Bryan J Huang, MD, FHM

The case

A 72-year-old male with COPD presents to the emergency department with increased dyspnea and cough. He is afebrile, and oxygen saturation is 87% on room air. WBC count is 9.5 with a normal differential, and chest x-ray is read by the radiologist as atelectasis versus early consolidation in the left lower lobe. Should antibiotics be initiated?

Background

The problem: Antibiotic overuse

With the increasing prevalence of antibiotic resistance in our nation’s hospitals, the need for robust antibiotic stewardship programs has continued to rise in importance. In 2016, the CDC reported a fatal case of septic shock due to a carbapenem-resistant strain of Klebsiella resistant to all tested antibiotics.¹ This case received much media coverage; moreover, this patient represented only one of the approximately 23,000 patients infected with antibiotic-resistant bacteria in the United States who die each year. Although various approaches to curbing antibiotic resistance are being pursued, judicious antibiotic use is central to success. Current evidence suggests that up to 30% of antibiotics are not optimally prescribed,² leaving a significant opportunity for improvement.

Lower respiratory infections account for a substantial proportion of antibiotic utilization in the United States. In a recent study, acute respiratory conditions generated 221 antibiotic prescriptions per 1,000 population, but only half of these were deemed appropriate.² The inability to reliably discern viral from bacterial etiology is a driver of excess antibiotic use.

Dr Graham Beards/en.wikipedia/CC BY-SA 4.0

The procalcitonin assay has been touted as a possible solution to this problem. Multiple studies have evaluated its utility as a tool to help discriminate between bacterial infection and viral or noninfectious etiologies.
 

What is procalcitonin?

Thyroidal c-cells convert the prohormone procalcitonin to calcitonin, which is stored in secretory granules for release in response to fluctuations in calcium levels via a classical neuroendocrine feedback loop. Alternatively, procalcitonin can be synthesized in nonthyroidal parenchymal cells, and high levels of proinflammatory mediators secreted in response to bacterial endotoxin drive increased procalcitonin production. Interestingly, interferon gamma, up-regulated in viral infections, reduces procalcitonin production. Nonthyroidal parenchymal cells lack mechanisms for efficient conversion of procalcitonin to calcitonin and do not contain secretory granules to facilitate its regulated release. Hence bacterial infections correlate with higher serum procalcitonin levels.³ 

Evidence

Can procalcitonin guide antibiotic therapy in patients with acute respiratory illness while reducing antibiotic utilization?

The ability of procalcitonin to selectively identify bacterial infection makes it a potentially promising tool to advance the antibiotic stewardship agenda. Multiple randomized controlled trials have explored the use of procalcitonin-guided antibiotic therapy for treatment of lower respiratory tract infections such as acute bronchitis, exacerbations of COPD, and pneumonia. Each study discussed below was done in Switzerland, involved the same key investigator (Mirjam Christ-Crain, MD, PhD), and shared a similar design in which a threshold for low procalcitonin values (less than 0.1 mcg/L) and high procalcitonin values (greater than 0.25 mcg/L) was prespecified. Antibiotic therapy was strongly discouraged for patients with low procalcitonin and encouraged for those with high procalcitonin; antibiotics were not recommended for patients with intermediate values, but the treating physician was allowed ultimate discretion (Figure 1). All studies compared a procalcitonin-guided treatment group to a standard care group, in which antibiotics were prescribed by the treating physician based on established clinical guidelines.

Figure 1. Procalcitonin treatment algorithm

 

Procalcitonin Level (mcg/L)	Likelihood of bacterial infection	Antibiotic treatment
less than 0.1	Absent	Strongly discouraged
0.1-0.25	Unlikely	Discouraged
0.25-0.5	Possible	Encouraged
greater than 0.5	Present	Strongly encouraged

Figure 1. Procalcitonin treatment algorithm

In a study focusing on outpatients presenting to their primary care physicians with acute respiratory tract infection, 53 primary care physicians in Switzerland recruited 458 patients. There was no significant difference in time to symptom resolution, as determined by patient report during an interview 14 days after initial presentation; however, 97% of patients in the standard-care group received antibiotics, compared with 25% in the procalcitonin-guided group. Equal numbers of patients (30% in each group) reported persistent symptoms at 28-day follow-up. Among the cohort of patients with upper respiratory infections or acute bronchitis, procalcitonin guidance reduced antibiotic prescriptions by 80%.⁴

In a blinded, single-center, randomized, controlled trial of 226 patients presenting to a university hospital with a COPD exacerbation severe enough to require a change in the baseline medication regimen, procalcitonin-guided therapy allowed for an absolute reduction of antibiotic use by 32% without an impact on outcomes. Rates of clinical improvement, ICU utilization, recurrent exacerbations, hospital length of stay, and mortality did not differ between the groups.⁵

