David J. Samson, MS

Study 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, intensification, and/or discontinuation of antibiotic therapy when compared to clinical criteria for infection alone?

Search Strategy

MEDLINE and EMBASE were searched from January 1, 1990 through December 16, 2011, and the Cochrane Controlled Trials register was searched with no date restriction for randomized and nonrandomized comparative studies using the following search terms: procalcitonin AND chronic obstructive pulmonary disease; COPD; critical illness; critically ill; febrile neutropenia; ICU; intensive care; intensive care unit; postoperative complication(s); postoperative infection(s); postsurgical infection(s); sepsis; septic; surgical wound infection; systemic inflammatory response syndrome OR postoperative infection. In addition, a search for systematic reviews was conducted in MEDLINE, the Cochrane Database of Systematic Reviews, and Web sites of the National Institute for Clinical Excellence, the National Guideline Clearinghouse, and the Health Technology Assessment Programme. Gray literature, including databases with regulatory information, clinical trial registries, abstracts and conference papers, grants and federally funded research, and manufacturing information was searched from January 1, 2006 to June 28, 2011.

Study Selection

A single reviewer screened abstracts and selected studies looking at procalcitonin‐guided antibiotic therapy. Second and third reviewers were consulted to screen articles when needed. Studies were included if they fulfilled all of the following criteria: (1) randomized, controlled trial or nonrandomized comparative study; (2) adult and/or pediatric patients with known or suspected local or systemic infection, including critically ill patients with sepsis syndrome or ventilator‐associated pneumonia, adults with respiratory tract infections, neonates with sepsis, children with fever of unknown source, and postoperative patients at risk of infection; (3) interventions included initiation, intensification, and/or discontinuation of antibiotic therapy guided by procalcitonin plus clinical criteria; (4) primary outcomes included antibiotic usage (antibiotic prescription rate, total antibiotic exposure, duration of antibiotic therapy, and days without antibiotic therapy); and (5) secondary outcomes included morbidity (antibiotic adverse events, hospital and/or intensive care unit length of stay), mortality, and quality of life.

Studies with any of the following criteria were excluded: published in non‐English language, not reporting primary data from original research, not a randomized, controlled trial or nonrandomized comparative study, not reporting relevant outcomes.

Data Extraction and Quality Assessment

A single reviewer abstracted data and a second reviewer confirmed accuracy. Disagreements between reviewers were resolved by group discussion among the research team and final quality rating was assigned by consensus adjudication. Data elements were abstracted into the following categories: quality assessment, applicability and clinical diversity assessment, and outcome assessment. Quality of included studies was assessed using the US Preventive Services Task Force framework[17] by at least 2 independent reviewers. Three quality categories were used: good, fair, and poor.

Data Synthesis and Analysis

The decision to incorporate formal data synthesis in this review was made after completing the formal literature search, and the decision to pool studies was based on the specific number of studies with similar questions and outcomes. If a meta‐analysis could be performed, subgroup and sensitivity analyses were based on clinical similarity of available studies and reporting of mean and standard deviation. The pooling method involved inverse variance weighting and a random effects model.

The strength of evidence was graded using the Methods Guide,[16] a system based on the Grading of Recommendations Assessment, Development and Evaluation Working Group.[18] The following domains were addressed: risk of bias, consistency, directness, and precision. The overall strength of evidence was graded as high, moderate, low, or insufficient. The final strength of evidence grading was made by consensus adjudication among the authors.

Adult ICU Patients: Procalcitonin‐Guided Antibiotic Discontinuation

Five studies[19, 20, 21, 22, 23] (N=938) addressed procalcitonin‐guided discontinuation of antibiotic therapy in adult ICU patients. Four studies conducted superiority analyses for mortality with procalcitonin‐guided therapy, whereas 1 study conducted a noninferiority analysis. Absolute procalcitonin values for discontinuation of antibiotics ranged from 0.25 to 1 ng/mL. Physicians in control groups administered antibiotics according to their standard practice.

Antibiotic Usage

The absolute reduction in duration of antibiotic usage with procalcitonin guidance in these studies ranged from 1.7 to 5 days, and the relative reduction ranged from 21% to 38%. Meta‐analysis of antibiotic duration in adult ICU patients was performed (Figure 2A).

Figure 2

Adult ICU Patients: Procalcitonin‐Guided Antibiotic Intensification

Two studies[24, 33] (N=1272) addressed procalcitonin‐guided intensification of antibiotic therapy in adult ICU patients. The Jensen et al. study[33] was a large (N=1200), high‐quality study that used a detailed algorithm for broadening antibiotic therapy in patients with elevated procalcitonin. The Jensen et al. study also educated physicians about empiric therapy and intensification of antibiotic therapy. A second study[24] was too small (N=72) and lacked sufficient details to be informative.

Adult Patients With Respiratory Tract Infections

Eight studies[25, 26, 27, 28, 29, 30, 34, 35] (N=3492) addressed initiation and/or discontinuation of antibiotics in adult patients with acute upper and lower respiratory tract infections, including community‐acquired pneumonia, acute exacerbation of chronic obstructive pulmonary disease, and acute bronchitis. Settings included primary care clinics, emergency departments, and hospital wards. Physicians in control groups administered antibiotics according to their own standard practices and/or evidence‐based guidelines. All studies encouraged initiation of antibiotics with procalcitonin levels >0.25 ng/mL, and 4 studies strongly encouraged antibiotics with procalcitonin levels >0.5 ng/mL.

