1. Procalcitonin-Guided Antibiotic Therapy
Prepared for:
Agency for Healthcare Research and Quality (AHRQ)
Procalcitonin-Guided Antibiotic Therapy
This slide set is based on a comparative effectiveness review (CER), Procalcitonin-Guided Antibiotic Therapy, Comparative Effectiveness Review No. 78, which was developed by the Blue Cross Blue Shield Association Technology Evaluation Center Evidence-based Practice Center, Chicago, IL, for the Agency for Healthcare Research and Quality (AHRQ) under Contract No. HHSA I and is available online at
CERs are comprehensive systematic reviews of the literature. For this CER, the existing body of evidence on the effects of using procalcitonin for guiding antibiotic therapy was reviewed. The literature included in this review was identified in searches for studies in the MEDLINE®, EMBASE®, Cochrane Database of Systematic Reviews, National Institute for Clinical Excellence, the National Guideline Clearinghouse, and the Health Technology Assessment Programme databases using relevant search terms. This systematic review included 18 studies that compared procalcitonin-guided versus clinical criteria-guided initiation, discontinuation, or change of antibiotic therapy in over 6,000 patients (including critically ill adults and pediatric patients with suspected infection and patients with respiratory tract infections). Only randomized controlled trials and nonrandomized studies were included. Outcomes were antibiotic usage, mortality, morbidity, adverse drug events of antibiotic therapy, and hospital or intensive care unit length of stay. Searches were conducted for studies published in the English language between January 1, 1990, and December 16, 2011.
Reference:
Soni NJ, Samson DJ, Galaydick JL, et al. Procalcitonin-Guided Antibiotic Therapy. Comparative Effectiveness Review No. 78 (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; August AHRQ Publication No. 12-EHC124-EF. Available at

2. Outline of Material
Introduction to procalcitonin and its role in guiding antibiotic therapy in adult and pediatric patients with suspected infections
Systematic review methods
The clinical questions addressed by the comparative effectiveness review
Results of studies and evidence-based conclusions about the effects of using procalcitonin versus clinical criteria to guide antibiotic therapy in adult and pediatric patients with suspected local or systemic infections
Gaps in knowledge and future research needs
What to discuss with patients and their caregivers
Outline of Material
The material in this presentation covers the results and conclusions from a systematic comparative effectiveness review entitled Procalcitonin-Guided Antibiotic Therapy. It begins with an introduction to procalcitonin and its role in guiding antibiotic therapy in adults and pediatric patients with suspected local or systemic infections. It also covers methods used to plan and execute the systematic review, clinically important questions the review sought to answer, results of the review, evidence-based conclusions about the effects of using procalcitonin to guide antibiotic therapy in patients with local or systemic infections, gaps in knowledge, and the future research needs uncovered by the systematic review.
Reference:
Soni NJ, Samson DJ, Galaydick JL, et al. Procalcitonin-Guided Antibiotic Therapy. Comparative Effectiveness Review No. 78 (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; August AHRQ Publication No. 12-EHC124-EF. Available at
Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ Comparative Effectiveness Review No. 78.
Available at

3. Background: The Need for Biomarkers To Guide Antibiotic Therapy for Bacterial Infections
The early initiation and appropriate use of antibiotics are important factors in managing:
Critically ill patients with suspected bacterial infections such as sepsis
Patients with bacterial upper and lower respiratory tract infections in the ambulatory care or hospital setting
Pediatric patients with suspected bacterial infections, including neonates with suspected sepsis
Patients in the postoperative setting with suspected infections
A key challenge associated with antibiotic therapy is the overuse and misuse of antibiotics, which can result in adverse effects and add to the increasing problem of antibiotic resistance.
However, the duration of antibiotic therapy that is appropriate for these patients is often undefined, and clinical features offer limited guidance.
Background: The Need for Biomarkers To Guide Antibiotic Therapy for Bacterial Infections
The early initiation and appropriate use of antibiotics are important factors in managing several patient populations including:
Critically ill patients with suspected bacterial infections such as sepsis — Sepsis is a condition with high morbidity and mortality for which clinical diagnostic criteria lack sensitivity and specificity. Rapid diagnosis of sepsis and early initiation of antibiotic and goal-directed therapies have demonstrated a reduction in mortality. Other infections in critically ill patients that require early initiation of antibiotics include ventilator-associated pneumonia, neutropenic fever, and bacteremia.
Patients with upper and lower respiratory tract infections — Approximately 75 percent of all antibiotics prescribed in the ambulatory care setting are for acute upper and lower respiratory tract infections (RTIs). However, most acute RTIs are viral and do not benefit from antibiotic treatment. Upper bacterial RTIs (i.e., sinusitis, pharyngitis, and tonsillitis) and lower bacterial RTIs (i.e., pneumonia and bronchitis) may require antibiotic therapy. Clinical and microbiological evaluations lack the sensitivity and specificity to differentiate bacterial from viral RTIs.
Pediatric patients with suspected infections — These patients include those with localized infections such as pneumonia, urinary tract infection, and meningitis and those with systemic infections such as neutropenic fever, bacteremia, sepsis, and septic shock. Neonates with suspected sepsis are a particularly important group.
Patients in the postoperative setting with suspected infections — Patients with surgical site infections fall into this category.
A key clinical challenge associated with antibiotic therapy is that the overuse and misuse of antibiotics—including continuing antibiotics longer than necessary—can result in adverse effects and add to the increasing problem of antibiotic resistance.
However, the duration of antibiotic therapy that is appropriate for these patient populations is often undefined, and clinical features are of limited help in guiding discontinuation of therapy.
References:
Soni NJ, Samson DJ, Galaydick JL, et al. Procalcitonin-Guided Antibiotic Therapy. Comparative Effectiveness Review No. 78 (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; August AHRQ Publication No. 12-EHC124-EF. Available at
Pierrakos C, Vincent JL. Sepsis biomarkers: a review. Crit Care 2010;14(1):R15. PMID:
Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ Comparative Effectiveness Review No. 78. Available at
Pierrakos C, Vincent JL. Crit Care 2010;14(1):R15. PMID:

4. Background: Procalcitonin and Its Role as a Biomarker of Bacterial Infections
Several serum biomarkers have been identified with the potential to help diagnose local and systemic infections and guide their clinical management, particularly antibiotic therapy.
Procalcitonin is the most extensively studied biomarker among these.
Procalcitonin is the precursor of the hormone calcitonin; its levels have been found to increase during infections and different degrees of inflammation.
The primary utility of procalcitonin is suggested to be in establishing the presence of local or systemic bacterial infections and in guiding their management.
Procalcitonin is often used with algorithms to guide care in association with clinical impressions.
Background: Procalcitonin and Its Role as a Biomarker of Bacterial Infections
Several serum biomarkers have been identified in recent years with potential uses to help diagnose local and systemic infections, differentiate bacterial and fungal infections from viral syndromes or noninfectious conditions, prognosticate, and ultimately guide management, particularly antibiotic therapy.
Currently, there are at least 178 serum biomarkers that have potential roles in managing patients with infections. Among these, procalcitonin is the most extensively studied biomarker.
Procalcitonin is the prohormone precursor of calcitonin that is expressed primarily in the C-cells of the thyroid gland and to a smaller extent in the neuroendocrine tissue of other organs, such as the lungs and intestines. The final step in the conversion of procalcitonin to calcitonin is inhibited by various cytokines and bacterial endotoxins and, therefore, high levels of cytokines and/or bacterial endotoxins cause procalcitonin levels to rise. Cytokines are released nonspecifically in response to inflammation and infection, but endotoxins are released specifically during bacterial infections because they are derived primarily from the Gram-negative bacterial cell wall. There is some evidence that procalcitonin is more specific for bacterial infections, with serum levels rising and falling more rapidly in bacterial infection.
The primary diagnostic utility of procalcitonin is thought to be in establishing the presence of local or systemic bacterial infections and in guiding their management.
Procalcitonin is often used with algorithms to guide care in association with clinical impressions.
References: Soni NJ, Samson DJ, Galaydick JL, et al. Procalcitonin-Guided Antibiotic Therapy. Comparative Effectiveness Review No. 78 (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; August AHRQ Publication No. 12-EHC124-EF. Available at
Jones AE, Fiechtl JF, Brown MD, et al. Procalcitonin test in the diagnosis of bacteremia: a meta-analysis. Ann Emerg Med 2007 Jul;50(1): PMID:
Pierrakos C, Vincent JL. Sepsis biomarkers: a review. Crit Care 2010;14(1):R15. PMID:
Tang H, Huang T, Jing J, et al. Effect of procalcitonin-guided treatment in patients with infections: a systematic review and meta-analysis. Infection 2009 Dec;37(6): PMID:
Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ Comparative Effectiveness Review No. 78. Available at
Jones AE, Fiechtl JF, Brown MD, et al. Ann Emerg Med 2007 Jul;50(1): PMID:
Pierrakos C, Vincent JL. Crit Care 2010;14(1):R15. PMID:
Tang H, Huang T, Jing J, et al. Infection 2009 Dec;37(6): PMID:

