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ICUGATE Predisposing Factors

VIEWS: 14 PAGES: 30

									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                         • Fusarium
     Candida spp.                       • Scedosporidium
   Ubiquitous in our environment        • Trichosporin
     Aspergillus spp.
     Cryptococcus spp.
     Mucor spp.

 Endemic geographically restricted
     Blastomyces sp.
     Coccidioides sp.
     Histoplasma sp.
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; 31:545-53
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


                                                   18 July 2011   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            1970s       1980s      1990s        2000s

Griseofulvin                              Ketaconazole Fluconazole
                             Econazole,                             Itra (IV)
               AMBd          miconazole(IV)                         Caspofung
                                                       Itraconazole
                                                                    Voricon
               5FC
                                                       Terbinafine
               miconazole (top)
                                                       AMB lipid
                                                       Formulations
               clotrimazole (top)
                                                       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                                  Phospholipid Bilayer
            AMB
                              Ergosterol

       Zymosterol                               14 Me-fecosterol


            Azoles            Lanosterol
                                                  Azoles
                Terbinafine
                              Squalene

								
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