ANTIFUNGAL

Dr Siti Maisharah Sheikh Ghadzi

School of Pharmaceutical Sciences
Universiti Sains Malaysia
Email: maisharah@usm.my
Learning Outcomes

1 2 3 4
Identify the risk Explain the diagnosis Compare the available Discuss the most
factors of invasive of fungal infection antifungal drugs common fungal
fungal infections • Spectrum of activity infections
• PKPD
• Side effects
Risk factors of Fungal Infection

central venous broad-spectrum extensive surgical

fungal colonization
catheters antibiotic use procedures

neutropenia or immunosuppression
neutrophil dysfunction (e.g., premature
TPN
(commonly in cancer infants, burn patients
patient) and patients with AIDS)
Diagnostic tests for
fungal infection
• definitive or microbiologically confirmed
diagnosis
• presumptive diagnosis (high probability)
Diagnostic tests for
fungal infection
• Tests to diagnose and monitor therapeutic
responses
a. Direct examination of the specimen :
Histologic examination of biopsy specimens
• Visualise the fungal form
b. Culture : most definitive method for
diagnosing or monitoring a fungal infection
• Specimens inoculated onto several
different types of fungal media
Diagnostic tests for fungal infection cont..

Antigen detection Antibody detection

• Fungi synthesize polysaccharides that • Detection of antibody can be useful for

cannot be broken down by human some fungal diseases but not for others
enzymatic systems.
• These polysaccharides can accumulate
within the body and be excreted in the
urine.
• These fungal antigens can be detected
by using antibodies that specifically
recognize a particular species of fungus,
thereby providing a diagnosis.
 Classification
of Fungi

What Are Fungal Infections? - Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Classification-of-
Fungi_fig2_51177380 [accessed 25 Mar, 2020]
Types of fungal infections
Common types of Invasive fungal infections

Candidiasis

Aspergillosis

Opportunistic infection in immunocompromised

Endemic mycosis
10
Antifungal
Agents
Azoles comparison
• Azole:
• Imidazoles
• Clotrimazole
• Ketoconazole
• Miconazole
• Triazoles
• Fluconazole
• Itraconazole
• Terconazole
• voriconazole
• posaconazole
https://www.uspharmacist.com/article/the-fungus-among-us-an-antifungal-review
https://www.uspharmacist.com/article/the-fungus-among-us-an-antifungal-review
Imidazole
Fluconazole
Itraconazole
Voriconazole
Voriconazole- side effects
Voriconazole- side effects
Posaconazole
Polyenes
Amphotericin B
Amphotericin B

• nephrotoxicity, hematologic toxicity, and infusion-related reactions

• reducing adverse events
• Premedication with acetaminophen and heparin are common measures
taken to prevent infusion-related reactions such as fever, headache, and
thrombophlebitis
• normal saline before the initiation of therapy can decrease drug-induced
nephrotoxicity
• avoiding other nephrotoxins
• switching to other formulations of amphotericin
• correcting electrolyte abnormalities such as hypokalaemia and
hypomagnesemia
Nystatin
Terbinafine
Echinocandins
Echinocandins
https://www.uspharmacist.com/article/the-fungus-among-us-an-antifungal-review
Micafungin
Anidulafungin
Indication of antifungal
therapy
Based on spectrum of activity
Nett JE, Andes DR. Antifungal Agents: Spectrum of
Activity, Pharmacology, and Clinical Indications. Infect
Dis Clin North Am [Internet]. 2016;30(1):51–83.
Available from:
http://dx.doi.org/10.1016/j.idc.2015.10.012

32
PKPD of
antifungal
agents
 ECHINOCAND
IN
POLYENES
AZOLES AZOLES
POLYENES

PYRAMIDINE
ANALOG

POLYENES

ECHINOCANDI
N

AZOLES
Pharmacist’s monitoring plan
Efficacy, safety and interaction

36
Parameters to monitor the efficacy of
antifungal therapy
• Temperature
• WBC
• ESR
• C-reactive protein
• Blood culture
• Others

37
Parameters to monitor the safety of
antifungal therapy
• Determine significant side effects of antifungal agents
• e.g., monitor renal function – calculate CrCL to monitor
incidence of nephrotoxicity secondary to amphotericin B
• e.g., monitor liver function - monitor AST, ALT and other
biomarkers of liver function e.g., globulin to ensure no incidence
of liver impairment secondary to fluconazole

