MODULE 04: BASIC PATHOLOGIES II
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I. OVERVIEW OF MYCOSES
A. NATURE OF HUMAN FUNGAL INFECTIONS
 More difficult to treat compared to bacterial and viral infections
o Fungi invade when the the body is at its weakest state (i.e.
immunocompromised)
o Fungi have a thicker cell wall
 Have recently increased in incidence, severity, and susceptibility due to
the following:
o Advances in surgery
o Cancer chemotherapy
o Use of broad-spectrum antimicrobials in critically ill patients
o Use of immunosuppressant drugs in transplant patients
o HIV-AIDS epidemics
 May be classified as superficial or systemic
o Systemic fungal infections are typically fatal for immunocompromised
patients
B. THE FUNGAL CELL
 Specific components of the fungal cell are targeted by different antifungal
agents (04.44, 2023)
o Cell Wall
 Targeted by echinocandins
o Cell Membrane
 Targeted by amphotericin B, nystatin, azoles & terbinafine
o Cytoskeleton
 Targeted by griseofulvin
o Nucleus
 Targeted by flucytosine
Table 1. Targets of Antifungal Agents
FUNGAL CELL COMPONENT
Cell Wall (w/ glucans)
Cell Membrane (w/ ergosterol)
Cytoskeleton (w/ microtubules)
Nucleus (with nucleic acids)
ANTIFUNGAL AGENTS
Echinocandins
Amphotericin B, Nystatin
Azoles
Terbinafine
Griseofulvin
Flucytosine
ACTIVE RECALL
1. Antifungal agents target all of the following fungal cell components,
except:
a) Nucleus
b) Mitochondria
c) Cytoskeleton
d) Plasma Membrane
2. True or False. Fungi have a thicker cell wall than gram positive bacteria
ANSWERS: 1B, 2True
Table 2. Overview of Different Organism Responsible for Fungal Infections
CUTANEOUS MYCOSES
Fungus
Disease
Dermatophytes
Dermatophytosis
Malassezia furfur
Tinea Versicolor
Cladosporium
Tinea Nigra
SUBCUTANEOUS MYCOSES
Fungus
Disease
Sporothrix
Sporotrichosis
Cladosporium, etc.
Chromomycosis
(Various)
Mycetoma
SYSTEMIC MYCOSES
Fungus
Disease
Coccidiodes
Coccidioidomycosis
Histoplasma
Histoplasmosis
Cryptococcus
Blastomycosis
Paracoccidiodes
Paracoccidioidomycosis
OPPORTUNISTIC MYCOSES
Fungus
Disease
Candida
Candidiasis
Cryptococcus
Cryptococcosis
Aspergillus
Aspergillosis
Mucor & Rhizopus
Mucormycosis
Pneuomocystis
Pneumonia
II. DRUGS FOR SUBCUTANEOUS AND SYSTEMIC MYCOSES
A. AMPHOTERICIN B
 The “penicillin of antifungal agents” (Cuenca, 2020)
o First line, broad spectrum antifungal used in empiric antimicrobial
therapy
 Remains the drug of choice in most cases despite its potential to be toxic
o It has a tendency to harm host cell cholesterol instead of just fungal cell
ergosterol
o It has a very slow renal excretion, which can lead to nephrotoxicity
 An amphoteric polyene macrolide
o Polyenes are compounds that attack ergosterol molecules
Figure 1. Components of a fungal cell and the targets of antifungal drugs
(Katzung, 14th ed)
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MOA
 Binds to ergosterols in the fungal cell membrane, which leads to:
o Pore formation
 Causing an increased cell permeability
o Leakage of cellular content
 Majorly K+ ions
 Ionophores form complexes with ions and facilitate their transport
across membranes
o And then eventually, fungal cell death
 May be fungistatic or fungicidal, depending on:
o The organism it is targeting
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o The concentration of the drug
 Has a relative specificity
o It usually targets ergosterols in the fungal cell membrane, but it can also
bind to cholesterols in host cell membrane, which may cause harm to
the host
o To counter this potential toxicity, the drug is usually delivered via a
lipid-associated delivery system (liposomal) rather than a colloid
suspension