Antibiotic Usage

Procalcitonin guidance reduced antibiotic duration, antibiotic prescription rate, and total antibiotic exposure. Absolute reduction in antibiotic duration ranged from 1 to 7 days, and relative reductions ranged from 13% to 55%. Four of the 8 studies reported sufficient details to be pooled into a meta‐analysis (Figure 3A) with a statistically significant pooled mean difference of 2.35 days favoring procalcitonin (95% CI: 4.38 to 0.33). Procalcitonin guidance also reduced antibiotic prescription rate with absolute reductions ranging from 2% to 7% and relative reductions ranging from 1.8% to 72%. Meta‐analysis of prescription rates from 8 studies (Figure 3B) yielded a statistically significant pooled risk difference of 22% (95% CI: 41% to 4%). Total antibiotic exposure was consistently reduced in the 4 studies reporting this outcome.

Figure 3

Neonates With Sepsis

One study[31] (N=121) evaluated procalcitonin‐guided antibiotic therapy for suspected neonatal sepsis. Neonatal sepsis was suspected on the basis of risk factors and clinical signs and symptoms. Antibiotic initiation or discontinuation was based on a procalcitonin nomogram. Antibiotic therapy in the control group was based on the physician's assessment. The quality of this study was rated good, and strength of evidence was rated moderate for antibiotic usage and insufficient for morbidity and mortality outcomes.

Children Ages 1 to 36 Months With Fever of Unknown Source

One study[36] (N=384) evaluated procalcitonin‐guided antibiotic therapy for fever of unknown source in children 1 to 36 months of age, but the overall strength of evidence was judged insufficient to draw conclusions.

Adult Postoperative Patients at Risk of Infection

One study[32] (N =250) monitored procalcitonin in consecutive patients after colorectal surgery to identify patients at risk of infection who might benefit from prophylactic antibiotic therapy. Two hundred thirty patients had normal procalcitonin levels. Twenty patients with elevated procalcitonin levels (>1.5 ng/mL) were randomized to receive prophylactic antibiotic therapy with ceftriaxone or no antibiotics. The strength of evidence was judged insufficient to draw conclusions from this study.

Summary of the Main Findings

Diagnosis of sepsis or other serious infections in critically ill patients is challenging because clinical criteria for diagnosis overlap with noninfectious causes of the systemic inflammatory response syndrome. Initiation of antibiotic therapy for presumed sepsis is necessary while diagnostic evaluation is ongoing, because delaying antibiotic therapy is associated with increased mortality.[37, 38, 39] Our review found that procalcitonin guidance significantly reduced antibiotic usage in adult ICU patients by reducing the duration of antibiotic therapy, rather than decreasing the initiation of antibiotics, without increasing morbidity or mortality.

In contrast, the use of procalcitonin as an indicator of need for intensification of antibiotic therapy in adult ICU patients should be discouraged because this approach was associated with increased morbidity. The large, well‐designed study by Jensen[33] showed that antibiotic intensification in response to elevated procalcitonin measurement was associated with increased morbidity: a longer ICU LOS, an increase in days on mechanical ventilation, and an increase in days with abnormal renal function. The authors concluded that the increased morbidity could only be explained by clinical harms of increased exposure to broad‐spectrum antibiotics.

Clinical and microbiological evaluations are neither sensitive nor specific for differentiating bacterial from viral respiratory tract infections. Procalcitonin can guide initiation of antibiotic therapy in adults with suspected bacterial respiratory tract infection. Our review showed that procalcitonin guidance significantly reduced antibiotic usage with respect to antibiotic prescription rate, duration of antibiotic therapy, and total exposure to antibiotic therapy in adult patients with respiratory tract infections.

The role of procalcitonin‐guided therapy in other populations is less clear. One study in postoperative colorectal surgery patients reported that elevated procalcitonin levels may identify patients at risk for infection who benefit from prophylactic antibiotic therapy.[32] Patients with elevated procalcitonin levels who received prophylactic antibiotic therapy had a significant decrease in the incidence and severity of systemic infections, whereas patients with normal procalcitonin levels did not require any additional surgical or medical therapy. Although these findings are promising, more data in postoperative patients are needed.

The utility of procalcitonin in pediatric settings is a significant gap in the present literature. One study[31] in neonates with suspected sepsis showed a significant decrease in the proportion of neonates started on empiric antibiotic therapy and a decrease in the duration of antibiotic therapy with procalcitonin guidance. However, there was insufficient evidence that procalcitonin guidance does not increase morbidity or mortality.

Comparison to Other Systematic Reviews

Six systematic reviews of procalcitonin guidance in the management of patients with infections were published prior to our review.[9, 10, 11, 12, 13, 14] Our systematic review differs from past reviews in the number of studies included and the pooling of studies according to patient population, type and severity of infection, and different uses of procalcitonin measurements, either for initiation, discontinuation, or intensification of antibiotic therapy. Previous systematic reviews included 7 to 14 studies, whereas ours included 18 randomized, controlled trials. One previous review[13] included and pooled the Jensen et al. study[33] with other studies of adult ICU patients. We evaluated the Jensen et al. study separately because it uniquely looked at procalcitonin‐guided antibiotic intensification in adult ICU patients, in contrast to other studies that looked at procalcitonin‐guided antibiotic discontinuation. We addressed pediatric populations separately from adult patients, and recognizing that there are distinct groups within the pediatric population, we separately grouped neonates and children ages 1 to 36 months. Despite these differences, our review and other systematic reviews, we came to similar conclusions: procalcitonin‐guided antibiotic decision making compared to clinical criteria‐guided antibiotic decision making reduces antibiotic usage without increasing morbidity or mortality.

