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Soni NJ, Samson DJ, Galaydick JL, et al. Procalcitonin-Guided Antibiotic Therapy [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012 Oct. (Comparative Effectiveness Reviews, No. 78.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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Procalcitonin-Guided Antibiotic Therapy [Internet].

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Background and Objectives

Sepsis is a condition with high morbidity and mortality for which clinical diagnostic criteria lack sensitivity and specificity. Rapid diagnosis of sepsis and early initiation of antibiotic and goal-directed therapies have demonstrated a reduction in mortality. Conversely, overuse and misuse of antibiotics can result in adverse events and add to the increasing problem of antibiotic resistance. Several serum biomarkers have been identified in recent years with potential uses to help diagnose local and systemic infections, differentiate bacterial and fungal infections from viral syndromes or noninfectious conditions, prognosticate, and ultimately guide management, particularly antibiotic therapy. Among these potential uses of serum biomarkers, there is particular interest in finding a biomarker for diagnosis of sepsis. Currently, there are at least 178 serum biomarkers that have potential roles in the management of patients with infections, and 34 have been studied specifically as a diagnostic tool for sepsis. Among these, procalcitonin is the most extensively studied biomarker.1,2

Serum levels of procalcitonin were recognized to be elevated in patients with infections during the early 1990s, and since that time, numerous studies have investigated the potential roles of procalcitonin in diagnosing and managing of local and systemic infections.3-5 Procalcitonin is the prohormone precursor of calcitonin that is expressed primarily in C-cells of the thyroid gland and to a smaller extent in neuroendocrine tissue of other organs, such as the lungs and intestines. The final step in conversion of procalcitonin to calcitonin is inhibited by various cytokines and bacterial endotoxins and, therefore, high levels of cytokines and/or bacterial endotoxins cause procalcitonin levels to rise. Cytokines are released nonspecifically in response to inflammation and infection, but endotoxins are released specifically during bacterial infections because they are derived primarily from the Gram-negative bacterial cell wall. There is some evidence that procalcitonin is more specific for bacterial infections, with serum levels rising and falling more rapidly in bacterial infection.6,7

Although viruses, parasites, and fungi can increase procalcitonin levels due to systemic inflammation, procalcitonin's primary diagnostic utility is thought to be in establishing the presence of local or systemic bacterial infections particularly in bacterial sepsis. In case of fungal infection, the diagnostic utility of procalcitonin is limited because the levels do not rise until 1 to 2 days after the onset of infection. A greater increase in procalcitonin levels would be anticipated in Gram-negative versus Gram-positive bacterial infections due to the release of endotoxin from the Gram-negative bacterial cell wall; however, only few studies have demonstrated higher levels of procalcitonin with Gram-negative bacterial infections when compared to Gram-positive bacterial infections.5 Procalcitonin appears to be a promising serum biomarker for infection, but its exact utility in diagnosing and managing patients with suspected infections remains unclear.

The U.S. Food and Drug Administration (FDA) has cleared for marketing at least three procalcitonin quantitative assays that are commercially available (see Table 1), but the optimal approach to laboratory testing of procalcitonin has yet to be clarified. The labeled indication is the same for all three assays. According to the approved labels, these assays are intended for use in conjunction with other laboratory findings and clinical assessments to aid in the risk assessment of critically ill patients on their first day of intensive care unit (ICU) admission, for progression to severe sepsis and septic shock.8-10 Quantitative and qualitative (semi-quantitative) assays for measuring procalcitonin are currently available. The qualitative tests use test strips, are rapid (results available in less than 30 minutes), and are designed for point-of-care testing. The quantitative tests use a luminescence immunoassay platform, are slower (results available in a few hours), and are designed for once or twice daily batch testing. Most studies supporting the use of procalcitonin have used the quantitative test, which is neither rapid nor available at the bedside. Whether or not the semiquantitative test will yield similar results to the quantitative test is unknown.4,11

Table 1. FDA-cleared procalcitonin assays.

Table 1

FDA-cleared procalcitonin assays.

The purpose of this systematic review is to synthesize comparative studies examining the use of procalcitonin in the management of patients with presumed local or systemic infection. Although important, the analytic validity of quantitative and qualitative procalcitonin testing is beyond the scope of this comparative effectiveness review. However, diagnostic accuracy studies that look at the use of procalcitonin in determining the cause of fever or other symptoms and signs of systemic or localized infections will be discussed briefly, since these studies are the basis for the cutoff procalcitonin levels used in the randomized controlled trials (RCTs). The comparator in the diagnostic accuracy studies is usually clinical criteria for the diagnosis of the particular infection, such as the criteria for the diagnosis of systemic inflammatory response syndrome (SIRS) and sepsis, which were developed at a 1992 consensus conference.12 Unfortunately, clinical criteria for sepsis require identifying a source of infection, which may be difficult. Microbiological evaluation may be helpful, but insensitivity of cultures is problematic. These same issues are also true for clinical criteria for the diagnosis of neonatal sepsis, pneumonia, and other respiratory tract infections.13

In healthy people, procalcitonin levels are very low. In systemic infections, including sepsis, procalcitonin levels are generally greater than 0.5–2 ng/mL, but often reach levels of greater than 10 ng/mL, and higher levels correlate with the severity of illness and prognosis. Studies indicate procalcitonin is superior to C-reactive protein, interleukin-6, and interleukin-8 for diagnosis of sepsis.14 Lower respiratory tract infections (LRTIs) are often less serious, although patients with severe community acquired pneumonia (CAP) may have life-threatening disease. Procalcitonin levels in patients with suspected respiratory tract infection (RTI) may be useful in determining if patients require antibiotic therapy. In RTIs, the levels of procalcitonin are not necessarily as elevated, and a cutoff of greater than 0.25 ng/mL seems to be most predictive of a bacterial respiratory tract infection requiring antibiotic therapy, while a level less than 0.25 ng/mL signals resolution of the infection.15,16

