Fungal Infections

  • Facts
    • Cryptococcosis disease occurs after 2.8%–8% of solid- organ transplants, and is the third-commonest invasive fungal infection in this setting, after Candida and Aspergillus. 
    • PCP is common in AIDS
  • Tests for Fungus: 
    • Two serum fungal diagnostic tests, 
      • the b-(1-3)-D glucan test and 
      • the galactomannan test, may aid in the detection of common invasive fungal infections. 
    • The sensitivity of a single serum test is extremely low, and a single negative result should not be used to rule out the diagnosis of an invasive fungal infection 
    • Serial serum monitoring for either of these fungal wall elements can be used to guide initiation of preemptive antifungal therapy in high-risk patients. 
    • The b-(1-3)-D glucan test detects most of the relevant fungal pathogens, including Candida species, Aspergillus species, Pneumocystis species, and Fusarium species (but not the zygomycetes agents or Cryptococcus species), with high levels of sensitivity and specificity reported in small studies 
      • Positive test means we need to further identify if it is Candida, or Aspiergillus, or Pneumocystis species NEJM 2015
      • Among patients with AML or MDS undergoing chemotherapy, b-(1-3)-D glucan assay has been found to be 63%–90% sensitive and .95% specific for early detection of proven or probable fungal infections, including candidiasis, fusariosis, tricho- sporonosis, and aspergillosis 
    • The galactomannan assay detects only Aspergillus species (and Penicillium species, which is a rare pathogen in the United States) and does not detect other pathogenic fungi, although cross-reactivity to Histoplasma capsulatum has been described
      • In patients with hematologic malignancies or HSCT, galactomannan sensitivity was only 58%–65% and specificity was only 65%–95% 
  • Candida Infections
    • Orophyrangeal Candidiasis (Thrush)
      • Topical or Oral (100-200 Fluonazole) for 7-14 days for Non-HIV; Only ORAL for HIV
    • Esophageal
      • Only Oral for longer duration i.e 21 days
      • Higher dose (200-400 mg Fluconazole as compared to 100 -200 mg in Thrush)
    • Vulvovaginitis
      • Topical 3-7 days (based on drugs used); If oral One time Fluconazole 150 mg 
    • Cystitis
      • Remove catheter if possible
      • Asymptomatic: No treatment needed except in high risk patient population
      • Symptomatic: If disseminated candidiasis, treat like candidemia; otherwise Fluconazole 


Hepatosplenic Candidiasis NEJM 2007


PCP


Radiological Features of PCP 
CXR

Although up to 90% of chest x-rays in patients with PCP are abnormal, appearances are often non-specific. Between 10-15% of patients with PCP have normal chest radiographs and close to 30% have non-specific or inconclusive findings  .

Features which are highly suggestive of PCP in patients with CD4 counts below 200/mm3  include

Pleural effusions are normally not a feature being seen in less than 5% of cases .

HRCT chest

High resolution computed tomography (HRCT) is more sensitive and may be used to exclude PCP in patients with clinical suspicion for PCP but normal or inconclusive chest radiographs.

Features include:

    • ground-glass pattern predominantly involving perihilar or mid zones there may be a mid, upper or lower zone predilection depending on whether the patient is on prophylactic aerosolised medication
      • if they are, then the poorly ventilated upper zones are prone to infection , whereas in those who are not the lower zones are more frequently involved
      • there may be relative preservation of previously irradiated areas
    • reticular opacities or septal thickening may also be present
    • a crazy paving pattern may therefore be seen when both ground-glass opacities and septal thickening are superimposed on one another pneumatoceles are seen in up to 30% of cases 
    • pleural effusions are rare 
    • lymphadenopathy is uncommon (10%)
  • References:  above content is from
  • additional reading

