Antifungal agents and their use in general medical practice

1. Antifungals in Medicine
By: Interns
-Sumnima Shrestha
-Vivek Ghosh
Dept. of Int. Medicine
GMCTH6/28/2017 1

2. Objectives
 Classification of fungal infections
 Risk factors
 Fungal diseases
 Diagnosis
 Antifungal drugs
-Classification
-Pharmacology
 Guidelines for treatment
 Specific conditions and management
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3. Fungal infections
 Anatomically
Fungal infections
Superficial Cutaneous Subcutaneous
Systemic
-outer skin -Epidermal -Subcutaneous -
layer layer
-immune -immune -immune response -immune
Response(-) response(+) (+)
response(+)
-T. versicolor-Dermato -Sporotrichosis -Invasive
phytes Maduramycosis fungal inf6/28/2017 3

4. Tinea versicolor infection
Dermatophytosis
Sporotrichosis Maduramycosis
Invasive candidiasis
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5.  Epidemiologically
Fungal infections
Endemic Opportunistic
-acquired from -acquired by
immunoco-
Environment mpromised hosts
-not normal flora -part of normal flora
-Coccidioidomycosis -Aspergillosis,6/28/2017 5

6. Risk Factors
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7. Risk factors
 Aspergillus:
COPD, Severe burn, Previous
cardiac disease
 Cryptococcosis and Pneumocystis:
Advanced HIV infection,
Decompensated liver cirrhosis,
Autoimmune diseases
 Mucormycosis:
Chronic infection of paranasal
sinuses, Massive injuries, Prolonged
acidosis
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8. Affected Organs
 Candidiasis:
-Mucocutaneous
-Invasive:
Candidaemia
Esophagus
CNS
Eye
Heart
Kidney
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9. Affected Organs
 Aspergillosis:
Pulmonary, Sinus, Brain, Skin, Heart,
Eye
 Cryptococcosis
CNS, Pulmonary, Disseminated
 Pneumocystis
Pulmonary, Disseminated
 Mucormycosis
Rhinocerebral, Pulmonary, GI,
Cutaneous 6/28/2017 9

10. Diagnosis of Fungal Infections
 Definite diagnosis: Histopathologic
identification of fungi with evidence of
inflammation
 Culture
 Biomarkers: Galactomannan (Aspergillus)
Serum Beta-D glucan
(Candida)
 PCR
 Stains: India Ink (Cryptococcus)
Periodic Acid Schiff
Gomori methenamine silver
Calcofluor white
 Radiology
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11. 6/28/2017 11Ground glass opacities seen in Pneumocystis carinii

12. Current diagnostics
Infection Culture/
Histo
Biomarker
(Ab)
Biomarker (Ag) Response
to Rx
Aspergillosis Yes -invasive No GM/BDG/PCR Increasing
evidence
Cryptococcosis Routine No Ag/PCR Yes (CSF Ag)
Histoplasmosis Culture -
delay
Limited Ag Yes (Ag)
Mucormycosis Yes -
invasive
No Investigational No
Other moulds Yes –
invasive
No Investigational No
Candidaisis Routine Investigational
(anti-mannan)
PCR/mannan/B
DG
No
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13. Classification of Antifungals
 Antibiotics
Polyene: AmB, Nystatin, Natamycin
Heterocyclic Benzofuran: Griseofulvin
 Azoles
Imidazoles:
Topical (Clotrimazole, Miconazole, Oxiconazole)
Systemic (Ketoconazole)
Triazoles: Fluconazole, Itraconazole, Voriconazole
 Echinocandins: Caspofungin, Anidulafungin, Micafungin
 Antimetabolite: Flucytosine
 Allyamine: Terbinafine
 Other topical agents: Tolnaftate, Undecylenic acid, Benzoic acid,
Butenafine, Ciclopirox olamine6/28/2017 13

14. Mechanism of Action
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15. Urine
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16. Amphotericin B
◦ Broadest spectrum
◦ DOC for mucor, 2nd line agent for candidiasis,
aspergillosis
◦ poorly absorbed from the GI tract
 oral administration: GI luminal infection
◦ IV administration
 poor CSF levels following IV:
 intrathecal drug administration may be required in some cases of
fungal meningitis
 Adverse Effects:
◦ Infusion reaction
◦ Nephrotoxicity
◦ Convulsions (with intrathecal administration)
 Lipid formulations- ABCD, ABLC, liposomal
AMB:
-same efficacy, higher dosages needed
lesser nephrotoxicity & transfusion reactions6/28/2017 16