5. Background: Cutoffs for Procalcitonin Used in Clinical Practice
In healthy people, the levels of procalcitonin are very low.
In systemic bacterial infections, including sepsis, the level of procalcitonin is generally ≥0.5 ng/mL, with higher levels being associated with severe disease.
In patients with suspected respiratory tract infection, a cutoff >0.25 ng/mL is predictive of a bacterial infection.
A level <0.25 ng/mL signals resolution of the infection.
In neonates, a nomogram accounting for the time from birth in hours is recommended for assessing procalcitonin cutoffs.
The cutoff level of procalcitonin to identify postoperative patients with infection may be higher than that used for other patient groups due to cytokine release during surgery.
Background: Cutoffs for Procalcitonin Used in Clinical Practice
In healthy people, procalcitonin levels are very low. In systemic bacterial infections, including sepsis, procalcitonin levels are generally ≥0.5 ng/mL; higher levels correlate with the severity of illness and prognosis. Studies indicate that procalcitonin is superior to C-reactive protein, interleukin-6, and interleukin-8 for diagnosing sepsis.
Procalcitonin levels in patients with suspected respiratory tract infection (RTI) may be useful in determining if patients require antibiotic therapy. In patients with RTIs, the levels of procalcitonin are not necessarily as elevated; a cutoff >0.25 ng/mL seems to be most predictive of a bacterial RTI requiring antibiotic therapy, while a level <0.25 ng/mL signals resolution of the infection.
In neonates, there is normally a characteristic increase in procalcitonin after birth, with a rapid return to normal by 48 to 72 hours. In this circumstance, the elevated procalcitonin levels are an acute-phase reactant in response to the stress of the birth process, yet an incremental increase is still detectable in infants with neonatal sepsis. A nomogram for procalcitonin cutoffs that accounts for the time from birth in hours is recommended.
In postoperative patients, the stress of surgery may increase procalcitonin levels; however, the increase in procalcitonin in patients with infection, including those with a subclinical infection or those at high risk of infection, is incremental. Postoperatively, the procalcitonin cutoff level to identify patients with infection or at risk of infection may be higher than that used for other patient groups due to cytokine release during surgery.
References: Soni NJ, Samson DJ, Galaydick JL, et al. Procalcitonin-Guided Antibiotic Therapy. Comparative Effectiveness Review No. 78 (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; August AHRQ Publication No. 12-EHC124-EF. Available at
Chiesa C, Panero A, Rossi N, et al. Reliability of procalcitonin concentrations for the diagnosis of sepsis in critically ill neonates. Clin Infect Dis 1998 Mar;26(3): PMID:
Christ-Crain M, Müller B. Biomarkers in respiratory tract infections: diagnostic guides to antibiotic prescription, prognostic markers and mediators. Eur Respir J 2007 Sep;30(3): PMID:
Luyt CE, Guérin V, Combes A, et al. Procalcitonin kinetics as a prognostic marker of ventilator-associated pneumonia. Am J Respir Crit Care Med 2005 Jan 1;171(1): PMID:
Simon L, Gauvin F, Amre DK, et al. Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis. Clin Infect Dis 2004 Jul 15;39(2): PMID:
Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ Comparative Effectiveness Review No. 78. Available at
Chiesa C, Panero A, Rossi N, et al. Clin Infect Dis 1998 Mar;26(3): PMID:
Christ-Crain M, Muller B. Eur Respir J 2007 Sep;30(3): PMID:
Luyt CE, Guerin V, Combes A, et al. Am J Respir Crit Care Med 2005 Jan 1;171(1): PMID:
Simon L, Gauvin F, Amre DK, et al. Clin Infect Dis 2004 Jul 15;39(2): PMID:

6. Uncertainties Related to the Use of Procalcitonin To Guide Antibiotic Therapy
Earlier studies have investigated the potential roles of procalcitonin in diagnosing and managing local and systemic infections.
Some evidence indicates that procalcitonin, when compared with other markers, is more specific for bacterial infections.
However, its clinical utility in diagnosing and managing patients with suspected infections remains unclear.
This review focused on the clinical utility of procalcitonin in managing patients with suspected infections.
Although questions about the clinical utility of procalcitonin in the diagnosis of patients with suspected infections persist, they were not addressed in this review.
Uncertainties Related to the Use of Procalcitonin To Guide Antibiotic Therapy
Earlier studies have investigated the potential roles of procalcitonin in diagnosing and managing local and systemic infections. Some evidence indicates that procalcitonin, when compared with other markers, is more specific for bacterial infections, with serum levels rising at the onset of infection and falling rapidly as the infection resolves.
However, the clinical utility of procalcitonin in diagnosing and managing patients with suspected infections remains unclear. This review focused on the clinical utility of procalcitonin in managing patients with suspected infections. Although questions about the clinical utility of procalcitonin in the diagnosis of patients with suspected infections persist, they were not addressed as part of this review.
Reference: Soni NJ, Samson DJ, Galaydick JL, et al. Procalcitonin-Guided Antibiotic Therapy. Comparative Effectiveness Review No. 78 (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; August AHRQ Publication No. 12-EHC124-EF. Available at
Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ Comparative Effectiveness Review No. 78.
Available at

7. Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development
Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, members of the public, and others.
A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue. The research questions and the results of the report are subject to expert input, peer review, and public comment.
The results of these reviews are summarized into Clinician Research Summaries and Consumer Research Summaries for use in decisionmaking and in discussions with patients. The Research Summaries and the full report, with references for included and excluded studies, are available at
Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development
Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, members of the public, and others. A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue. The research questions and the results of the report are subject to expert input, peer review, and public comment. The results of these reviews are summarized into Clinician Research Summaries and Consumer Research Summaries for use in decisionmaking and in discussions with patients. The Clinician Research Summary and the full report, with references for included and excluded studies, are available at A Consumer Research Summary was not prepared for this topic.
Reference: Soni NJ, Samson DJ, Galaydick JL, et al. Procalcitonin-Guided Antibiotic Therapy. Comparative Effectiveness Review No. 78 (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; August AHRQ Publication No. 12-EHC124-EF. Available at
Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ Comparative Effectiveness Review No. 78.
Available at

