WHY, WHEN AND HOW?

1. WHY, WHEN AND HOW?

2. EARLY PRE-EMPTIVE THERAPY FOR HEMATOGENOUS CANDIDIASIS

3. DISASTERS

4. CRUCIAL ELEMENTS IN AVOIDANCE OF DISASTERS High awareness Early recognition Knowledge on behavior of the offender Early treatment

5. CRUCIAL ELEMENTS IN AVOIDANCE OF DISASTERS High awareness Early recognition Knowledge on behavior of the offender Early treatment

6. ENEMY AMONGST US?

7. CRUCIAL ELEMENTS IN AVOIDANCE OF DISASTERS High awareness Early recognition Knowledge on behavior of the offender Early treatment

8. SCREEN THEM ALL?

9. INFECTION specificity frequency of occurrence COLONIZATION DIAGNOSTIC TESTS FOR INVASIVE CANDIDIASIS culture histology antigen antibody enolase mannan PCR 1-3-ß-D-glucan C-Reactive Protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6)

10. 100% 90 80 70 60 Philips Uzun 50 Mora 40 30 20 10 0 RISK FACTORS FOR INVASIVE CANDIDIASISPhilips 1998, Uzun 2001, Mora-Duarte 2002 diabetes renal insufficiency cvc hyperalimentation hematol malignancy antibacterials surgery immunosuppression

11. COLONIZATION-INVASION Initial situation integument damage invasion

12. CRUCIAL ELEMENTS IN AVOIDANCE OF DISASTERS High awareness Early recognition Knowledge on behavior of the offender Early treatment

13. RISK FACTORS FOR CANDIDA INFECTIONSEdwards jr JE et al. Ann Intern Med 1978 • USE OF: • antibiotics • immunosuppressants • hyperalimentation • polyethylene catheters • prosthetic devices • heroin • ABDOMINAL SURGERY I AM HERE TO HELP YOU!!!

14. 12 dialysis ventilation POST-OPERATIVE CANDIDEMIA: RISK FACTORS AND OUTCOMESOLOMKIN et al, Arch Surg 1982;117:1272-5 antibacterials 51 complex abdominal surgery i.v. nutrition 63 cases 66% damaged mucosa + Candida colonization 42 deaths in hospital

15. RISK FACTORS FOR INVASIVE CANDIDOSIS Rex & Sobel Clin Infect Dis 2001 32;1191 Risk factor Cancer ICU Therapy-induced neutropenia GvHD, mucosal barrier injury Recurrent GI tract perforation (surgery) Candida colonization Broad-spectrum antibiotics Hemodialysis Central venous catheter Hyperalimentation Severity of illness Neonatal ICU (H2 blockers, intubation) Burns, diabetes mellitus Risk factor Cancer ICU Therapy-induced neutropenia GvHD, mucosal barrier injury Recurrent GI tract perforation (surgery) Candida colonization Broad-spectrum antibiotics Hemodialysis Central venous catheter Hyperalimentation Severity of illness Neonatal ICU (H2 blockers, intubation) Burns

16. COLONIZER OR AGGRESSIVE PATHOGEN?

17. anti- bacterials Damaged mucosa neutropenia cath- eter colonization FACTORS ANNOUNCING OCCURRENCE OF INVASIVE CANDIDA INFECTIONS

18. fever Underlying disease selection chemical damage mucosa antibacterials Instruments knife puncture skin gut colonization RISK FACTOR SELECTION Risk factors Infection +

19. - + +++ 14 24 8 - + +++ 7 13 15 Colonization Acute Invasive Candidiasis 1 0 0 0 1 8 INVASIVE CANDIDIASIS AFTER COLONIZATION AND BACTEREMIAGUIOT et al, Clin Infect Dis 1994; 18:525-32 53% 81 patients Bacteremia 46 35 YES NO

20. peritonitis 830 patients Candida bacterial 60 152 candidemias 6 MORTALITY 47% Candida peritonitis 54 INVASIVE CANDIDA INFECTIONS IN CRITICALLY ILL SURGICAL PATIENTSNOLLA et al. ICAAC 2001, Chicago. Abstr J-1628 Risk factors: -prior antibacterials -repeated surgery -Candida colonization (non-albicans)

21. Central venous catheter GI tract GI tract insult Normal commensal flora selection infection Candida species Disease translocation MODEL FOR INVASIVE CANDIDIASISBlijlevens, Donnelly, De Pauw. Brit J Haematol 2002;117:259-64 antibiotics injury

22. ALKALINE PHOSPHATASE 45% mucositis granulocytes 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 DISSEMINATION "BULL’S EYES" OCCURRENCE OF CANDIDIASIS IN RELATION TO NEUTROPENIAGoodrich et al. J Infect Dis 1991; 164:731-40 Hepatosplenic candidiasis candidemia bacteremia

23. CRUCIAL ELEMENTS IN AVOIDANCE OF DISASTERS High awareness Early recognition Knowledge on behavior of the offender Early treatment

