Overview of Basic Medical Mycology

Overview of Basic Medical Mycology
    

•  Some Fungal Genera and Species Implicated in Fungal Rhinosinusitis:
          

            With increasing number of immunosuppressant patients with various aetiological factors, fungal infections
            have increased. For deep seated fungal infections, very powerful drugs like Amphotericin B, Flucystosine
           and several azoles are used. 
          
          
           Treatment of invasive fungal rhinosinusitis
          
           Concepts and Principles:
            Medical advances have led to increased numbers of immunocompromised patients living longer in the
           general environment and a concomitant rise in fungal infections. This has advanced the authors’ recent
           experience with antifungal therapies. This clinical experience has had a series of positive aspects. (1) There
           has been improvement in education on antifungal therapy in the medical community. (2) Better control
           methods for underlying diseases (i.e. highly active antiretroviral therapy, reduction in chemotherapy-induced
           neutropenia, more options for antirejection therapies) have been developed. (3) Identification of specific risk
           factors or groups continue to be identified. (4) Standardized antifungal susceptibility testing for yeasts is now
           available for clinical decisions. (5) Safe triazoles (fluconazole and itraconazole) have demonstrated a positive
           impact for antifungal prophylaxis, empiric, and therapeutic strategies (6) Improvements in the formulations of
           amphotericin B have produced a less toxic product. (7) Some important pivotal clinical studies in mycoses
           management have been completed (8) There continues to be enthusiasm in the pharmaceutical industry to
           identify new antifungal targets and drugs.
         
           Unfortunately, there are still many negative aspects in the use of antifungal agents for the invasive mycoses.
           (1) There remains a need for potent fungicidal regimens and there are still a limited number of agents available
           (2) For most fungal infections, there are poorly-defined lengths of therapy and lack of precision on proper
           dosing (3) There is no approved standardized system for antifungal susceptibility testing of molds. (4)
           Toxicities and drug interaction issues frequently occur with present antifungal agents (5) Clinical data suggest
           poor outcomes for certain fungal infections, such as invasive aspergillosis despite present therapies. (6) Costs
           of new antifungals can be prohibitive for some patients and their health care systems. (7) Despite the
           frequency of fungal infections, the complexity of these patients makes it difficult to study new strategies and
           drugs. Pivotal outcome studies remain few. (8) Nonculturable diagnostic tests for early detection of fungal
           infections of Candida and aspergillus remain to be either created or clinically validated. (9) Antifungal drug
           resistance continues to persist and new strategies to combat this problem are necessary. Table 1 lists the
           potential strategies to use for management of antifungal drug resistance.
       
           Table 2 identifies a series of principles that the clinician should consider whenever faced with treatment of an
            invasive mycosis. Expert medical mycology advice, however, is often necessary for serious invasive disease
            in these complex cases. Excellent, recent comprehensive reviews are available on several aspects of
            antifungal agents: drug resistance and mechanisms, use in pregnancy, drug interactions, drug
            pharmacokinetics, and use in children, and may be helpful resources in the management of certain cases.
       
       
           Table 1 STRATEGIES TO OVERCOME ANTIFUNGAL DRUG RESISTANCE
        

     
        Table 2 ANTIFUNGAL TREATMENT PRINCIPLES
   
             ¨ Correct identification of the fungus is essential.
    
             ¨ Use of standard, published antifungal regimens depends on fungus identified and clinical syndrome.
   
             ¨ Clinician should consider initial therapy as an induction phase with optimization in both dose and antifungal
               drug, which gives maximum fungicidal activity at the site of infection; consider combination therapy in
               certain cases.
   
             ¨ Control of the underlying medical or immunosuppressive conditions is mandatory.
   
             ¨ Clinician must pay particular attention to drug interactions, pharmacokinetics and resulting toxicities; this
               may require measurement of drug levels in certain circumstances.
    
             ¨ After apparent stabilization of clinical symptoms and signs of infection with treatment consideration of a
               consolidating drug regimen in dose or drug to complete a defined course of therapy is required.
    
