of stay (LOS)
o No overall effect seen in ICU or hospital LOS
ICU LOS weighted mean difference -1.5 (95% CI -4.5 to +1.05, p=0.25)
Hospital LOS weighted mean difference -1.86 (95% CI -4.75 to +1.04, p=0.21)
Recurrent infections
o No evidence of an increase for the PCT guided strategy
Risk ratio 1.26 (95% CI 0.68-2.35. p=0.46)
Cost analysis
o Using average antibiotic costs, assuming PCT assay price of $49, and 2 days less of abx therapy
Cost savings of $470 per patient episode in comparison to usual care
o Using more expensive antibiotic costs Cost savings of $1134 per patient episode
Authors PCT-guided therapy is associated with approximately 2 days of reduction in antibiotic usage
Conclusions o Reduction due to early discontinuation of antibiotics rather than less initiation of empirical
antibiotics
No difference in hospital mortality
o Cannot exclude a 7% risk increase (or smaller) in hospital mortality
The magnitude of cost savings associated with PCT measurements will be a function of the costs of
antibiotics commonly used, their duration, the frequency of use and the cost of the PCT assays.
Strengths Approximately 1000 patients have been studied in these five randomized controlled trials
Only looked at randomized controlled trials
Adjusted for methodologic quality of the studies
Included an economic analysis
Weaknesses Approximately 75% of studied patients had a medical, compared to surgical admission
Compliance to algorithm varied between studies, physician non-compliance was >50% in two of the
studies
All studies used different arbitrarily derived PCT cut off values
Meta-analysis dominated by one large trial (Bouadma n=621)







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Table 8: Summary of randomized controlled trials of procalcitonin use in the ICU
Studies Population/Exclusions/ Infection PCT Algorithm Antibiotic
(n) Algorithm Overruling Exposure
Nobre et - Sepsis and septic shock 69% pneumonia -Baseline PCT 1 mcg/L reevaluated at 37% in
al. - 24% surgical day 5; discontinue abx when: abx
(ProSEP) - Excluded difficult to treat -PCT dropped by 90% from baseline exposure
(79) organisms, -Absolute value <0.25 mcg/L
immunosuppressed, and Baseline PCT 1 mcg/L reevaluated at
neutropenic day 3; discontinue abx when:
- Exclusion rate 72% -PCT < 0.1 mcg/L, and clinical evaluation
-Algorithm overruling rules out severe infection
19%
Hochreiter - SICU patients w/ infection 54% peritonitis Discontinue abx when: 20% in
et al. and 2 SIRS criteria 39% pneumonia PCT decreased to < 1 mcg/L OR abx
(ProSICU) - 100% surgical If initial PCT value was > 1 mcg/L, but had exposure
(28) - Excluded pt. w/ therapy dropped to 25-35% of the initial value
limitations over three days
- Exclusion rate 72%
- Algorithm overruling not
reported
Stolz et al. - Mechanically ventilated 100% VAP - Level < 0.25 mcg/L discontinuation of 27% abx
(ProVAP) patients w/ ventilator antibiotics strongly encouraged free days
(101) associated pneumonia - Level 0.25-0.5 mcg/L or a decrease of
- 90% medical 80% compared with day 0
- Excluded discontinuation of antibiotics encouraged
immunosuppressed - Level 0.5 mcg/L or decrease by <80%
- Exclusion rate 38% compared with day 0 discontinuation
- Algorithm overruling of antibiotics discouraged
16% - Level >1 mcg/L discontinuation of
antibiotics strongly discouraged
Bouadma - ICU patients w/ suspected 63% pneumonia - Conc. <0.25 mcg/L stopping abx 33% in
et al. bacterial infection strongly encouraged abx
(ProRATA) - 90% medical - Decrease by 80% from peak conc. or exposure
(621) - 16% immuno- conc. 0.25 and <0.5 mcg/L stopping
compromised abx encouraged
- Excluded bone-marrow - Decrease by <80% from peak conc., and
transplant, chemo induced conc. 0.5 mcg/L continuing of abx
neutropenia, infx requiring encouraged
long term abx - Increase of conc. compared w/ peak
- Exclusion rate 52% conc. and conc. 0.5 mcg/L changing of
- Algorithm overruling abx strongly encouraged
53%