8. Rating the Strength of Evidence From the Comparative Effectiveness Review
The strength of evidence was classified into four broad categories:
High
Further research is very unlikely to change the confidence in the estimate of effect.
Moderate
Further research may change the confidence in the estimate of effect and may change the estimate.
Low
Further research is likely to change the confidence in the estimate of effect and is likely to change the estimate.
Insufficient
Evidence either is unavailable or does not permit estimation of an effect.
Rating the Strength of Evidence From the Comparative Effectiveness Review
Throughout this slide set, strength of evidence ratings are assigned to findings of the report. Strength of evidence is typically assigned to reviews of medical treatments after assessing four domains: risk of bias, consistency, directness, and precision. Although these categories were developed to assess the strength of treatment studies, the domains apply also to studies of prevalence and screening. Available evidence for each Key Question was assessed for each of these four domains; the domains were combined qualitatively to develop the strength of evidence for each Key Question.
Reference: Soni NJ, Samson DJ, Galaydick JL, et al. Procalcitonin-Guided Antibiotic Therapy. Comparative Effectiveness Review No. 78 (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; August AHRQ Publication No. 12-EHC124-EF. Available at
Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ Comparative Effectiveness Review No. 78.
Available at

9. The Clinical Question Addressed by This Comparative Effectiveness Review
Key Question: In selected populations of patients with suspected local or systemic infection, what are the effects of using procalcitonin measurement plus clinical criteria for infection to guide initiation, discontinuation, or a change of antibiotic therapy when compared with clinical criteria for infection alone on:
Intermediate outcomes, such as initiation, discontinuation or change of antibiotic therapy, antibiotic usage, and length of stay?
Health outcomes, such as morbidity, mortality, function, quality of life, and adverse events of antibiotic therapy (persistent or recurrent infection and antibiotic resistance)?
The Clinical Question Addressed by This Comparative Effectiveness Review
This comparative effectiveness review attempted to address the key question listed on this slide:
Key Question: In selected populations of patients with suspected local or systemic infection, what are the effects of using procalcitonin measurement plus clinical criteria for infection to guide initiation, discontinuation or a change of antibiotic therapy, when compared with clinical criteria for infection alone on:
- Intermediate outcomes, such as initiation, discontinuation or change of antibiotic therapy, antibiotic usage, and length of stay?
- Health outcomes, such as morbidity, mortality, function, quality of life, and adverse events of antibiotic therapy (persistent or recurrent infection and antibiotic resistance)?
Reference: Soni NJ, Samson DJ, Galaydick JL, et al. Procalcitonin-Guided Antibiotic Therapy. Comparative Effectiveness Review No. 78 (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; August AHRQ Publication No. 12-EHC124-EF. Available at
Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ Comparative Effectiveness Review No. 78.
Available at

10. Effects of Using Procalcitonin To Guide Antibiotic Therapy in Critically Ill Adult Patients in the ICU (1 of 2)
In the studies that used procalcitonin-based algorithms , physicians could consider other clinical information and over-ride algorithms based on their judgment.
Procalcitonin guidance reduced antibiotic usage. Strength of Evidence: High
Using procalcitonin guidance to discontinue antibiotic therapy did not increase morbidity, as indicated by length of stay in the ICU. Strength of Evidence: Moderate
Using procalcitonin guidance to discontinue antibiotic therapy did not increase mortality (in-hospital, 28-day, or overall mortality).
Evidence for this finding was rated low due to disagreement on the appropriate noninferiority margin. Strength of Evidence: Low
Effects of Using Procalcitonin To Guide Antibiotic Therapy in Critically Ill Adult Patients in the ICU (1 of 2)
In the studies included in this review that used procalcitonin-based algorithms, physicians could consider other clinical information and over-ride algorithms based on their clinical judgment.
There was high-strength evidence that procalcitonin guidance reduced antibiotic usage. Five studies reported on antibiotic usage; of these, three were good-quality studies and two were fair-quality studies. The duration of antibiotic therapy was reduced in the procalcitonin-guided arm of all five studies. The absolute difference ranged from -1.7 to -5.0 days, with a percent reduction of 21 to 38 percent. Three studies that reported sufficient information for pooling and yielded a statistically significant pooled mean difference of 2.05 days (95-percent confidence interval [95% CI]: -2.59, -1.52) favoring procalcitonin guidance.
Using procalcitonin guidance did not increase morbidity. The strength of evidence for this finding was rated moderate. Five studies reported on morbidity; of these, four assessed morbidity in terms of intensive care unit (ICU) length of stay and one reported ICU-free days alive. Three studies could be included in the meta-analysis. The pooled mean difference was 0.33 days, but the 95% CI was between days and 2.53 days, suggesting that neither procalcitonin nor the control are favored.
Using procalcitonin guidance did not increase mortality (in-hospital mortality, 28-day mortality, or overall mortality). The strength of evidence for this finding was rated low. Five studies reported on mortality; of these, three reported 28-day mortality and in-hospital mortality and two reported overall mortality. A meta-analysis was performed to pool mortality data from all five studies. The results showed a pooled point estimate of a 0.4-percentage point reduction in mortality (95% CI: -6 percent, 5 percent) favoring the procalcitonin-guided therapy group. The strength of evidence for this finding was rated low because of disagreement on the appropriate noninferiority margin.
Reference: Soni NJ, Samson DJ, Galaydick JL, et al. Procalcitonin-Guided Antibiotic Therapy. Comparative Effectiveness Review No. 78 (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; August AHRQ Publication No. 12-EHC124-EF. Available at
Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ Comparative Effectiveness Review No. 78.
Available at