             ¨ Follow-up for relapse/reinfection after treatment should be at least 6 months to a year depending on fungus
              and type of infection.
        

• Diagnosis and Management of Invasive Fungal Rhinosinusitis
  An algorithm for approaching the immunocompromised patients with suspected invasive fungal rhinosinusitis has been provided by Gillespie and O’Molley.
  
  
  

  Underlying
  Immunocompromised State
     Leukeemia/Lymphoma
    AIDS
  Insulin dependent diabetes mellitus
  Aplastic anemias
  

     

  

  Symptoms
  1)Fever of unknown origin while on appropriate antibiotics 
  and/or
  2)Localizing symptoms (facial pain/edema, nasal congestions.rhinorrhea)
  

  Associated Risk Factors
  
  Heavy steroid use Broad spectrum antibiotics(>2 drugs)
  Prolonged antibiotic use(> 2weeks) 
  CD4 count < 50 # / mm3
  WBC < 500# / mm3
  

               

     Evaluation
  1) Rigid nasal endoscopy – mucosal discoloration, crusts, ulcerations
  2) Axial/Coronal CT scan – intranasal edema, sinusitis, bony erosion
  3) MRI with gadolinium – if orbital or intracranial spread is suspected.
      

  

  

  Gross Disease 
  1)  High dose amphotericin B (>1.25mg/kg/day)
  2) Liposomal amphotericin if disease progresses or if serum creatinine >2.5 mg/dL
  3) Surgery  
    — Complete resection to   
          bleeding margin
    — Biopsy and culture for
         speciation
    — Second look procedure in
        48-72hours if residual
       disease is suspected

  Suspected Disease
  (1) Selective frozen section  biopsy of suspicious lesions  or middle turbinate in clinic or operating room 
  (2) Antrap tap and lavage for culture
  

                        

    

                                    Follow-up
               1) Weekly rigid nasal endoscopy until neutropenia resolves
                  2) Amphotericin B-total dose of 2 grams

      
  REVIEW OF SPECIFIC ANTIFUNGAL DRUGS
     
  Amphotericin B Deoxycholate
     
  For last 40 yrs amphotericin B (a polyene microlide) remains standard drug for most life-threatening systemic fungal infection. The antifungal activity of this drug is caused by its ability to bind preferentially to ergosterol, a major component of the fungal cell membrane, resulting in increasing permeability with leakage of intracellular components and ultimate cell death.
     
  Orally administered has minimal absorption and therefore, intravenous dosing is required.
     
  Dosage : 0.25 to 1mg/kg once daily in 5% dextrose solutions are recommended. Maximum daily doses of 1.2mg/kg in adults and 1.5mg/kg in children are reserved for very severe infection. Vital signs are monitored during administration.
      
  Toxicities:
  (1)   Infusion-related reactions are common.
  (2)  Thrombophlebitis is common – to reduce the severity of this reaction decrease the rate of infusion and by
        adding heparin to the infusion (1000units/L). It should be administered by central line and rotate the site
        of infusion which should be lowly concentrated.
  (3)  Hypokalemia – particularly with renal dysfunction patients.
  (4)  Nephrotoxicity – This can be reduced by way of a normal saline bolus, 500 to 1000mL in adult patients,
        administered before and following the amphotericin infusion.
  (5)  Decrease in haemoglobin.
       
  Lipid Based Formulation of Amphotericin B
  To avoid or reduce toxicity lipid-based amphotericin like Amphotericin-B lipid complex (ABLC, Abelcet), amphotericin B cholesteryl sulfate complex (ABCD, Amphotec), and liposomal amphotericin B (Ambisome).
      
  These are potentially delivered preferentially into reticuloendothelial tissues like liver and spleen and to some extent in lungs.
      
  In authors opinion these lipid-based drugs are not as effective but the larger daily doses could be administered for therapeutic efficacy.
      
  Azoles – Imidazoles and Triazoles: Mainly for the treatment of cutaneous and mucocutaneous candidiasis.
  Ketoconazole has been used systemically for several invasive fungal lesion.
  Mode of action- works primarily by inhibiting the cytochrome P-450 dependent enzyme lanosterol 14-a-demethylase which is necessary for the conversion of lanosterol to ergosterol.
      