VI. Conclusions
a. In the ICU, in patients with sepsis predominantly of pulmonary origin and/or VAP,
procalcitonin-guided antimicrobial therapy has shown on average to reduce the duration of
antibiotic therapy by 2-3 days.
b. No statistically detectable adverse outcomes have been associated with the shorter
duration of antibiotics.
i. Only one study powered to detect this difference
ii. Heyland et al. meta-analysis cannot exclude a 7% risk increase in hospital mortality
c. Procalcitonin has shown to be most effective when serial level measurements are used as a
follow up tool to assist clinicians in deciding when it is most appropriate to discontinue
antibiotics on a patient-by-patient basis.
d. General limitations of the trials include high rate of patients exclusion, high rate of
algorithm overruling, and long duration of antibiotic therapy in the control group.

Gonzalez 14

VII. Recommendations for Procalcitonin Use in the ICU
a. For patients with sepsis of pulmonary origin and/or VAP
i. As a follow-up tool to assist clinicians decision of knowing when it is appropriate to
discontinue antibiotics
ii. Most robust data from Bouadma et al. cut off values
iii. Algorithm
1. If patient is not immunocompromised
2. If patient has not had surgery in the past 24hrs
3. If patient is not pregnant
4. If the patient is clinically improving
5. Discontinue antibiotics if procalcitonin level is <0.5 mcg/L or has dropped by
80% or more from baseline
iv. Factors to consider
1. Conditions that may keep PCT levels low
2. Conditions that may falsely elevate PCT levels
3. PCT value which is rising or not declining is a poor prognostic indicator and
suggests infection is not controlled, consider further diagnostic evaluation
v. When to order levels
1. At baseline when antibiotics are initiated
2. Once patient begins to improve clinically, every 1-2 days
b. NOT recommended for use in antibiotic initiation in the ICU
i. Two RCTs looking at this question show PCT based strategies for initiation are
relatively ineffective
1. Layios et al.29
a. No difference in proportion of pts. given antimicrobials (PCT group:
88% and Control: 87%) and of ICU days during which antimicrobials
were given (PCT group: 64% and Control: 60%)
b. Initial PCT level <0.25 mcg/mL in 28% of confirmed infections
c. Initial PCT level >1 mcg/mL in 29% of no confirmed infection
2. Bouadma et al.18
a. Ninety three (30%) had initial PCT levels <0.5 mcg/L (the cutoff point
for discouraging antimicrobial initiation) Abx only withheld for 28
pts. (9%)

VIII. Other potential areas of use for procalcitonin20-24
a. Non-ICU inpatient ProHOSP trial showed reduced antibiotic initiation and promoted early
antibiotic de-escalation in patients with respiratory tract infections (CAP, ECOPD, acute
bronchitis); relative reduction- 35% antibiotic duration, 12.2% prescription rates20
b. Emergency department and primary care settings for patients w/ upper and lower
respiratory tract infections, Briel et al. and Burkhardt et al. showed reduction in antibiotic
prescription rates by 72% and 42%, respectively22,23

IX. Gaps in Knowledge and Future Research Needs
a. Use in immunocompromised, neutropenic, and pediatric populations
b. Appropriate procalcitonin cutoff levels in different populations



Gonzalez 15
X. Study in pipeline25
a. Stop Antibiotics on guidance of Procalcitonin Study (SAPS): a randomized prospective
multicenter investigator-initiated trial to analyse whether daily measurements of
procalcitonin versus a standard-of-care approach can safely shorten antibiotic duration in
intensive care unit patients--calculated sample size: 1816 patients






















