11. Effects of Using Procalcitonin To Guide Antibiotic Therapy in Critically Ill Adult Patients in the ICU (2 of 2)
In this review, antibiotic intensification included a change in the antibiotic regimen or broadening the spectrum of antibiotic therapy.
Procalcitonin-guided intensification of antibiotic therapy was associated with greater duration of use and increased total exposure to antibiotics. Strength of Evidence: Moderate
Procalcitonin-guided intensification of antibiotic therapy was associated with increased morbidity, including increase in intensive care unit (ICU) length of stay, days on mechanical ventilation, and days with abnormal renal function. Strength of Evidence: Moderate
Effects of Using Procalcitonin To Guide Antibiotic Therapy in Critically Ill Adult Patients in the ICU (2 of 2)
There was moderate-strength evidence that procalcitonin-guided intensification of antibiotic therapy in critically ill adult patients in the intensive care unit (ICU) was associated with greater duration of use and increased total exposure to antibiotics. The evidence to support this finding came from one good-quality study. In this study that included 1,200 patients, procalcitonin-guided intensification resulted in a 2-day (50-percent) increase in the duration of antibiotic therapy. It also resulted in greater antibiotic exposure with a 7.9-percent increase in number of days on three or more antibiotics in the ICU (P = 0.002).
Procalcitonin-guided intensification of antibiotic therapy was associated with increased morbidity (including increase in ICU length of stay, days on mechanical ventilation, and days with abnormal renal function). The strength of evidence for this finding was rated moderate. Two studies reported on procalcitonin-guided antibiotic intensification; one was a fair-quality study and the other was a good-quality study. The fair-quality study showed a 3.3-day reduction in ICU stay, which was not statistically significant. The good-quality study showed a significant 1-day increase in ICU length of stay. Furthermore, this larger good-quality study demonstrated a significant increase in organ dysfunction, specifically an extra five days of mechanical ventilation and an additional five days of abnormal renal function, both of which were statistically significant.
Reference: Soni NJ, Samson DJ, Galaydick JL, et al. Procalcitonin-Guided Antibiotic Therapy. Comparative Effectiveness Review No. 78 (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; August AHRQ Publication No. 12-EHC124-EF. Available at
Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ Comparative Effectiveness Review No. 78.
Available at

12. Effects of Using Procalcitonin To Guide Antibiotic Therapy in Patients With RTIs in the Ambulatory Care or Hospital Setting (1 of 2)
Patient populations with respiratory tract infections (RTIs) included those with acute exacerbations of chronic obstructive pulmonary disease, community-acquired pneumonia, bronchitis, sinusitis, tonsillitis, or pharyngitis.
In the studies that used procalcitonin-based algorithms , physicians could consider other clinical information and over-ride algorithms based on their judgment.
Procalcitonin guidance reduced duration of use of and prescription rates of antibiotics. Strength of Evidence: High
Procalcitonin guidance reduced total antibiotic exposure. Strength of Evidence: Moderate
Effects of Using Procalcitonin To Guide Antibiotic Therapy in Patients With RTIs in the Ambulatory Care or Hospital Setting (1 of 2)
Patient populations with respiratory tract infections (RTIs) included in this review were those with acute exacerbations of chronic obstructive pulmonary disease, community-acquired pneumonia, bronchitis, sinusitis, tonsillitis, or pharyngitis in the outpatient, emergency department, or hospital setting.
In the studies included in this review that used procalcitonin-based algorithms, physicians could consider other clinical information and over-ride algorithms based on their clinical judgment.
There was high-strength evidence that procalcitonin reduced duration of antibiotic use. Antibiotic duration was reported in seven studies. The duration of antibiotic therapy was reduced with procalcitonin-guided therapy in six of the seven studies, and the absolute reduction ranged from -1.0 to -7.1 days, with a relative reduction of to -55 percent. The absolute reduction was statistically significant in four of the five studies for which p-values were either reported or calculated. A meta-analysis of the four studies found a statistically significant pooled mean difference of days favoring procalcitonin (95-percent confidence interval [95% CI]: -4.38, -0.33).
There was high-strength evidence that procalcitonin reduced prescription rates for antibiotics. The antibiotic prescription rate was reported in all eight studies. An absolute reduction in antibiotic prescription rate was demonstrated with procalcitonin-guided therapy in seven of the eight studies. The absolute reduction in prescription rates ranged from -1.8 to -72 percent, and the reductions were statistically significant in all seven studies. Only one study reported an absolute increase in prescription rate by 6.0 percent, which was not statistically significant. A meta-analysis of eight studies yielded a statistically significant pooled risk difference of -22 percent (95% CI: -41% to -4%).
There was moderate-strength evidence that procalcitonin guidance reduced total antibiotic exposure. Four studies reported on total antibiotic exposure, which accounted for the use of multiple agents, as well as duration of therapy. Two studies reported the total exposure per 1,000 patient-days with relative reductions of 0.52 and 0.49, which were both highly statistically significant. One study reported an absolute reduction of percent, which was highly statistically significant. One study reported a statistically significant relative risk of 0.55, but no additional details were given.
Reference: Soni NJ, Samson DJ, Galaydick JL, et al. Procalcitonin-Guided Antibiotic Therapy. Comparative Effectiveness Review No. 78 (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; August AHRQ Publication No. 12-EHC124-EF. Available at
Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ Comparative Effectiveness Review No. 78.
Available at

