Transcript Slide 1
Recent Update In The Management Of
Invasive Candidiasis
DR
MUHAMMAD J MOTIWALA
MD, FACP,
AL MAFRAQ HOSPITAL
ABU DHABI-UAE
Overview
Invasive Fungal Infections
Antifungal Agents
Polyenes
Azoles
Glucan Synthesis Inhibitors
IDSA Treatment Guidelines
Review of our Fungal “Players”
Opportunistic fungi
• Newly emerging fungi
Normal flora
Candida spp.
Ubiquitous in our environment
Aspergillus spp.
Cryptococcus spp.
Mucor spp.
Endemic geographically restricted
Blastomyces sp.
Coccidioides sp.
Histoplasma sp.
• 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
Kidney
Heart
Heart-Lung/Lung
Pancreas
Liver
5 - 42%
5 – 14%
5 – 32%
15 – 36%
18 – 38%
7 – 42 %
Bone Marrow Transplant
15 - 25%
Intensive Care Unit
17%
Singh, N. CID 2000; 31:545-53
Vincent 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;34:857-863
Eggimann 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):244-51
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
17 July 2015
23
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
Antifungal Drug Development
1950s
1960s
Griseofulvin
1970s
1980s
1990s
2000s
Ketaconazole Fluconazole
AMBd
Econazole,
miconazole(IV)
5FC
miconazole (top)
clotrimazole (top)
Itra (IV)
Caspofung
Itraconazole
Voricon
Terbinafine
AMB lipid
Formulations
Itraconazole
Micafung
Anidulofung
Posacon
Ravucon
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
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.
Antifungal Agents- Sites of action
Echinocandins
Inhibit fungal cell wall
biosynthesis
Griseofulvin
Inhibits mitotic
spindle formation
B-1,3 Glucan Synthase
Caspofungin
B-1,6 Glucan
B-1,3 Glucan
Cell Wall
AMB
Phospholipid Bilayer
Ergosterol
Zymosterol
Azoles
Terbinafine
14 Me-fecosterol
Lanosterol
Squalene
Azoles