17. Flucytosine
 penetrates well into body fluid compartments --
including the CSF
◦ Synergism with amphotericin B, azoles
◦ Resistance: rapidly develops and monotherapy
 Adverse Effects: Pancytopenia
◦ Narrow therapeutic window (toxicity of higher levels;
rapid development of resistance at lower, sub-
therapeutic levels)
 not used in monotherapy
-In combination with amphotericin B for:
cryptococcal meningitis
-in combination with a terconazole for:
chromoblastomycosis
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18. Azoles
Fluconazole-
 No effect on aspergillus, Moulds, C. krusei
 Highest penetration into csf, eye and urine
 Primary therapy/step down therapy for susceptible strains
 Adverse effects: fulminant hepatitis, allergic rash, Fatal
cases of Stevens-Johnson syndrome, alopecia
Itraconazole-
 Primarily used for dimorphic fungi, chronic forms of
aspergillus
 use with caution in liver and renal failure,
 Negative ionotropy- cardiac failure, edema, hypokalemia,
hepatotoxic
 Increases concentration of several drugs TDM needed
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19. Voriconazole
Good oral bioavailability, not affected by gastric ph, give on
empty stomach
IV dose- steady state levels within 24 hrs
Crosses BBB, High epithelial lining fluid/ plasma ratio
Eliminated by the liver, modify dose in child A and B- 50%
IV preparation – careful in renal failure – beta cyclodextrin
Dosing based on ideal body wt, individualise dose, children ,
elderly
Adverse effects- rash, hepatic, visual hallucinations, periostitis
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20. Echinocandins
 Primary therapy for invasive candidiasis
 Second line or as part of combination therapy for
aspergillosis
 Do not penetrate CNS, eye and urine, only parenteral
 Effective on biofilms, important to give loading dose
 Infusion reactions, hypokalemia, hemolytic anemia
 No major drug interactions – caspofungin and micafungin
have with tacrolimus, rifampicin and cyclosporin
 Caspofungin dose adjustment in mod –severe hepatic
dysfunction and optimised in obese pts6/28/2017 20

21. Adverse Effects
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22. Guidelines for Treatment
 Early diagnosis of invasive fungal infections
difficult
 Delay in starting antifungal treatment by 6-24 hr
or absence of source control in 48 hrs increase
risk of death
 70% of antifungal treatment in icu is emperical/
preemptive
 Over use of antifungal can lead to resistance
/cost/ mask inf
Prophylaxis Pre emptive
Emperic Definitive
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23. Types of treatment
Risk Factors(+) Risk Factors(+) Risk
Factors(+)
Biomarkers(-) Biomarkers(+) Biomarkers(-)
Clinical Signs(-) Clinical Signs(-)
Clinical Signs(+/-)
Prophylaxis Pre-emptive Empirical
treatment treatment6/28/2017 23

24. 6/28/2017 24In case of suspected

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29. Cryptococcal Meningitis
 Clinical Features: s/s of chronic meningitis (headache, fever,
sensorium deficit, CN paresis, vision deficit and
meningismus)
 Diagnosis:
CSF examination: India ink stain, Mononuclear cells
pleocytosis, increased protein and CRAg detection
Culture: Blood and CSF
 Treatment:
-AmB 0.5-1mg/kg/day + Flucytosine 100mg/kg/day for 6-
10wks OR
-AmB+Flucytosine for 2 wks +Fluconazole 400mg/day for at
least 10 wks
-In HIV infected pts:
Induction phase: AmB 0.7-1mg/kg/day+Flucytosine
100mg/day for 2wks f/b Fluconazole 400mg/day for at least
10 wks
Maintenance: Fluconazole 200mg/day lifelong
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30. Pneumocystis carinii
pneumonia Clinical Features: fever, dry cough, respiratory distress
In immunocompetent pts: shorter duration and s/s begin
after glucocorticoid dose has been tapered
 Diagnosis:
CXR: b/l diffuse infiltrates beginning in perihilar region,
pneumothorax, atypical(nodular densities, cavitary lesions)
HRCT: ground glass opacities at early stage
HPE: Methenamine silver stain, Wright-Giemsa stain,
Immunofluroscent with Monoclonal Ab
PCR
 Treatment:
DOC: TMP-SMX (5mg/kg TMP, 25mg/kg SMX) q6-8hrly
PO/IV
Adjunctive Agents: Prednisone 40mg BD 5 days, 40mg QID
5days, 20mg QID 11 days PO/IV
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31. Summary
 Development of an IFI in increases the morbidity, mortality and
costs of hospitalisation
 Therapies are often started late increasing mortality
 Early diagnosis and appropriate treatment improve outcomes
 Combination of risk factors, clinical features, imaging,
biomarkers and microbiology to be used to identify the patient
with invasive fungal infection and start emperic treatment
 Treatment:
-Candidiasis- echinocandins / azoles
-Invasive aspergillosis- voriconazole/ LAMB
-Mucormycosis- liposomal amphotericin
-Cryptococcal meningitis- AmB+Flucytosine
-Pneumocystis- TMP+SMX
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32. References
 Harrison’s Principles of Internal Medicine, 18th Edition
 Robbins and Cotran Pathologic Basis of Disease, 8th Edition
 Essentials of Medical Pharmacology, K. D Tripathi, 6th Edition
 Textbook of Microbiology, Ananthanarayan and Panikar’s, 8th Edition
 Guidelines for the use of antifungal agents in the treatment of
invasive Candida and mould infections, Monica A. Slavin et al,
Victorian Infectious Diseases Service, Royal Melbourne Hospital
 Lin Y-Y, Shiau S, Fang C-T (2015) Risk Factors for Invasive
Cryptococcus neoformans Diseases: A Case-Control Study PLoS
ONE 10(3): e0119090. doi:10.1371/journal.pone.0119090
 Fungal infections in the ICU, Elizabeth S. Doods Ashley, PSAP-VII,
Critical and Urgent Care
 www.cdc.gov/fungal/diseases
 Antifungal therapy in the ICU: how, when and whom?,Jesus Rico-
Feijoo, ESA
 Invasive Fungal Infections in the ICU: How to Approach,How to
Treat? Elisabeth Paramythiotou
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