1. Dr Muhammad J Motiwala MD, FACP, Al Mafraq Hospital Abu Dhabi-UAE
Recent Update In The Management Of Invasive Candidiasis
Dr Muhammad J Motiwala MD, FACP, Al Mafraq Hospital Abu Dhabi-UAE

2. Overview Invasive Fungal Infections Antifungal Agents
Polyenes
Azoles
Glucan Synthesis Inhibitors
IDSA Treatment Guidelines

3. 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

4. Rank order of nosocomial bloodstream pathogens and their associated mortality1
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
Serratia species
1.4 26 10
Viridans streptococci 23

7. 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

9. Incidence of Invasive Fungal Infections
Solid Organ Transplant %
Kidney – 14%
Heart – 32%
Heart-Lung/Lung 15 – 36%
Pancreas 18 – 38%
Liver – 42 %
Bone Marrow Transplant %
Intensive Care Unit 17%
Singh, N. CID 2000; 31:545-53
Vincent JL. Intensive Care Med 1998; 24:

10. 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:
National Center for Health Statistics ( )
Lin S et al. CID 2001;32:

11. Challenges
Delaying antifungal therapy until blood cultures are positive is associated with increased mortality
Diagnostic limitations

13. 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:
Paphitou NI. Med Mycol. 2005;43:

14. 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:
Eggimann P. Lancet Infect Dis. 2003;3:

15. CI is ratio of # of sites positive to total number of sites tested.
CCI is CI times the ratio of # of sites with heavy growth to the total # of positive sites.

16. Which antifungal to choose?
Candida speciation may take up to 5 days
and fluconazole susceptibility testing may take an additional 5 days 
In patients who are critically ill, hypotensive with multi-organ failure, most authorities would favour the initial use of IV amphotericin. This recommendation was based on efficacy trends that favoured IV amphotericin over Iv fluconazole (but were not statistically different) and that candidemia was cleared faster with IV amphotericin compared to fluconazole

17. 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 17

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

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

21. 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:

23. 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
25 March 2017 23

24. 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 24

25. ANTI FUNGAL AGENTS

26. Antifungal Drug Development
1950s
1960s
1970s
1980s
1990s
2000s
Griseofulvin
Ketaconazole
Fluconazole
Itraconazole
Terbinafine
AMB lipid
Formulations
Econazole,
miconazole(IV)
Itra (IV)
Caspofung
Voricon
Micafung
Anidulofung
Posacon
Ravucon
AMBd
5FC
miconazole (top)
clotrimazole (top)

27. 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

28. Biochemical Targets for Antifungal Chemotherapy
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.

29. Antifungal Agents- Sites of action
Echinocandins
Inhibit fungal cell wall
biosynthesis
Griseofulvin
Inhibits mitotic
spindle formation

30. B-1,3 Glucan Synthase
Caspofungin
B-1,6 Glucan
B-1,3 Glucan
Cell Wall
Phospholipid Bilayer
AMB
Ergosterol
Zymosterol
14 Me-fecosterol
Azoles
Lanosterol
Azoles
Terbinafine
Squalene