13. Effects of Using Procalcitonin To Guide Antibiotic Therapy in Patients With RTIs in the Ambulatory Care or Hospital Setting (2 of 2)
Procalcitonin guidance did not increase mortality, hospital length of stay, or intensive care unit admission rates. Strength of Evidence: Moderate
Evidence was insufficient to determine the effect of procalcitonin guidance on antibiotic-associated adverse events. Strength of Evidence: Insufficient
Effects of Using Procalcitonin To Guide Antibiotic Therapy in Patients With RTIs in the Ambulatory Care or Hospital Setting (2 of 2)
There was moderate-strength evidence that procalcitonin guidance did not increase mortality, hospital length of stay, or intensive care unit (ICU) admission rates.
- Overall mortality results were consistent and did not suggest higher mortality rates with procalcitonin-guided therapy when compared with the control arm. Mortality rates in patients in the control arm ranged from 0 to 13.2 percent. The absolute differences between the procalcitonin and control arms ranged from -3.6 to 1.0 percent. Six studies reported 28-day mortality; none of the differences in 28-day mortality were statistically significant.
- Five studies reported hospital length of stay. Hospital length of stay was reduced with procalcitonin-guided therapy in four of five studies, with an absolute reduction in days ranging from -0.5 to -1. The differences were not statistically significant in any of the studies.
- Five studies reported the need for ICU admission. ICU admission rates were reduced with procalcitonin-guided therapy with absolute reductions ranging from -0.7 to -2.5 percent. None of the reductions in ICU admissions was statistically significant.
Three studies reported on antibiotic adverse effects; however, the data were inconsistent and imprecise. Two studies reported percentages with absolute differences of -8.2 percent and 2.8 percent, and one study reported an absolute difference of -1.1 days that was statistically significant. The data for this outcome were limited and did not permit conclusions about the impact of procalcitonin-guided therapy on antibiotic-associated adverse events; the strength of evidence for this finding was rated insufficient.
Reference:
Soni NJ, Samson DJ, Galaydick JL, et al. Procalcitonin-Guided Antibiotic Therapy. Comparative Effectiveness Review No. 78 (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; August AHRQ Publication No. 12-EHC124-EF. Available at
Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ Comparative Effectiveness Review No. 78.
Available at

14. Effects of Using Procalcitonin To Guide Antibiotic Therapy in Pediatric Patients
Procalcitonin guidance reduced the use of antibiotic therapy for suspected early neonatal sepsis. Strength of Evidence: Moderate
The evidence was insufficient to determine if procalcitonin guidance reduced antibiotic usage in children aged 1–36 months with fever. Strength of Evidence: Insufficient
Effects of Using Procalcitonin To Guide Antibiotic Therapy in Pediatric Patients
Procalcitonin guidance reduced the use of antibiotic therapy in neonates with suspected sepsis. The strength of evidence for this finding was rated moderate. A single study of 101 neonates reported on procalcitonin-guided antibiotic usage. The duration of antibiotic use was significantly decreased overall by 22.4 hours (24% reduction; 0.002), with the greatest differences seen for the 80 to 85 percent of neonates who had possible infection or were unlikely to have infection and little difference for the small proportion of neonates with proven or probable P =infection. The proportion of neonates on antibiotics for 72 or more hours was significantly reduced overall by 27 percent (P = 0.012). There were no deaths in either arm. A small, statistically insignificant reduction in morbidity (assessed as infection recurrence rates) was observed.
The strength of evidence was judged insufficient to permit conclusions on outcomes of procalcitonin-guided antibiotic therapy for fever of unknown source in children 1–36 months of age. A single study was identified that reported on procalcitonin guidance for antibiotic therapy in children aged 1–36 months with fever. There were no differences in the antibiotic prescription rates or hospitalization rate, although rates were low for both arms with only one-quarter of children being hospitalized and receiving antibiotics.
Reference: Soni NJ, Samson DJ, Galaydick JL, et al. Procalcitonin-Guided Antibiotic Therapy. Comparative Effectiveness Review No. 78 (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; August AHRQ Publication No. 12-EHC124-EF. Available at
Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ Comparative Effectiveness Review No. 78.
Available at

