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Here comes PCT

Here comes PCT . David Gilbert, MD. Disclosures. Advisory/Consultant: Pfizer, Bayer, Schering-Plough, Pacific Bioscience, Advanced Life Science, Wyeth, Roche, Johnson and Johnson, Achaogen Speaker: Merck. Major Problem.

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Here comes PCT

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  1. Here comes PCT David Gilbert, MD

  2. Disclosures • Advisory/Consultant: Pfizer, Bayer, Schering-Plough, Pacific Bioscience, Advanced Life Science, Wyeth, Roche, Johnson and Johnson, Achaogen • Speaker: Merck

  3. Major Problem • Increasing resistance of major bacterial pathogens to licensed antibacterials • Discovery and development of new antibacterials is at a low ebb. • Hence, we need to be good stewards of the drugs that are still active.

  4. How to reduce empiric use of antibacterials? • Rapid point of care microbial diagnosis. Especially helpful in respiratory tract infections. Example: rapid test for gp.A streptococci • Multiplex PCRs for common viral and bacterial pathogens would be ideal. A few are FDA approved. Clinical integration slow.

  5. Surrogate Markers of Bacterial Invasive Disease • Until such time as multiplex PCRS are available, we are left with surrogate markers • Have used fever, WBCs, C-reactive protein levels and ESR in this way for many years. Too insensitive and non-specific • A new biomarker is procalcitonin (PCT). • See what you think?

  6. Procalcitonin • The 116-aminoacid precursor (prohormone) of the 32-aminoacid hormone—calcitonin • Calcitonin produced in neuroendocrine C-cells of thyroid and K-cells of the lung • Pro-CT produced in all parenchymal tissues and monocytes/macrophages Crit.Care Medicine 2008; 36; 941&1684

  7. Calcitonin lowers serum calcium Produced only in thyroid and selected lung cells Levels do not increase in response to bacterial infection. ProCT is intimately involved with the inflammatory process Produced by monocytes, fat cells, R-E system, adrenal, G-I tract and more Rapid large increases in serum levels within 3-6 hrs of onset of bacterial infection Calcitonin vs ProCT

  8. What is physiologic role of PCT? • Not yet completely understood • Increases synthesis of nitric oxide • Antibody to PCT increases survival of septic pigs

  9. What elevates serum levels of PCT? • Acute local and invasive bacterial infections. • Low perfusion states that may allow translocation of normal flora: major surgical procedures, trauma with shock, severe burns, severe cardiogenic shock, ischemic bowel • Systemic fungal infections; falciparum malaria • Small cell lung Ca; Medullary thyroid Ca • Clinically, interested in PCT levels in RTIs and Sepsis

  10. PCT serum levels • Levels rise within 3-6 hrs of onset of bacterial infection. • Degree of elevation correlates with severity of bacterial infection • FDA-approved Immunoassay is sensitive,rapid, and specific. • Levels range from < 0.05 to over 1,000 ng/ml • Sequential levels useful in diagnosis, prognosis, and assist in duration of therapy • Low levels have excellent negative predictive value

  11. PCT Levels as Guide to Therapy of Respiratory Tract Infections(RTIs) • Bulk of data from Switzerland • Used sensitive PCT assay • If randomized to PCT group, use of antibacterials encouraged or discouraged by PCT result • Assumption: If patients recovered without an antibacterial, likely that no serious bacterial infection was present

  12. PCT-Guided Therapy of AECB* • Randomized controlled blinded trial at Univ. Hosp. in Switzerland • Patients Admitted from ER with steroids and inhalers and then randomized • Group 1. Standard therapy by attending MD. PCT levels kept blinded • Group 2. PCT levels provided and, depending on result, discouraged or encouraged, use of antibiotics Chest 2007; 131:9-19

  13. PCT-Guided Therapy of AECB • PCT levels available within 1 hour, 24/7 • If PCT level < 0.1 ng/ml: “No bacterial infection. Discourage use of antibiotics” • If PCT level > 0.25 ng/ml: “Use of antibiotics encouraged” • Outcome assessment: Antibiotic use acutely and over 6 months. Need for ICU and other secondary endpoints

  14. Results: AECB *Did not correlate with PCT levels

  15. AECB study limitations • One hospital; only inpatients • Ultimately need large multicenter trial that includes both inpatients and outpatients • Future study: If PCT serum level < 0.1 ng/ml, randomize to either placebo or antibiotic • Hopefully include sputum cultures and viral studies

  16. PCT Guidance of Antibiotic Therapy of CAP* • Randomized, controlled, blinded trial in Swiss University Hospital • Patients admitted from ER with CAP • All had PCT levels • Controls: Treating MDs not given results of PCT serum level • PCT group: Treating MDs given results with suggestions as to antibiotic use.