Another study by Dr. Christ-Crain looked at whether procalcitonin could be used to determine duration of antibiotic therapy in hospitalized pneumonia patients. In a similarly designed randomized, nonblinded trial with two arms, a procalcitonin group (n = 151) and a standard care group (n = 151), procalcitonin levels were checked at 4, 6, and 8 days, with similar cutoffs regarding levels for which antibiotics were encouraged or discouraged. Antibiotic treatment duration was reduced from a median of 12 days in the standard-care group to 5 days in the procalcitonin group (P less than .001). There was no difference in the success rate of treatment, readmission rate, or death rate between the two groups.⁶These initial studies were limited by their relatively small size and narrow scope. The ProHOSP study was the first large, multicenter study to address the utility of procalcitonin-guided antibiotic therapy. Design was similar, although the decision to treat with antibiotics was more rigorously controlled by the centralized study personnel. The study enrolled 1,359 patients in the emergency departments of six Swiss tertiary-care hospitals. Most patients had pneumonia, but 17% had COPD exacerbation and 11% had acute bronchitis. No difference in death, ICU admission, readmission, or disease-specific complications was noted. Antibiotic exposure was reduced by 34.8% in the procalcitonin group, with a mean of 8.7 days versus 5.7 days on antibiotics.⁷In combination, the studies above support the use of procalcitonin to guide decisions about antibiotic use in patients with lower respiratory tract infections; antibiotic use can be significantly reduced without adverse outcomes. Further, sequential monitoring of procalcitonin levels may help guide duration of antibiotic therapy. These studies all had fairly high rates of follow-up and the ProHOSP study, in particular, had a large, representative sample and a rigorous methodology to standardize antibiotic prescription in the control group.

Limitations include the possible impact of the Hawthorne effect, as physicians knew their antibiotic usage patterns were being monitored, which may impact generalizability of the findings to a real-world setting. Similarly, it is difficult to control for a spillover effect as providers exposed to the procalcitonin-guided algorithm became more comfortable with a restrictive prescribing approach. The costs of the additional procalcitonin assay must be weighed against the benefits. Incidence and cost of other adverse effects of antibiotic use (rates of Clostridium difficile, renal insufficiency, urticarial drug eruptions, etc.) were not addressed. The rapid assay currently has limited availability in the United States, though that is changing. Finally, recent additional studies (unrelated to procalcitonin) have suggested shorter antibiotic treatment durations for patients with pneumonia.⁸

 

Is there evidence for using procalcitonin to guide treatment in the broader population of ICU patients?

While there is good evidence for using procalcitonin to guide antibiotic use in patients with acute respiratory illness, the evidence for using procalcitonin in the broader cohort of critically-ill patients with sepsis is less well established.

The most promising results were reported by the Stop Antibiotics on Procalcitonin guidance Study (SAPS). Published in July 2016, this was a prospective, multicenter, randomized, controlled, open-label study of patients admitted to the ICU (not limited to respiratory illness) in the Netherlands. A total of 1,575 patients were assigned to the procalcitonin-guided group or the standard-of-care group. In the procalcitonin-guided group, procalcitonin levels were checked daily, and physicians were given nonbinding advice to discontinue antibiotics if procalcitonin levels decreased by greater than 80% from peak levels or to below 0.5 mcg/L.

Sheep purple/flickr/CC BY 2.0 /en.wikipedia/CC BY-SA 4.0

Patients received an average of 7.5 daily defined antibiotic doses in the procalcitonin-guided group versus 9.3 daily defined doses in the standard-of-care group (P less than .0001). The median duration of antibiotic treatment in the procalcitonin arm was 5 days versus 7 days in the control group (P less than .0001). Mortality at 28 days was 20% in the procalcitonin group and 25% in the control group (P = .0122). At 1 year, mortality was 36% in the procalcitonin group and 43% in the control group (P = .0188). The authors hypothesized that the unexpected decrease in mortality in the procalcitonin group may have been due to earlier consideration of alternate illness etiologies in patients with a low procalcitonin level or decreased antibiotic side effects.⁹While the SAPS trial supports decreased antibiotic usage in ICU patients with the use of the procalcitonin assay, there are some important limitations. First, the trial was done in the Netherlands, where baseline antibiotic usage was comparatively low. Second, daily procalcitonin level monitoring was not continued for patients transferred out of the ICU while still on antibiotics. Further, guidelines for antibiotic discontinuation were nonbinding, and in many cases physicians did not stop antibiotics based on procalcitonin guidelines suggested by the study authors.

Earlier trials regarding the procalcitonin assay in the critical care setting similarly showed some promise but also concerns. One trial reported a 25% reduction in antibiotic exposure and noninferiority of 28-day mortality, but there was a nonsignificant 3.8% absolute increase in mortality at 60 days.¹⁰ Another trial reported similar survival in the procalcitonin group but more side effects and longer ICU stays.¹¹Ultimately, while the SAPS trial supports the potential use of procalcitonin in critically-ill patients, these patients likely have complex sepsis physiology that requires clinicians to consider a number of clinical factors when making antibiotic decisions.

Back to the case

The case illustrates a common emergency department presentation where clinical and radiographic features are not convincing for bacterial infection. This patient has an acute respiratory illness, but is afebrile and lacks leukocytosis with left shift, and x-rays are indeterminate for pneumonia. The differential diagnosis also includes COPD exacerbation, viral infection, or noninfectious triggers of dyspnea.