38
Parameters to monitor the interaction of
antifungal therapy
• More focus on the CYP enzyme inducers or inhibitors
• Determine the parameters indicate the effect of drug-drug
interaction
• Antifungal that require active medication review
• Fluconazole
• voriconazole

39
Management of antifungal side effect

40
Managing Infusion-Related Toxicity of
Amphotericin B
• manifested by fever, chills, muscle spasms, vomiting, headache, and
hypotension
• ameliorated by slowing the infusion rate or decreasing the daily dose
• premedication with antipyretics, antihistamines, meperidine, or
corticosteroids
• test dose of 1 mg intravenously to gauge the severity of the reaction
• serve as a guide to an initial dosing regimen and premedication strategy

41
Nephrotoxicity secondary to Amphotericin B
• Most significant delayed toxicity
• The irreversible form of nephrotoxicity usually occurs in the setting of
prolonged administration (> 4 g cumulative dose).
• Renal toxicity commonly presents with renal tubular acidosis and severe
potassium and magnesium wasting
• Sodium loading
• blunt the vasoconstriction and tubular-glomerular feedback
• Administration of 500 ml -1000 ml of NaCl before and after amphotericin B
infusion

42
Candidiasis
Candidiasis

most common Candidemia and

major causes of
healthcare-associated invasive candidiasis:
morbidity and
bloodstream infections Focus of attention in
mortality
in US hospitals clinical trials

no single trial has

demonstrated clear
superiority of one
therapeutic agent over
another.
 Albicans

Glabrata

Candida spp. Tropicalis

Parapsilosis

Krusei
 Candidemia Candidiasis

• non-neutropenic • Intraabdominal
patients • Osteoarticular
• neutropenic patients • CNS
• UTI
Candidiasis - • Vulvovaginal
Types • Oropharyngeal
• Oesophageal
• Chronic disseminated
• Intravascular e.g.
endocarditis
• Endophthalmitis
 1. High mortality
• Earlier therapy a/w better overall outcomes
Challenges in • Significant limitation to early diagnosis

candidemia • Rapid diagnostic assays- slow development

• Continue rely on cultures to establish diagnosis
and invasive 2. High variability across geograpci location, unit of
the species causing candidemia- challenges in
candidiasis virulence, pathogenicity, susceptibility

therapy 3. No single clinical trials demonstrated the clear

superiority of one therapeutic agent over another
4. Emergence of MDR candida spp
 • History of azole and echinocandin exposure
• Hx of intolerance to antifungal agent
Selection of • Dominant Candida spp
therapy – • Current susceptibility and resistant test
history • Severity of illness
• Co morbidities
taking • Evidence of CNS, cardiac valves and visceral
organ involvement
Aspergillosis
Aspergillus spp.

• Aspergillus : ubiquitous mold that grows well on a variety of substrates, including

soil, water, decaying vegetation, moldy hay or straw, and organic debris.
• > 300 species of Aspergillus - three species are most commonly pathogenic:
Aspergillus fumigatus, Aspergillus flavus, and Aspergillus niger.
• The varying degrees of pathogenicity of each species depend on their relative
geographic prevalence, conidial size and shape, thermotolerance, and production of
mycotoxins.
• E.g transport of A. fumigatus conidia into the lungs is facilitated by their smaller
diameter in comparison with A. flavus and A. niger.
Aspergillosis

• A spectrum of diseases attributed to allergy, colonization, or tissue invasion

caused by members of the fungal genus Aspergillus.
• acquired by inhalation of airborne conidia
• sinopulmonary disease the most frequent clinical manifestation
• The use of high-efficiency particulate air (HEPA) filters in operating rooms
and laminar flow rooms and removal of immunocompromised patients from
hospital renovation sites can be helpful in preventing infection in this
population.
Types of Aspergillosis

chronic (and Allergic forms of

invasive
saprophytic) forms aspergillosis
aspergillosis
of aspergillosis (ABPA)
Invasive Aspergillosis

• Phagocytes (neutrophils, monocytes, and macrophages) rather than

antibodies or lymphocytes constitute the primary host defense system against
invasive disease with aspergillosis.
• Prolonged neutropenia appears to be the most important predisposing factor
to the development of invasive aspergillosis, accounting for the high
frequency of disease in patients with acute leukemia.
Invasive Aspergillosis

