Procalcitonin serial testing to inform treatment of sepsis

Antibiotic misuse contributes to Clostridium difficile infection

The incidence and severity of Clostridium difficile infection (CDI) has increased dramatically within the past two decades, making the Clostridium difficile bacterium the most common cause of nosocomial infections in developed countries. Responsible for almost half a million infections in the U.S. each year, CDI is associated with significant morbidity and mortality.⁸

Patients at increased risk of CDI include those receiving antibiotic therapy or patients who are immunocompromised through chemotherapy treatment or HIV infection.⁹ Due to resultant diarrhea and the development of potentially life-threatening complications such as sepsis, CDI represents a substantial clinical burden.

It has been estimated that excess healthcare costs related to CDI could be as much as $4.8 billion for acute-care facilities alone.¹⁰ In a meta-analysis, the average CDI-attributable cost per case was $20,085 for community-acquired CDI and $34,149 for hospital-acquired CDI. These figures were associated with an average length of stay of 5.7 days for community-acquired CDI and 7.8 days for hospital-acquired CDI.¹¹

An average 20.9 percent recurrence rate has been reported for healthcare-associated CDI, resulting in an estimated 61,400 first recurrent infections.¹⁰ Given the challenges of treating recurrences, and because almost all antibiotics are associated with an increased risk of CDI, initiatives aimed to reduce CDI incidence should target reduced antimicrobial exposure through effective antibiotic stewardship programs.¹²

Current methods to identify systemic bacterial infections require improvement

Signs of bacterial and viral infections frequently overlap, including elevated body temperature, heart rate, respiratory rate, and leukocyte count. Although these parameters can be monitored easily, they are often inadequate to determine the nature of the infection. Further information can be gained by culturing urine, cerebrospinal fluid (CSF), bronchial fluid, or blood. However, such tests are time-consuming (up to 48 hours for urine, CSF, and bronchial fluid, 50-60 hours for blood) and negative cultures do not exclude infection.^2,13
Since time is crucial when treating sepsis, measurement of a relevant biomarker is far more appropriate.

Common biomarkers of sepsis include c-reactive protein (CRP), lactate, and the cytokine interleukin-6 (IL-6).¹⁴ However, all of these have limitations. Relevant elevated CRP levels cannot be measured until 6 to 12 hours after an infectious challenge and takes 24 to 48 hours to peak adding considerable time to diagnosis.¹⁵ Lactate is not specific to bacterial infections but instead poor tissue perfusion. Lactate is also elevated in individuals with acute myocardial infarction, hypotension, and heart failure, reducing its utility as a sepsis biomarker.¹⁶ Cytokines such as IL-6, tumor necrosis factor-α (TNF-α), IL-1β, and IL-10 show low specificity for bacterial infections and increase only briefly or intermittently.^2,14 Furthermore, the variability in the course of time and individual patient kinetics for secretion of cytokines limits their use for diagnosis.

Due to its improved sensitivity, specificity, and kinetics as compared to CRP, lactate, and IL-6, PCT is the preferred biomarker of sepsis. PCT is a 14.5kDa prohormone encoded by the CALC-1 gene, belonging to the calcitonin super-family of peptides. The production of calcitonin is exclusive to the parafollicular cells (C cells) of the thyroid. In healthy individuals, PCT is produced only in the thyroid, but in the presence of an infection may be produced by extra-thyroidal tissues.^2,25 In healthy individuals, circulatory PCT levels are very low (0.05ng/mL).^2,17

In the presence of bacterial infection, PCT expression is induced in virtually all tissues and organs. This occurs either directly via microbial toxins or indirectly through a humoral or a cell-mediated host immune response. Since non-neuroendocrine parenchymal tissues lack the ability to cleave PCT to calcitonin, a dramatic increase in serum PCT levels result.17 With viral or parasitic infections, serum PCT levels are less likely to increase.¹⁵ In contrast, CRP is positive for infectious and non-infectious reasons whenever inflammation is involved and is elevated in the presence of a viral infection.¹⁴

In a study comparing IL-6 to procalcitonin as a biomarker of sepsis, PCT demonstrated a far greater specificity of 97 percent vs. 67 percent, and a negative predictive value of 88 percent vs. 39 percent providing substantial support for its utility as a sepsis biomarker.¹⁸

In addition to the early and highly specific diagnosis of severe systemic bacterial infection and sepsis, PCT affords the ability to monitor the patient response to antibiotic therapy and the course of the disease.¹⁹ Remaining elevated until the bacterial infection resolves, PCT levels have a half-life of 25 – 30 hours^2,19 providing physicians with a means to assess the therapeutic effect of treatment.

