dr muhammad j motiwala md, facp, al mafraq hospital abu dhabi-uae
DESCRIPTION
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”. - PowerPoint PPT PresentationTRANSCRIPT
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