Procalcitonin Assay - Controlling Unnecessary Antibiotic Use

The increase in antibiotic resistance is becoming an alarming concern in medical science and practice. The growing incidence of morbidity and mortality, and high healthcare cost burden due to treatment failure, are some of the outcomes of resistance to antimicrobial agents. Extensive use of antibiotic is mostly responsible for the development of antibiotic resistance. 

VIDAS® B.R.A.H.M.S. PCT™ manufactured by bioMérieux Inc. in Marcy l'Etoile (France), is one of the recently developed diagnostic tools which has the capability to provide an accurate result in an emergency condition and have potentials to differentiate bacterial and viral infection. [1] In February 23, 2017, the U.S. Food and Drug Administration (FDA) provided approval for extensive use of the Vidas Brahms PCT Assay to assist clinical practitioners for determining commencing or discontinuing antibiotic therapy in patients with lower respiratory tract infections, such as community-acquired pneumonia, and also for suspending antibiotic therapy in patients with sepsis. [2] The U.S. FDA agency, which is working under the U.S. Department of Health and Human Services is primarily responsible for governing the safety and efficacy of drugs, medical device, vaccines and other biological products use for human and veterinary purposes.

Community-acquired pneumonia (CAP) is a type of lower respiratory tract infection with multiple clinical manifestations including a cough, chest pain, chills, rigors, fever, fatigue, breathing difficulty (dyspnea). CAP can be acquired from the long-term health care settings or outside of a hospital. The medical advancement is unable to control CAP incidences and globally it has become a major cause of morbidity, mortality, and economic burden. According to published article in American Health & Drug Benefits, annually almost 5.6 million US patients are affected with CAP and is in the sixth position as a leading cause of death in elderly people (aged ≥ 65 years). [3] Even in the USA, children bellow 5 years of age are frequently hospitalized due to pneumonia and bronchiolitis, which are considered to be the most common lower respiratory tract infection. [4] Notably, the burden of hospitalization for severe LRTI, including pneumonia is greatest among children aged below 1 year and the sixth leading cause of death among different age group children. [5] Pneumonia Research News published an article in June 2016, has clearly mentioned with evidence that clinicians mostly prescribes redundant antibiotics due to the difficulty of identification of a resistant strain of bacteria responsible for CAP. This highly requires precise and quick diagnostic tool for confirmation of bacterial strain to solve the overburden of antibiotic use and to restrict the growth of antibiotic resistance pathogens. [6]

Another, Community-acquired disease, which provides a devastating outcome of infection is sepsis, specifically for elderly patients or critically ill patients. In the United States, the prevalence of severe sepsis is almost 300 cases per 100 000 population. [7] The progression of sepsis occurs through systemic inflammatory response syndrome and the condition become progressive that worsen with time and leads to organ dysfunction. [8] The absence of target therapy and imprecise antibiotic therapy is the only therapeutic approach for treating sepsis [9] and the antibiotic resistance is one of the primary difficulty to treat sepsis. [8] Therefore, identification of pathogen is an important criterion to provide empirical treatment to the patient with sepsis. [9]

The problem associated with identification of microbes, especially in respiratory tract infection is due to viral and bacterial infections as is prevalent in the respiratory tract. Mostly children with LTRIs are affected with viral infections. The febrile episodes of infection insist patients get admitted in hospitals. However, the failure to accurately identify the causative microorganism influences to prescribe antibiotics. It is always ideal to have good diagnostic tests that can establish the reason for LRTIs which can render in reducing overall use of antibiotics and provide a targeted use of antibiotics. It is a need of the hour to have a rapid identification of viral infections which can further help to control nosocomial transmission. [10]

Biomarkers can be sensitively measured in the human body and have been used as a potential diagnostic tool. The proper selection of biomarker is essential for considering its efficacy to detect infectious diseases based on their ability to offer early identification, ascertain extremely precise diagnosis, establish a correct prognosis, undeviating molecular-based therapy and examine the evolution of the disease. [11] First time in 1993 it was considered that serum procalcitonin (PCT) level has an association with bacterial infection and since then researchers worked on it to make it a potential biomarker for bacterial infection and sepsis. [12]

PCT is a prohormone of calcitonin, which is secreted by the thyroid gland. However, a wide range of cellular component are able to secrete PCT in response to the systemic inflammatory reaction, including sepsis/ severe sepsis due to bacterial infection and triggers the elevation of PCT levels. Mild systemic bacterial infection, associated with the minor inflammatory response can potentially alter serum PCT levels. However, localized infections cannot increase serum PCT level. Providing highly specific result and quick response is the main advantages of using PCT as a biomarker for bacterial infection and sepsis diagnosis. In septic condition, the infection can be detectable within 3 to 6 hours. In healthy human being, the PCT value is normal and that is considered as 0.5 ng/mL, but this value increases with severity of the bacterial infection and can reach between 10 and 100 ng/mL. However, PCT levels do not change or fall down in viral infections, autoimmune processes, and chronic inflammatory conditions. The accuracy of PCT test has potentially to increase the efficiency of clinical diagnosis, as it can assist to differentiate the patient with a systemic inflammatory reaction syndrome related to a bacterial infection, including sepsis or not related to an infectious cause. [12]

In certain conditions, serum PCT level is increased without the interference of bacterial infection and sepsis, which include: 