  Drug Interactions – Triazoles
  Cisapride, terfenadine, astemizole have been reported. Other drugs include benzodiazepines, oral hypoglycemics and digoxin. Some drugs hasten metabolism and therfore reduced dose. H2 antagonist reducing acid secretion decreases absorption of itraconazole. Other drugs like antiviral agents and proton pump inhibitors should be avoided.
     
  Flucytosine
  This is a cytosine analogue, originally formulated as an antineoplastic drug and prevents DNA synthesis. 
      
  It is used in combination with amphotericin-B in very severe cases. The dose in serious infections is 100mg/kg/day divided into four doses. Renal function is to be monitored and as per impairment of renal function the dose has to be modified.
     
  1) This combination is of choice in cryptococcal meningitis and also in HIV infected patients.
     
  2) Occasionally and in systemic candidiasis.
      
  This is available orally in USA and 80% is absorbed by G.I. tract.
      
  Terbinafine
  An allylamine compound for oral use especially in cutaneous and nail fungus infection. Antifungal activity is caused by inhibition of the enzyme squalene epoxidase, resulting in depletion of ergosterol and causing cell death. 
      
      
  PREVENTION WITH PROPHYLACTIC ANTIFUNGAL DRUGS:
      
  Several principles require consideration when selecting an effective prophylaxis regimen. These include (1) targeting pathogens most likely to cause infection; (2) identifying subsets of patients at highest risk for fungal sinusitis; (3) limiting prophylaxis to the period of time when risk is greatest; (4) choosing a safe, well-tolerated drug with minimal toxicity and interactions; (5) monitoring patients for drug-related side effects and development of resistance to the agent; and (6) evaluating the cost of a regimen in relation to its efficacy.
     
  Because Aspergillus species are the most common cause of invasive fungal sinusitis in immunocompromised patietns, drugs active against this pathogen should be an integral part of any successful prophylactic regimen. Invasive Candida infection of the sinuses is rare and should not be a target of prophylaxis. Infections caused by the zygomycetes (Mucor, Rhizopus), Pseudallescheria, Alternaria, Bipolaris, and others are uncommon enough that antifungal prophylaxis is not feasible.
     
  Fungus Balls
      
  This consists of tangled mats of hyphae in the sinuses and also referred in literature as Mycetomas (not technically correct)
      
  These balls have no evidence of invasion on histopathology. These patients are immunocompetent and are treated best with surgical removal of these balls. It has very low rate of recurrence and requires no systemic antifungal therapy.
      
  Saprophytic Fungal Infestation
      
  This refers to the presence of the fungal spores on mucous crusts within nose and paranasal sinuses. Usually seen on endoscopic inspection. Observed after following endoscopic sinus surgery. The treatment required is cleaning the crusts and saline irrigation repeatedly.
       
       
  ALLERGIC FUNGAL RHINOSINUSITIS
     
   Allergic fungal sinusitis is the most common, 7% in USA of all sinus surgeries have been reported. Noninvasive and similar to allergic bronchopulmonary aspergillosis.
      
  Allergic fungal rhinosinusistis (AFRs) is defined as patients with an allergic response to the fungus which demonstrates an allergic mucinous response. These are immunocompetent pateints. Because of IgE hypersensitivity to the fungus, the patient produces eosinophilic allergic mucin. Polyps occur because of the persistent inflammation.
      
  Diagnosis is achieved by histopathologic examination of the mucin coupled with special fungi stain.
      
  1) Presence of eosinophilic allergic mucin, laminated frequently with inflammatory cells.
  2) Charcot-Leyden crystals.
  3) Hyphae scattered through mucin.
  4) Evidence of fungal atophy.
      
  These features are the diagnostic of allergic fungal sinusitis, inspite of the fact that culture may not grow any fungus.
     