15. Effects of Using Procalcitonin To Guide Antibiotic Therapy in Postoperative Patients
Evidence was insufficient to determine if procalcitonin guidance can identify postoperative patients at risk of developing infections who might benefit from pre-emptive antibiotic therapy. Strength of Evidence: Insufficient
Effects of Using Procalcitonin To Guide Antibiotic Therapy in Postoperative Patients
Evidence was insufficient to determine if procalcitonin guidance can identify postoperative patients at risk of developing infections who might benefit from pre-emptive antibiotic therapy. A single study evaluated outcomes in 20 postoperative patients with elevated procalcitonin levels who were randomized to receive either prophylactic or pre-emptive antibiotic therapy or standard care (control). Procalcitonin-guided pre-emptive antibiotic therapy reduced the duration of antibiotic therapy by 3.5 days when compared with the control arm; however, this difference was not statistically significant. Patients in the control arm had a significantly prolonged hospital length of stay (12 days longer; P = 0.057) and a significantly higher incidence of systemic infection (P = 0.07). However, due to small size of the study, the strength of evidence for this finding was rated insufficient.
Reference: Soni NJ, Samson DJ, Galaydick JL, et al. Procalcitonin-Guided Antibiotic Therapy. Comparative Effectiveness Review No. 78 (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; August AHRQ Publication No. 12-EHC124-EF. Available at
Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ Comparative Effectiveness Review No. 78.
Available at

16. Conclusions (1 of 2)
Procalcitonin guidance for antibiotic discontinuation reduced antibiotic usage in adult patients in intensive care units (ICUs) without increasing mortality.
However, there was uncertainty related to the evidence on mortality.
The use of procalcitonin to guide antibiotic intensification rather than discontinuation in adult patients in ICUs resulted in increased antibiotic usage, which was associated with increased morbidity.
Conclusions (1 of 2)
The strength of evidence was judged to be high that procalcitonin guidance reduces antibiotic usage. The absolute difference in duration of antibiotic use, the measure that was reported by all five studies, ranged from -1.7 to -5.0 days, with relative reductions that ranged from 21 to 38 percent. The strength of evidence was judged low that procalcitonin-guided antibiotic therapy in the intensive care unit (ICU) does not increase mortality. Evidence on mortality was downgraded to low based on uncertainty about the appropriate noninferiority margin for this outcome.
There is moderate-strength evidence that procalcitonin-guided intensification of antibiotic therapy that broadens the spectrum of bacterial coverage does not improve outcomes in critically ill patients and, in fact, may have adverse consequences. A large (n = 1,200), good-quality trial found greater duration and increased total exposure to antibiotics with procalcitonin guidance. There was also increased morbidity, including significant increases in ICU length of stay, days on mechanical ventilation, and days with abnormal renal function.
Reference: Soni NJ, Samson DJ, Galaydick JL, et al. Procalcitonin-Guided Antibiotic Therapy. Comparative Effectiveness Review No. 78 (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; August AHRQ Publication No. 12-EHC124-EF. Available at
Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ Comparative Effectiveness Review No. 78.
Available at

17. Conclusions (2 of 2)
Procalcitonin guidance for initiating and discontinuing antibiotic therapy significantly reduced antibiotic prescription rates and duration of use in patients with acute respiratory tract infections (including acute exacerbations of chronic obstructive pulmonary disease, community-acquired pneumonia, and acute bronchitis) in the ambulatory care or hospital setting.
Data to support a role for procalcitonin guidance in the pediatric population were lacking in the literature.
However, there was moderate-strength evidence showing that procalcitonin guidance resulted in reduced antibiotic usage in neonates with suspected early sepsis.
Conclusions (2 of 2)
There was high-strength evidence that procalcitonin guidance reduces antibiotic duration and prescription rates in patients with respiratory tract infections (including acute exacerbations of chronic obstructive pulmonary disease, community-acquired pneumonia, and acute bronchitis) in the ambulatory care or hospital setting. There was moderate-strength evidence of reduction in total antibiotic exposure in patients with respiratory tract infections in the ambulatory care or hospital setting. Absolute reduction in duration of antibiotic therapy ranged from 1 to 7 days, with relative reductions ranging from -13 to -55 percent. Absolute reduction in prescription rates ranged from -2 to -7 percent, with relative reductions ranging from -1.8 to -72 percent. There was moderate-strength evidence that procalcitonin guidance did not increase mortality, hospital length of stay, or ICU admission rates. There was insufficient evidence to judge effects on days of restricted activity or on antibiotic adverse events.
One good-quality study provided moderate-strength evidence that procalcitonin guidance reduces the use of antibiotic therapy for suspected early neonatal sepsis. The overall duration of antibiotic use was reduced by 22.4 hours (22.0%). Further, the proportion of neonates on antibiotics for longer than 72 hours was reduced by 27 percent. The strength of evidence was judged insufficient to permit conclusions on mortality and morbidity due to the small study size.
Evidence was insufficient to determine the effects of using procalcitonin-guided antibiotic therapy in children aged 1–36 months with suspected infections and in postoperative patients with suspected infections.
Reference: Soni NJ, Samson DJ, Galaydick JL, et al. Procalcitonin-Guided Antibiotic Therapy. Comparative Effectiveness Review No. 78 (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; August AHRQ Publication No. 12-EHC124-EF. Available at
Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ Comparative Effectiveness Review No. 78.
Available at