Limitations

An important limitation of this review was the uncertainty about the noninferiority margin for morbidity and mortality in adult ICU patients. Only the Bouadma et al. study[23] did a power analysis and predefined a margin for noninferiority for 28‐ and 60‐day mortality. Meta‐analysis of all 5 ICU studies showed a pooled point estimate of 0.43% in mortality and a 95% CI of 6% to 5% for difference in mortality between procalcitonin‐guided therapy versus standard care. A 10% noninferiority margin for mortality has been recommended by the Infectious Diseases Society of America and American College of Chest Physicians, but there is concern that a 10% margin for mortality may be too high. Presently, 2 large trials are in progress that may yield more precise estimates of mortality in the future.

Differences in reporting of total antibiotic exposure and morbidity outcomes limited our ability to pool data. Total antibiotic exposure is conventionally reported as mean days per 1000 days of follow‐up, but some studies only reported relative or absolute differences. Likewise, morbidity was reported with different severity of illness scales, including Sepsis‐Related Organ Failure Assessment, Simplified Acute Physiology (SAP) II, SAP III, and Acute Physiology and Chronic Health Evaluation II, which limited comparisons across studies.

Research Gaps

We identified gaps in the available literature and opportunities for future research. First, the safety and efficacy of procalcitonin‐guided antibiotic therapy needs to be studied in patient populations excluded from current randomized controlled studies, such as immunocompromised patients and pregnant women. Patients who are immunocompromised or have chronic conditions, such as cystic fibrosis, account for a significant percentage of community‐acquired respiratory tract infections and are often treated empirically.[29, 30] Second, standardized reporting of antibiotic adverse events and emergence of antibiotic resistance is needed. Strategies to reduce antibiotic usage have been associated with reductions in antibiotic adverse events, such as Clostridium difficile colitis and superinfection with multi‐drug resistant Gram‐negative bacteria.[37, 40, 41] Few studies in our review reported allergic reactions or adverse events of antibiotic therapy, [25, 27, 34] and only 1 reported antibiotic resistance.[19] Third, procalcitonin guidance should be compared to other strategies to reduce antibiotic usage, such as structured implementation of practice guidelines and antibiotic stewardship programs.[42] One single‐arm study describes how procalcitonin can be used in antibiotic stewardship programs to decrease the duration of antibiotic therapy,[43] but additional studies are needed. Finally, generalizing results from those studies that were conducted primarily in Europe would depend on similar use of and adherence to study‐based algorithms. Newer observational studies have demonstrated reduced antibiotic usage with implementation of procalcitonin algorithms in real‐life settings in Europe, but algorithm adherence was significantly less in the United States.[44, 45]

In summary, our systematic review found that procalcitonin‐guided antibiotic therapy can significantly reduce antibiotic usage in adult ICU patients without affecting morbidity or mortality. Procalcitonin should not be used to guide intensification of antibiotic therapy in adult ICU patients because this approach may increase morbidity. In adults with respiratory infections, procalcitonin guidance can significantly reduce antibiotic usage without adversely affecting morbidity or mortality. There is insufficient evidence to recommend procalcitonin‐guided antibiotic therapy in neonates with sepsis, children with fever of unknown source, or postoperative patients at risk for infection.

Study 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, intensification, and/or discontinuation of antibiotic therapy when compared to clinical criteria for infection alone?

Search Strategy

MEDLINE and EMBASE were searched from January 1, 1990 through December 16, 2011, and the Cochrane Controlled Trials register was searched with no date restriction for randomized and nonrandomized comparative studies using the following search terms: procalcitonin AND chronic obstructive pulmonary disease; COPD; critical illness; critically ill; febrile neutropenia; ICU; intensive care; intensive care unit; postoperative complication(s); postoperative infection(s); postsurgical infection(s); sepsis; septic; surgical wound infection; systemic inflammatory response syndrome OR postoperative infection. In addition, a search for systematic reviews was conducted in MEDLINE, the Cochrane Database of Systematic Reviews, and Web sites of the National Institute for Clinical Excellence, the National Guideline Clearinghouse, and the Health Technology Assessment Programme. Gray literature, including databases with regulatory information, clinical trial registries, abstracts and conference papers, grants and federally funded research, and manufacturing information was searched from January 1, 2006 to June 28, 2011.

Study Selection

A single reviewer screened abstracts and selected studies looking at procalcitonin‐guided antibiotic therapy. Second and third reviewers were consulted to screen articles when needed. Studies were included if they fulfilled all of the following criteria: (1) randomized, controlled trial or nonrandomized comparative study; (2) adult and/or pediatric patients with known or suspected local or systemic infection, including critically ill patients with sepsis syndrome or ventilator‐associated pneumonia, adults with respiratory tract infections, neonates with sepsis, children with fever of unknown source, and postoperative patients at risk of infection; (3) interventions included initiation, intensification, and/or discontinuation of antibiotic therapy guided by procalcitonin plus clinical criteria; (4) primary outcomes included antibiotic usage (antibiotic prescription rate, total antibiotic exposure, duration of antibiotic therapy, and days without antibiotic therapy); and (5) secondary outcomes included morbidity (antibiotic adverse events, hospital and/or intensive care unit length of stay), mortality, and quality of life.