In this scenario, obtaining procalcitonin levels is useful in the decision to initiate or withhold antibiotic treatment. An elevated procalcitonin level suggests a bacterial infection and would favor initiation of antibiotics for pneumonia. A low procalcitonin level makes a bacterial infection less likely, and a clinician may consider withholding antibiotics and consider alternate etiologies for the patient’s presentation.

Bottom line

Procalcitonin can be safely used to guide the decision to initiate antibiotics in patients presenting with acute respiratory illness. Use of the procalcitonin assay has been shown to reduce antibiotic utilization without an increase in adverse outcomes. There is potential but less conclusive evidence for procalcitonin usage in the broader population of ICU patients with sepsis.
 

Bryan J. Huang, MD, FHM, and Gregory B. Seymann, MD, SFHM, are in the division of hospital medicine, University of California, San Diego.

 

• Key Points
• Elevated procalcitonin levels suggest the presence of bacterial infection.
• In patients presenting with acute respiratory illness, procalcitonin levels can be used to guide the decision to initiate or withhold antibiotics, improving antibiotic stewardship.
• Sequential monitoring of procalcitonin levels may help guide duration of antibiotic therapy.
• There is potential but less conclusive evidence for procalcitonin usage in the broader population of ICU patients with sepsis.


•  

References

1. Chen L, Todd R, Kiehlbauch J, Walters M, Kallen A. Notes from the field: pan-resistant New Delhi metallo-beta-lactamase-producing Klebsiella pneumoniae – Washoe County, Nevada, 2016. MMWR Morb Mortal Wkly Rep 2017; 66(1):33.

2. Fleming-Dutra KE, Hersh AL, Shapiro DJ, et al. Prevalence of inappropriate antibiotic prescriptions among US ambulatory care visits, 2010-2011. JAMA 2016;315(17):1864-73.

3. Christ-Crain M, Muller B. Procalcitonin in bacterial infections – hype, hope, more or less? Swiss Med Wkly. 2005;135(31-32):451-60.

4. 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): 2000-7.

5. 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.

6. Christ-Crain M, Stolz D, Bingisser R, et al. Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial. Am J Respir Crit Care Med. 2006;174(1):84-93.

7. Schuetz P, Christ-Crain M, Thomann R, et al. Effect of procalcitonin-based guidelines vs. standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA 2009; 302(10): 1059-66.

8. Uranga A, Espana PP, Bilbao A, et al. Duration of antibiotic treatment in community-acquired pneumonia: a multicenter randomized clinical trial. JAMA Intern Med. 2016;176(9):1257-65.

9. de Jong E, van Oers JA, Beishiozen A, et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis. 2016;16(7):819-27.

10. Bouadma L, Luyt CE, Tubach F, et al. Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet 2010;375(9713):463-74.

11. Jensen J-U, Lundgren B, Hein L, et al. The procalcitonin and survival study (PASS) – a randomised multicenter investigator-initiated trial to investigate whether daily measurements biomarker procalcitonin and proactive diagnostic and therapeutic responses to abnormal procalcitonin levels, can improve survival in intensive care unit patients. BMC infectious diseases. 2008;8:91-100.

 

Additional reading

1. Schuetz P, Christ-Crain M, Thomann R, et al. Effect of procalcitonin-based guidelines vs. standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA 2009;302(10):1059-66.

2. de Jong E, van Oers JA, Beishiozen A, et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis. 2016;16(7):819-27.

3. Schuetz P, Muller B, Christ-Crain M, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev. 2012;(9):CD007498.

The case

A 72-year-old male with COPD presents to the emergency department with increased dyspnea and cough. He is afebrile, and oxygen saturation is 87% on room air. WBC count is 9.5 with a normal differential, and chest x-ray is read by the radiologist as atelectasis versus early consolidation in the left lower lobe. Should antibiotics be initiated?

Background

The problem: Antibiotic overuse

With the increasing prevalence of antibiotic resistance in our nation’s hospitals, the need for robust antibiotic stewardship programs has continued to rise in importance. In 2016, the CDC reported a fatal case of septic shock due to a carbapenem-resistant strain of Klebsiella resistant to all tested antibiotics.¹ This case received much media coverage; moreover, this patient represented only one of the approximately 23,000 patients infected with antibiotic-resistant bacteria in the United States who die each year. Although various approaches to curbing antibiotic resistance are being pursued, judicious antibiotic use is central to success. Current evidence suggests that up to 30% of antibiotics are not optimally prescribed,² leaving a significant opportunity for improvement.

Lower respiratory infections account for a substantial proportion of antibiotic utilization in the United States. In a recent study, acute respiratory conditions generated 221 antibiotic prescriptions per 1,000 population, but only half of these were deemed appropriate.² The inability to reliably discern viral from bacterial etiology is a driver of excess antibiotic use.

Dr Graham Beards/en.wikipedia/CC BY-SA 4.0

The procalcitonin assay has been touted as a possible solution to this problem. Multiple studies have evaluated its utility as a tool to help discriminate between bacterial infection and viral or noninfectious etiologies.
 

What is procalcitonin?

