1. Epidemiology of invasive fungal infections in the ICU Vanya Gant Divisional Clinical Director for infection UCLH

2. Declarations of interest Advisory panels – Astellas – Pfizer – MSD – Gilead Instrument manufacturers – None Software manufacturers – None

3. What fungi?

4. Nosocomial bloodstream infection (there may be differences in the UK…) Edmond et al Clin Infect Dis 1999; 29: 239-44 Wenzel and Edmond Emerging Infect Dis 2001;7:174-7

5. Are fungi important? Candida spp. Pseudomonas aeruginosa ESBLs etc Staphylococcus aureus MRSA > MSSA (afer adjusting for antibiotic) Enterococcus / VRE Coagulase negative staphylococci 0% 40%

6. Invasive Candida spp in the pre-term and critically ill child Severe, life-threatening Third most common agent of late- onset infection Incidence – 5.5 – 20% in ELBW (<1000g) – 2.6 to 10% - VLBW 1000 – 1500g Crude mortality as high as 15 – 30% Attributable mortality 6 – 22% Castagnola et al, Drugs 69: 45 -50;2009; Benjamin et al; Pediatrics 117:84 – 92; 2007

7. Incidence of invasive fungal infections in NICU Aurora project (Italian; multicentre) Overall incidence 1.3% Crude mortality 23.8% 1500g infants -4.3% 2500g infants -0.2% C parapsilosis-61.9% Montagna et al; J prev Med Hyg 51:125 – 130; 2010

8. Invasive candida and the ELBW infant 13 Centre US study 137/1515 (9%) – invasive candidiasis (out of 6697 episodes of “sepsis ? cause” – Blood (96) – CSF (9) – Urine (by catheterisation) 52 – Other sterile body fluid (10) Large variation in incidence (2 – 28% with >50 infants enrolled) 34% mortality with IC; 14% without IC

9. Predisposing factors for invasive infection Prematurity Antibiotics (prerequisite) prior GI tract colonisation Congenital immunodeficiency (presents later)

10. Site to site variation in incidence (>2kg infants)

11. Large datasets reveal… 709,325 infants at 322 NICUs; 14 years 2063 (0.3%) infants with 2101 episodes of invasive candidiasis Decrease in IC: 3.6 episodes per 1000 patients to 1.4 episodes per 1000 patients: all infants 24.2 to 11.6 episodes per 1000 patients ELBW infants 82.7 to 23.8 episodes per 1000 patients among infants with a birth weight <750 g Increase in fluconazole prophylaxis: 3.8 per 1000 patients in 1997 to 110.6 per 1000 patients in 2010 Decrease in broad-spectrum antibacterial antibiotics: 275.7 per 1000 patients in 1997 to 48.5 per 1000 patients in 2010: all infants Empirical antifungal therapy increased: 4.0 per 1000 patients in 1997 to 11.5 per 1000 patients in 2010.

12. Incidence of IC by year and birth weight

13. Declining incidence of C albicans bloodstream infections

14. Non-albicans bloodstream infections: incidence and time series

15. Antibiotic use by year and birthweight

16. Fluconazole prophylaxis by year and birth weight

17. Fluconazole prophylaxis: the evidence Cochrane review: 11 eligible trials 1136 participating VLBW infants prophylactic fluconazole versus placebo – RR 0.41 (95% CI 0.27 - 0.61) – typical risk difference: -0.09 (95% CI 0.14, -0.05) – NNT: 9 (95% CI 6 - 17) – no statistically significant difference in risk of death – RR : 0.61 (95% CI 0.37 - 1.03) – typical risk difference: -0.05 (95% CI -0.11 - 0.00)] Austin N, McGuire W Cochrane Database Syst Rev. 2013 Apr 30;4:CD003850. doi: 10.1002/14651858.CD003850.pub4.

18. Fluconazole prophylaxis? 119 ICU patients with “risk factors” CVCs, TPN, antibiotics, ventilation prospective double blind study 800 mg loading dose followed by 400mg fluconazole per day or placebo Candidosis: 22% in fluconazole group versus 24% placebo arm Mortality, hospitalisation antibiotic usage not affected No evidence of benefit Ables et al Infect Dis Clin Pract 2000;9:169.

