Müge AYDOĞDU, Gül GÜRSEL, Ezgi ÖZYILMAZ, Türkan ÖZİŞ

1. RISK FACTORS FOR TREATMENT FAILURE IN PATIENTS WITH VENTILATOR ASSOCIATED PNEUMONIA (VAP) RECEIVING APPROPRIATE ANTIBIOTIC THERAPY Müge AYDOĞDU, Gül GÜRSEL, Ezgi ÖZYILMAZ, Türkan ÖZİŞ Gazi University School of Medicine ICU of Pulmonary Diseases Department, ANKARA

2. INTRODUCTION • Ventilator –associated pneumonia (VAP) is a frequent nosocomial infection among patients admitted to the intensive care unit (ICU), prolonging ICU length of stay and increasing the risk of death. • Treatment failure can be anticipated in 30-40% of patients developing VAP, and this situation is associated with an additional increase in mortality.

3. Causes of treatment failure in VAP; • Therapy-related risk factors (inadequate initial therapy) • Bacteriologic risk factors (infection with antibiotic-resistant pathogen, superinfection) • Patient risk factors (underlying fatal or serious illness, comorbidities)

4. AIM • Awareness of modifiable risk factors for treatment failure and early recognition may decrease mortality. • In this study, it was aimed to determine potential risk factors for treatment failure in patients with VAP receiving appropriate antibiotic therapy.

5. METHOD • Prospective observational cohort study • Among the 136 patients with VAP, 89 of them receiving appropriate antibiotic therapy were included in the study..

6. After 48 hours of mechanical ventilation, surveillance cultures were obtained from all patients for ETA (every second day), urine and blood weekly. • The results of cultures were obtained with in 48 hours. • Microbiologically confirmed (growth > 105 cfu/mL in ETA) clinical findings (CPIS>6) were used for the diagnosis of VAP. • Appropriate antibiotic therapy: Coverage of all the pathogens isolated by the antimicrobial therapy administered emprically or within 24-36 hours of the microbiological diagnosis.

7. Criteria for treatment response in VAP; • Fever ≤ 38 °C • Leukocyte count ≤ 10000/mm³ • PaO2 / FiO2 ≥ 250 • No or ≤ 10ˉ² cfu/ml bacterial growth in ETA samples

8. Mean duration of resolution; • 5 days for fever • 8 days for leucocyte count • 6 days for PaO2/FiO2 • 10 days for microbiological resolution • Mean duration for resolution of all parameters is 9 days • Mean duration for resolution after excluding microbial results is 6 days (Dennesen PJ, van der Ven AJ, Kessels AG, Ramsay G, Bonten MJ. Resolution of infectious parameters after antimicrobial therapy in patients with ventilator associated pneumonia. Am J Respir Crit Care Med 2001; 163:1371-1375)

9. Treatment failure; • . • Lack of clinical (in first 5 days of therapy) and microbiological (in first 10 days of the therapy) response to therapy

10. Student’s t test, chi square tests, ROC curves and logistic regression analyses were used for statistical analysis.

11. RESULTS

12. Admission Diagnosis of the Patients

13. Responsible pathogens of VAPs

14. Demographic characteristics of the patients TS: Treatment success TF: Treatment failure

15. Microbiologic characteristics of the patient groups

16. Potential risk factors for treatment failure

17. Risk factors for treatment failure

18. DISCUSSION • Among those identified risk factors, the daily carbohydrate intake is especially important since it is a modifiable one. • In ICUs there are several reasons for giving low carbohydrate diet; such as cessation of enteral nutrition due to diarrhea or during weaning trial, underlying diabetes mellitus or for the prevention of hyperglycemia

19. It is well known that low carbohydrate intake causes depression in immune system and neutrophil function. • So, a minumum of 180-200 gr/day carbohydrate intake might improve outcome in VAP by preventing development of immunesuppression. Aydıntuğ S, Sonyürek P, Soysal D Klinik Nütrisyon, Abboth Nutrition International, II. Basım, 2006 Nompleggi JD. Basic principles of nutritional support in the Intensive Care Unit. in Intensive Care Medicine; eds. Irwin RS, Rippe JM. 5th edition, 2053-2056 Christmas JW, McCain RW. A sensible approach to the nutritional support of mechanically ventilated critically ill patients. Intensive Care Med 1993;19: 129-136

20. Sepsis induced lymphocytopenia seems to correlate with immuncompromise and with mortality. • This lymphocytopenia seems to be induced by increased apoptosis signals. • In a murine model use of an inhibitor of apoptosis seemed to restore immunity. Wunderink RG. Nosocomial pneumonia, including ventilator-aasociated pneumonia. Proc Am Thorac Soc, Vol 2, pp 440-444, 2005 Hotchkiss RS, Swanson PE, Freeman BD et al. Apoptotic cell death in patients with sepsis, shock and multiple organ dysfunction. Crit Care Med 1999; 27:1230-51 Le Tulzo Y, Pangault C, Gacouin A et al. Early circulating lymphocyte apoptosis in human septic shock is associated with poor outcome. Shock 2002: 18; 487-494

21. Another risk factor for treatment failure is infection with multi drug resistant strains of Acinetobacter Baumanii. • There are some measures proposed for preventing the emergence of resistant strains;

22. The appropriate antibiotic should be used in optimal dose with correct route of administration (oral, iv, or aerosol) for adequate time period. • Treatment must be reevaluated on day two or three on the basis of culture results and clinical outcome • Treatment should be stopped if diagnosis of infection becomes unlikely or narrower spectrum drugs should be used once the agent of infection is identified. Unnecessary antibiotics should be stopped. (deescalation). *Chastre J. Ventilator-Associated Pneumonia: What is New? Surgical Infections.Supplement 2, 2006, Volume 7, 81-86. *Luna CM, Niederman MS. What is the natural history of resolution of nosocomial pneumonia? Seminars in Respiratory and Critical Care Medicine 2002; volume 23, number 5; 471-479

23. Patterns of treatment failure • Rapid deterioration within 72 hours; Uncontrolled systemic inflammmation processes resulting in severe respiratory failure (eg, ARDS) or severe sepsis and septic shock. • Failure to improve 72 hours after treatment initiation; Extrapulmonary reasons should be investigated. • Initial improvement followed by deterioration; recurrence, superinfection or pneumonia related complications, such as abscess or empyema formation. • Slow but progressive improvement (Delayed resolution); Not a real treatment failure but a failure to respond with in the expected time course of symptom and sign resolution. Richard G. Wunderink, MD Clinics in Chest Medicine, 1995, Volume 16, 1, 173-193)

24. In our patient group, although there were no significant difference among the recurrence rates (TS %11 vs TF %7, p=0.396), • The rate of resistance development and superinfection was found significantly higher in the treatment failure group.

25. CONCLUSION • These results suggest that, patients with higher VAP-APACHE II scores, lower lymphocyte number and carbohydrate intake and infected with Acinetobacter Baumanii are at risk for treatment failure during VAP. • The recognition of these risk factors and modification of them may improve outcome in VAP by decreasing mortality and morbidity. • Future studies should attempt to determine whether new therapeutic strategies could markedly improve VAP outcomes when further risk factors for treatment failure are identified.

26. Thank you!