• Predisposing factors:
• glucocorticoid therapy, particularly following chronic administration or with
higher dosages (30 to 200 mg/day of prednisone),
• cytotoxic agents,
• recent or concurrent therapy with broad-spectrum antimicrobial agents,
• chronic hepatitis, alcoholism,
• diabetes mellitus, chronic granulomatous disease, leukopenia (<1000
cells/mm3), leukemia (particularly acute lymphocytic or myelogenous leukemia),
• lymphoma, and acute rejection of an organ transplant.
Invasive Aspergillosis

• AIDS patients may be at less risk for aspergillosis than other fungal infections
because the primary cellular defect in AIDS patients is in the T-lymphocytes,
whereas neutrophils and macrophages constitute the primary lines of defense
to infection with aspergillosis.
• Aspergillosis was reported as a late complication of disease in AIDS patients
Types of invasive Aspergillosis

invasive
Aspergillus disseminated
pulmonary
sinusitis aspergillosis
aspergillosis (IPA)
Invasive Aspergillosis: treatment

• Triazoles are preferred agents for treatment and prevention of IA in most

patients -Voriconazole
• For patients receiving triazole-based therapy for IA, prolonged azole
prophylaxis, or other therapies for which drug interactions with azoles are
anticipated-TDM is recommended after steady state achieved
Invasive Aspergillosis: treatment

• AmB deoxycholate and its lipid derivatives are appropriate options for initial
and salvage therapy of Aspergillus infections when voriconazole cannot be
administered.
• AmB deoxycholate should be reserved for use in resource limited settings in
which no alternative agents are available.
• Lipid formulations of AmB should be considered in settings in which azoles
are contraindicated or not tolerated
• Aerosolized formulations of AmB may be considered as prophylaxis in patients
with prolonged neutropenia
Invasive Aspergillosis: treatment

• Echinocandins are effective in salvage therapy (either alone or in combination)

against IA
• routine use as monotherapy for the primary treatment of IA is NOT RECOMMENDED
• treatment of IPA be continued for a minimum of 6–12 weeks
• largely dependent on the degree and duration of immunosuppression, site of disease,
and evidence of disease improvement
• For patients with successfully treated IPA who require subsequent
immunosuppression, secondary prophylaxis should be initiated to prevent recurrence
Opportunistic infection
in Cryptococcal Disease

immunocompromised
OI in immunocompromised:
Cryptococcal Disease

• Cryptococcal meningoencephalitis – common manifestation

• 3 risk groups:
• HIV infected individuals
• Organ transplant recipients
• Non-HIV-infected and non transplant hosts
Cryptococcal meningoencephalitis in
HIV-Infected Individuals

• Primary therapy: induction and consolidation

• Amphotericin B (AmB) deoxycholate (AmBd; 0.7–1.0 mg/kg per day
intravenously [IV]) plus flucytosine (100 mg/kg per day orally in 4 divided
doses for at least 2 weeks
• followed by fluconazole (400 mg [6 mg/kg] per day orally) for a minimum
of 8 weeks
Cryptococcal meningoencephalitis in
HIV-Infected Individuals

• Primary therapy: induction and consolidation

• Alternative:
• AmBd (0.7 mg/kg per day IV) plus fluconazole (800 mg per day orally) for 2 weeks
followed by fluconazole (800 mg per day orally) for a minimum of 8 weeks
• Fluconazole (800 mg per day orally; 1200 mg per day is favored) plus flucytosine
(100 mg/kg per day orally) for 6 weeks
• Fluconazole (800–2000 mg per day orally) for 10–12 weeks; a dosage of 1200 mg
per day is encouraged if fluconazole alone is used
• Itraconazole (200 mg twice per day orally) for 10–12 weeks
Cryptococcal meningoencephalitis in
HIV-Infected Individuals

• Maintenance (suppressive) and prophylactic therapy

• Fluconazole (200 mg per day orally)
• Itraconazole (200 mg twice per day orally; drug-level monitoring
strongly advised)
Cryptococcal meningoencephalitis in non
HIV-Infected. Non-transplant Individuals

• AmBd (0.7–1.0 mg/kg per day IV) plus flucytosine (100 mg/kg per day
orally in 4 divided doses) for at least 4 weeks for induction therapy
 • Comparing antifungal agents based on
• Spectrum of activity
• Efficacy – fungicidal effect
CONCLUSION • Monotherapy vs combination
• Duration of therapy
Selection of • Individualization therapy

antifungal • Special population

• Immunocompromised vs compromised
therapy • Paediatric vs geriatric
• Pregnant women
• PKPD – distribution to the infection site
• Interaction
THANK YOU