Thyroidal c-cells convert the prohormone procalcitonin to calcitonin, which is stored in secretory granules for release in response to fluctuations in calcium levels via a classical neuroendocrine feedback loop. Alternatively, procalcitonin can be synthesized in nonthyroidal parenchymal cells, and high levels of proinflammatory mediators secreted in response to bacterial endotoxin drive increased procalcitonin production. Interestingly, interferon gamma, up-regulated in viral infections, reduces procalcitonin production. Nonthyroidal parenchymal cells lack mechanisms for efficient conversion of procalcitonin to calcitonin and do not contain secretory granules to facilitate its regulated release. Hence bacterial infections correlate with higher serum procalcitonin levels.³ 

Evidence

Can procalcitonin guide antibiotic therapy in patients with acute respiratory illness while reducing antibiotic utilization?

The ability of procalcitonin to selectively identify bacterial infection makes it a potentially promising tool to advance the antibiotic stewardship agenda. Multiple randomized controlled trials have explored the use of procalcitonin-guided antibiotic therapy for treatment of lower respiratory tract infections such as acute bronchitis, exacerbations of COPD, and pneumonia. Each study discussed below was done in Switzerland, involved the same key investigator (Mirjam Christ-Crain, MD, PhD), and shared a similar design in which a threshold for low procalcitonin values (less than 0.1 mcg/L) and high procalcitonin values (greater than 0.25 mcg/L) was prespecified. Antibiotic therapy was strongly discouraged for patients with low procalcitonin and encouraged for those with high procalcitonin; antibiotics were not recommended for patients with intermediate values, but the treating physician was allowed ultimate discretion (Figure 1). All studies compared a procalcitonin-guided treatment group to a standard care group, in which antibiotics were prescribed by the treating physician based on established clinical guidelines.

Figure 1. Procalcitonin treatment algorithm

 

Procalcitonin Level (mcg/L)	Likelihood of bacterial infection	Antibiotic treatment
less than 0.1	Absent	Strongly discouraged
0.1-0.25	Unlikely	Discouraged
0.25-0.5	Possible	Encouraged
greater than 0.5	Present	Strongly encouraged

Figure 1. Procalcitonin treatment algorithm

In a study focusing on outpatients presenting to their primary care physicians with acute respiratory tract infection, 53 primary care physicians in Switzerland recruited 458 patients. There was no significant difference in time to symptom resolution, as determined by patient report during an interview 14 days after initial presentation; however, 97% of patients in the standard-care group received antibiotics, compared with 25% in the procalcitonin-guided group. Equal numbers of patients (30% in each group) reported persistent symptoms at 28-day follow-up. Among the cohort of patients with upper respiratory infections or acute bronchitis, procalcitonin guidance reduced antibiotic prescriptions by 80%.⁴

In a blinded, single-center, randomized, controlled trial of 226 patients presenting to a university hospital with a COPD exacerbation severe enough to require a change in the baseline medication regimen, procalcitonin-guided therapy allowed for an absolute reduction of antibiotic use by 32% without an impact on outcomes. Rates of clinical improvement, ICU utilization, recurrent exacerbations, hospital length of stay, and mortality did not differ between the groups.⁵

Another study by Dr. Christ-Crain looked at whether procalcitonin could be used to determine duration of antibiotic therapy in hospitalized pneumonia patients. In a similarly designed randomized, nonblinded trial with two arms, a procalcitonin group (n = 151) and a standard care group (n = 151), procalcitonin levels were checked at 4, 6, and 8 days, with similar cutoffs regarding levels for which antibiotics were encouraged or discouraged. Antibiotic treatment duration was reduced from a median of 12 days in the standard-care group to 5 days in the procalcitonin group (P less than .001). There was no difference in the success rate of treatment, readmission rate, or death rate between the two groups.⁶These initial studies were limited by their relatively small size and narrow scope. The ProHOSP study was the first large, multicenter study to address the utility of procalcitonin-guided antibiotic therapy. Design was similar, although the decision to treat with antibiotics was more rigorously controlled by the centralized study personnel. The study enrolled 1,359 patients in the emergency departments of six Swiss tertiary-care hospitals. Most patients had pneumonia, but 17% had COPD exacerbation and 11% had acute bronchitis. No difference in death, ICU admission, readmission, or disease-specific complications was noted. Antibiotic exposure was reduced by 34.8% in the procalcitonin group, with a mean of 8.7 days versus 5.7 days on antibiotics.⁷In combination, the studies above support the use of procalcitonin to guide decisions about antibiotic use in patients with lower respiratory tract infections; antibiotic use can be significantly reduced without adverse outcomes. Further, sequential monitoring of procalcitonin levels may help guide duration of antibiotic therapy. These studies all had fairly high rates of follow-up and the ProHOSP study, in particular, had a large, representative sample and a rigorous methodology to standardize antibiotic prescription in the control group.

