10.1515 - CCLM 2022 1072
10.1515 - CCLM 2022 1072
Opinion Paper
Philipp Schuetz*
response markers, Procalcitonin (PCT) has generated much in 3,336 procalcitonin-guided patients vs. 336 [10%] in
interest due to its higher specificity towards bacterial 3,372 controls [p=0.037]). Similar effects were also seen
infection compared to C-reactive protein (CRP) or white for other respiratory infections and clinical settings.
blood cell count (WBC) [6, 7]. PCT also has a superior Another meta-analysis of 11 trials and 4,482 patients
prognostic [8] and kinetic profile to track infections – mak- investigated the effects of applying PCT in patients
ing it useful to assess response to treatment [7, 9–12]. with sepsis [14]. Those randomized to the PCT protocol
The goal of this narrative review is to discuss different experienced an earlier discontinuation of antibiotics
studies and clinical trials that have investigated clinical ef- and significant reductions in mean treatment duration
fects of using PCT for the purpose of antibiotic stewardship, from 10.4 to 9.3 days. Here again, mortality in PCT-guided
and to provide practical advice on how to best integrate PCT patients was significantly lower compared to the control
into clinical care. Thereby, several milestone studies about group (21.1 vs. 23.7%, p=0.03). In a further meta-analysis
PCT that were published in Clinical Chemistry and Laboratory of individuals with positive blood cultures, PCT reduced
Medicine (CCLM) over the last years are particularly high- both antibiotic exposure (by 2.86 days) and mortality
lighted and critically discussed. (16.6 vs. 20.0%) [17]. A subgroup analysis demonstrated
the strongest effects for pneumonia caused by Strepto-
coccus pneumoniae (−4.52 days) and urogenital infections
caused by Escherichia coli (−4.21 days).
Clinical trials investigating
PCT-guided antibiotic stewardship
In addition to a large body of observational data [13],
How to implement PCT in clinical
several interventional trials have compared PCT protocols practice
with control groups regarding antibiotic use and clinical
outcomes [14, 15]. Most trials focused on patients with Based on these trials, important considerations for PCT
respiratory infection and/or sepsis. Although the pro- use in clinical practice must be made. The interpretation
tocols followed slightly different PCT guidelines, there of PCT results varies according to clinical setting, specific
were some similarities: PCT cut-off values in low risk patient situation, and type of illness.
patients were used to identify individuals for whom In low risk patients in primary care, a marker such
bacterial infection was unlikely and antibiotic treatment as PCT can rule out bacterial disease and reduce anti-
could be stopped, or withheld [16]. If the probability biotic initiation [18]. Two large primary care PCT trials
for bacterial infection was high, the protocol focused examined a total of 1,008 patients with lower and up-
on PCT kinetics and cessation of antibiotics when PCT per respiratory tract infections – whereby a low PCT
levels dropped to normal ranges, or by at least 80–90%. of ≤0.25 μg/L prohibited the use of antibiotics [18, 19].
PCT protocols had varying cut-offs for low or higher Antibiotic initiation was reduced from 63% in control
acuity/severity: for emergency department and medical group patients to 23% in PCT-guided patients; with a
ward patients, a PCT<0.25 μg/L recommended no use of significant reduction in antibiotic exposure from 4.6
antibiotics, while in intensive care patients a PCT<0.5 μg/L to 1.6 days and no difference in clinical outcomes.
advocated discontinuation of antibiotics. Currently, the most significant limitation to the use of
There are several meta-analyses which have investi- PCT in primary care is the lack of highly sensitive
gated the effectiveness and safety of utilizing PCT to guide point-of-care tests. Furthermore, other markers such as
antibiotic treatment. One individual patient data meta- CRP – where tests are more widely available and less
analysis of 26 trials focusing on respiratory infections expensive – have shown benefit in primary care patients
reported that PCT guidance was associated with a 2.4-day despite their lower specificity regarding bacterial
reduction in antibiotic exposure (5.7 vs. 8.1 days). This infections [20]. As corresponding large scale head-to-
was due to decreased rates of antibiotic initiation in low- head trials are lacking, further study is needed to
risk patient (i.e., bronchitis or COPD patients) and shorter compare PCT-guided care with other biomarkers such as
treatment courses in high risk patients (i.e., pneumonia CRP. Cost-effectiveness and country-specific reimburse-
patients) [7, 15]. Importantly, use of PCT resulted in ment of PCT must also be addressed.
reductions of antibiotic-related side-effects (16 vs. 22%), Several trials of mostly respiratory infection patients
and in significantly lowered mortality (286 [9%] deaths have investigated PCT in the emergency department
824 Schuetz: Procalcitonin to diagnose infections and manage antibiotic treatment
Figure 1: Clinical algorithm for PCT use in different clinical settings. (A) Suggested PCT protocol in low and moderate severity patients [31].
