42 Chapter 3 PCT in this decision making [20]. Furthermore, PCT levels associate with severity of illness in patients with severe pneumonia [22] and decreasing PCT levels associate with improved survival rates [23]. Likewise, in a prospective observational study conducted in 858 patients with sepsis inability to decrease PCT by > 80% from baseline to day 4 and day 28 was an independent predictor of mortality [24]. While the use of PCT as a biomarker for the diagnosis of sepsis is limited because PCT levels also rise in noninfectious diseases, it differentiates better between infectious and noninfectious causes of critical illness than C-reactive protein (CRP), lipopolysaccharide binding protein (LBP) and interleukin (IL)-6 [25]. Different PCT algorithms have been developed to help decision-making regarding the start and duration of antibiotic treatment. In patients with acute respiratory infections the use of PCT algorithms reduces the initiation of antibiotic treatment (mostly in primary care settings) and duration of antibiotic treatment (mostly in emergency departments (EDs) and ICU settings) without affecting mortality [26]. Similarly, a randomized controlled trial found a decrease of 4.5% in use of antibiotics without differences in mortality, diagnostic or therapeutic procedures in patients with severe sepsis or septic shock [27]. In a prospective, multicenter, randomized, controlled, open-label intervention trial in 15 hospitals in the Netherlands involving 1575 patients PCT guidance of antibiotic therapy, consisting of a non-binding advice to discontinue antibiotics if PCT concentration decreased by 80% or PCT levels were below 0.5 ng/ml, was associated with a reduced consumption of antibiotics and a diminished mortality at 28 days (20% versus 27% in the standard-of-care group)[12]. This suggests that PCT concentrations might assist in identifying bacterial infections, which may result in more adequate diagnosis and treatment [12]. Yet another randomized controlled trial in critically ill patients, using a PCT algorithm wherein a 0.1 ng/ml cut-off determined antibiotic cessation, found no reduction in duration of antibiotic treatment [28]. A recent investigation determined utilization of PCT and associated outcomes in the “real world” clinical setting of ICU’s in the United States [29]. Among > 20,000 critically ill patients in 107 hospitals with PCT testing available, 18% of patients had PCT levels checked; in this population the use of PCT was not associated with improved antibiotic utilization or other clinical outcomes [29]. Hence, current data on the use of PCT for antibiotic stewardship in critically ill sepsis patients are not consistent. Examples of other well studied protein biomarkers are CRP [30], LBP [31], IL-6 [31], soluble triggering receptor expressed on myeloid cells-1 (sTREM-1)[32, 33] and soluble urokinase plasminogen activator receptor (suPAR)[34], all with a lower sensitivity and specificity as a biomarker for sepsis compared to PCT. The biggest potential of PCT so far seems to be to help reduce exposition to antibiotics in patients with acute respiratory infections and perhaps as a stimulant to physicians to safely reduce the duration of antibiotic treatment in critically ill patients with a presumed bacterial infection. Nonetheless, PCT cannot be used as a single diagnostic test for sepsis, as false negative results could lead to mortality. Considering the weak evidence for the use of PCT in clinical settings the Surviving Sepsis Guidelines stress the point that a clinical decision to initiate, alter or stop antimicrobial treatment should never be based solely on changes in any current biomarker, including PCT [11].
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