18. Applicability of the Findings of This Review
This systematic review found that procalcitonin guidance for antibiotic discontinuation reduces antibiotic usage for adult patients in both medical and surgical intensive care units (ICUs) and, therefore, is applicable to clinical practice related to antibiotic discontinuation in the ICU settings.
This systematic review found that procalcitonin guidance for initiating and discontinuing antibiotic therapy for patients with respiratory tract infections in the ambulatory care or hospital setting significantly reduced antibiotic prescription rates and duration of use and, hence, is applicable to these patient populations.
Certain populations of interest were excluded from one or more studies of procalcitonin guidance reviewed in this report. Thus, findings from this review should not be extrapolated to these high-risk groups.
Applicability of the Findings of This Review
This systematic review found that procalcitonin guidance for antibiotic discontinuation reduces antibiotic usage for adult patients in both medical and surgical intensive care units (ICUs); thus, the evidence from this review is applicable to clinical practice related to antibiotic discontinuation in the ICU setting.
Approximately 75 percent of all antibiotics prescribed in the ambulatory care setting are for acute respiratory tract infections (RTIs), most of which are viral and do not benefit from antibiotic treatment. Clinical and microbiological evaluations lack the sensitivity and specificity to differentiate bacterial from viral RTIs. This systematic review found that procalcitonin guidance for initiating and discontinuing antibiotic therapy for patients with RTIs in the ambulatory care or hospital setting significantly reduced antibiotic prescription rates and duration of use and, hence, is applicable to patients with respiratory tract infections in the hospital or ambulatory care setting.
Certain populations of interest were excluded from one or more of the studies of procalcitonin guidance reviewed in this report. Thus, findings from this review should not be extrapolated to these high-risk groups including pregnant women, immunocompromised patients, and patients with chronic infections such as endocarditis.
Reference: Soni NJ, Samson DJ, Galaydick JL, et al. Procalcitonin-Guided Antibiotic Therapy. Comparative Effectiveness Review No. 78 (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; August AHRQ Publication No. 12-EHC124-EF. Available at
Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ Comparative Effectiveness Review No. 78.
Available at

19. Gaps in Knowledge and Future Research Needs (1 of 2)
Assessing the effect of using procalcitonin guidance in patients who are immunocompromised is an important research need, as this patient population may gain significant clinical benefit from potentially reduced antibiotic usage.
Future studies are needed to assess procalcitonin-guided initiation and discontinuation of antibiotics in pediatric populations in both inpatient and outpatient settings.
Future studies are needed to assess the effects of procalcitonin-guided antibiotic usage and total exposure on antibiotic-associated adverse reactions, superinfections, or the development of antibiotic resistance.
Gaps in Knowledge and Future Research Needs (1 of 2)
The review identified several knowledge gaps and research needs in the current literature on the use of procalcitonin to guide antibiotic therapy in various patient populations that include:
- The need for conducting research studies to assess the effect of using procalcitonin guidance in patients who are immunocompromised, as this patient population may gain significant clinical benefit from potentially reduced antibiotic usage
- The need for future research on the effects of procalcitonin-guided initiation and discontinuation of antibiotic therapy for pediatric populations in inpatient and outpatient settings
- The need for evaluations of the effects of procalcitonin-guided antibiotic exposure on antibiotic-associated adverse effects, superinfections, or the development of antibiotic resistance in future research studies
Reference: Soni NJ, Samson DJ, Galaydick JL, et al. Procalcitonin-Guided Antibiotic Therapy. Comparative Effectiveness Review No. 78 (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; August AHRQ Publication No. 12-EHC124-EF. Available at
Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ Comparative Effectiveness Review No. 78.
Available at

20. Gaps in Knowledge and Future Research Needs (2 of 2)
More research is needed regarding the effect on mortality of reduced antibiotic usage resulting from procalcitonin-guided antibiotic therapy.
For a more pertinent comparative effectiveness approach, different comparators should have been selected, such as antibiotic stewardship programs and structured implementation of practice guidelines.
Additional future research needs include the determination of the appropriate procalcitonin cutoff level in different populations, and assessment of the cost-effectiveness of using procalcitonin to guide antibiotic therapy.
Gaps in Knowledge and Future Research Needs (2 of 2)
Other knowledge gaps and research needs that were identified in the current literature on the use of procalcitonin to guide antibiotic therapy in various patient populations include:
- The need for additional research about the effect on mortality of reduced antibiotic usage resulting from procalcitonin guidance
- The importance of selecting different comparators such as antibiotic stewardship programs and structured implementation of practice guidelines when conducting comparative effectiveness reviews in the future
- The need to determine the appropriate procalcitonin cutoff level in various patient populations, and the need to evaluate the cost-effectiveness of using procalcitonin to guide antibiotic therapy
Reference: Soni NJ, Samson DJ, Galaydick JL, et al. Procalcitonin-Guided Antibiotic Therapy. Comparative Effectiveness Review No. 78 (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; August AHRQ Publication No. 12-EHC124-EF. Available at
Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ Comparative Effectiveness Review No. 78.
Available at