Studies with any of the following criteria were excluded: published in non‐English language, not reporting primary data from original research, not a randomized, controlled trial or nonrandomized comparative study, not reporting relevant outcomes.

Data Extraction and Quality Assessment

A single reviewer abstracted data and a second reviewer confirmed accuracy. Disagreements between reviewers were resolved by group discussion among the research team and final quality rating was assigned by consensus adjudication. Data elements were abstracted into the following categories: quality assessment, applicability and clinical diversity assessment, and outcome assessment. Quality of included studies was assessed using the US Preventive Services Task Force framework[17] by at least 2 independent reviewers. Three quality categories were used: good, fair, and poor.

Data Synthesis and Analysis

The decision to incorporate formal data synthesis in this review was made after completing the formal literature search, and the decision to pool studies was based on the specific number of studies with similar questions and outcomes. If a meta‐analysis could be performed, subgroup and sensitivity analyses were based on clinical similarity of available studies and reporting of mean and standard deviation. The pooling method involved inverse variance weighting and a random effects model.

The strength of evidence was graded using the Methods Guide,[16] a system based on the Grading of Recommendations Assessment, Development and Evaluation Working Group.[18] The following domains were addressed: risk of bias, consistency, directness, and precision. The overall strength of evidence was graded as high, moderate, low, or insufficient. The final strength of evidence grading was made by consensus adjudication among the authors.

Adult ICU Patients: Procalcitonin‐Guided Antibiotic Discontinuation

Five studies[19, 20, 21, 22, 23] (N=938) addressed procalcitonin‐guided discontinuation of antibiotic therapy in adult ICU patients. Four studies conducted superiority analyses for mortality with procalcitonin‐guided therapy, whereas 1 study conducted a noninferiority analysis. Absolute procalcitonin values for discontinuation of antibiotics ranged from 0.25 to 1 ng/mL. Physicians in control groups administered antibiotics according to their standard practice.

Antibiotic Usage

The absolute reduction in duration of antibiotic usage with procalcitonin guidance in these studies ranged from 1.7 to 5 days, and the relative reduction ranged from 21% to 38%. Meta‐analysis of antibiotic duration in adult ICU patients was performed (Figure 2A).

Figure 2

Adult ICU Patients: Procalcitonin‐Guided Antibiotic Intensification

Two studies[24, 33] (N=1272) addressed procalcitonin‐guided intensification of antibiotic therapy in adult ICU patients. The Jensen et al. study[33] was a large (N=1200), high‐quality study that used a detailed algorithm for broadening antibiotic therapy in patients with elevated procalcitonin. The Jensen et al. study also educated physicians about empiric therapy and intensification of antibiotic therapy. A second study[24] was too small (N=72) and lacked sufficient details to be informative.

Adult Patients With Respiratory Tract Infections

Eight studies[25, 26, 27, 28, 29, 30, 34, 35] (N=3492) addressed initiation and/or discontinuation of antibiotics in adult patients with acute upper and lower respiratory tract infections, including community‐acquired pneumonia, acute exacerbation of chronic obstructive pulmonary disease, and acute bronchitis. Settings included primary care clinics, emergency departments, and hospital wards. Physicians in control groups administered antibiotics according to their own standard practices and/or evidence‐based guidelines. All studies encouraged initiation of antibiotics with procalcitonin levels >0.25 ng/mL, and 4 studies strongly encouraged antibiotics with procalcitonin levels >0.5 ng/mL.

Antibiotic Usage

Procalcitonin guidance reduced antibiotic duration, antibiotic prescription rate, and total antibiotic exposure. Absolute reduction in antibiotic duration ranged from 1 to 7 days, and relative reductions ranged from 13% to 55%. Four of the 8 studies reported sufficient details to be pooled into a meta‐analysis (Figure 3A) with a statistically significant pooled mean difference of 2.35 days favoring procalcitonin (95% CI: 4.38 to 0.33). Procalcitonin guidance also reduced antibiotic prescription rate with absolute reductions ranging from 2% to 7% and relative reductions ranging from 1.8% to 72%. Meta‐analysis of prescription rates from 8 studies (Figure 3B) yielded a statistically significant pooled risk difference of 22% (95% CI: 41% to 4%). Total antibiotic exposure was consistently reduced in the 4 studies reporting this outcome.

Figure 3

Neonates With Sepsis

One study[31] (N=121) evaluated procalcitonin‐guided antibiotic therapy for suspected neonatal sepsis. Neonatal sepsis was suspected on the basis of risk factors and clinical signs and symptoms. Antibiotic initiation or discontinuation was based on a procalcitonin nomogram. Antibiotic therapy in the control group was based on the physician's assessment. The quality of this study was rated good, and strength of evidence was rated moderate for antibiotic usage and insufficient for morbidity and mortality outcomes.

Children Ages 1 to 36 Months With Fever of Unknown Source

One study[36] (N=384) evaluated procalcitonin‐guided antibiotic therapy for fever of unknown source in children 1 to 36 months of age, but the overall strength of evidence was judged insufficient to draw conclusions.