Limitations include the possible impact of the Hawthorne effect, as physicians knew their antibiotic usage patterns were being monitored, which may impact generalizability of the findings to a real-world setting. Similarly, it is difficult to control for a spillover effect as providers exposed to the procalcitonin-guided algorithm became more comfortable with a restrictive prescribing approach. The costs of the additional procalcitonin assay must be weighed against the benefits. Incidence and cost of other adverse effects of antibiotic use (rates of Clostridium difficile, renal insufficiency, urticarial drug eruptions, etc.) were not addressed. The rapid assay currently has limited availability in the United States, though that is changing. Finally, recent additional studies (unrelated to procalcitonin) have suggested shorter antibiotic treatment durations for patients with pneumonia.⁸

 

Is there evidence for using procalcitonin to guide treatment in the broader population of ICU patients?

While there is good evidence for using procalcitonin to guide antibiotic use in patients with acute respiratory illness, the evidence for using procalcitonin in the broader cohort of critically-ill patients with sepsis is less well established.

The most promising results were reported by the Stop Antibiotics on Procalcitonin guidance Study (SAPS). Published in July 2016, this was a prospective, multicenter, randomized, controlled, open-label study of patients admitted to the ICU (not limited to respiratory illness) in the Netherlands. A total of 1,575 patients were assigned to the procalcitonin-guided group or the standard-of-care group. In the procalcitonin-guided group, procalcitonin levels were checked daily, and physicians were given nonbinding advice to discontinue antibiotics if procalcitonin levels decreased by greater than 80% from peak levels or to below 0.5 mcg/L.

Sheep purple/flickr/CC BY 2.0 /en.wikipedia/CC BY-SA 4.0

Patients received an average of 7.5 daily defined antibiotic doses in the procalcitonin-guided group versus 9.3 daily defined doses in the standard-of-care group (P less than .0001). The median duration of antibiotic treatment in the procalcitonin arm was 5 days versus 7 days in the control group (P less than .0001). Mortality at 28 days was 20% in the procalcitonin group and 25% in the control group (P = .0122). At 1 year, mortality was 36% in the procalcitonin group and 43% in the control group (P = .0188). The authors hypothesized that the unexpected decrease in mortality in the procalcitonin group may have been due to earlier consideration of alternate illness etiologies in patients with a low procalcitonin level or decreased antibiotic side effects.⁹While the SAPS trial supports decreased antibiotic usage in ICU patients with the use of the procalcitonin assay, there are some important limitations. First, the trial was done in the Netherlands, where baseline antibiotic usage was comparatively low. Second, daily procalcitonin level monitoring was not continued for patients transferred out of the ICU while still on antibiotics. Further, guidelines for antibiotic discontinuation were nonbinding, and in many cases physicians did not stop antibiotics based on procalcitonin guidelines suggested by the study authors.

Earlier trials regarding the procalcitonin assay in the critical care setting similarly showed some promise but also concerns. One trial reported a 25% reduction in antibiotic exposure and noninferiority of 28-day mortality, but there was a nonsignificant 3.8% absolute increase in mortality at 60 days.¹⁰ Another trial reported similar survival in the procalcitonin group but more side effects and longer ICU stays.¹¹Ultimately, while the SAPS trial supports the potential use of procalcitonin in critically-ill patients, these patients likely have complex sepsis physiology that requires clinicians to consider a number of clinical factors when making antibiotic decisions.

Back to the case

The case illustrates a common emergency department presentation where clinical and radiographic features are not convincing for bacterial infection. This patient has an acute respiratory illness, but is afebrile and lacks leukocytosis with left shift, and x-rays are indeterminate for pneumonia. The differential diagnosis also includes COPD exacerbation, viral infection, or noninfectious triggers of dyspnea.

In this scenario, obtaining procalcitonin levels is useful in the decision to initiate or withhold antibiotic treatment. An elevated procalcitonin level suggests a bacterial infection and would favor initiation of antibiotics for pneumonia. A low procalcitonin level makes a bacterial infection less likely, and a clinician may consider withholding antibiotics and consider alternate etiologies for the patient’s presentation.

Bottom line

Procalcitonin can be safely used to guide the decision to initiate antibiotics in patients presenting with acute respiratory illness. Use of the procalcitonin assay has been shown to reduce antibiotic utilization without an increase in adverse outcomes. There is potential but less conclusive evidence for procalcitonin usage in the broader population of ICU patients with sepsis.
 

Bryan J. Huang, MD, FHM, and Gregory B. Seymann, MD, SFHM, are in the division of hospital medicine, University of California, San Diego.

 

• Key Points
• Elevated procalcitonin levels suggest the presence of bacterial infection.
• In patients presenting with acute respiratory illness, procalcitonin levels can be used to guide the decision to initiate or withhold antibiotics, improving antibiotic stewardship.
• Sequential monitoring of procalcitonin levels may help guide duration of antibiotic therapy.
• There is potential but less conclusive evidence for procalcitonin usage in the broader population of ICU patients with sepsis.


•  

References

1. Chen L, Todd R, Kiehlbauch J, Walters M, Kallen A. Notes from the field: pan-resistant New Delhi metallo-beta-lactamase-producing Klebsiella pneumoniae – Washoe County, Nevada, 2016. MMWR Morb Mortal Wkly Rep 2017; 66(1):33.

2. Fleming-Dutra KE, Hersh AL, Shapiro DJ, et al. Prevalence of inappropriate antibiotic prescriptions among US ambulatory care visits, 2010-2011. JAMA 2016;315(17):1864-73.

