Pharmacology Consult

Biomarker-guided antimicrobial stewardship: The next target, or missing the mark?

Sepsis is a common and serious condition that can lead to significant morbidity and mortality. Because early and effective antibiotic therapy is a critical component of treatment, there is ongoing interest in increasingly rapid and reliable diagnosis. In conjunction with clinical evaluation, biomarkers have emerged as potentially useful diagnostic tools and may additionally have a role later in therapy to evaluate clinical response and guide cessation of antibiotics (Table 1).

Procalcitonin

Procalcitonin (PCT) is the most studied new biomarker to date. It is an amino acid produced in the thyroid to drive the intracellular production and secretion of calcitonin. In the setting of a bacterial infection, PCT production and extracellular release occurs throughout the body, and baseline serum concentrations (typically < 0.1 ng/mL) rise rapidly. This response is unique to bacterial infections. Although a viral infection may yield a modest elevation in PCT, serum concentrations generally remain below 0.25 ng/mL. In contrast, a bacterial infection will cause a more dramatic increase in PCT, making it a potentially useful tool to differentiate between bacterial and viral infections (Table 2).

Leah Molloy

Algorithms for PCT-guided antibiotic therapy have been developed wherein elevated concentrations predictive of bacterial infection prompt antibiotic initiation, and serial levels are then measured to gauge response and dictate antibiotic discontinuation. An early 2017 Cochrane meta-analysis failed to identify a mortality difference when PCT was used to guide treatment in patients with sepsis. Not included in this analysis was the large Stop Antibiotics on Procalcitonin guidance Study, which found reduced mortality (20% vs. 25%; P = .0122) and shorter duration of treatment (5 vs. 7 days; P < .01) among patients in the PCT-guided group. Another meta-analysis of PCT in acute respiratory tract infections identified reduced mortality (8.6% vs. 10%; P = .037) and shorter duration of treatment (5.7 vs. 8.1 days; P < .001) with PCT-guided therapy. A common limitation of the studies was low prescriber adherence to recommended discontinuation of antibiotics.

False-positive PCT results have been reported and can be attributed to a variety of clinical situations including, but not limited to, severe trauma, surgery, cardiogenic shock or impaired organ perfusion and severe renal impairment. Impaired renal function also slows the elimination of PCT, which must be considered when serial values are interpreted to assess a patient’s response to therapy. Physiological elevations in PCT have been described in newborns during the first 72 hours of life, necessitating adjustment for age-adjusted normal values. Nonetheless, PCT has been studied in the diagnosis and treatment duration of neonatal sepsis, resulting in shorter durations of antibiotic exposure (55.1 vs. 65 hours; P < .01) and hospitalization (123 vs. 126.5 hours; P < .01), with no adverse impact on clinical outcomes.

C-reactive protein

C-reactive protein (CRP) is a well-known marker of inflammation synthesized in the liver. Although readily available in most hospital settings and easy to trend, CRP is widely known to be limited as a diagnostic tool by its lack of specificity for infection and slow onset and time to peak concentration. However, CRP-guided treatment has been evaluated and in one study was found to be as useful as PCT to reduce antibiotic exposure.

Presepsin

CD14 is a cell membrane lipopolysaccharide receptor that binds peptidoglycans and other bacterial surface structures. Upon binding to a bacterial pathogen, CD14 is released into the bloodstream as soluble CD14 (sCD14) that is later cleaved to sCD14 subtype (sCD14-ST), known as presepsin. Studies to date have investigated presepsin only as a potential diagnostic tool to identify sepsis or to predict prognosis rather than dictating response to therapy or guiding duration of antibiotic treatment. In combination with clinical risk scores, presepsin may improve diagnosis and severity staging of sepsis.

Other biomarkers

Soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) is the extracellular form of a receptor protein expressed and released at an increased rate in the setting of infection and has been identified as a potential early predictor of mortality among sepsis patients. Soluble urokinase plasminogen activator receptor (suPAR) is another cell membrane protein that undergoes cleavage and systemic release in response to a variety of infections that may have utility as a severity of illness marker. The future roles of these biomarkers in clinical practice continue to be evaluated.

Current guideline recommendations

Although new data are constantly emerging and not all literature was available at the time, three current national guidelines comment on biomarkers. In general, use of biomarkers as a diagnostic tool for pneumonia is not currently endorsed in the Infectious Diseases Society of America (IDSA) guideline for hospital-acquired and ventilator-associated pneumonia (strong recommendation, moderate-quality evidence), though a role for serial PCT measurements as a means to decrease antibiotic use in critically ill adults is suggested in the IDSA/Society for Healthcare Epidemiology of America antimicrobial stewardship guideline (weak recommendation, moderate-quality evidence). Additionally, authors of the Surviving Sepsis guideline suggest that PCT may be used to shorten the duration of antimicrobial therapy in patients with sepsis, and to support stopping antibiotics in patients initially diagnosed with sepsis who later had minimal evidence of infection (weak recommendation, low quality of evidence).

Biomarkers continue to evolve as useful adjuncts to clinical assessment and other laboratory markers in the diagnosis and monitoring of critically ill patients. No single test can supersede clinical judgment and global presentation; however, these advances toward improved accuracy in diagnosis and monitoring have important implications for antimicrobial stewardship.