Adult Postoperative Patients at Risk of Infection

One study[32] (N =250) monitored procalcitonin in consecutive patients after colorectal surgery to identify patients at risk of infection who might benefit from prophylactic antibiotic therapy. Two hundred thirty patients had normal procalcitonin levels. Twenty patients with elevated procalcitonin levels (>1.5 ng/mL) were randomized to receive prophylactic antibiotic therapy with ceftriaxone or no antibiotics. The strength of evidence was judged insufficient to draw conclusions from this study.

Summary of the Main Findings

Diagnosis of sepsis or other serious infections in critically ill patients is challenging because clinical criteria for diagnosis overlap with noninfectious causes of the systemic inflammatory response syndrome. Initiation of antibiotic therapy for presumed sepsis is necessary while diagnostic evaluation is ongoing, because delaying antibiotic therapy is associated with increased mortality.[37, 38, 39] Our review found that procalcitonin guidance significantly reduced antibiotic usage in adult ICU patients by reducing the duration of antibiotic therapy, rather than decreasing the initiation of antibiotics, without increasing morbidity or mortality.

In contrast, the use of procalcitonin as an indicator of need for intensification of antibiotic therapy in adult ICU patients should be discouraged because this approach was associated with increased morbidity. The large, well‐designed study by Jensen[33] showed that antibiotic intensification in response to elevated procalcitonin measurement was associated with increased morbidity: a longer ICU LOS, an increase in days on mechanical ventilation, and an increase in days with abnormal renal function. The authors concluded that the increased morbidity could only be explained by clinical harms of increased exposure to broad‐spectrum antibiotics.

Clinical and microbiological evaluations are neither sensitive nor specific for differentiating bacterial from viral respiratory tract infections. Procalcitonin can guide initiation of antibiotic therapy in adults with suspected bacterial respiratory tract infection. Our review showed that procalcitonin guidance significantly reduced antibiotic usage with respect to antibiotic prescription rate, duration of antibiotic therapy, and total exposure to antibiotic therapy in adult patients with respiratory tract infections.

The role of procalcitonin‐guided therapy in other populations is less clear. One study in postoperative colorectal surgery patients reported that elevated procalcitonin levels may identify patients at risk for infection who benefit from prophylactic antibiotic therapy.[32] Patients with elevated procalcitonin levels who received prophylactic antibiotic therapy had a significant decrease in the incidence and severity of systemic infections, whereas patients with normal procalcitonin levels did not require any additional surgical or medical therapy. Although these findings are promising, more data in postoperative patients are needed.

The utility of procalcitonin in pediatric settings is a significant gap in the present literature. One study[31] in neonates with suspected sepsis showed a significant decrease in the proportion of neonates started on empiric antibiotic therapy and a decrease in the duration of antibiotic therapy with procalcitonin guidance. However, there was insufficient evidence that procalcitonin guidance does not increase morbidity or mortality.

Comparison to Other Systematic Reviews

Six systematic reviews of procalcitonin guidance in the management of patients with infections were published prior to our review.[9, 10, 11, 12, 13, 14] Our systematic review differs from past reviews in the number of studies included and the pooling of studies according to patient population, type and severity of infection, and different uses of procalcitonin measurements, either for initiation, discontinuation, or intensification of antibiotic therapy. Previous systematic reviews included 7 to 14 studies, whereas ours included 18 randomized, controlled trials. One previous review[13] included and pooled the Jensen et al. study[33] with other studies of adult ICU patients. We evaluated the Jensen et al. study separately because it uniquely looked at procalcitonin‐guided antibiotic intensification in adult ICU patients, in contrast to other studies that looked at procalcitonin‐guided antibiotic discontinuation. We addressed pediatric populations separately from adult patients, and recognizing that there are distinct groups within the pediatric population, we separately grouped neonates and children ages 1 to 36 months. Despite these differences, our review and other systematic reviews, we came to similar conclusions: procalcitonin‐guided antibiotic decision making compared to clinical criteria‐guided antibiotic decision making reduces antibiotic usage without increasing morbidity or mortality.

Limitations

An important limitation of this review was the uncertainty about the noninferiority margin for morbidity and mortality in adult ICU patients. Only the Bouadma et al. study[23] did a power analysis and predefined a margin for noninferiority for 28‐ and 60‐day mortality. Meta‐analysis of all 5 ICU studies showed a pooled point estimate of 0.43% in mortality and a 95% CI of 6% to 5% for difference in mortality between procalcitonin‐guided therapy versus standard care. A 10% noninferiority margin for mortality has been recommended by the Infectious Diseases Society of America and American College of Chest Physicians, but there is concern that a 10% margin for mortality may be too high. Presently, 2 large trials are in progress that may yield more precise estimates of mortality in the future.

Differences in reporting of total antibiotic exposure and morbidity outcomes limited our ability to pool data. Total antibiotic exposure is conventionally reported as mean days per 1000 days of follow‐up, but some studies only reported relative or absolute differences. Likewise, morbidity was reported with different severity of illness scales, including Sepsis‐Related Organ Failure Assessment, Simplified Acute Physiology (SAP) II, SAP III, and Acute Physiology and Chronic Health Evaluation II, which limited comparisons across studies.

