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ICUGATE Predisposing Factors


									Recent Update In The Management Of
        Invasive Candidiasis

              DR   MUHAMMAD J MOTIWALA
                             MD, FACP,
                    AL MAFRAQ HOSPITAL
                         ABU DHABI-UAE

 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

 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.

 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
 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

    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:                Clinical Benefits
   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
 Tolerability/ side effects
 Drug-Drug interactions
 Costs
      Antifungal Drug Development
  1950s          1960s            1970s       1980s      1990s        2000s

Griseofulvin                              Ketaconazole Fluconazole
                             Econazole,                             Itra (IV)
               AMBd          miconazole(IV)                         Caspofung
               miconazole (top)
                                                       AMB lipid
               clotrimazole (top)
                     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
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:
                    Antifungal Agents- Sites of action

                                                         Inhibit fungal cell wall

Inhibits mitotic
spindle formation
                        B-1,3 Glucan Synthase
B-1,6 Glucan

                                                           B-1,3 Glucan

Cell Wall                                  Phospholipid Bilayer

       Zymosterol                               14 Me-fecosterol

            Azoles            Lanosterol

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