(B) Suggested PCT protocol in critical care patients [31].
also relatively low in some atypical infections – including large number of new PCT immunoassays are currently
mycoplasma [35]. Some clinical conditions such as kid- being developed (including point-of-care tests [38]),
ney failure and dialysis may influence PCT kinetics [36], which will require careful analysis and clinical evaluation
although one large individual patient meta-analysis [39–45]. The expansion of PCT assays also necessitates
suggested that use of PCT in patients with impaired evaluation of result comparability among tests and stan-
kidney function works well and is associated with shorter dardized calibration to support safe usage of PCT in
antibiotic courses and lower mortality rates [37]. Finally, a clinical routine [46–48]. Finally, cost-effectiveness
826 Schuetz: Procalcitonin to diagnose infections and manage antibiotic treatment
analyses are needed to evaluate how widespread PCT 3. Mitsuma SF, Mansour MK, Dekker JP, Kim J, Rahman MZ, Tweed-
testing would affect health care budgets – in comparison Kent A, et al. Promising new assays and technologies for the
diagnosis and management of infectious diseases. Clin Infect Dis
with the resulting benefits for clinical outcomes and
2013;56:996–1002.
antibiotic resistance patterns [49, 50]. 4. Jee Y, Carlson J, Rafai E, Musonda K, Huong TTG, Daza P, et al.
Antimicrobial resistance: a threat to global health. Lancet Infect
Dis 2018;18:939–40.
Concluding remarks 5. Hey J, Thompson-Leduc P, Kirson NY, Zimmer L, Wilkins D, Rice B,
et al. Procalcitonin guidance in patients with lower respiratory
tract infections: a systematic review and meta-analysis.
The medical community is highly interested in reducing Clin Chem Lab Med 2018;56:1200–9.
unnecessary antibiotic exposure in patients with acute res- 6. Bartoletti M, Antonelli M, Bruno Blasi FA, Casagranda I,
piratory illness and low risk for bacterial infection, as well as Chieregato A, Fumagalli R, et al. Procalcitonin-guided antibiotic
shortening therapy in cases of known bacterial infections. therapy: an expert consensus. Clin Chem Lab Med 2018;56:
1223–9.
Essentially, the aim is to shift from fixed antibiotic doses to
7. Zhydkov A, Christ-Crain M, Thomann R, Hoess C, Henzen C,
individualized treatment. As a marker of host defense Werner Z, et al. Utility of procalcitonin, C-reactive protein and
response, PCT has shown promising results for respiratory white blood cells alone and in combination for the prediction of
infections and sepsis. PCT should not be used as a sub- clinical outcomes in community-acquired pneumonia. Clin Chem
stitute for good clinical practice, but rather be part of the Lab Med 2015;53:559–66.
8. Sager R, Wirz Y, Amin D, Amin A, Hausfater P, Huber A, et al. Are
overall assessment of a patient. Decisions pertaining to
admission procalcitonin levels universal mortality predictors
initiation and cessation of antibiotic treatment remains
across different medical emergency patient populations? Results
strongly dependent on evaluating all available clinical from the multi-national, prospective, observational TRIAGE
and diagnostic parameters, including a thorough assess- study. Clin Chem Lab Med 2017;55:1873–80.
ment of the patient and severity of illness. Furthermore, 9. Schuetz P, Birkhahn R, Sherwin R, Jones AE, Singer A, Kline JA,
PCT usage should not delay or impede initiation of et al. Serial procalcitonin predicts mortality in severe sepsis
patients: results from the multicenter procalcitonin MOnitoring
empirical treatment in high-risk situations. Host response
SEpsis (MOSES) study. Crit Care Med 2017;45:781–9.
markers such as PCT, however, remain the best line of 10. Sager R, Kutz A, Mueller B, Schuetz P. Procalcitonin-guided
defense against diagnostic uncertainty and antibiotic diagnosis and antibiotic stewardship revisited. BMC Med 2017;
overuse. Further research is needed to explore the optimal 15:15.
application of biomarkers in combination with pathogen- 11. Lippi G, Cervellin G. Procalcitonin for diagnosing and monitoring
bacterial infections: for or against? Clin Chem Lab Med 2018;56:
directed tests. Importantly, medical Journals such as
1193–5.
Clinical Chemistry and Laboratory Medicine (CCLM) have
12. Schuetz P, Hausfater P, Amin D, Amin A, Haubitz S, Faessler L,
played a critical role in reviewing and dissemination the et al. Biomarkers from distinct biological pathways improve early
high-quality evidence about assays for PCT measurement, risk stratification in medical emergency patients: the
observational research regarding association with out- multinational, prospective, observational TRIAGE study. Crit Care
comes among different populations, and interventional 2015;19:377.
13. Schuetz P, Aujesky D, Muller C, Muller B. Biomarker-guided
research proofing its effectiveness for patient care.
personalised emergency medicine for all – hope for another
hype? Swiss Med Wkly 2015;145:w14079.
Research funding: None declared. 14. Wirz Y, Meier MA, Bouadma L, Luyt CE, Wolff M, Chastre J, et al.
Author contributions: Single author contribution. Effect of procalcitonin-guided antibiotic treatment on clinical
Competing interests: Dr. Schuetz reports grants from outcomes in intensive care unit patients with infection and sepsis
patients: a patient-level meta-analysis of randomized trials.
bioMerieux, Thermofisher, and Roche Diagnostics (paid
Crit Care 2018;22:191.
to the Institution).
15. Schuetz P, Wirz Y, Sager R, Christ-Crain M, Stolz D, Tamm M, et al.
Informed consent: Not applicable. Effect of procalcitonin-guided antibiotic treatment on mortality in
Ethical approval: Not applicable. acute respiratory infections: a patient level meta-analysis. Lancet
Infect Dis 2018;18:95–107.
16. Schuetz P, Bolliger R, Merker M, Christ-Crain M, Stolz D, Tamm M,
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