Disclosure: Molloy reports no relevant financial disclosures.

Sepsis is a common and serious condition that can lead to significant morbidity and mortality. Because early and effective antibiotic therapy is a critical component of treatment, there is ongoing interest in increasingly rapid and reliable diagnosis. In conjunction with clinical evaluation, biomarkers have emerged as potentially useful diagnostic tools and may additionally have a role later in therapy to evaluate clinical response and guide cessation of antibiotics (Table 1).

Procalcitonin

Procalcitonin (PCT) is the most studied new biomarker to date. It is an amino acid produced in the thyroid to drive the intracellular production and secretion of calcitonin. In the setting of a bacterial infection, PCT production and extracellular release occurs throughout the body, and baseline serum concentrations (typically < 0.1 ng/mL) rise rapidly. This response is unique to bacterial infections. Although a viral infection may yield a modest elevation in PCT, serum concentrations generally remain below 0.25 ng/mL. In contrast, a bacterial infection will cause a more dramatic increase in PCT, making it a potentially useful tool to differentiate between bacterial and viral infections (Table 2).

Leah Molloy

Algorithms for PCT-guided antibiotic therapy have been developed wherein elevated concentrations predictive of bacterial infection prompt antibiotic initiation, and serial levels are then measured to gauge response and dictate antibiotic discontinuation. An early 2017 Cochrane meta-analysis failed to identify a mortality difference when PCT was used to guide treatment in patients with sepsis. Not included in this analysis was the large Stop Antibiotics on Procalcitonin guidance Study, which found reduced mortality (20% vs. 25%; P = .0122) and shorter duration of treatment (5 vs. 7 days; P < .01) among patients in the PCT-guided group. Another meta-analysis of PCT in acute respiratory tract infections identified reduced mortality (8.6% vs. 10%; P = .037) and shorter duration of treatment (5.7 vs. 8.1 days; P < .001) with PCT-guided therapy. A common limitation of the studies was low prescriber adherence to recommended discontinuation of antibiotics.

False-positive PCT results have been reported and can be attributed to a variety of clinical situations including, but not limited to, severe trauma, surgery, cardiogenic shock or impaired organ perfusion and severe renal impairment. Impaired renal function also slows the elimination of PCT, which must be considered when serial values are interpreted to assess a patient’s response to therapy. Physiological elevations in PCT have been described in newborns during the first 72 hours of life, necessitating adjustment for age-adjusted normal values. Nonetheless, PCT has been studied in the diagnosis and treatment duration of neonatal sepsis, resulting in shorter durations of antibiotic exposure (55.1 vs. 65 hours; P < .01) and hospitalization (123 vs. 126.5 hours; P < .01), with no adverse impact on clinical outcomes.

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C-reactive protein

C-reactive protein (CRP) is a well-known marker of inflammation synthesized in the liver. Although readily available in most hospital settings and easy to trend, CRP is widely known to be limited as a diagnostic tool by its lack of specificity for infection and slow onset and time to peak concentration. However, CRP-guided treatment has been evaluated and in one study was found to be as useful as PCT to reduce antibiotic exposure.

Presepsin

CD14 is a cell membrane lipopolysaccharide receptor that binds peptidoglycans and other bacterial surface structures. Upon binding to a bacterial pathogen, CD14 is released into the bloodstream as soluble CD14 (sCD14) that is later cleaved to sCD14 subtype (sCD14-ST), known as presepsin. Studies to date have investigated presepsin only as a potential diagnostic tool to identify sepsis or to predict prognosis rather than dictating response to therapy or guiding duration of antibiotic treatment. In combination with clinical risk scores, presepsin may improve diagnosis and severity staging of sepsis.

Other biomarkers

Soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) is the extracellular form of a receptor protein expressed and released at an increased rate in the setting of infection and has been identified as a potential early predictor of mortality among sepsis patients. Soluble urokinase plasminogen activator receptor (suPAR) is another cell membrane protein that undergoes cleavage and systemic release in response to a variety of infections that may have utility as a severity of illness marker. The future roles of these biomarkers in clinical practice continue to be evaluated.

Current guideline recommendations

Although new data are constantly emerging and not all literature was available at the time, three current national guidelines comment on biomarkers. In general, use of biomarkers as a diagnostic tool for pneumonia is not currently endorsed in the Infectious Diseases Society of America (IDSA) guideline for hospital-acquired and ventilator-associated pneumonia (strong recommendation, moderate-quality evidence), though a role for serial PCT measurements as a means to decrease antibiotic use in critically ill adults is suggested in the IDSA/Society for Healthcare Epidemiology of America antimicrobial stewardship guideline (weak recommendation, moderate-quality evidence). Additionally, authors of the Surviving Sepsis guideline suggest that PCT may be used to shorten the duration of antimicrobial therapy in patients with sepsis, and to support stopping antibiotics in patients initially diagnosed with sepsis who later had minimal evidence of infection (weak recommendation, low quality of evidence).

Biomarkers continue to evolve as useful adjuncts to clinical assessment and other laboratory markers in the diagnosis and monitoring of critically ill patients. No single test can supersede clinical judgment and global presentation; however, these advances toward improved accuracy in diagnosis and monitoring have important implications for antimicrobial stewardship.

Disclosure: Molloy reports no relevant financial disclosures.