3. Christ-Crain M, Muller B. Procalcitonin in bacterial infections – hype, hope, more or less? Swiss Med Wkly. 2005;135(31-32):451-60.

4. 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): 2000-7.

5. 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.

6. Christ-Crain M, Stolz D, Bingisser R, et al. Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial. Am J Respir Crit Care Med. 2006;174(1):84-93.

7. Schuetz P, Christ-Crain M, Thomann R, et al. Effect of procalcitonin-based guidelines vs. standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA 2009; 302(10): 1059-66.

8. Uranga A, Espana PP, Bilbao A, et al. Duration of antibiotic treatment in community-acquired pneumonia: a multicenter randomized clinical trial. JAMA Intern Med. 2016;176(9):1257-65.

9. de Jong E, van Oers JA, Beishiozen A, et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis. 2016;16(7):819-27.

10. Bouadma L, Luyt CE, Tubach F, et al. Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet 2010;375(9713):463-74.

11. Jensen J-U, Lundgren B, Hein L, et al. The procalcitonin and survival study (PASS) – a randomised multicenter investigator-initiated trial to investigate whether daily measurements biomarker procalcitonin and proactive diagnostic and therapeutic responses to abnormal procalcitonin levels, can improve survival in intensive care unit patients. BMC infectious diseases. 2008;8:91-100.

 

Additional reading

1. Schuetz P, Christ-Crain M, Thomann R, et al. Effect of procalcitonin-based guidelines vs. standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA 2009;302(10):1059-66.

2. de Jong E, van Oers JA, Beishiozen A, et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis. 2016;16(7):819-27.

3. Schuetz P, Muller B, Christ-Crain M, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev. 2012;(9):CD007498.

The case

A 72-year-old male with COPD presents to the emergency department with increased dyspnea and cough. He is afebrile, and oxygen saturation is 87% on room air. WBC count is 9.5 with a normal differential, and chest x-ray is read by the radiologist as atelectasis versus early consolidation in the left lower lobe. Should antibiotics be initiated?

Background

The problem: Antibiotic overuse

With the increasing prevalence of antibiotic resistance in our nation’s hospitals, the need for robust antibiotic stewardship programs has continued to rise in importance. In 2016, the CDC reported a fatal case of septic shock due to a carbapenem-resistant strain of Klebsiella resistant to all tested antibiotics.¹ This case received much media coverage; moreover, this patient represented only one of the approximately 23,000 patients infected with antibiotic-resistant bacteria in the United States who die each year. Although various approaches to curbing antibiotic resistance are being pursued, judicious antibiotic use is central to success. Current evidence suggests that up to 30% of antibiotics are not optimally prescribed,² leaving a significant opportunity for improvement.

Lower respiratory infections account for a substantial proportion of antibiotic utilization in the United States. In a recent study, acute respiratory conditions generated 221 antibiotic prescriptions per 1,000 population, but only half of these were deemed appropriate.² The inability to reliably discern viral from bacterial etiology is a driver of excess antibiotic use.

Dr Graham Beards/en.wikipedia/CC BY-SA 4.0

The procalcitonin assay has been touted as a possible solution to this problem. Multiple studies have evaluated its utility as a tool to help discriminate between bacterial infection and viral or noninfectious etiologies.
 

What is procalcitonin?

Thyroidal c-cells convert the prohormone procalcitonin to calcitonin, which is stored in secretory granules for release in response to fluctuations in calcium levels via a classical neuroendocrine feedback loop. Alternatively, procalcitonin can be synthesized in nonthyroidal parenchymal cells, and high levels of proinflammatory mediators secreted in response to bacterial endotoxin drive increased procalcitonin production. Interestingly, interferon gamma, up-regulated in viral infections, reduces procalcitonin production. Nonthyroidal parenchymal cells lack mechanisms for efficient conversion of procalcitonin to calcitonin and do not contain secretory granules to facilitate its regulated release. Hence bacterial infections correlate with higher serum procalcitonin levels.³ 

Evidence

Can procalcitonin guide antibiotic therapy in patients with acute respiratory illness while reducing antibiotic utilization?

The ability of procalcitonin to selectively identify bacterial infection makes it a potentially promising tool to advance the antibiotic stewardship agenda. Multiple randomized controlled trials have explored the use of procalcitonin-guided antibiotic therapy for treatment of lower respiratory tract infections such as acute bronchitis, exacerbations of COPD, and pneumonia. Each study discussed below was done in Switzerland, involved the same key investigator (Mirjam Christ-Crain, MD, PhD), and shared a similar design in which a threshold for low procalcitonin values (less than 0.1 mcg/L) and high procalcitonin values (greater than 0.25 mcg/L) was prespecified. Antibiotic therapy was strongly discouraged for patients with low procalcitonin and encouraged for those with high procalcitonin; antibiotics were not recommended for patients with intermediate values, but the treating physician was allowed ultimate discretion (Figure 1). All studies compared a procalcitonin-guided treatment group to a standard care group, in which antibiotics were prescribed by the treating physician based on established clinical guidelines.