Gonzalez 16
References:
1. Antibiotic Resistance: Threat Report 2013. Centers for Disease Control and Prevention. 16 Sept 2013. U.S. Department of
Health and Human Services. 27 Sept 2013. <http://www.cdc.gov/drugresistance/threat-report-2013/>
2. Wenzel RP, Fowler AA. Acute bronchitis. N Engl J Med 2006; 355:2125-2130.
3. Hayashi Y, Paterson DL. Strategies for reduction in duration of antibiotic use in hospitalized patients. Clin Infect Dis
2011;52:1232-40.
4. Schuetz P, Werner A, Christ-Crain M, et al. Procalcitonin for guidance of antibiotic therapy. Expert Rev Anti Infect Ther
2010;8:575-587.
5. McGee KA, Baumann NA. Procalcitonin Clinical Utility in Diagnosing Sepsis. Clinical Laboratory News. 2009;35(7).
6. Christ-Crain M, Muller B. Procalcitonin in bacterial infections hype, hope, more or less? Swiss Med Wkly 2005;135:451-460.
7. Brahms:Procalcitonin and Sepsis. 20 Sept 2013. Thermo Scientific. 2012<http://procalcitonin.com/>
8. Muller B, Becker K, Schachinger H, et al. Calcitonin precursors are reliable marker of sepsis in a medical intensive care unit.
Crit Care Med 2000;28(4):977-983.
9. Bone RC, Sibbald WJ, Sprung CL, et al. The ACCP-SCCM consensus conference on sepsis and organ failure. Chest
1992;101(6):1481.
10. Dellinger R, Levy M, Rhodes A, et al. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis
and Septic Shock: 2012. Crit Care Med 2013 Feb;41(2):580-637.
11. IDSA Guideline Committee. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and
healthcare-associated pneumonia. Am J Respir Crit Care Med 2005; 171:388-416.
12. Singh N, Rogers P, Atwood CW, et al. Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the
intensive care unit. A proposed solution for indiscriminate antibiotic prescription. Am J Respir Crit Care Med 2000 Aug;162(2Pt
1):505-11.
13. Schuetz P, Albrich W, Mueller B, et al. Procalcitonin for diagnosis of infection and guide to antibiotic decisions: past,
present, and future. BMC Medicine 2011;9:107.
14. Nobre V, Harbarth S, Graf J-D, et al. Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a
randomized trial. Am J Respir Crit Care Med 2008;177(5):498-505.
15. Stolz D, Smyrnios N, Eggimann P, et al. Procalcitonin for reduced antibiotic exposure in ventilator-associated pneumonia: a
randomized study. Eur Respir J 2009;34(6):1364-1375.
16. Hochreiter M, Kohler T, Schweiger AM, et al. Procalcitonin to guide duration of antibiotic therapy in intensive care patients:
a randomized prospective controlled trial. Crit Care 2009;13(3):R83.
17. Schroeder S, Hochreiter M, Koehler T, et al. Procalcitonin (PCT)-guided algorithm reduces length of antibiotic treatment in
surgical intensive care patients with severe sepsis: results of a prospective randomized study. Langenbecks Arch Surg
2009;394(2):221-226.
18. Bouadma L, Luyt C, Tubach F, et al. PRORATA trial group. Use of procalcitonin to reduce patients exposure to antibiotics in
intensive care units (PRORATA trial): a multicenter randomized controlled trial. Lancet 2010;375(9713):463-474.
19. Heyland DK, Johnson AP, Reynolds SC, et al. Procalcitonin for reduced antibiotic exposure in the critical care setting: A
systematic review and an economic evaluation. Crit Care Med 2011;(9)37:1792-1799.
20. Schuetz P, Christ-Crain M, Wolbers M, et al. Effect of procalcitonin-based guidelines compared to standard guidelines on
antibiotic use in lower respiratory tract infections: the Randomized-Controlled Multicenter ProHOSP Trial. JAMA
2009;302(10):1059-1066.
21. Stolz D, Christ-Crain M, Bingisser R, et al. Antibiotic treatment of exacerbations of COPD: a randomized, controlled trial
comparing procalcitonin-guidance with standard therapy. Chest 2007;131(1):9-19.
22. Briel M, Schuetz P, Mueller B, et al. Procalcitonin-guided antibiotic use vs a standard approach for acute respiratory tract
infections in primary care. Arch Intern Med 2008;168(18):2000-2007.
23. Burkhardt O, Ewig S, Haagen U, et al. Procalcitonin guidance and reductions of antibiotic use in acute respiratory tract
infection. Eur Respir J 2010;36(3):601-607.
24. Assink-de Jong E, de Lange DW, van Oers JA, et al. Stop Antibiotics on guidance of Procalcitonin Study (SAPS): a randomised
prospective multicenter investigator-initiated trial to analyse whether daily measurements of procalcitonin versus a standard-
of-care approach can safely shorten antibiotic duration in intensive care unit patients--calculated sample size: 1816 patients.
BMC infect Dis 2013 Apr 16;13:178.
25. Jean-Roger Le Gall, MD; Stanley Lemeshow, PhD; Fabienne Saulnier, MD. (1993). A New Simplified Acute Physiology Score
(SAPS II) Based on a European/North American Multicenter Study. JAMA 1993;270:2957-2963.
26. Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ
dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care
Medicine. Intensive Care Med 1996 Jul;22(7):707-10.
27. Fagon JY, Chastre J, Novara A, et al. Characterization of intensive care unit patients using a model based on the presence or
absence of organ dysfunctions and/or infection: The ODIN model. Int Care Med 1993;19:137-144.
28. Jensen et al. Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve
survival in the intensive care unit. Crit Care Med 2011;39:2048-58.
29. Layios et al. Procalcitonin-Guided Antibiotic Use in the Critically Ill. Crit Care Med 2012;40:2304.