PCT has utility as a diagnostic guide

Since its identification as a reliable biomarker of sepsis, PCT has been studied in a wide range of infections. These include respiratory infections, post-operative infections, and ventilator-associated pneumonia. Importantly, PCT has also demonstrated proven utility to distinguish bacterial from viral meningitis17 and has been used to evaluate the severity of CDI and other bacterial infections.^20,21

A further advantage of PCT over other sepsis biomarkers is its use to diagnose bacterial infection in neutropenic patients.¹⁷ Measurement of PCT levels can also be employed to distinguish sepsis from non-infectious systemic inflammatory response syndrome (SIRS) since normal or very low PCT plasma concentrations have a high negative predictive value to rule out SIRS.²² Finally, PCT can be used in the differential diagnosis of urinary tract infections and urosepsis, as well as diagnosing catheter-related bloodstream infections (CRBSI) in critically ill patients.^{20, 23}

PCT serial testing is essential for accurate results

For PCT testing to be effective, a baseline reading followed by serial measurements at 24-hour intervals is necessary. Although the baseline measurement can be used to indicate the presence of a systemic bacterial infection—prompting the initiation of antibiotic therapy—it should not be used in isolation to make clinical decisions. Serial measurements of PCT are essential.²⁴

With effective antibiotic therapy, PCT, with a half-life of 24-hours, should show an approximate reduction of 50 percent with each day of treatment. PCT levels measured daily over the 72-hour treatment regimine should show a decline of 80 percent or more from the initial baseline.²¹

Empowering physicians to assess the severity of sepsis, PCT serial testing appears to be an effective tool to guide clinical decision-making. Because clinical decisions are based upon serial measurements of PCT, it is important to use an immunoassay with high precision and sensitivity. This is especially pertinent when patients exhibit only low levels of the prohormone upon presentation.

PCT serial testing represents a major innovation for antibiotic stewardship

Due to its capacity to differentiate between bacterial and viral infections better than other biomarkers, PCT is an extremely powerful diagnostic assay. In initiating early antibiotic treatment or making an antibiotic switch where necessary, PCT serves as a good prognostic marker in sepsis to predict patients at risk of deteriorating.²⁶ In combination, these features enhance clinical decision-making to promote responsible antibiotic stewardship.

As well as contributing to antibiotic effectiveness, serial monitoring of PCT levels helps improve patient outcomes and reduce adverse effects, such as CDI, AMR, and lower respiratory tract infections (LRTI) through more efficacious treatment. In addition, PCT serial testing positively impacts healthcare utilization and cost-effectiveness for sepsis. This is achieved by reducing antibiotic therapy days, days in the ICU, and days spent on a regular ward, all lowering hospital costs by an estimated 20-30 percent.²⁷

Proven efficacy of PCT serial testing

With a pressing need for hospitals to provide early, effective antibiotic treatment while reducing unnecessary treatment days, high sensitivity and precision are fundamental to serial PCT testing. This is especially important in the lower ranges of PCT, where critical medical decisions to initiate an antibiotic protocol are to be made. A retrospective study of 2,152 patients in a center with an antibiotic stewardship program assessed the impact of incorporating a PCT algorithm to guide antibiotic management, publishing the results in 2017.21 The cohort with PCT testing experienced:

• 47 percent reduction in median days of antibiotic therapy, from 17 to nine days, with an associated reduction in costs of antibiotics
• 50 percent reduction in all-cause 30-day readmission rate, from 22.4 percent to 11.1 percent
• 50 percent reduction in adverse drug events from anti-microbials, from 16.2 to 8.1 percent
• 62 percent reduction in all-cause hospital mortality, from 7.6 to 2.9 percent deaths
• 64 percent reduction in CDI, from 2.5 to 0.9 percent

Although serial PCT testing requires upfront investments such as equipment, supplies, and staff education, these costs are more than offset by downstream savings which do not compromise patient outcomes.²⁷ Incorporating PCT algorithms for antibiotic treatment may be useful in decreasing hospital spending per patient by reducing the number of hospital days, the number of blood cultures, and days on antibiotic therapy.

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