Although procalcitonin assays have shown promising results over the years, there are still several limitations that require consideration before implementing these tests in everyday clinical practice. For instance, it has been shown that PCT serum levels can also become elevated among patients during times of noninfectious conditions, such as with trauma, burns, carcinomas (medullary C-cell, small cell lung, & bronchial carcinoid), immunomodulator therapy that increase proinflammatory cytokines, cardiogenic shock, first 2 days of a neonate's life, during peritoneal dialysis treatment, and in cirrhotic patients (Child-Pugh Class C). Furthermore, PCT levels have found to be falsely elevated in patients suffering from various degrees of chronic kidney disease which can, in turn, alter baseline results making the determination of an underlying bacterial infection difficult to establish. Thus, it is vital for the clinician to rule out the above scenarios to ensure there are no confounding issues that may be obscuring the PCT measurements.[4][10][4]

The cost-effectiveness of PCT assays needs to be considered as well because they currently suffer from overuse in the emergency setting leading to extraneous costs. The average price of the test is roughly $9.44, which is relatively inexpensive. However, this cost does not take into account the amount that insurance charges nor does it include the cost it requires to obtain the sample. Salinas et al. discovered that of 142644 PCT assays performed in a calendar year, 44.1% could have been avoided based on clinical presentation and outcome, which would have saved $594390 annually. Within the Intensive Care setting, Kip et al. performed a randomized control trial to determine the cost-effectiveness of PCT assays among septic patients. They determined that PCT assays improved mortality rates and decreased the clinical course of antibiotics, however, they found that the cost per patient was $2704 (on average) greater than the patients who did not receive the PCT assays during their hospital stay. Therefore, clinicians need to use precaution when ordering PCT assays to ensure cost-effective medical practice.[11][12]

Procalcitonin has a set half-life that provides clinicians and researchers with a rough timeline of when levels should begin to decrease (approximately 50% reduction over 24 hours) following physiological control of the systemic infection. Current clinical practice utilizes a variety of PCT cut-off levels to determine the initiation and discontinuation of antibiotic therapy. The clinical scenario and setting play a fundamental role as to which cut-off level should be employed. However, most research has shown that PCT levels display clinical significance when they are in the range of 0.1 to 0.5 ng/mL. Further, research has shown that PCT levels less than 0.1 ng/mL have been shown to have a high negative predictive value (96.3%) for excluding bacterial infections.[5][6][2]

The following clinical scenarios have utilized various PCT cut-off levels to determine the source of an infective process as well as when antibiotic therapy could be utilized/discontinued[6]:

Arthritis: 

• PCT cut-off level: 0.1 to 0.25 ng/mL
• Role of PCT: Discriminate infective (septic) arthritis from non-infective arthritis.  
• Type of Study: Observational

Bacteremic Infections

• PCT cut-off level: 0.25 ng/mL
• Role of PCT: To rule out bacteremic infections. 
• Type of Study: Observational

Blood Stream Infection (primary): 

• PCT cut-off level: 0.1 ng/mL
• Role of PCT: Differentiate between true infection and a contaminated sample. 
• Type of Study: Observational

Bronchitis (acute)/Chronic Obstructive Pulmonary Disease (COPD) Exacerbations: 

• PCT cut-off level: 0.1 to 0.5 ng/mL
• Role of PCT: Reduce (unnecessary) antibiotic exposure in the ED and inpatient setting without adverse outcomes. 
• Type of Study: Randomized Control Trial  

Endocarditis: 

• PCT cut-off level: 2.3 ng/mL
• Role of PCT: High diagnostic accuracy for predicting acute endocarditis. 
• Type of Study: Observational

Meningitis: 

• PCT cut-off level: 0.5 ng/mL
• Role of PCT: Differentiate viral from bacterial meningitis and subsequently reduced antibiotic exposure.
• Type of Study: Before-After

Neutropenia: 

• PCT cut-off level: 0.1 to 0.5 ng/mL
• Role of PCT: Identify systemic bacterial infections within neutropenic patients. 
• Type of Study: Observational

Pneumonia: 

• PCT cut-off level: 0.1 to 0.5 ng/mL
• Role of PCT: Reduce antibiotic exposure during hospitalization without adverse outcomes.

Postoperative Fever: 

• PCT cut-off level:0.1 to 0.5 ng/mL
• Role of PCT: Differentiate post-operative infections from non-infectious fever. 
• Type of Study: Observational

Postoperative Infections: 

• PCT cut-off level: 0.5 to 1.0 ng/mL
• Role of PCT: Minimize antibiotic treatment in surgical ICU without detrimental outcomes. 
• Type of Study: Randomized Control Trial

Severe Sepsis/Shock

• PCT cut-off level: 0.25 to 0.5 ng/mL
• Role of PCT: Limit antibiotic treatment in the ICU without detrimental outcomes.
• Type of Study: Randomized Control Trial

Upper Respiratory Tract Infections

• PCT cut-off level: 0.1 to 0.25 ng/mL
• Role of PCT: Limit antibiotic treatment in the ICU without detrimental outcomes.
• Type of Study: Randomized Control Trial

Urinary Tract Infections: 