The cutoffs for other clinical situations may be quite different. For example, neonates normally show a characteristic increase in procalcitonin after birth, with a rapid return to normal by 48 to 72 hours. In this circumstance, the elevated procalcitonin levels are an acute phase reactant in response to the stress of the birth process, yet an incremental increase is still detectable in infants with neonatal sepsis. Unlike adults with systemic bacterial or fungal infection, sepsis, or RTIs that require antibiotic therapy, a nomogram for procalcitonin cutoffs that accounts for the time from birth in hours must be used.17 Likewise, the stress of surgery may increase procalcitonin levels, but again, there is an incremental increase in patients with infection, including subclinical or high risk of infection. Postoperatively, the procalcitonin cutoff level to identify patients with infection or at risk of infection may be higher than that used for other patient groups. Although procalcitonin may have a role in diagnosis and identification of patients who need initiation of systemic antibiotics, it may have greater applicability in guiding decisions about when to discontinue antibiotic therapy as procalcitonin levels quickly return to less than 0.25 ng/mL as infection resolves.18

Most of the RCTs of procalcitonin-guided diagnosis or management use one of the BRAHMS assays cleared for use in the United States and currently being marketed by bioMerieux. The recommendations for clinical cutoffs being marketed are in consensus with the cutoff used and evaluated in the RCTs looking at the use of procalcitonin in patient management. Most of these RCTs of procalcitonin-guided diagnosis or management involve two clinical entities: sepsis/systemic bacterial infections and LRTIs. As a result, two different cutoffs for interpretation of results are being marketed for these two clinical entities. A nomogram for neonates is also recommended.

Although the utility of procalcitonin in clinical management has been reviewed in other meta-analyses and systematic reviews, this report will afford valuable new information. Some of the previous reviews have been limited to selected populations, or have evaluated studies of distinct populations or different procalcitonin-guided therapies together. When this systematic review was initiated, the most recent meta-analysis of the effects of procalcitonin-guided therapy in patients with infections included seven RCTs published through November 2008.3 Since that time, the number of trials, including RCTs, studying procalcitonin-guided therapy has more than doubled. Further, there have also been several comprehensive literature reviews and two very recent systematic reviews of the use of procalcitonin to guide duration of antibiotic therapy in the ICU.19-21 Even though our understanding of the potential clinical benefits of procalcitonin assays is still evolving, clinicians have already begun to request that laboratories perform procalcitonin measurements and, therefore, another systematic review of the use of procalcitonin is needed at the present time. Furthermore, a comprehensive review evaluating different patient populations and all the potential uses of procalcitonin will identify the areas that require further prospective investigation and will serve as a roadmap for future research. The following Key Question and Analytic Framework outline the approach and key issues to be addressed in this review.

Key Questions

During the period the Key Questions were posted for public comment on the Effective Health Care Program Web site (, four general comments were received. The comments varied greatly from being supportive to being skeptical of procalcitonin's utility in diagnosing and managing infections. The contrasting opinions about procalcitonin's utility underscore the importance of performing a formal comparative effectiveness review. One comment questioned whether or not pediatric populations will be included in this review; in response, we note that pediatric populations have not been excluded from this review. Some studies have explored the use of procalcitonin in children with suspected infections, such as neonatal sepsis, urinary tract infections, and meningitis. The utility of procalcitonin as a screening tool for bacterial skin colonization or as a diagnostic tool for heat stroke is beyond the scope of this review and will not be included. No changes were made to the key clinical questions based on the public comments; however, the two Key Questions were combined into a single Key Question in the final report after further refinement.

Key Question: In selected populations of patients with suspected local or systemic infection, what are the effects of using procalcitonin measurement plus clinical criteria for infection to guide initiation, discontinuation, or a change of antibiotic therapy when compared with clinical criteria for infection alone on:

  • Intermediate outcomes, such as initiation, discontinuation, or change of antibiotic therapy; antibiotic use; and length of stay?
  • Health outcomes, such as morbidity, mortality, function, quality of life, and adverse events of antibiotic therapy (persistent or recurrent infection, and antibiotic resistance)?

The PICOTS (Patient, Intervention, Comparator, Outcome, Timing, and Setting) for the Key Question follows:

  • Patients
    • Adult patients with suspected infection, including, but not limited to, the following:
      • Local infections

        Acute exacerbation of chronic obstructive pulmonary disease


        Surgical site infection


      • Systemic infections

        Neutropenic fever



        Septic shock

    • Pediatric patients with suspected infection, including, but not limited to, the following:
      • Local infections


        Urinary tract infection


      • Systemic infections

        Neutropenic fever



        Septic shock

  • Interventions
    • Initiation, discontinuation, or intensification of antibiotics therapy guided by procalcitonin plus clinical criteria for infection
  • Comparators
    • Initiation, discontinuation, or intensification of antibiotic therapy guided by clinical criteria for infection alone
  • Outcomes
    • Intermediate outcomes
      • Antibiotic exposure
      • Duration of antibiotic therapy
      • Length of stay
    • Health outcomes
      • Morbidity
      • Mortality
      • Function
      • Quality of life as measured by validated scales
    • Adverse events
      • Persistent or recurrent infection
      • Antibiotic resistance
  • Timing
    • Three months
  • Settings
    • Outpatient: ambulatory clinics, urgent care centers
    • Inpatient: hospital wards, intensive care units, emergency departments


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