Research Gaps

We identified gaps in the available literature and opportunities for future research. First, the safety and efficacy of procalcitonin‐guided antibiotic therapy needs to be studied in patient populations excluded from current randomized controlled studies, such as immunocompromised patients and pregnant women. Patients who are immunocompromised or have chronic conditions, such as cystic fibrosis, account for a significant percentage of community‐acquired respiratory tract infections and are often treated empirically.[29, 30] Second, standardized reporting of antibiotic adverse events and emergence of antibiotic resistance is needed. Strategies to reduce antibiotic usage have been associated with reductions in antibiotic adverse events, such as Clostridium difficile colitis and superinfection with multi‐drug resistant Gram‐negative bacteria.[37, 40, 41] Few studies in our review reported allergic reactions or adverse events of antibiotic therapy, [25, 27, 34] and only 1 reported antibiotic resistance.[19] Third, procalcitonin guidance should be compared to other strategies to reduce antibiotic usage, such as structured implementation of practice guidelines and antibiotic stewardship programs.[42] One single‐arm study describes how procalcitonin can be used in antibiotic stewardship programs to decrease the duration of antibiotic therapy,[43] but additional studies are needed. Finally, generalizing results from those studies that were conducted primarily in Europe would depend on similar use of and adherence to study‐based algorithms. Newer observational studies have demonstrated reduced antibiotic usage with implementation of procalcitonin algorithms in real‐life settings in Europe, but algorithm adherence was significantly less in the United States.[44, 45]

In summary, our systematic review found that procalcitonin‐guided antibiotic therapy can significantly reduce antibiotic usage in adult ICU patients without affecting morbidity or mortality. Procalcitonin should not be used to guide intensification of antibiotic therapy in adult ICU patients because this approach may increase morbidity. In adults with respiratory infections, procalcitonin guidance can significantly reduce antibiotic usage without adversely affecting morbidity or mortality. There is insufficient evidence to recommend procalcitonin‐guided antibiotic therapy in neonates with sepsis, children with fever of unknown source, or postoperative patients at risk for infection.

Study 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, intensification, and/or discontinuation of antibiotic therapy when compared to clinical criteria for infection alone?

Search Strategy

MEDLINE and EMBASE were searched from January 1, 1990 through December 16, 2011, and the Cochrane Controlled Trials register was searched with no date restriction for randomized and nonrandomized comparative studies using the following search terms: procalcitonin AND chronic obstructive pulmonary disease; COPD; critical illness; critically ill; febrile neutropenia; ICU; intensive care; intensive care unit; postoperative complication(s); postoperative infection(s); postsurgical infection(s); sepsis; septic; surgical wound infection; systemic inflammatory response syndrome OR postoperative infection. In addition, a search for systematic reviews was conducted in MEDLINE, the Cochrane Database of Systematic Reviews, and Web sites of the National Institute for Clinical Excellence, the National Guideline Clearinghouse, and the Health Technology Assessment Programme. Gray literature, including databases with regulatory information, clinical trial registries, abstracts and conference papers, grants and federally funded research, and manufacturing information was searched from January 1, 2006 to June 28, 2011.

Study Selection

A single reviewer screened abstracts and selected studies looking at procalcitonin‐guided antibiotic therapy. Second and third reviewers were consulted to screen articles when needed. Studies were included if they fulfilled all of the following criteria: (1) randomized, controlled trial or nonrandomized comparative study; (2) adult and/or pediatric patients with known or suspected local or systemic infection, including critically ill patients with sepsis syndrome or ventilator‐associated pneumonia, adults with respiratory tract infections, neonates with sepsis, children with fever of unknown source, and postoperative patients at risk of infection; (3) interventions included initiation, intensification, and/or discontinuation of antibiotic therapy guided by procalcitonin plus clinical criteria; (4) primary outcomes included antibiotic usage (antibiotic prescription rate, total antibiotic exposure, duration of antibiotic therapy, and days without antibiotic therapy); and (5) secondary outcomes included morbidity (antibiotic adverse events, hospital and/or intensive care unit length of stay), mortality, and quality of life.

Studies with any of the following criteria were excluded: published in non‐English language, not reporting primary data from original research, not a randomized, controlled trial or nonrandomized comparative study, not reporting relevant outcomes.

Data Extraction and Quality Assessment

A single reviewer abstracted data and a second reviewer confirmed accuracy. Disagreements between reviewers were resolved by group discussion among the research team and final quality rating was assigned by consensus adjudication. Data elements were abstracted into the following categories: quality assessment, applicability and clinical diversity assessment, and outcome assessment. Quality of included studies was assessed using the US Preventive Services Task Force framework[17] by at least 2 independent reviewers. Three quality categories were used: good, fair, and poor.

Data Synthesis and Analysis

The decision to incorporate formal data synthesis in this review was made after completing the formal literature search, and the decision to pool studies was based on the specific number of studies with similar questions and outcomes. If a meta‐analysis could be performed, subgroup and sensitivity analyses were based on clinical similarity of available studies and reporting of mean and standard deviation. The pooling method involved inverse variance weighting and a random effects model.

The strength of evidence was graded using the Methods Guide,[16] a system based on the Grading of Recommendations Assessment, Development and Evaluation Working Group.[18] The following domains were addressed: risk of bias, consistency, directness, and precision. The overall strength of evidence was graded as high, moderate, low, or insufficient. The final strength of evidence grading was made by consensus adjudication among the authors.

