Ria Dancel, MD 11/13/2009

1. Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial.JAMA. 302(10):1059-66. (Sept 2009) Ria Dancel, MD 11/13/2009

2. Question: In adults with lower respiratory tract infection (LRTI), is antibiotic treatment based on a procalcitonin driven algorithm inferior to treatment based on current guidelines, in terms of adverse events?

3. Rationale • Antibiotic overuse – we all know the pitfalls: resistance, cost, adverse events, C. Diff • 75% of patients with LRTI are prescribed antibiotics despite predominantly viral etiology • Procalcitonin (PCT) is the precursor of calcitonin. • Low or undetectable in healthy subjects • Increases in proportion to severity of bacterial disease (infection, septicemia, meningitis) • Falls quickly in response to appropriate antibiotic therapy • Most importantly, PCT remains low in viral illness, making it a unique acute phase reactant that can potentially distinguish bacterial from viral infections Prior studies have suggested that algorithms using PCT cutoffs have decreased antibiotic use but these studies were small and insufficiently powered to show whether they caused more complications

4. Study Design • Investigator initiated, multicenter, noninferiority RCT • 6 tertiary care centers in Switzerland • Duration from 10/2006-3/2008 • Power: • Based on previous intervention trials, authors assumed overall adverse outcome risk of at most 20% • Planning committee agreed that cut-off for inferiority would be risk greater than 27.5% • Minimum sample size calculated to be 1002 patients to achieve 90% power • Randomized concealed via centralized website

5. Inclusion criteria • 18 years or older, from community or nursing home • LRTI < 28 days in duration • 1 respiratory symptom (cough, sputum production, dyspnea, tachypnea, pleuritic pain) • PLUS 1 auscultory finding (rales, crepitation) • OR 1 sign of infection (fever > 38, shivering, WBC > 10K or < 4K)

6. Definitions • CAP = LRTI with new infiltrate on CXR • COPD defined by postbronchodilator spirometric criteria set by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) • Acute bronchitis = LRTI in the absence of an underlying lung disease or focal chest signs and infiltrates on chest radiograph

7. Exclusion criteria • Inability to give written consent due to language restriction or dementia • Active IVDA • Severe immunosuppression other than corticosteroid use • Life threatening comorbidities leading to possible imminent death • HAP (development of PNA > 48 hrs after admission or within 14 days of recent hospitalization) • Chronic infection necessitating antibiotic use

8. Study protocol for intervention group (PCT group) • PCT levels were communicated to physicians caring for patients allocated to PCT group along with treatment recommendations based on following protocol • PCT < 0.1  Abx strongly discouraged, remeasure PCT in 6-24 hrs • PCT 0.1 – 0.25  Abx discouraged, remeasure PCT in 6-24 hrs • PCT 0.25 – 0.5  Abx encouraged, remeasure PCT on days 3, 5, 7 • PCT > 0.5 • Abx strongly encouraged, remeasure PCT on days 3, 5, 7 • If abx were started, they were discontinued according to the same cutoffs

9. Study protocol for intervention group (PCT group)

10. Study protocol for control group • For CAP: • Abx encouraged for 5-10 days • Abx for 14 days for Legionella CAP • Abx for at least 10 days in necrotizing CAP • For COPD: • Abx encouraged for 5-10 days if pt had severe COPD • Abx encouraged for 5-10 days if pt had purulent sputum + either increased dyspnea OR increased sputum volume • For acute bronchitis (no focal signs, no underlying lung dz): • Abx discouraged UNLESS • Purulent sputum + increased risk (age > 75 and fever, CHF, insulin dependent DM, serious neurological disorder) • Abx for 3-5 days

11. Primary non-inferiority endpoint Composite of adverse outcomes within 30 days of ED admission of: • Death • ICU admission • Persistence or development of PNA • Disease specific complications (abscess, empyema, ARDS) • Recurrence of LRTI in need of antibiotics

12. Secondary superiority endpoints • Duration of IV or PO abx • Adverse effects of abx • LOS

13. Assessment of outcomes • Outcomes during the hospital stay assessed by unblinded physicians • At 30 days, outcomes assessed by blinded medical students via telephone interviews

14. Patient flowchart Retained 92.6% Retained 94.4%

15. Patient demographics

16. Primary outcome OR 0.76 (95% CI 0.57-1.01), favoring PCT group

17. Kaplan Meier Curves for Primary outcome

18. Secondary outcomes

19. Validity • Randomized? Yes, concealed by website • Were the groups similar at start of trial? Yes • Blinded? Pts were blinded. BUT outcomes assessed during the hospitalization by unblinded physicians  Introduces bias! (Detection bias of subjective outcomes, Hawthorne effect) • Adequate follow-up? Yes • Large dropout? No. >90% of pts randomized were assessed at 30 days • Intention to treat analysis? Yes

20. Validity • Was the noninferiority margin defined a priori on the basis of statistical reasoning and clinical judgment? Yes. Based on previous intervention trials, authors assumed overall adverse outcome rate of 20% (in this trial overall adverse outcome of control group was 18.9%, so this was a good assumption). Inferiority was defined a priori as overall adverse outcome of >27.5%. • Was the noninferiority assessment adequately powered? Sample size of 1002 was calculated to give power of 90%. 1381 pts were randomized

21. Conclusions This study showed that patients treated by a procalcitonin based algorithm did no worse than control patients with regard to the composite of adverse events The PCT algorithm decreased antibiotic prescribing, duration of exposure to antibiotics and adverse reactions to antibiotics

22. Further thoughts • Could we come to the same conclusion if we used a CRP guided algorithm? • What if we ignored biomarkers altogether and just treated LRTI with 3-5 days of antibiotics instead of 5-10 days?

23. References • Schuetz P, Christ-Crain M, Thomann R, Falconnier C, Wolbers M, Widmer I, Neidert S, Fricker T, Blum C, Schild U, Regez K, Schoenenberger R, Henzen C, Bregenzer T, Hoess C, Krause M, Bucher HC, Zimmerli W, Mueller B; ProHOSP Study Group. Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA. 302(10):1059-66. (2009) • M. Assicot, D. Gendrel, H. Carsin, J. Raymond, J. Guilbaud and C. Bohuon, High serum procalcitonin concentrations in patients with sepsis and infection, Lancet341 (1993), pp. 515–518. • Dandona P, Nix D, Wilson MF, Aljada A, Love J, Assicot M, Bohuon C. Procalcitonin increase after endotoxin injection in normal subjects. J Clin Endocrinol Metab.79(6):1605-8. (1994) • D. Gendrel, M. Assicot, J. Raymond, F. Moulin, C. Francoual, J. Badoual and C. Bohuon, Procalcitonin as a marker for the early diagnosis of neonatal infection, J. Pediatr.128 (1996) • K.L. Becker, E.S. Nylen, J.C. White, B. Muller and R.H. Snider Jr., Clinical review 167: procalcitonin and the calcitonin gene family of peptides in inflammation, infection, and sepsis: a journey from calcitonin back to its precursors, J. Clin. Endocrinol. Metab.89 (2004), pp. 1512–1525 • Müller B, Becker KL, Schächinger H, Rickenbacher PR, Huber PR, Zimmerli W, Ritz R. Calcitonin precursors are reliable markers of sepsis in a medical intensive care unit. Crit Care Med. 28:977–983 (2000) • Gendrel D, Raymond J, Assicot M, Moulin F, Iniguez JL, Lebon P, Bohuon C. Measurement of procalcitonin levels in children with bacterial or viral meningitis. Clin Infect Dis.24:1240–1242 (1997)

24. Becker et al., 2004