  • Antifungal Therapy
    • Polyenes Macrolide : MOA: disrupts fungal cell wall synthesis by binding to sterols, primarily ergosterol. This cause pores formation causing leakage of cellular components and cell death:
      • AMP-B:
        • Is an amphoteric polyene macrolide
          • polyene: Containing many double bonds
          • macrolide: containing a large lactone ring of 12 or more atoms
        • nearly insoluble in water
        • Formulatoins
          • Fungizone (micelles) (24 $ / day)
          • AmBisome (spheres) (1300$ / day)
          • Amphotec (Discks) (660 $ / day)
          • Abelcet (ribbons) (570 $ / day)
        • effective against all fungus; some display intrinsic AMP-B resistance (C. lusitaniae; Pseudallescheria boydii)
        • Cryptococcus and Zygomycetes infection that are often resistant to Echinocandins are often treated with AMP - B
        • use usually limited to RAPIDLY reduce fungal burden as the INITIAL induction regimen mostly in serious infections
          • Immunosuppressed patients
          • severe fungal pneumonia
          • severe cryptococal menigitis
          • Dissemintated infection with endemic mycoses
    • Azoles : MOA: works primarily by inhibiting  lanosterol 14-alpha-demethylase (cytochrome P450-dependent enzyme). This blocks the conversion of lanosterol to ergosterol, a vital component of the cellular membrane of fungi -
      • Type (based on number on N in azole ring) 
        • Imidazole: Ketoconazole, Miconazole, Clotrimazole
          • 2 N in five-membered azole ring
          • Lesser degrees of selectivity to fungal Cty P450 enzymes. Hence, more toxic. 
        •  Triazoles: Fluconazole, , Voriconazole, Pasoconazole, Itraconazole
          • 3 N in five -membered azole ring
          • Fluconazole has good bioavailability; also has least hepatic effect on hepatic micro enzyme, and tolerated better.
            • thus provides an option to use at much higher dose
            • can pass and go into CNS (hence, used in meningitis)
            • fluconazole activity among dimorphic fungi is limited to coccidiomycosis
      • Useful in treatment of broad range of fungal infection including intrinsically resistant P. boydii to AMB-B
    • Echinocandins: MOA: noncompetitive inhibitors of the synthesis of 1,3-beta-D-glucan: 
      • C. glabrata or C. krusei (Preferred treatment compared to Azoles)
      • Caspofungin (initial dose of 70 mg on the first day of treatment, followed by 50 mg daily);
      • Anidulafungin is given at an initial dose of 200 mg on the first day, followed by 100 mg daily.
      • Micafungin for candidemia, dose of 100 mg daily was used in the European studies. 
      • Note: Echinocandians are not well absorbed orally, hence, has to be given IV
      • Echinocandins have no activity against Cryptococcus, and Trichosporon even though they are yeast. However, they work on almost all species of Candia. There is some concern for resistance to Candida Parapsirolis. 
    • Other Drugs
      • Flucytosine: 
        • MOA: (PYRIMIDINE ANALOG) taken up by fungal cells via the enzyme cytosine perm ease - converted intracellular into 5-FU. Undergoes further modification to FdUMP and FUTP (Fluorouridine triphosphate). FUTP inhibit DNA and RNA respectively. 
      • Terbinafine
        • MOA: like Azoles, it interferes with ergosterol synthesis. Mechanism is different thought. Instead of interacting with Cty P450 enzyme, it inhibits squalene epoxidase. This leads to accumulation of squalene which is toxic to the fungus.  
        • Dose: 250 mg / day; 12 weeks treatment has cure rate unto 90% 
        • Like Griseofulvin it is keratophilic medication (used for onychomycosis), and unike Griseofulvin, it is fungicidal
        • Adverse effects are rare (GI upset, and headache)
    • Topical Anti-fungal
      • Topical Azoles (imidazoels)
      • Nystatin:
        • is like polyene macrolide like AMP - B
        • too toxic for pareneteral use, hence used topically
        • little absorption in skin or gut 
          • Use: 
            • Oral or vulvovaginal candidiasis
            • Intertriginous candidal infection
    • Specific Therapy
      • Candidal Infection
        • Albicans: Fluconazole
        • Non-albicans: Voriconazole
      • Blasto or Histo (AMP B or Itra for mild) / Coccido (Flu) / Crypto (AMP B + 5 FU then Flucytosine) :
      • Molds (Aspergillus, Fusarium): Voriconazole
      • Mucorale (Mucor, Rhizopus): Posaconazole, AMP B
      • Dermatophytes : TerbinafineePregnancy: AMP B
    • References
      • Antifungal Drugs Treatment Guidelines
      • Chapter 48, Lange Pharmacology, 13th edition
Comments