24. INVESTMENT IN THE FUTURE

25. tissue involvement 80% 60 40 20 days with pos culture 1 2 3 4 5 TISSUE INVOLVEMENT IN RELATION TO DURATION OF CANDIDEMIA IN BMT Goodrich et al. J Infect Dis 1991; 164:731-40

26. mortality 80% 60 40 20 mixed infections multiple organs tissue invasion MORTALITY OF CANDIDEMIA IN BMT Goodrich et al. J Infect Dis 1991; 164:731-40 yes no

27. RESPONSE RATES DEPENDING ON TIME OF INTERVENTION Abele-Horn et al. Infection 1996: 24:426-32 74% 51% Within 1 week after onset of symptoms More than 1 week

28. infection specific symptom aspecific symptom Candida (refractory) fever suppressive Rx basic disease Peter Donnelly & Ben dePauw TIMING OF THE INTERVENTION prophylaxis empirical pre-emptive

29. Microbiology I.D. GUIDE PREVENTION

30. PROPHYLAXIS WITH FLUCONAZOLEIN BONE MARROW TRANSPLANTATIONGOODMAN et al. N.ENGL.J.MED 1992, 326: 845 PLACEBO n = 177 FLUCONAZOLE n = 179 SYSTEMIC FUNGUS SYSTEMIC CANDIDIASIS SUPERFICIAL FUNGUS SYSTEMIC AMPHO-B FATAL FUNGUS 3% 0% 8% 56% 1% 16% 10% 33% 66% 6%

31. FLUCONAZOLE 400 mg/day AS PROPHYLAXISIN LIVER TRANSPLANT RECIPIENTSWINSTON et al. Ann.Intern.Med. 1999;131:729-37 PLACEBO n = 117 FLUCONAZOLE n = 119 SYSTEMIC FUNGUS* SUPERFICIAL FUNGUS* COLONIZATION OVERALL SURVIVAL FUNGAL DEATH RATE 6% 4% 70 --> 28% 11% 2% 23% 28% 60 --> 90% 14% 13% *C. glabrata prevalent species

32. FLUCONAZOLE vs PLACEBO AS PROPHYLAXISAGAINST CANDIDIASIS IN SURGICAL PATIENTSPELZ et al. Ann Surg 2001; 233:542-8 PLACEBO n = 130 FLUCONAZOLE n = 130 SURGERY MEAN ICU DAYS PRE-EXISTENT CANDIDA COLONIZATION CANDIDA INFECTIONS CANDIDEMIA DEATH OVERALL CANDIDA RELATED 91% 1 78% 9% 0% 11% n.a. 92% 1 89% 15% 2% 12% n.a.

33. TOTAL INCIDENCE OF CANDIDEMIA IN US ICU’S Trick et al CID 2002; 35: 627-32. NNIS data from 1116 ICUs/ 311 hospitals. From data for 3,041,585 patients Candidemia per 10,000 CVC days 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 year 1989 1990 91 92 93 94 95 96 97 98 1999

34. COLONIZATION-PROPHYLAXIS-INVASION Initial situation prophylaxis integument damage invasion

35. 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 C. glabrata 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 EVOLVING CANDIDEMIAS IN US ICU’S Trick et al CID 2002; 35: 627-32. NNIS data from 1116 ICUs/ 311 hospitals. From data for 3,041,585 patients Candidemia per 10,000 CVC days C. albicans C. krusei C. parapsilosis C. tropicalis

36. EMPIRICAL ????

37. continue antibiotics n=64 persisting FUO or CDI and neutropenia add 0.6 mg/kg/day amphotericin n=68 50% DEFERVESCENCE with prophylaxis no prophylaxis CDI granulocytes <100 DEFERVESCENCE with prophylaxis no prophylaxis CDI granulocytes <100 69% 61 61 61 61 6 IFI C.tropicalis C.albicans 2 C.albicans (oral) 1 Aspergillus 1 Mucor 1 IFI C. tropicalis fungemia 78 78 45 45 75 75 41 41 69 69 46 46 EARLY EMPIRICAL ANTIFUNGAL THERAPY IN FEBRILE NEUTROPENICS EORTC. Am J Med 1989; 86:668-72

38. persisting FUO and neutropenia (n=50) add 0.5 mg/kg/day amphotericin n=18 stop all antibiotics n=16 continue n=16 6% 6% 36% 1 aspergillosis 1 P boydii 1 aspergillosis 1 mixed 4 candidiasis THE BASIS FOR EMPIRICAL ANTIFUNGAL THERAPY IN FEBRILE NEUTROPENICS PIZZO et al Am J Med 1982; 72:101-10 fungal infections

39. CANDIDATES FOR EARLY PROTECTION Clinically ill Damaged gut epithelium Colonized by Candida strains Neutropenic Central venous line Receiving antibacterials No prophylaxis Diabetes mellitus Recent corticosteroids

40. EMPIRICAL