Gonzalez 17
Appendix A1
Antibiotic Resistant Microorganism Estimated Annual Estimated Annual
Number of Cases Number of Deaths

Carbapenem-resistant Enterobacteriaceae (CRE) 9,300 610

Drug-resistant Neisseria gonorrhoeae (any drug) 246,000 <5

Multidrug-resistant Acinetobacter (three or more drug classes) 7,300 500

Drug-resistant Campylobacter (azithromycin or ciprofloxacin) 310,000 28

Drug-resistant Candida (fluconazole) 3,400 220

Extended-spectrum -lactamase producing Enterobacteriaceae 26,000 1,700


(ESBLs)
Vancomycin-resistant Enterococcus (VRE) 20,000 1,300

Multidrug-resistant Pseudomonas aeruginosa (three or more drug 6,700 440


classes)
Drug-resistant non-typhoidal Salmonella (ceftriaxone, ciprofloxacin, 100,000 40
5 or more drug classes)
Drug-resistant Shigella (azithromycin or ciprofloxacin) 27,000 <5

Methicillin-resistant Staphylococcus aureus (MRSA) 80,000 11,000

Streptococcus pneumonia 1,200,000 7,000

Drug-resistant tuberculosis 1,402 50

Vancomycin-resistant Staphylococcus aureus (VRSA) <5 <5

Erythromycin-resistant Group A Streptococcus 1,300 160

Clindamycin-resistant Group B Streptococcus 7,600 440

Summary Totals for Antibiotic-Resistant Infections 2,049,442 23,488



Appendix B: Clinical Pulmonary Infection Score (CPIS) criteria and interpretation12
Patient Characteristic 0 1 2
Temp, F 97.7 to <101.1 101.2 to <102 <96.8 or >102.1
WBC, mm3 >4000 to <11000 <4000 or >11000 <4000 or >11000 + bands
>50%
PaO2/FiO2 >240 or ARDS - <240 without ARDS
CXR No infiltrate Diffuse/patchy infiltrate Localized infiltrate
CXR progression No progression - + progression
Tracheal secretions Rare Abundant Abundant + purulent
Tracheal aspirate of Rare/light or no growth Moderate or heavy -
pathogenic bacteria
(semiquantitive)
Tracheal aspirate of Rare/light or no growth* Moderate or heavy* -
pathogenic bacteria
(semiquantitive)
* +1 point if same bacteria seen on gram stain
Total score >6 clinical diagnosis of VAP
CPIS 6 after 72h consider simplification/discontinuation of antibiotic therapy




Gonzalez 18
Appendix C 26-28

Simplified Acute Physiology Score (SAPS II)
Designed to measure the severity of disease for patients admitted to the ICU (>18 yr) and calculates probability of
hospital mortality.
Must use worst corresponding variables upon 24hr of admission. The score is calculated and results in an integer
between 0 163 and a predicted mortality between 0-100%. No new score can be calculated unless the patient is
discharged and readmitted to the ICU.
Variables used: 1) age 2) heart rate 3) SBP 4) Body temp 5) If on mechanical ventilation PaO2/FiO2 6) Urinary
output 7) BUN 8) WBC count 9) Potassium 10) Sodium 11) Bicarbonate 12) Bilirubin 13) Glasgow Coma Score 14)
Chronic disease (cancer, AIDS) 15) Type of admission (medical, surgical)

SAPS (III)
Designed to provide a real-life predicted mortality for a patient by following a well defined procedure, based on a
statistical mathematical model that needs calibration.
Total score can range from 0 217.
Twenty Variables used: Age, length of stay before ICU admission, intra-hospital location before ICU, co-morbidities,
use of therapeutic options before ICU admission (vasoactive drugs), planned or unplanned admission, reason for ICU
admission, surgical status, site of injury, acute infection at ICU admission, estimated GCS, total bilirubin, body temp.,
creatinine, heart rate, leukocytes, hydrogen ion concentration, platelets, systolic blood pressure, oxygenation