• Neonates within 48 hours after born have elevated serum PCT level due physiological elevation.
• After major surgical intervention or traumatic injury, severe burn, OKT3 antibodies therapy or administration of pro-inflammatory cytokines may influence medications.
• Acute malaria attack caused by plasmodium falciparum or persistent fungal infections
• Lung cancer, carcinoma in C-cell of thyroid gland, cardiogenic shock or prolonged organ perfusion anomaly. [12]

VIDAS® B.R.A.H.M.S. PCT™ gives a result within 20 minutes with and fully automated test procedure. The clinical trial report showed that over a period of time, the decision algorithm supported by the detection of virtual reduction of plasma PCT levels permits a considerable antibiotic therapy reduction time and the duration of ICU reside days, without providing any noticeable adverse event to patients. In addition, clinical study report also mentioned that the potentiality of PCT measurement can able to reduce 65% antibiotic exposure in patients with lower respiratory tract infection in primary care settings. [1]

The recent go-ahead from FDA for the widespread use of the Vidas Brahms PCT Assay can provide the official recognition of safety and efficacy of this diagnostic tool. It is expected that this regulatory action will be supportive and helpful to restrict the overuse of antibiotics and also can slow down the progression of multi-drug resistance bacterial strength.



References

1. VIDAS® B.R.A.H.M.S PCT™. ; BIOMÉRIEUX; Retrieve from http://www.biomerieux-diagnostics.com/vidas-brahms-pct
2. FDA clears test to help manage antibiotic treatment for lower respiratory tract infections and sepsis, (2017); FDA News Release; Retrieve from https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm543160.htm
3. Jonah Broulette, Holly Yu, Bruce Pyenson, Kosuke Iwasaki, Reiko Sato; The Incidence Rate and Economic Burden of Community-Acquired Pneumonia in a Working-Age Population; Am Health Drug Benefits. 2013 Sep-Oct; 6(8): 494–503. Retrieve from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031734/
4. Eric M. Foote, Rosalyn J. Singleton, Robert C. Holman, Sara M. Seeman, Claudia A. Steiner, Michael Bartholomew, Thomas W. Hennessy;  Lower respiratory tract infection hospitalizations among American Indian/Alaska Native children and the general United States child population; Int J Circumpolar Health. 2015; 74: 10.3402/ijch.v74.29256. Published online 2015 Nov 5. doi: 10.3402/ijch.v74.29256; Retrieve from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636865/
5. Adena H. Greenbaum,; Jufu Chen,; Carrie Reed, Suzanne Beavers, David Callahan, Deborah Christensen, Lyn Finelli, Alicia M. Fry; Hospitalizations for Severe Lower Respiratory Tract Infections; Pediatrics 2014;134: 3; Retrieve from http://pediatrics.aappublications.org/content/134/3/546
6. Margarida Azevedo, (2016); Unnecessary Antibiotics Still Prescribed for Community-Acquired Pneumonia Due to Difficulties Identifying Resistant Strains; Pneumonia Research News; Retrieve from https://pneumoniaresearchnews.com/2016/06/17/unnecessary-prescription-of-antibiotics-still-prevalent-due-to-difficulties-in-identifying-antibiotic-resistant-staphylococcus-aureus-community-acquired-pneumonia/
7. Florian B Mayr, Sachin Yende, Derek C Angus; Epidemiology of severe sepsis; Virulence. 2014 Jan 1; 5(1): 4–11. Published online 2013 Dec 11. doi: 10.4161/viru.27372; Retrieve from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916382/
8. Siri Tandberg Nygå, Nina Langeland, Hans K Flaatten, Rune Fanebust, Oddbjørn Haugen, Steinar Skrede; Aetiology, antimicrobial therapy and outcome of patients with community acquired severe sepsis: a prospective study in a Norwegian university hospital; BMC Infectious Diseases201414:121; DOI: 10.1186/1471-2334-14-121; Retrieve from http://bmcinfectdis.biomedcentral.com/articles/10.1186/1471-2334-14-121
9. Andrew T. Pavia; Viral Infections of the Lower Respiratory Tract: Old Viruses, New Viruses, and the Role of Diagnosis. Clin Infect Dis 2011; 52 (suppl_4): S284-S289. doi: 10.1093/cid/cir043; Retrieve from https://academic.oup.com/cid/article/52/suppl_4/S284/422205/Viral-Infections-of-the-Lower-Respiratory-Tract
10. In Seok Yang, Chunsun Ryu, Ki Joon Cho, Jin Kwang Kim, Swee Hoe Ong, Wayne P. Mitchell, Bong Su Kim, Hee-Bok Oh, Kyung Hyun Kim; IDBD: Infectious Disease Biomarker Database; Nucleic Acids Res. 2008 Jan; 36(Database issue): D455–D460. Published online 2007 Nov 3. doi: 10.1093/nar/gkm925; Retrieve from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2238845/
11. Richard Mayeux; Biomarkers: Potential Uses and Limitations; NeuroRx. 2004 Apr; 1(2): 182–188. Retrieve from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC534923/
12. Solution For Emergency Diagnostics; Procalcitonin: A Novel Biomarker for Bacterial Infections and Sepsis; BIOMÉRIEUX, INC. Retrieve from http://www.biomerieux-usa.com/sites/subsidiary_us/files/15_pct_scientific_booklet_v10.pdf