      

  Endoscopic Mucosal Staging       System in Allergic Fungal Sinusitis

  Stage 

    Endoscopic Finding

  0 
  I. 
  II.
  III.

    No mucosal edema or allergic mucin
    Mucosal edema with or without allergic mucin
    Polypoid edema with or without allergic mucin
    Sinus polyps with fungal debris or allergic mucin.

  Imaging:
  CT finding shows areas of hyperattenuation within sinus cavity. These areas correspond with areas of hypointensity on T1 -weighted MR images and signal void on T2-weighted MR images. CT scan may show patterns like star-filled sky, ground glass or serpiginous pattern. There may be areas of expansion by thinning of bones and goes pushing in surrounding sinus or postorbital region. Almost in 50% AFRs patients involve sinus unilaterally.
     
  BENT and KUHN Diagnostic Criteria for allergic Fungal Rhinosinusitis
     
  1. Type of hypersensitivity
  2. Nasal polyps
  3. Characteristic CT scan findings
  4. Positive fungal stain or culture
  5. Allergic mucin with fungal elements and no tissue invasion
     
  Suggested work-up for suspected Allergic Fungal Rhinosinusitis.
      
  1. Total eosinophil count
  2. Total serum IgE
  3. Antigen-specific IgE, both fungal and other inhalants, by in vitro testing and/or skin tests
  4. Fungal antigen-specific IgG
  5. Precipitating antibodies
  6. Microscopic evaluation of mucin evacuated intraoperatively
  7. Fungal culture of mucin evacuated intraoperatively.
     
  (A) Traditional Surgical Therapy
  The use of open antrostomies with radical removal of mucosa, intranasal sphenoethmoidectomies and Lynch frontoethmoidectomies was accomplished. Removal of polyps and clearing of Charcot-Leyden crystals, eosinophilic mucin.
      
  The surgical aims have three goals to achieve 
  (1) complete extirpation of mucin and fungal debris.
  (2) Next goal is to achieve permanent drainage and ventilation of the affected sinuses.
  (3) To achieve postoperative access to the previously diseased areas. 
  (4) Postoperative care begins immediately in the form of saline irrigations.
     
  (B) Perioperative management includes prevention of recurrence and the role of steroids and antifungal agents.
      
  Allergic fungal rhinosinusitis is persistent disease with frequent recurrences.
  (a) Antifungal treatment is required only in immunocompromised patients like diabetics. Once this goal is
       achieved no antifungal therapy is needed.
  (b) Immunotherapy is under trial by administration of fungal antigens.
  (c) Systemic perioperative steroids
     
  Treatment Protocol of Steroid Therapy:
     
  The authors recommendation is to begin oral prednisone in a dose of 0.4mg/kg (~40mg) per day for 4 days. The dose is then decreased by 0.1mg/kg per day in cycles of 4 days until a dose of 20mg/day, or 0.2mg/kg/day, whichever is greater, is reached. This is continued until the 1-month postoperative visit, when it is adjusted to 0.2mg/kg/day. This dose then is maintained and the patient is followed monthly with both nasal endoscopy and total serum IgE levels. The patient’s weight and prednisone dose are recorded at each visit. The condition of the nasal and sinus mucous membrane is endoscopically staged according to Kupferberg et al. The prednisone dose then is adjusted based on maintenance of Stage 0. 
      
  Each patient’s total serum IgE level, prednisone dose and clinical stage are plotted monthly. After maintaining normal mucosa (Stage 0) for 4 consecutive months while receiving a dose of 0.2mg prednisone/kg/day, the prednisone is reduced to 0.1mg/kg/day. Intranasal steroid powder spray is simultaneously started at triple the allergic rhinitis dose (one spray in each nostril 3 times daily, as opposed to once daily). If the patient stays at Stage 0 for 2 additional months, the prednisone is tapered to zero and the intranasal steroid spray is continued for at least 1 year. Endoscopy and serum IgE level determinations are continued monthly for 6 months and then bimonthly for 3 to 5 years. Patients need to be followed up to 5 years after the prednisone therapy because the authors’ longest time to recurrence after surgery and without postoperative oral prednisone treatment has been 34 months.