Recent Update In The Management Of Invasive

Candidiasis

Overview

Invasive Fungal Infections Antifungal Agents

Polyenes Azoles Glucan Synthesis Inhibitors

IDSA Treatment Guidelines

Review of our Fungal “Players”

Opportunistic fungi Normal flora

Candida spp. Ubiquitous in our environment

Aspergillus spp. Cryptococcus spp. Mucor spp.

Endemic geographically restricted

Blastomyces sp. Coccidioides sp. Histoplasma sp.

• Newly emerging fungi

• Fusarium• Scedosporidium• Trichosporin

Rank order of nosocomial bloodstream pathogens and their associated mortality

1 Coagulase negative-staphylococci 30.9 21

2 Staphylococcus aureus 15.7 25

3 Enterococci 11.1 32

4 Candida species 9 38

5 Escherichia coli 5.7 24

6 Klebsiella species 5.4 27

7 Enterobacter species 4.5 28

8 Pseudomonas species 4.4 33

9 Serratia species 1.4 26

10 Viridans streptococci 1.4 23

Predisposing Factors to Fungal Infections (IFI)

Broad spectrum antibiotics Immunosuppression Corticosteroids Prolonged hospitalization (ICU Stay) TPN (intravascular catheter use) Prolonged neutropenia Hemodialysis /Acute Renal Failure Diabetes Mellitus Mechanical Ventilation Recent gastrointestinal / Cardiac surgery Burns Colonization

Incidence of Invasive Fungal Infections

Solid Organ Transplant 5 - 42% Kidney 5 – 14% Heart 5 – 32% Heart-Lung/Lung 15 – 36% Pancreas 18 – 38% Liver 7 – 42 %

Bone Marrow Transplant 15 - 25%

Intensive Care Unit 17%

Singh, N. CID 2000; 31:545-53Vincent JL. Intensive Care Med 1998; 24: 206-216

Mortality Rates

Candidemia has a mortality rate of ~40%. Invasive aspergillosis continues to be a

highly lethal opportunistic infection: 375% increase in mortality due to

Aspergillus species from 1980 to 1997. Overall mortality rate in patients with

invasive aspergillosis is reported to be 58%.

Mortality continues to be high regardless of the antifungal therapy used.

Edmond MB et al. CID 1999;29:239-44.National Center for Health Statistics (1980-1997)Lin S et al. CID 2001;32:358-66.

Challenges

Delaying antifungal therapy until blood cultures are positive is associated with increased mortality

Diagnostic limitations

Clinical approaches to assess risk

Fungal colonizing index: the greater the number of positive sites, the greater the increased risk for invasive infection

Combine colonization with other risk factors: surgery on admission, TPN, and sepsis

No colonisation index but include variables: ≥ 4 days in ICU, CVC, DM, new hemodialysis, TPN, and broad-spectrum antibiotics

Pittet D. Ann Surg. 1994;220:751-758.Paphitou NI. Med Mycol. 2005;43:235-243

Colonization in ICU patients

Prevalence of colonization in ICU is high (50% to 70% or more) compared with relatively low rate of infection, so predictive value of colonization is poor

However colonisation with unexplained fever, leukocytosis, and hypotension may indicate invasive candidiasis

Ostrosky-Zeichner L. Crit Care Med. 2006;34:857-863Eggimann P. Lancet Infect Dis. 2003;3:685-702

Which antifungal to choose?

Candida speciation may take up to 5 days

and fluconazole susceptibility testing may take an additional 5 days 

Targeted anti-fungal therapy

The “challenging” wisdom

Withhold Antifungal therapy unless positive diagnostic test

Advantages Directed therapy, ?less cost, less anti-fungal

toxicity

Disadvantages Variable sensitivity and specificity diagnostic

tests Unproven benefit in reducing mortality, ?costs

Treatment options of invasive fungal infections in adults.Swiss Med Wkly. 2006 Jul 22;136(29-30):447-63

Spellberg BJ et al. Clin Infect Dis. 2006 Jan 15;42(2):244-51Spellberg BJ et al. Clin Infect Dis. 2006 Jan 15;42(2):244-51

Diagnostic Dilemma

Clinical Setting: with other risk factors Radiology: applicable more for

Aspergillus Cultures: Low yield and longer time Staining: GMS and Calcofluor white PCR Assay: not widely available 1-3 Beta Glucan Assay: Galactomannan Assay: For Aspergillus PNA FISH:

PNA FISH: Clinical Benefits Summary

Rapid and accurate identification of bloodstream pathogens direct from positive blood cultures

Simple to implement and easy to use

Maintains species morphology

Actionable PNA FISH results for 95% of BC+

Development of new therapeutic guidelines

Improved patient safety

Early appropriate and effective antibiotic therapy

Reduction in mortality Reduction in unnecessary antimicrobial and antifungal use

Reduction in hospital length of stay (LOS)

Significant cost savings

23April 20, 2023

Antifungal choice

Organism (proven, suspected) Site of disease Host factors (eg age, neutropenia,

mucositis) History of antifungal therapy

and/or prophylaxis Tolerability/ side effects Drug-Drug interactions Costs

ANTI FUNGAL AGENTS

1950s1950s 1960s1960s 1970s1970s 1980s1980s 1990s1990s

GriseofulvinGriseofulvin

AMBdAMBd

5FC5FC

miconazole (top)miconazole (top) clotrimazole (top)clotrimazole (top)

KetaconazoleKetaconazoleEconazole, Econazole, miconazole(IV)miconazole(IV)

FluconazoleFluconazole ItraconazoleItraconazole TerbinafineTerbinafine

AMB lipid AMB lipid FormulationsFormulations

Itraconazole Itraconazole

2000s2000s

Itra (IV)Itra (IV)CaspofungCaspofungVoriconVoricon

MicafungMicafungAnidulofungAnidulofungPosaconPosaconRavuconRavucon

Antifungal Drug DevelopmentAntifungal Drug Development

Antifungal agents

Polyenes (cell membrane) Conventional Amphotericin B Lipid formulations

Ambisome, Abelcet, Amp B Colloidal Dispersion

Triazoles (sterol synthesis) Fluconazole, Itraconazole, Voriconazole, Posaconazole Ravuconazole

Echinocandins (cell wall) Caspofungin Anidulofungin, Micafungin

Allyamines (sterol synthesis) Terbinafine

Arrangement of the biomolecular components of the cell wall accounts for the individual identity of the organism. Although, each organism has a different biochemical composition, their gross cell wall structure is similar.

Antifungal agents targeted towards:

Inhibition of fungal cell wall synthesis – caspofungin is a -glucan synthesis inhibitor; several more compounds are under investigation

Inhibition of fungal cell membrane synthesis – ergosterol is the target (cell membranes of fungi and mammals contain different sterols): polyenes, azoles, triazoles, alkylamines

Inhibition of cell division – microtubule effects: griseofulvin; DNA: flucytosine.

Biochemical Targets for Antifungal Chemotherapy

Antifungal Agents- Sites of action

EchinocandinsInhibit fungal cell wallbiosynthesis

GriseofulvinInhibits mitoticspindle formation

Ergosterol

Zymosterol 14 Me-fecosterol

Lanosterol

Squalene

B-1,6 Glucan

B-1,3 Glucan

Cell Wall Phospholipid Bilayer

B-1,3 Glucan SynthaseCaspofungin

Azoles Azoles

AMB

Terbinafine