• PCT cut-off level: 0.25 ng/mL
• Role of PCT: Determine the extent of renal involvement. 
• Type of Study: Observational

Ventilator-Associated Pneumonia[6]: 

• PCT cut-off level: 0.1 to 0.25 ng/mL
• Role of PCT: Minimize antibiotic treatment without detrimental outcomes. 
• Type of Study: Randomized Control Trial

Once the clinician establishes the cut-off level, it is then important to determine how often PCT measurements should be repeated to determine adequate control. Current clinical data suggests that PCT serum levels should be remeasured after 6 to 24 hours, absent evidence of spontaneous clinical improvement (eg, hemodynamic instability). Following antibiotic initiation, the recommendation is that PCT values be assessed every one to two days to ensure adequate coverage. Further, antibiotic courses should be discontinued as soon as PCT levels drop below 0.1 ng/mL or 80 to 90% below the initial measurement.[6]

Algorithms have since been established for the ED and ICU setting which provide clinicians with a quick method for determining when to initiate or discontinue antibiotics. In the ED, an algorithm has been established for determining when to start antibiotic therapy in patients with respiratory tract infections. Recommendations are that antibiotics be utilized when PCT levels are above 0.25 ng/mL and that PCT levels be repeated on days 3,5, and 7 and to stop antibiotics if they fall below 0.25 ng/mL or drop by 80 to 90%. If PCT remains elevated then consider new treatment options. In the ICU, an algorithm has been instituted to determine when antibiotic treatment should be discontinued in patients with sepsis. The algorithm recommends that antibiotic coverage should be discontinued when PCT levels drop below 0.5 ng/mL or a decrease of 80% from the peak value. However, if PCT levels continue to remain elevated (over 0.5 ng/mL), then it is advised to continue the antibiotic course or consider changing the treatment entirely. These algorithms have been used with great success in clinical trials and have proven to reduce overall antibiotic use thus improving antibiotic stewardship. However, further research is needed to ensure these results can be adequately repeated on a larger scale and by utilizing more clinical trials versus observational studies.[6]

It is well-documented that early diagnosis of a bacterial infection can lead to a decrease in mortality and morbidity among all patients. Efficient diagnosis of bacterial infections allows physicians to initiate antibiotic therapy when it is deemed appropriate, thus preventing the misuse and overuse of antibiotics. As antibiotic resistance continues to rise, it has become ever more important for clinicians to determine different algorithms and laboratory tests that help sustain current antibiotic parameters. Unfortunately, most of the first-line tests for determining infection, such as blood cultures and C-reactive protein (CRP), lack the efficiency and specificity needed to treat patients promptly. Therefore, procalcitonin serum assays have been developed to provide physicians and nurses with an earlier detection method for determining the origin of a systemic inflammatory response (eg, bacterial versus non-bacterial). Early detection, in turn, limits the development of antibacterial resistance as well as patient exposure to antibiotics when they are no longer warranted. 

The prognostic value of procalcitonin has also shown clinical significance by providing physicians with a positive correlation between disease severity and elevated PCT serum levels, especially within septic patients. Although PCT assays have shown great promise, the cost-effectiveness of these tests continues to be a topic of debate. Current research has shown that these tests are already being overused because there are currently no adequate guidelines in place for when these tests should and should not be obtained. Therefore, the clinical significance of these tests needs to be more thoroughly researched on a large scale and by way of randomized clinical trials (gold standard) so that guidelines can be implemented to ensure the practice of cost-effective medicine.[5][6][7][11][12]

As bacterial drug resistance continues to rise across the globe, it has become of utmost importance to enhance antibiotic stewardship. Procalcitonin (PCT) provides healthcare providers with a more specific marker (specificity of ~79%) for determining the presence of bacterial infections when compared to current measures. Therefore, PCT assays can be utilized to determine if antibiotics need to be initiated, discontinued, or changed based on changing serum levels thus decreasing the overall use or misuse of antibiotics. Moreover, the assays have also been shown to be useful as a prognostic indicator for patients in the critical care setting, however, further research needs to be performed in this respect to determine if PCT assays are adequate for this purpose. [4][6]

Procalcitonin has utility in a number of clinical scenarios, however, current research suggests that PCT levels are most useful in the setting of acute exacerbations of Chronic Obstructive Pulmonary Disease (COPD) patients to determine when and if antibiotics should be initiated. The European Respiratory Society/American Thoracic Society guidelines currently state that the use of antibiotics in the setting of COPD exacerbations is controversial because there is inadequate research showing improvement in clinical outcomes following the use of antibiotics. Therefore, they recommend further effectiveness studies and/or the use of biomarkers to determine when antibiotics are clinically appropriate. A biomarker, such as procalcitonin, can thus be utilized to determine if antibiotics are appropriate in the setting of acute COPD exacerbations, which in turn, improves antibiotic stewardship and reduces morbidity associated with unnecessary antibiotic use. [6][13]

Overall, procalcitonin levels provide a promising lab value for identifying bacterial infections, however, this test is limited based on the clinical setting and patient population for which it is utilized. Therefore, further research studies (eg, Randomized Clinical Trials) need to be conducted prior to implementing procalcitonin guidelines for everyday clinical practice.