29 nov pct guided antibiotic use

Procalcitonin is an excellent biomarker for antibiotic use in bacterial infections alone. POCT guided PCT levels can help decide whether to add antibiotics or not in opd settings for respiratory tract infection.

1. Procalcitonin guided targeted antibiotic therapy Prof. Ashok Rattan, MD, MAMS, Common Wealth Fellow, INSA DFG Fellow, SEARO Temporary Advisor, WHO Lab Director (CAREC/PAHO) Advisor: Pathkind Labs Knowledge Forum, R & D and Quality

2. Acute Respiratory Tract Infection Most frequent cause for medical consultation Heterologous set of conditions : Upper respiratory Tract Infection Lower respiratory Tract Infection Acute Bronchitis Acute Lobar Pneumonia Acute exacerbation of COPD Community Acquired Pneumonia

3. Medico social impact of pneumonia Medical Impact A frequent disorder 25 / 10,000 More frequent in <5 & > 60 yrs Seasonality : winter High mortality: 5 th frequent cause worldwide More in < 5 and > 60 yrs Frequent comorbidities Social Impact Healthcare resources even in USA 10 million visits / year 600,000 hospitalization / year Quality of life 18 th DALY D30 persistence of symptoms SF-36 long term changes Usual activities (d7 OPD; d21 IPD) Healthcare related costs OPD $ 2212; IPD $ 27,661 Annual cost $ 17 billion

4. Levin M et al CMI 2018; 24: 1158

5. Diagnostic methods Traditional 1. Sputum culture 2. Urine antigen S.pneumoniae L.pneumophila 3. Blood culture 4. X Ray Chest Modern 1. RT PCR or 2. Multiplex PCR 3. Antigen detection 4. PCT 5. Culture of sputum 6. Blood culture 7. X Ray Chest 8. CT Chest

6. Antibiotic use Biomarker Wishlist Clinical outcome: 1. Better clinical decision making & 2. Better clinical outcome No negative effect on mortality Decrease in incidence of Clostidium difficle infection after antibiotic use Decrease is adverse drug event 2. Reduce cost:

7. Economic evaluation of procalcitonin-guided antibiotic therapy in acute respiratory infections: a US health system perspective Schuetz P et al Clin Chem Lab Med 2015; 53(4): 583–592

8. Is it Bacterial or Viral Infection ?

9. Procalcitonin guided targeted antibiotic therapy POCT Procalcitonin Quantitative Iquant analyser by J Mitra SD Biosensor F 200 Manesar Minividas by Biomerieux Wondfo Finecare

10. 1.Kryptor (BRAHMS, Germany) 2. Atellica IM 1600 (Siemens) 3. Cobas e801 (Roche) 119 serum samples with PCT values < 5 ug/L (ng/ml) Medical Decision Points 0.25 and 0.5 ug/L (ng/ml) High correlation r 2 = 0.97 and 0.99

11. Economic evaluation of procalcitonin-guided antibiotic therapy in acute respiratory infections: a US health system perspective Schuetz P et al Clin Chem Lab Med 2015; 53(4): 583–592 Unfortunately & Paradoxically this test is NOT USED in India Reason cited by some is PCT is Too Costly It is a sent out test & not POCT

12. Infants < 90 day in ER were tested for PCT in ER during 5 months (n = 126) 14 (11.1%) were diagnosed with bacterial infection 4 (3.2%) had invasive bacterial infections POCT PCT had excellent diagnostic accuracy At an end point off 1 ng/ml, accuracy becomes 100%, specificity 92%

13. Performance characteristics of POCT PCT Precision (CLSI EP 5 A2): 6 samples containing 0.27, 0.61 1.30, 2.40, 5.48 & 9.12 ng/ml were tested over 10 days, 2 runs a day in 2 replicate, CV was calculated and should be < 10% Sensitivity (CLSI EP 17 A2): LOB, LOD, LOQ was 0.04; 0.11; 0.21 ng/ml Linearity: (CLSI EP 6A) eleven level linearity set was prepared by mixing a pooled PCT spiked plasma containing 10.52 ng/ml linear regression results were r 2 = 0.999; slope = 1.01 Method comparison: (CLSI EP 9 A2): 40 serum samples were tested by POCT and reference method. Linear regression r 2 = 0.98; slope = 0.99

14. 60 pts had Salmonella Typhi isolated on blood culture by Bactec PCT before treatment ranged from 0.05 to 4 ng/ml Median PCT in confirmed typhoid cases was 0.22 ng/ml High PCT value was found only in severe sepsis (5%) PCT cannot be used as a specific biomarker for typhoid fever

15. 189 cases of ricketsiosis were studied which included 115 cases of Q fever (60.8%) 55 cases of scrub typhus (28.1%) 19 cases of murine typhus (10.1%) Mean CRP in acute phase was 78.2 + 63.7 mg/l Mean PCT in acute phase was 1.05 + 1.40 ng/ml Only 10.8% had CRP levels > 150 mg/l Only14.2% had PCT levels > 2 ng/ml

16. Charles et al (2006) retrospectic study of 50 nonsurgical patients with positive blood culture: 35 bacteriemia & 15 candidemia Mean PCT level in patients with bacterimia was 9.75 ng/ml candemia 0.65 ng/ml PCT values > 5.5 ng/ml had NPV of 100% for candidimia .