  17. AJRCCM 2006; 174:84

  18. Chest 2007;131:9

  19. AJRCCM 2006; 174:84

  20. High Levels of PCT in the “septic” patient • Increases likelihood of bacterial sepsis; Differentiates bacterial from viral infection • Predicts prognosis of bacterial sepsis • Differentiation of infectious and non-infectious etiologies of inflammation. • As a guide to the duration of antibiotic therapy.

  21. PCT: Marker of Sepsis in ICU* *CCM 2000:28:977. PCT level of >0.5 ng/ml

  22. How well does PCT differentiate bacterial and viral infections?* • 360 children admitted from ER with temperature > 38.5o C. • Responsible pathogen identified. • Divided into 3 groups: • Gp. 1: Invasive bacterial infection • Gp. 2: Localized bacterial infection • Gp. 3: Viral infection Ped. Inf. Dis. 1999; 18: 875-81

  23. PCT: Bacterial or viral infection?

  24. Correlation of Peak PCT Level and 90 Day Mortality* CCM 2006;34:2596

  25. PCT is low in non-bacterial infectious causes of SIRS* • Viral infections: unless bacterial super-infection • ARDS (CCM 1999; 27:2172) • Sterile necrotizing pancreatitis (Gut 1997; 41:832) • Post-liver transplant rejection (CCM 2000; 28:555) SIRS= Systemic Inflammatory Response Syndrome

  26. ARDS:Bacterial or not? CCM 1999;27:2175

  27. Sequential PCT levels can shorten antibiotic therapy in septic patients* • Randomized, controlled, open intervention trail in ICU septic and septic shock patients. • Daily PCT levels • Standard of care vs. “stop” rules • Stop if PCT fell 90% from baseline peak • Stop if absolute value of < 0.25 ng/ml • Stop if baseline < 1 and level now <0.1 AJRCCM 2008;177:498

  28. PCT levels at PPMC • Ultra-sensitive, FDA-approved assay available 24/7 starting 9/15/08 • Results in < I hr. • Cost: $68 (CBC $30; Antibiotic $20-120) • Encourage use: ER, ICU, Hospitalists, Primary Care Physicians, and others.

  29. Procalcitonin Levels: Summary • Sensitive and specific biomarker for bacterial infection • PCT levels augment, do not replace, clinical assessment of patients with RTIs, suspected and proven sepsis • Will hopefully result in reduced use of empiric antibiotics • Sequential levels hopefully will decrease the duration of antibiotic therapy in some patients.

  30. Antibiotic Stewardship • CDC,FDA, NIH, CMS all looking for ways to avoid overuse of antibiotics for non-bacterial Respiratory Tract Infections. • Procalcitonin needs further study, but based on current evidence, low ProCT levels (<0.25 ng/ml), suggest a low priority for antimicrobial therapy in patients with upper and lower respiratory tract infections.

  31. Can we rapidly discriminate bacterial from viral RTI? • Sinusitis, otitis, acute bronchitis, AECB, and even CAP • Clinical picture often does not allow discrimination • ESR, CRP no help • Eventually, point of care multiplex PCR • For now, rapid procalcitonin (ProCT) assay available.

  32. Procalcitonin Serum Levels • FDA-approved antibody based assay system • Very sensitive: quantifies levels from 0.05 to 1000 ng/ml • Answers in less than 1 hour.

  33. ProCT and Viral Infections • Of 236 viral infections, only 3 had serum ProCT levels > 2 ng/ml • Viral meningitis, < 1 ng/ml; bacterial meningitis, very high levels ( approx. 10 ng/ml) • Stimulated European studies designed to determine if ProCT levels could guide antibiotic use for RTIs Eur.resp.journal 2007;30:556

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