Figure 1. Procalcitonin treatment algorithm

 

Procalcitonin Level (mcg/L)	Likelihood of bacterial infection	Antibiotic treatment
less than 0.1	Absent	Strongly discouraged
0.1-0.25	Unlikely	Discouraged
0.25-0.5	Possible	Encouraged
greater than 0.5	Present	Strongly encouraged

Figure 1. Procalcitonin treatment algorithm

In a study focusing on outpatients presenting to their primary care physicians with acute respiratory tract infection, 53 primary care physicians in Switzerland recruited 458 patients. There was no significant difference in time to symptom resolution, as determined by patient report during an interview 14 days after initial presentation; however, 97% of patients in the standard-care group received antibiotics, compared with 25% in the procalcitonin-guided group. Equal numbers of patients (30% in each group) reported persistent symptoms at 28-day follow-up. Among the cohort of patients with upper respiratory infections or acute bronchitis, procalcitonin guidance reduced antibiotic prescriptions by 80%.⁴

In a blinded, single-center, randomized, controlled trial of 226 patients presenting to a university hospital with a COPD exacerbation severe enough to require a change in the baseline medication regimen, procalcitonin-guided therapy allowed for an absolute reduction of antibiotic use by 32% without an impact on outcomes. Rates of clinical improvement, ICU utilization, recurrent exacerbations, hospital length of stay, and mortality did not differ between the groups.⁵

Another study by Dr. Christ-Crain looked at whether procalcitonin could be used to determine duration of antibiotic therapy in hospitalized pneumonia patients. In a similarly designed randomized, nonblinded trial with two arms, a procalcitonin group (n = 151) and a standard care group (n = 151), procalcitonin levels were checked at 4, 6, and 8 days, with similar cutoffs regarding levels for which antibiotics were encouraged or discouraged. Antibiotic treatment duration was reduced from a median of 12 days in the standard-care group to 5 days in the procalcitonin group (P less than .001). There was no difference in the success rate of treatment, readmission rate, or death rate between the two groups.⁶These initial studies were limited by their relatively small size and narrow scope. The ProHOSP study was the first large, multicenter study to address the utility of procalcitonin-guided antibiotic therapy. Design was similar, although the decision to treat with antibiotics was more rigorously controlled by the centralized study personnel. The study enrolled 1,359 patients in the emergency departments of six Swiss tertiary-care hospitals. Most patients had pneumonia, but 17% had COPD exacerbation and 11% had acute bronchitis. No difference in death, ICU admission, readmission, or disease-specific complications was noted. Antibiotic exposure was reduced by 34.8% in the procalcitonin group, with a mean of 8.7 days versus 5.7 days on antibiotics.⁷In combination, the studies above support the use of procalcitonin to guide decisions about antibiotic use in patients with lower respiratory tract infections; antibiotic use can be significantly reduced without adverse outcomes. Further, sequential monitoring of procalcitonin levels may help guide duration of antibiotic therapy. These studies all had fairly high rates of follow-up and the ProHOSP study, in particular, had a large, representative sample and a rigorous methodology to standardize antibiotic prescription in the control group.

Limitations include the possible impact of the Hawthorne effect, as physicians knew their antibiotic usage patterns were being monitored, which may impact generalizability of the findings to a real-world setting. Similarly, it is difficult to control for a spillover effect as providers exposed to the procalcitonin-guided algorithm became more comfortable with a restrictive prescribing approach. The costs of the additional procalcitonin assay must be weighed against the benefits. Incidence and cost of other adverse effects of antibiotic use (rates of Clostridium difficile, renal insufficiency, urticarial drug eruptions, etc.) were not addressed. The rapid assay currently has limited availability in the United States, though that is changing. Finally, recent additional studies (unrelated to procalcitonin) have suggested shorter antibiotic treatment durations for patients with pneumonia.⁸

 

Is there evidence for using procalcitonin to guide treatment in the broader population of ICU patients?

While there is good evidence for using procalcitonin to guide antibiotic use in patients with acute respiratory illness, the evidence for using procalcitonin in the broader cohort of critically-ill patients with sepsis is less well established.

The most promising results were reported by the Stop Antibiotics on Procalcitonin guidance Study (SAPS). Published in July 2016, this was a prospective, multicenter, randomized, controlled, open-label study of patients admitted to the ICU (not limited to respiratory illness) in the Netherlands. A total of 1,575 patients were assigned to the procalcitonin-guided group or the standard-of-care group. In the procalcitonin-guided group, procalcitonin levels were checked daily, and physicians were given nonbinding advice to discontinue antibiotics if procalcitonin levels decreased by greater than 80% from peak levels or to below 0.5 mcg/L.

