Speciality
Spotlight

 




 

Otolaryngology


 

    

  






Overview of Basic Medical
Mycology

    

  •  Some
    Fungal Genera and Species Implicated in Fungal
    Rhinosinusitis:

            








Category

Genera 

    
Zygomycetes
   
Absidia

    Cunninghamella

    Mucor 

    Rhizomucor

    Rhizopus

       
    
Hyaline moulds 
   
Aspergillus

    Blastomyces dermatitidis

    Chrysosporium

    Fusarium

    Paecilomyces

    Penicillium

    Pseudallescheria boydii

    Scedosporium

    Scopulariopsis

       
   
Dermatiaceous moulds
   
Alternaria

    Bipolaris

    Cladosporium

    Curvularia

    Exserohilum

       
   
Ascomycetous yeasts
    
Candida

        
   
Basidiomycetes 
   
Coprinus

    Cryptococcus neoformans

    Schizophyllum

    Ustilago

         

           
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

        










Strategies

Tools

Immune
modulation
Cytokines/chemokines
Maximal
drug prescriptions/durations 
Clinical
trials
Antifungal
drug prophylaxis 
Identify
high-risk patients
Improvement
in drug tolerability 
Lipid
formulations and other new delivery
vehicles.
Surgery 
Radiographically
limited and 

heavy burden of organism disease.
Combination
therapies
Amphotericin
± flucytosine

Azoles ± terbinafine.
Drug
discovery 
New
targets and agents

     


        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




    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.

          


 



 

Speciality Spotlight

 

    
  

Overview of Basic Medical Mycology
    

  •  Some Fungal Genera and Species Implicated in Fungal Rhinosinusitis:
            

Category

Genera 

     Zygomycetes

    Absidia
    Cunninghamella
    Mucor 
    Rhizomucor
    Rhizopus
       

     Hyaline moulds 

    Aspergillus
    Blastomyces dermatitidis
    Chrysosporium
    Fusarium
    Paecilomyces
    Penicillium
    Pseudallescheria boydii
    Scedosporium
    Scopulariopsis
       

    Dermatiaceous moulds

    Alternaria
    Bipolaris
    Cladosporium
    Curvularia
    Exserohilum
       

    Ascomycetous yeasts

     Candida
        

    Basidiomycetes 

    Coprinus
    Cryptococcus neoformans
    Schizophyllum
    Ustilago
         

            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
        

Strategies

Tools

Immune modulation

Cytokines/chemokines

Maximal drug prescriptions/durations 

Clinical trials

Antifungal drug prophylaxis 

Identify high-risk patients

Improvement in drug tolerability 

Lipid formulations and other new delivery vehicles.

Surgery 

Radiographically limited and 
heavy burden of organism disease.

Combination therapies

Amphotericin ± flucytosine
Azoles ± terbinafine.

Drug discovery 

New targets and agents

     
        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


    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.
          

 

 

By |2022-07-20T16:43:24+00:00July 20, 2022|Uncategorized|Comments Off on Overview of Basic Medical Mycology

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