Sequential Organ Failure Assessment (SOFA) Score
SOFA score is a six-organ dysfunction/failure score measuring multiple organ failure daily. Each organ is graded from
0 (normal) to 4 (most abnormal), providing a daily score of 0-24 points.
Mortality rate increases as number of organs with dysfunction increases
Points 1 2 3 4
Respiration PaO2/Fi02, <400 <300 <200 <100
mmHg
Coagulation <150 <100 <50 <20
Platelets x 103/mm3
Liver 1.2-1.9 2.0-5.9 6.0-11.9 >12
Bilirubin, mg/dL
Cardiovascular MAP<70 Dopamine <5 or Dopamine >5 or Dopamine >15 or
Hypotension dobutamine (any dose) epinephrine <0.1 or epinephrine >0.1 or
norepinephrine <0.1 norepinephrine >0.1
Central Nervous System 13-14 10-12 6-9 <6
Glasgow Coma Score
Renal 1.2-1.9 2.0-3.4 3.5-4.9 or <500 >5 or <200 mL/day
Creatinine mg/dL or mL/day
Urine Output mL/day

Organ Dysfunction and/or Infection (ODIN) Score
Easily available data (within the first 24h of admission), when precise diagnostic evaluation is not possible
Less subjectivity
Discrimination comparable to SAPS II & APACHE II
Answer yes/no questions on variables of respiratory, cardiovascular, renal, neurologic, hepatic, hematologic
dysfunction and the presence of infection
Prediction of outcome is found using logistic regression analysis
Variables Coefficient Odds-ratio p-value
Constant -3.59 - <0.0001
Cardiovascular dysfunction 1.19 3.28 <0.0001
Renal dysfunction 1.18 3.25 <0.0001
Respiratory dysfunction 1.09 2.97 <0.0001
Neurologic dysfunction 0.99 2.69 <0.0001
Hematologic dysfunction 0.86 2.36 0.011
Hepatic dysfunction 0.57 1.78 0.055
Infection 0.53 1.70 0.002


Gonzalez 19
Appendix D: Overview of studies investigating the use of PCT in different types of infection13
Type of infection Study designs PCT cut-off (mcg/L) Benefit of Main conclusions
using PCT?
Abdominal infections Observational 0.25 ? PCT may help to exclude
ischemia and necrosis in bowel
obstruction
Arthritis 0.1-0.25 + PCT differentiates non-
infectious (gout) arthritis from
true infection
Bacteremic infections 0.25 ++ Low PCT levels help to rule out
bacteremic infections

Blood stream infection 0.1 ++ PCT differentiates
(primary) contamination from true
infection
Endocarditis 2.3 + PCT is an independent
predictor for acute
endocarditis with high
diagnostic accuracy
Pancreatitis 0.25-0.5 ? PCT correlates with severity
and extent of infected
pancreatitis
Neutropenia 0.1-0.5 + PCT is helpful at identifying
neutropenic patients with
systemic bacterial infection
Postoperative fever 0.1-0.5 + PCT differentiates non-
infectious fever from post-
operative infections
Urinary Tract Infection 0.25 + PCT correlates with severity of
urinary tract infections
Meningitis 0.5 + PCT reduces antibiotic
exposure during outbreak of
viral meningitis
Bronchitis Randomized 0.1-0.5 +++ PCT reduces antibiotic
Controlled Trials exposure in the ED without
adverse outcomes
COPD exacerbation 0.1-0.5 +++ PCT reduces antibiotic
exposure in the ED and
hospital without adverse
outcomes
Pneumonia 0.1-0.5; 80-90% +++ PCT reduces antibiotic
exposure in the hospital
without adverse outcomes
Postoperative 0.5-1.0; 75-85% ++ PCT reduces antibiotic
infections exposure in the surgical ICU
without adverse outcomes
Ventilator-associated 0.1-0.25 ++ PCT reduces antibiotic
pneumonia exposure without adverse
outcomes
Severe sepsis/ Shock 0.25-0.5; 80-90% +++ PCT reduces antibiotic
exposure in the ICU without
adverse outcomes
+ moderate evidence, ++ good evidence, +++ strong evidence

Gonzalez 20