19. (modifiable) Risk factors Central Line Broad spectrum antibiotics IV Lipid emulsions ET tube Antenatal antibiotics Benjamin DK et al; Pediatrics : 126;e865 – e873

20. The bottom line in the UK…(2014) >>95% of Candida spp. Fluconazole SENSITIVE About 50% of C glabrata Fluconazole SENSITIVE Long episodes of fluconazole exposure WILL bias this probability

21. Other impacts of azole usage? Impairment of white cell activity Adrenal suppression Immunomodulation –Anti-inflammatory Inhibit thromboxane and leukotrienes Decease tissue oxygen metabolism Sinuff T, Cook DJ, Peterson JC, et al. Development, implementation, and evaluation of a ketoconazole practice guideline for ARDS prophylaxis J Crit Care 1999 14: 1-6. Salartash K, Gallucci J, Quinn J, Catalano E, Slotman G The cardiopulmonary, eicosanoid, and tissue microanatomic effects of fluconazole during graded bacteremia Shock 1996 6: 206-212.

22. Colonisation of relevance? Invasive disease by sites colonised(%) Colonisation index ratio of >/= 0.5 calculated from number of non-contiguous sites colonised with the same strain over the number of sites sampled PPV = 67% Pittet et al.Ann Surgery 1994; 220: 751. Carriage index >10 5 yeast cells/ml saliva or gram of faeces Van Saene et al J.Hosp Infect 1999; 41:337. Colonised at 1 site Colonised at 2 sites C.albicans1517 C.tropicalis58100 Voss et al. J Clin Microbiol 1994; 32: 975

23. An outbreak of C parapsilosis in a NICU Rigoberto Hernández-Castro European Journal of Pediatrics 2009 169:1109 DOI: 10.1007/s00431-009-1109-7

24. Line removal and mortality AntifungalMortality (%) Line removedLine in situ Fluconazole17.941.2 Amphotericin B15.020.0 Combination00 AmBisome0Na Itraconazole0Na voriconazole0Na Not adequately treated 27.385.7 All patients15.748.8 Kibbler et al J Hosp Infect 2003; 54:18-24

25. Aspergillosis Rare Skin infections; associated with mucosal barrier breakdown in NEC Always think of water and ventilation Prematurity Steroids Mortality >60% Groll et al; Clin infect Dis 27:437 - 452

26. Risk-based: (Pre-emptive) Best approach in ICU patients based on risk factor analysis – colonisation at >2 non-contiguous sites colonisation index Carriage index Increasing fungal load – Vascular lines – los – underlying condition – parenteral feeding – Haemodialysis, haemfiltration etc

27. Standards of care: ask your lab! All fungi (yeasts and moulds) obtained from sterile sites, including blood, bronchoscopy fluids, and intravenous line tips should be speciated All fungi from urine of patients in intensive care, special care baby and burn units and any transplant patients should be speciated All patients with candidaemia should have central venous catheters removed or replaced within 48 h of candidaemia being documented All patients with candidaemia should be treated with a systemic antifungal agent at an appropriate dose, and breakthrough fungaemia treated with an alternative agent (unless all treatment is withdrawn [palliative care] Lancet Infect Dis 2003; 3: 230-240

28. Candida pneumonia? (adult) ICU patients with Candida isolated from bronchoscopic specimens over 5 year period 37 non-neutropenic patients adults identified 24/28 had PSB count >/= 10 3 cfu/ml none had pneumonia contamination confirmed or probable in 89% Jury is out for NICU patients Rello et al Chest 1998

29. Relevance of candiduria in NICU Presence mandates renal ultrasound..with regular repeats if normal Can lead to abscesses and obstructive uropathy

30. Detection of fungemia: Microbiology does it again - a breakneck speed

31. Conclusions The smaller the infant, the greater the risk The more antibiotics, the greater the risk Candida spp. Take a long time to grow – empiric therapy often justified Quality improvement Watch the lines Wash your hands Align empirical therapy to risk Use new antifungal agents rationally – not necessarily better than old Diagnostics: ? PCR/PCR-MS/beta D glucan Improve microbiological liaison Use surveillance to inform local strategies