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Patients received an average of 7.5 daily defined antibiotic doses in the procalcitonin-guided group versus 9.3 daily defined doses in the standard-of-care group (P less than .0001). The median duration of antibiotic treatment in the procalcitonin arm was 5 days versus 7 days in the control group (P less than .0001). Mortality at 28 days was 20% in the procalcitonin group and 25% in the control group (P = .0122). At 1 year, mortality was 36% in the procalcitonin group and 43% in the control group (P = .0188). The authors hypothesized that the unexpected decrease in mortality in the procalcitonin group may have been due to earlier consideration of alternate illness etiologies in patients with a low procalcitonin level or decreased antibiotic side effects.⁹While the SAPS trial supports decreased antibiotic usage in ICU patients with the use of the procalcitonin assay, there are some important limitations. First, the trial was done in the Netherlands, where baseline antibiotic usage was comparatively low. Second, daily procalcitonin level monitoring was not continued for patients transferred out of the ICU while still on antibiotics. Further, guidelines for antibiotic discontinuation were nonbinding, and in many cases physicians did not stop antibiotics based on procalcitonin guidelines suggested by the study authors.

Earlier trials regarding the procalcitonin assay in the critical care setting similarly showed some promise but also concerns. One trial reported a 25% reduction in antibiotic exposure and noninferiority of 28-day mortality, but there was a nonsignificant 3.8% absolute increase in mortality at 60 days.¹⁰ Another trial reported similar survival in the procalcitonin group but more side effects and longer ICU stays.¹¹Ultimately, while the SAPS trial supports the potential use of procalcitonin in critically-ill patients, these patients likely have complex sepsis physiology that requires clinicians to consider a number of clinical factors when making antibiotic decisions.

Back to the case

The case illustrates a common emergency department presentation where clinical and radiographic features are not convincing for bacterial infection. This patient has an acute respiratory illness, but is afebrile and lacks leukocytosis with left shift, and x-rays are indeterminate for pneumonia. The differential diagnosis also includes COPD exacerbation, viral infection, or noninfectious triggers of dyspnea.

In this scenario, obtaining procalcitonin levels is useful in the decision to initiate or withhold antibiotic treatment. An elevated procalcitonin level suggests a bacterial infection and would favor initiation of antibiotics for pneumonia. A low procalcitonin level makes a bacterial infection less likely, and a clinician may consider withholding antibiotics and consider alternate etiologies for the patient’s presentation.

Bottom line

Procalcitonin can be safely used to guide the decision to initiate antibiotics in patients presenting with acute respiratory illness. Use of the procalcitonin assay has been shown to reduce antibiotic utilization without an increase in adverse outcomes. There is potential but less conclusive evidence for procalcitonin usage in the broader population of ICU patients with sepsis.
 

Bryan J. Huang, MD, FHM, and Gregory B. Seymann, MD, SFHM, are in the division of hospital medicine, University of California, San Diego.

 

• Key Points
• Elevated procalcitonin levels suggest the presence of bacterial infection.
• In patients presenting with acute respiratory illness, procalcitonin levels can be used to guide the decision to initiate or withhold antibiotics, improving antibiotic stewardship.
• Sequential monitoring of procalcitonin levels may help guide duration of antibiotic therapy.
• There is potential but less conclusive evidence for procalcitonin usage in the broader population of ICU patients with sepsis.


•  

References

1. Chen L, Todd R, Kiehlbauch J, Walters M, Kallen A. Notes from the field: pan-resistant New Delhi metallo-beta-lactamase-producing Klebsiella pneumoniae – Washoe County, Nevada, 2016. MMWR Morb Mortal Wkly Rep 2017; 66(1):33.

2. Fleming-Dutra KE, Hersh AL, Shapiro DJ, et al. Prevalence of inappropriate antibiotic prescriptions among US ambulatory care visits, 2010-2011. JAMA 2016;315(17):1864-73.

3. Christ-Crain M, Muller B. Procalcitonin in bacterial infections – hype, hope, more or less? Swiss Med Wkly. 2005;135(31-32):451-60.

4. 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): 2000-7.

5. 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.

6. Christ-Crain M, Stolz D, Bingisser R, et al. Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial. Am J Respir Crit Care Med. 2006;174(1):84-93.

7. Schuetz P, Christ-Crain M, Thomann R, et al. Effect of procalcitonin-based guidelines vs. standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA 2009; 302(10): 1059-66.

8. Uranga A, Espana PP, Bilbao A, et al. Duration of antibiotic treatment in community-acquired pneumonia: a multicenter randomized clinical trial. JAMA Intern Med. 2016;176(9):1257-65.

9. de Jong E, van Oers JA, Beishiozen A, et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis. 2016;16(7):819-27.

10. Bouadma L, Luyt CE, Tubach F, et al. Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet 2010;375(9713):463-74.

11. Jensen J-U, Lundgren B, Hein L, et al. The procalcitonin and survival study (PASS) – a randomised multicenter investigator-initiated trial to investigate whether daily measurements biomarker procalcitonin and proactive diagnostic and therapeutic responses to abnormal procalcitonin levels, can improve survival in intensive care unit patients. BMC infectious diseases. 2008;8:91-100.

 

Additional reading

1. Schuetz P, Christ-Crain M, Thomann R, et al. Effect of procalcitonin-based guidelines vs. standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA 2009;302(10):1059-66.

2. de Jong E, van Oers JA, Beishiozen A, et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis. 2016;16(7):819-27.

3. Schuetz P, Muller B, Christ-Crain M, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev. 2012;(9):CD007498.