17. What is Procalcitonin (PCT) ? Schuetz P et al. BMJ Medicine 2011; 9: 107 116 amino acid precursor of calcitonin produced by Thyroid C cells & Neuroendocrine cells of the lungs Calcitonin is involved in calcium homostasis , while procalcitonin is not Many other cells can produce PCT after specific stimulation but lack enzyme to convert PCT  calcitonin Excessive production of PCT by many cells  rapid increase in blood levels

18. Normal Secretion Linscheid P et al. Endocrinology 2003; 144; 5578

19. In Healthy Individuals PCT level is very low as it is immediately processed to CT

20. PCT in Bacterial Infection Linscheid P et al. Endocrinology 2003; 144; 5578 Bacterial Infection (LPS) stimulates production of PCT from many somatic cells These cells lack the enzymes to cleave PCT  calcitonin PCT produced by these cells is rapidly released into blood stream Cytokines produced during viral infection inhibit PCT production

21. Production of PCT is ubiquitous in Sepsis Muller B et al. J Clin Endocrin Metab 2001; 86: 396 10 to 100 increase in calcitonin-1 gene activation in sepsis More widespread than other common cytokines like TNF α or IL- 6

22. Procalcitonin Rises Rapidly Dandona J Clin Endocrinol Metab 1994; 79; 1605

23. Kinetics of PCT makes it a better biomarker of bacterial infection Simon J et al. Clin Infect Dis 2004; 19: 206

24. Specificity & sensitivity of PCT makes it a better biomarker than CRP, IL -6 & Lactate Muller B et al. Crit Care 2000; 28:977; Simon L et al CID 2004; 39: 206

25. Serial measurement of PCT every 24 hours

26. Understanding Procalcitonin 1. Normal value is < 0.08 ng/mL [ug/L] 2. Elevated within 3 to 6 hours of bacterial infection 3. Peak in 6 to 12 hours 4. t ½ life is 24 to 30 hours 5. Cleared mainly by proteolysis 6. Some renal clearance 7. Maybe raised after major trauma / surgery 8. Not increased in Viral infections

27. Guidelines for Initiating antibiotics PCT value (ng/mL) PCT in ng/mL < 0.25 0.25 – 0.50 0.5 -- < 1 > 1 Antibiotic initiation Strongly discouraged Discouraged Encouraged Strongly Encouraged

28. Guidelines for Stopping, continuing or changing antibiotics PCT value (ng/mL) PCT in ng/mL < 0.25 > 0.25 – <0.50 Or Decline of >80% of peak value > 0.5 Or Decline < 80% of peak value > 0.5 Or Increase above PCT Value Antibiotic continuing Strongly discouraged continuing Discouraged continuing Encouraged Changing or Strongly Encouraged

29. For diagnosis of sepsis it can be combined with qSOFA

30. CRP guided use of PCT in Covid 19 Houghton R et al. medRxiv preprint Hypothesis: PCT < 0.5 ng/ml was associated with lower level of CRP 229 Covid-19 patients were studied CRP values below GM of entire patient population has a NPV for PCT < 0.5 of 97.6% at admission and NPV of 100% at 48 hours of admission CRP guided PCT testing algorithm can reduce cost & support antimicrobial stewardship strategies in Covid-19

31. CRP guided use of PCT in Covid 19 Houghton R et al. medRxiv preprint Baseline (at admission) FN TP TN FP

32. CRP guided use of PCT in Covid 19 Houghton R et al. medRxiv preprint after 48 hours of admission FN TP TN FP

33. Where is the evidence ?

34. Procalcitonin -guided diagnosis and antibiotic stewardship revisited Sager et al. BMC Medicine (2017) 15:15 1. Respiratory tract infections URTI Acute Bronchitis Acute execration of COPD Acute Lobar pneumonia 2. Sepsis 3. Abdominal infection, appendicitis, Acute pancreatitis 4. Endocariditis 5. Arthritis 6. UTI 7. Post operative infection 8. Neutropenia

35. High Serum Procalcitonin : Interpret with Caution Khan, Clin Microbiol 2017, 6:2 False elevated PCT values may occur in Severe stress following major surgery eg . Next day after Liver transplant Cardiac shock Autoimmune diseases Kawasaki’s disease Adult onset Still’s disease Medullary thyroid cancer Small cell lung cancer Cirrhosis of liver Pancreatitis PCT may not be elevated in Mycoplasma community acquired pneumonia Infected persons already on effective antibiotics

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37. Take home message PCT is the most specific of the commonly used biomarkers & has a number of advantages over pervious markers It is not perfect Interpret PCT values in the context of clinical condition Serial measurements, atleast 24 hours apart, may be helpful Strength of evidence varies depending upon the type & site of infection Be aware of conditions which may affect PCT values Technical Biological Good clinical judgement should always be applies ( donot treat or not treat a number)

38. I Thank you For your attention & Action

39. Procalcitonin > 0.5 ng/ml < 0.25 ng/ml

40. I Thank You for your attention