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Recent Update In The Management Of Invasive Candidiasis.

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Presentation on theme: "Recent Update In The Management Of Invasive Candidiasis."— Presentation transcript:

1 Recent Update In The Management Of Invasive Candidiasis

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 mortality 1Coagulase negative-staphylococci Staphylococcus aureus Enterococci Candida species938 5Escherichia coli Klebsiella species Enterobacter species Pseudomonas species Serratia species Viridans streptococci1.423



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 Transplant5 - 42% Kidney 5 – 14% Heart 5 – 32% Heart-Lung/Lung15 – 36% Pancreas18 – 38% Liver 7 – 42 % Bone Marrow Transplant % Intensive Care Unit17% Singh, N. CID 2000; 31: 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 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:


16 Which antifungal to choose? Candida speciation may take up to 5 days and fluconazole susceptibility testing may take an additional 5 days

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


19 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 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 2316 January 2014

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


26 1950s1960s1970s1980s1990s Griseofulvin AMBd5FC miconazole (top) clotrimazole (top) Ketaconazole Econazole,miconazole(IV) Fluconazole Itraconazole Terbinafine AMB lipid FormulationsItraconazole 2000s Itra (IV) CaspofungVoriconMicafungAnidulofungPosaconRavucon Antifungal Drug Development

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 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

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

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

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