Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-ra

1. Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised single-blinded intervention trialThe Lancet, Vol 363, 2004 N. Sritharan Journal club August 2006 Supervisor: Dr Keogh

2. Introduction First clinical signs of sepsis, not sensitive nor specific More typical signs e.g. hypotension and shock are late signs Thus demand for better markers of sepsis for clinical applications Many biomarkers of sepsis is available CRP, IL-6, IL-8,TNF Procalcitonin CRP has been most extensively studied, but is non-specific to bacterial sepsis, universally elevated in pro-inflammatory states, and its temporal profile does not suit rapid and early identification of bacterial SIRS Procalcitonin first discovered in 1993 as a marker of sepsis.CRP has been most extensively studied, but is non-specific to bacterial sepsis, universally elevated in pro-inflammatory states, and its temporal profile does not suit rapid and early identification of bacterial SIRS Procalcitonin first discovered in 1993 as a marker of sepsis.

3. Introduction Muller et al Critical Care Medicine in Apr 2000 demonstrated that PCT was superior to CRP, IL-6, lactate levels in predicting sepsis, with Sn = 89% & Sp = 94%.

4. Procalcitonin Superior to clinical signs of sepsis Uses include - Dx of bacterial infection Progression of infection/SIRS into sepsis, severe sepsis, or septic shock Assess response to treatment May be used to guide AB therapy

5. Procalcitonin Present normally only in C-cells of thyroid gland Most potently stimulated by bacterial endotoxin Viral and localised infection have lower plasma PCT levels than systemic infections Autoimmune and neoplastic disease does not induce PCT It is very stable and not degraded to hormonally active calcitonin Pro-calcitonin is an endogenous pre-cursor of calcitonin.Pro-calcitonin is an endogenous pre-cursor of calcitonin.

6. Pathophysiology PCT produced for a few hrs only, by monocytes adherent to tissues (not produced in circulating monocytes). Secreted PCT acts is chemotactic to other monocytic cells. Endogenous tissue cells also produce PCT but only after monocyte adhesion.

7. Aim To assess if a PCT-guided therapeutic strategy can reduce AB use in lower respiratory tract infections, with a new rapid & sensitive PCT assay (assay Sn of 0.06mcg/L, Cf. previously assay Sn of 0.3-0.5mcg/L)

8. Method A prospective, cluster-randomised controlled, single-blinded trial. Patients presenting with suspected lower respiratory tract infection to a single Swiss hospital between 16th Dec 2002 to 13th Apr 2003. Participants randomised into 1 of 2 groups standard AB treatment group PCT-guided AB group

9. Method Exclusion criteria Immunocompromised patients Nosocomial pneumonia To determine diagnosis all patients were evaluated with History & physical examination CXR Laboratory tests - FBC, UEC, CRP sputum & blood cultures Further workup: ABG, spirometry, bronchoscopy with bronchoalveolar lavage, ID consult.

10. Method In the PCT randomisation group - Serum PCT <0.1mcg/L ==> AB was strongly discouraged Serum PCT levels 0.1-0.25 mcg/L ==> AB was discouraged Serum PCT 0.25-0.5 mcg/L==> AB was advised Serum PCT >0.5mcg/L==> AB was strongly recommended

11. Method Both groups reassessed after 6-24hrs Remeasurement of PCT level in the PCT group F/U performed at day 10-14 & 4-6mths for COPD patients Analysis was performed on the basis of intention to treat Main endpoint = the use of antibiotics Secondary endpoints = clinical & laboratory outcome

12. Results 597 presented with suspected lower respiratory tract infection. 243 eligible for the study 119 randomised to standard care 124 to PCT-guided treatment Baseline characteristics were similar between the 2 groups Table 1 in the study shows that the baseline characteristics between the 2 groups were similar with respect to age, sex, smoking hx, antibiotic pre-treatment, cxr appearance.Table 1 in the study shows that the baseline characteristics between the 2 groups were similar with respect to age, sex, smoking hx, antibiotic pre-treatment, cxr appearance.

13. Results Final Dx : pneumonia 36% acute exacerbation of COPD 25% acute bronchitis 24% asthma 5% other 10%

14. Results Overall, 21% of patients tested +ve sputum cultures 7% of patients tested +ve blood cultures S. pneumoniae, H. influenzae & Pseudomonas spp. were the most common infectious organisms Overall, in combination of the 120 odd patients in each of the standard and PCT groups, 21% grew positive bacterial cultures on sputum, and 7% from blood cultures.Overall, in combination of the 120 odd patients in each of the standard and PCT groups, 21% grew positive bacterial cultures on sputum, and 7% from blood cultures.

15. Results 81% of patients tested had serological evidence of viral infection Parainfluenza virus type 3, influenza B, adenovirus were the most frequent The rate of physicians wanting to prescribe AB prior to PCT levels were similar in both groups At the end of the study, AB use in the PCT group was reduced by 47% compared to the standard-care group (95% CI : 0.4 - 0.55; p<0.0001)

16. Results The reduction in AB use was observed across all diagnostic subgroups. (figure 2) In the COPD group the reduction was 56% Clinical & laboratory outcomes were similar for both groups Quality of life scores Overall LOS LOS in ICU Readmission rates