Adult ICU Patients: Procalcitonin‐Guided Antibiotic Discontinuation

Five studies[19, 20, 21, 22, 23] (N=938) addressed procalcitonin‐guided discontinuation of antibiotic therapy in adult ICU patients. Four studies conducted superiority analyses for mortality with procalcitonin‐guided therapy, whereas 1 study conducted a noninferiority analysis. Absolute procalcitonin values for discontinuation of antibiotics ranged from 0.25 to 1 ng/mL. Physicians in control groups administered antibiotics according to their standard practice.

Antibiotic Usage

The absolute reduction in duration of antibiotic usage with procalcitonin guidance in these studies ranged from 1.7 to 5 days, and the relative reduction ranged from 21% to 38%. Meta‐analysis of antibiotic duration in adult ICU patients was performed (Figure 2A).

Figure 2

Adult ICU Patients: Procalcitonin‐Guided Antibiotic Intensification

Two studies[24, 33] (N=1272) addressed procalcitonin‐guided intensification of antibiotic therapy in adult ICU patients. The Jensen et al. study[33] was a large (N=1200), high‐quality study that used a detailed algorithm for broadening antibiotic therapy in patients with elevated procalcitonin. The Jensen et al. study also educated physicians about empiric therapy and intensification of antibiotic therapy. A second study[24] was too small (N=72) and lacked sufficient details to be informative.

Adult Patients With Respiratory Tract Infections

Eight studies[25, 26, 27, 28, 29, 30, 34, 35] (N=3492) addressed initiation and/or discontinuation of antibiotics in adult patients with acute upper and lower respiratory tract infections, including community‐acquired pneumonia, acute exacerbation of chronic obstructive pulmonary disease, and acute bronchitis. Settings included primary care clinics, emergency departments, and hospital wards. Physicians in control groups administered antibiotics according to their own standard practices and/or evidence‐based guidelines. All studies encouraged initiation of antibiotics with procalcitonin levels >0.25 ng/mL, and 4 studies strongly encouraged antibiotics with procalcitonin levels >0.5 ng/mL.

Antibiotic Usage

Procalcitonin guidance reduced antibiotic duration, antibiotic prescription rate, and total antibiotic exposure. Absolute reduction in antibiotic duration ranged from 1 to 7 days, and relative reductions ranged from 13% to 55%. Four of the 8 studies reported sufficient details to be pooled into a meta‐analysis (Figure 3A) with a statistically significant pooled mean difference of 2.35 days favoring procalcitonin (95% CI: 4.38 to 0.33). Procalcitonin guidance also reduced antibiotic prescription rate with absolute reductions ranging from 2% to 7% and relative reductions ranging from 1.8% to 72%. Meta‐analysis of prescription rates from 8 studies (Figure 3B) yielded a statistically significant pooled risk difference of 22% (95% CI: 41% to 4%). Total antibiotic exposure was consistently reduced in the 4 studies reporting this outcome.

Figure 3

Neonates With Sepsis

One study[31] (N=121) evaluated procalcitonin‐guided antibiotic therapy for suspected neonatal sepsis. Neonatal sepsis was suspected on the basis of risk factors and clinical signs and symptoms. Antibiotic initiation or discontinuation was based on a procalcitonin nomogram. Antibiotic therapy in the control group was based on the physician's assessment. The quality of this study was rated good, and strength of evidence was rated moderate for antibiotic usage and insufficient for morbidity and mortality outcomes.

Children Ages 1 to 36 Months With Fever of Unknown Source

One study[36] (N=384) evaluated procalcitonin‐guided antibiotic therapy for fever of unknown source in children 1 to 36 months of age, but the overall strength of evidence was judged insufficient to draw conclusions.

Adult Postoperative Patients at Risk of Infection

One study[32] (N =250) monitored procalcitonin in consecutive patients after colorectal surgery to identify patients at risk of infection who might benefit from prophylactic antibiotic therapy. Two hundred thirty patients had normal procalcitonin levels. Twenty patients with elevated procalcitonin levels (>1.5 ng/mL) were randomized to receive prophylactic antibiotic therapy with ceftriaxone or no antibiotics. The strength of evidence was judged insufficient to draw conclusions from this study.

Summary of the Main Findings

Diagnosis of sepsis or other serious infections in critically ill patients is challenging because clinical criteria for diagnosis overlap with noninfectious causes of the systemic inflammatory response syndrome. Initiation of antibiotic therapy for presumed sepsis is necessary while diagnostic evaluation is ongoing, because delaying antibiotic therapy is associated with increased mortality.[37, 38, 39] Our review found that procalcitonin guidance significantly reduced antibiotic usage in adult ICU patients by reducing the duration of antibiotic therapy, rather than decreasing the initiation of antibiotics, without increasing morbidity or mortality.

In contrast, the use of procalcitonin as an indicator of need for intensification of antibiotic therapy in adult ICU patients should be discouraged because this approach was associated with increased morbidity. The large, well‐designed study by Jensen[33] showed that antibiotic intensification in response to elevated procalcitonin measurement was associated with increased morbidity: a longer ICU LOS, an increase in days on mechanical ventilation, and an increase in days with abnormal renal function. The authors concluded that the increased morbidity could only be explained by clinical harms of increased exposure to broad‐spectrum antibiotics.

Clinical and microbiological evaluations are neither sensitive nor specific for differentiating bacterial from viral respiratory tract infections. Procalcitonin can guide initiation of antibiotic therapy in adults with suspected bacterial respiratory tract infection. Our review showed that procalcitonin guidance significantly reduced antibiotic usage with respect to antibiotic prescription rate, duration of antibiotic therapy, and total exposure to antibiotic therapy in adult patients with respiratory tract infections.