 Allows the drug to preferentially target fungal cell ergosterols rather
than host cell cholesterols
 Reduces toxicity without sacrificing efficacy
 Allows its contents to be released gradually, which permits the use
of larger doses





o Very important for immunosuppressed and those with severe fungal
infections
Not used for chronic therapy or relapse prevention
Can be taken on its own but it is suggested that it is combined with another
drug to reduce its toxicity
o Usually combined with flucytosine
Empiric therapy for those with high risks of leaving a systemic
fungal infection untreated (e.g. febrile neutropenic cancer patients
on broad spectrum antibiotics)
Intrathecal and local use
o To treat mycotic corneal ulcers and keratitis
Can also be used for as an antiprotozoal agent, specifically for:
o Leishmania braziliensis
o Naegleria fowleri
Adverse Effects
Figure 2. Mechanism of action of Amphotericin B
Pharmacokinetics
Absorption
 Most common route: parenteral
o 90% protein-bound
 Other routes used:
o Oral
 Poor absorption
 Effective only on the fungi along the GIT lumen
o Intrathecal (through spinal canal)
 Adverse effects may happen such as arachnoiditis
o Local
 Topical application
 Immediate (Infusion/IV)
o Fever, chills, muscle spasms, vomiting, headache and hypotension
 Management: slow down infusion, decrease the daily dose, give
premedication
 Premedication: Give other medication prior to starting the
patient on anti-fungal
 e.g. give Acetaminophen first to lessen the effects of fever or
chills before starting Amphotericin B
 Chronic/Cumulative
o Nephrotoxicity (most significant toxic reaction)
 Characterized by renal tubular acidosis and severe K+ and Mg2+
wasting
 Managed with Na+ Loading and adequate hydration
 Dose-dependent and increased toxicity with concurrent therapy,
specially with other nephrotoxic antibacterial agents such as
aminoglycosides
 >3-4g cumulative
o Hepatic dysfunction
o Anemia due to decreased erythropoietin because of damaged renal
tubular cells
o Seizures and chemical arachnoiditis (if given intrathecally)
o Thrombophlebitis
B. FLUCYTOSINE
 Other names: 5-fluorocytosine or 5-FC
 A water-soluble, synthetic, fluorinated cytosine (pyrimidine) analog
o Devoid of anticancer properties, but very potent
 The only antifungal agent that targets the nucleus of fungi
Distribution
 Widely distributed
o A reason for it being the first line antifungal
o Inflammation favors penetration into various body fluids
o However, only 2-3% reaches the CSF (poor distribution)
o Can cross the placenta
Metabolism & Excretion
 Mostly metabolized
 Renal excretion (very slow)
o The reason for it being very nephrotoxic
 Therefore, it is only used in initial treatment (not chronic)
 The goal is to replace with a less toxic drug over time
Antifungal Activity and Clinical Use
 Broadest spectrum of action
 Useful for any life-threatening fungal infections
 Drug of choice for systemic mycoses caused by:
o Candida albicans
o Cryptococcus neoformans
o Histoplasma capsulatum
o Blastomyces dermatitidis
o Coccidioides immitis
o Aspergillus fumigatus
 Initial Induction Regimen Therapy
o Amphotericin B is the first-line treatment when a fungal infection is
suspected based on signs and symptoms
o Replaced after a while to prevent chronic use (nephrotoxicity) or when
the specific fungus is already identified (by culture)
 Usually replaced with azoles
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BASIC PATHOLOGIES II: Lecture Title
MOA
 Inhibits nucleic acid synthesis
o Flucytosine is converted to 5-fluorouracil, which is responsible for
inhibiting DNA & RNA synthesis
 Several enzymes are involved in the action of Flucytosine
