Title: Dr Muhammad J Motiwala MD, FACP, Al Mafraq Hospital Abu Dhabi-UAE
1Dr Muhammad J MotiwalaMD, FACP,Al Mafraq
HospitalAbu Dhabi-UAE
- Recent Update In The Management Of Invasive
Candidiasis
2Overview
- Invasive Fungal Infections
- Antifungal Agents
- Polyenes
- Azoles
- Glucan Synthesis Inhibitors
- IDSA Treatment Guidelines
3Review 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
4Rank order of nosocomial bloodstream pathogens
and their associated mortality
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7Predisposing 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
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9Incidence 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 31545-53
- Vincent JL. Intensive Care Med 1998 24 206-216
10Mortality 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 199929239-44. National
Center for Health Statistics (1980-1997) Lin S et
al. CID 200132358-66.
11Challenges
- Delaying antifungal therapy until blood cultures
are positive is associated with increased
mortality - Diagnostic limitations
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13Clinical 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. 1994220751-758. Paphitou
NI. Med Mycol. 200543235-243
14Colonization 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.
200634857-863 Eggimann P. Lancet Infect Dis.
20033685-702
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16Which antifungal to choose?
- Candida speciation may take up to 5 days
- and fluconazole susceptibility testing may take
an additional 5 days
17Targeted anti-fungal therapyThe 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
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19Treatment options of invasive fungal infections
in adults.Swiss Med Wkly. 2006 Jul
22136(29-30)447-63
20Spellberg BJ et al. Clin Infect Dis. 2006 Jan
1542(2)244-51
21Diagnostic 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
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23PNA 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
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12 June 2013
24Antifungal 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
25ANTI FUNGAL AGENTS
26Antifungal Drug Development
1950s
1960s
1970s
1980s
1990s
2000s
Griseofulvin
Ketaconazole
Fluconazole Itraconazole Terbinafine AMB
lipid Formulations Itraconazole
Itra (IV) Caspofung Voricon Micafung Anidul
ofung Posacon Ravucon
Econazole, miconazole(IV)
AMBd 5FC miconazole (top) clotrimazole (top)
27Antifungal 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
28Biochemical 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.
29Antifungal Agents- Sites of action
Echinocandins Inhibit fungal cell
wall biosynthesis
Griseofulvin Inhibits mitotic spindle formation
30B-1,3 Glucan Synthase
Caspofungin
B-1,6 Glucan
B-1,3 Glucan
Phospholipid Bilayer
Cell Wall
AMB
Ergosterol
Zymosterol
14 Me-fecosterol
Lanosterol
Azoles
Azoles
Terbinafine
Squalene