The role of procalcitonin‐guided therapy in other populations is less clear. One study in postoperative colorectal surgery patients reported that elevated procalcitonin levels may identify patients at risk for infection who benefit from prophylactic antibiotic therapy.[32] Patients with elevated procalcitonin levels who received prophylactic antibiotic therapy had a significant decrease in the incidence and severity of systemic infections, whereas patients with normal procalcitonin levels did not require any additional surgical or medical therapy. Although these findings are promising, more data in postoperative patients are needed.

The utility of procalcitonin in pediatric settings is a significant gap in the present literature. One study[31] in neonates with suspected sepsis showed a significant decrease in the proportion of neonates started on empiric antibiotic therapy and a decrease in the duration of antibiotic therapy with procalcitonin guidance. However, there was insufficient evidence that procalcitonin guidance does not increase morbidity or mortality.

Comparison to Other Systematic Reviews

Six systematic reviews of procalcitonin guidance in the management of patients with infections were published prior to our review.[9, 10, 11, 12, 13, 14] Our systematic review differs from past reviews in the number of studies included and the pooling of studies according to patient population, type and severity of infection, and different uses of procalcitonin measurements, either for initiation, discontinuation, or intensification of antibiotic therapy. Previous systematic reviews included 7 to 14 studies, whereas ours included 18 randomized, controlled trials. One previous review[13] included and pooled the Jensen et al. study[33] with other studies of adult ICU patients. We evaluated the Jensen et al. study separately because it uniquely looked at procalcitonin‐guided antibiotic intensification in adult ICU patients, in contrast to other studies that looked at procalcitonin‐guided antibiotic discontinuation. We addressed pediatric populations separately from adult patients, and recognizing that there are distinct groups within the pediatric population, we separately grouped neonates and children ages 1 to 36 months. Despite these differences, our review and other systematic reviews, we came to similar conclusions: procalcitonin‐guided antibiotic decision making compared to clinical criteria‐guided antibiotic decision making reduces antibiotic usage without increasing morbidity or mortality.

Limitations

An important limitation of this review was the uncertainty about the noninferiority margin for morbidity and mortality in adult ICU patients. Only the Bouadma et al. study[23] did a power analysis and predefined a margin for noninferiority for 28‐ and 60‐day mortality. Meta‐analysis of all 5 ICU studies showed a pooled point estimate of 0.43% in mortality and a 95% CI of 6% to 5% for difference in mortality between procalcitonin‐guided therapy versus standard care. A 10% noninferiority margin for mortality has been recommended by the Infectious Diseases Society of America and American College of Chest Physicians, but there is concern that a 10% margin for mortality may be too high. Presently, 2 large trials are in progress that may yield more precise estimates of mortality in the future.

Differences in reporting of total antibiotic exposure and morbidity outcomes limited our ability to pool data. Total antibiotic exposure is conventionally reported as mean days per 1000 days of follow‐up, but some studies only reported relative or absolute differences. Likewise, morbidity was reported with different severity of illness scales, including Sepsis‐Related Organ Failure Assessment, Simplified Acute Physiology (SAP) II, SAP III, and Acute Physiology and Chronic Health Evaluation II, which limited comparisons across studies.

Research Gaps

We identified gaps in the available literature and opportunities for future research. First, the safety and efficacy of procalcitonin‐guided antibiotic therapy needs to be studied in patient populations excluded from current randomized controlled studies, such as immunocompromised patients and pregnant women. Patients who are immunocompromised or have chronic conditions, such as cystic fibrosis, account for a significant percentage of community‐acquired respiratory tract infections and are often treated empirically.[29, 30] Second, standardized reporting of antibiotic adverse events and emergence of antibiotic resistance is needed. Strategies to reduce antibiotic usage have been associated with reductions in antibiotic adverse events, such as Clostridium difficile colitis and superinfection with multi‐drug resistant Gram‐negative bacteria.[37, 40, 41] Few studies in our review reported allergic reactions or adverse events of antibiotic therapy, [25, 27, 34] and only 1 reported antibiotic resistance.[19] Third, procalcitonin guidance should be compared to other strategies to reduce antibiotic usage, such as structured implementation of practice guidelines and antibiotic stewardship programs.[42] One single‐arm study describes how procalcitonin can be used in antibiotic stewardship programs to decrease the duration of antibiotic therapy,[43] but additional studies are needed. Finally, generalizing results from those studies that were conducted primarily in Europe would depend on similar use of and adherence to study‐based algorithms. Newer observational studies have demonstrated reduced antibiotic usage with implementation of procalcitonin algorithms in real‐life settings in Europe, but algorithm adherence was significantly less in the United States.[44, 45]

In summary, our systematic review found that procalcitonin‐guided antibiotic therapy can significantly reduce antibiotic usage in adult ICU patients without affecting morbidity or mortality. Procalcitonin should not be used to guide intensification of antibiotic therapy in adult ICU patients because this approach may increase morbidity. In adults with respiratory infections, procalcitonin guidance can significantly reduce antibiotic usage without adversely affecting morbidity or mortality. There is insufficient evidence to recommend procalcitonin‐guided antibiotic therapy in neonates with sepsis, children with fever of unknown source, or postoperative patients at risk for infection.