• Epidemiology of invasive fungal infections in the ICU

Vanya Gant Divisional Clinical Director

for infection

UCLH

Declarations of interest

• Advisory panels– Astellas– Pfizer– MSD– Gilead

• Instrument manufacturers– None

• Software manufacturers– None

What fungi?

Nosocomial bloodstream infection(there may be differences in the UK…)

Edmond et al Clin Infect Dis 1999; 29: 239-44Wenzel and Edmond Emerging Infect Dis 2001;7:174-7

Are fungi important?

Candida spp.

Pseudomonas aeruginosa

ESBLs etc

Staphylococcus aureusMRSA > MSSA (afer adjusting for antibiotic)

Enterococcus / VRECoagulase negative staphylococci 0%

40%

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

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

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

Predisposing factors for invasive infection

• Prematurity• Antibiotics• (prerequisite) prior GI tract colonisation• Congenital immunodeficiency (presents later)

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

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.

Incidence of IC by year and birth weight

Declining incidence of C albicans bloodstream infections

Non-albicans bloodstream infections: incidence and time series

Antibiotic use by year and birthweight

Fluconazole prophylaxis by year and birth weight

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.

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.

(modifiable) Risk factors

• Central Line• Broad spectrum antibiotics• IV Lipid emulsions• ET tube• Antenatal antibiotics

Benjamin DK et al; Pediatrics : 126;e865 – e873

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

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 prophylaxisJ 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.

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• >105 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.albicans 15 17

C.tropicalis 58 100

Voss et al . J Clin Microbiol 1994; 32: 975

An outbreak of C parapsilosis in a NICU

Rigoberto Hernández-CastroEuropean Journal of Pediatrics

2009169:1109

DOI: 10.1007/s00431-009-1109-7

Line removal and mortalityAntifungal Mortality (%)

Line removed Line in situ

Fluconazole 17.9 41.2

Amphotericin B 15.0 20.0

Combination 0 0

AmBisome 0 Na

Itraconazole 0 Na

voriconazole 0 Na

Not adequately treated

27.3 85.7

All patients 15.7 48.8

Kibbler et al J Hosp Infect 2003; 54:18-24

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 Dis27:437 - 452

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

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

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 >/= 103cfu/ml• none had pneumonia• contamination confirmed or probable in 89%• Jury is out for NICU patients

Rello et al Chest 1998

Relevance of candiduria in NICU

• Presence mandates renal ultrasound• ..with regular repeats if normal• Can lead to abscesses and obstructive

uropathy

Detection of fungemia:

Microbiology does it again - a breakneck speed

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