o Cytosine permease - rarely found in human cells
 Allows 5-FC to be taken up inside the fungal cell
o Cytosine deaminase – rarely found in human cells
 Allows 5-FC to be deaminated to 5-FU (fluorouracil)
o Ribonucleotide reductase
 Converts 5-FU to 5-FUMP (5-fluorouridine monophosphate)
 5-FUMP can then enter two pathways:
o Interfering in protein synthesis (via RNA inhibition)
 5-FUMP → 5-FUDP (fluorouridine diphosphate) → 5-FUTP
(fluorouridine triphosphate) → leads to a faulty RNA
o Inhibiting thymidylate synthetase
 5-FUMP → 5-FdUMP (fluorodeoxyuridine monophosphate) →
leads to inhibition of thymidylate synthetase
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ACTIVE RECALL
2. 5-FC belongs to which class of substances
a) Folic acid analog
b) Pyrimidine analog
c) Purine analog
d) Cytosol analog
3. True or False. Amphotericin B is generally advised to be taken in
combination with other drugs to reduce its toxic effects
ANSWERS: 1B, 2 True
REVIEW QUESTIONS
Figure 2. Mechanism of action of Flucytosine
Pharmacokinetics
Absorption
 Most common route: oral
 Well-absorbed
o Serum concentrations peak 1-2 hours after oral dose
Distribution
 Widely distributed
o Poorly protein-bound
o Penetrates well into body fluid compartments
o Good CSF penetration
Metabolism & Excretion
 Renal excretion
o Rapid rise in levels may lead to renal impairment
Antifungal Activity and Clinical Use
 Monotherapy
o Rarely used (restricted)
o For select cases of non-life-threatening infections
o Generally not as effective due to resistance
 Combination Therapy
o Flucytosine is known to have a high incidence of primary or
acquired resistance
 To avoid flucytosine resistance, it is usually combined with other
antifungals
o Flucytosine + Itraconazole
 Used to treat chromoblastomycosis
o Flucytosine + Amphotericin B
 Used to treat cryptococcis (cryptococcal meningitis) and candidiasis
 This combination leads to an enhanced penetration through
amphotericin-damaged fungal cell membranes
 Amphotericin B increases cell permeability, thus allowing more
flucytosine to penetrate the cell and affect nucleic acids
1. Amphotericin B is usually taken in a combination therapy. Flucytosine is
commonly used in initial induction regimen therapy.
a) Only Statement 1 is true
b) Only Statement 2 is true
c) Both statements are true
d) Both statements are false
2. Which enzyme is responsible for converting 5-FC to 5-FU
a) Cytosine kinase
b) Cytosine deaminase
c) Cytosine permase
d) Ribonucleotide reductase
3. Amphotericin B is usually delivered via a lipid-associated delivery system
because:
a) It allows the drug to preferentially bind host cell cholesterol
b) It reduces the drug’s toxicity and efficacy
c) It allows its contents to be released gradually, which permits the use of
larger doses
d) All of the above
ANSWERS:
1D, 2B, 3C
EXPLANATIONS:
1. D. Both statements are false – It’s the other way around.
3. C. It allows its contents to be released gradually, which permits the use of
larger doses – A is false because it preferentially binds fungal cell ergosterol.
B is false because it only reduces the drugs toxicity, while allowing its efficacy
to be unchanged.
REFERENCES
REQUIRED


Katzung, 14th ed.
04.44, 2023
Adverse Effects
 Hematologic effects
o Bone marrow suppression with pancytopenia
 Hepatic injury
 Renal failure
 Gastrointestinal distress
o Toxic enterocolitis
o Nausea
o Vomiting
o Diarrhea
 Contraindications:
o Extreme caution in patients with renal impairment
o Pregnancy and breastfeeding
 Has a narrow therapeutic window
o Increased risk for toxicity
o AIDS, Azotemia, increased drug concentrationsLess toxic than
amphotericin B
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