THE SCHOOL OF SCIENCE, ENGINEERING, AND HEALTH

DEPARTMENT OF SCIENCE & ENGINEERING

BMS 304: MEDICAL MYCOLOGY JANUARY 2023

GROUP B

1. CHRISTELLE OUEDRAOGO 21-0607

2. LOUISE OMONDI 21-0436
3. STACY WANGANGA 20-1335
4. JEDD ARAP NGENO 21-0264

ASSIGNMENT ON ANTIFUNGAL DRUGS

SUBMITTED TO

DR MONICA OPIYO

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ANTIFUNGAL DRUGS

1. AMPHOTERICIN B

It is an antifungal drug with the ability to treat a wide range of fungal infections especially
the severe, life threatening and invasive fungal infections such as Cryptococcus, aspergillus
and candida. It is a polyene macrolide antibiotic. It has poor absorption thus mostly opted to
be administered intravenously. As a result of the adverse effects that are caused by
conventional amphotericin B several lipid formulations have been developed so as to
minimize the adverse effects.

Mechanism of action

Amphotericin B works by binding itself through ion channels onto the ergosterol which is a
sterol that is found on the membrane of the fungal cell. The ergosterol regulates the fluidity
of the fungal cell and also regulates how permeable the fungal cell is. When amphotericin
binds to the ergosterol it causes the intracellular components of the fungal cell to leak out
leading to fungal cell death.

Amphotericin B to some extent also possesses the ability to bind to cholesterol which is a key
component in numerous mammalian cells. Fungal cells contain more cholesterol than
mammalian cells thus the toxicity caused by amphotericin b to mammalian cells is lower than
the toxicity to fungal cells.

There are several available formulations of amphotericin B

 Intravenous formulation: Amphotericin B is by itself insoluble in pH 7 normal

saline. Thus, formulations have been developed so as to improve the bioavailability.

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  deoxy=cholate formulation: This formulation uses sodium deoxy chocolate so as to
improve the solubility of amphotericin b when it is administered intravenously.
 Liposomal formulation. So, as to make amphotericin b more tolerable and reduce its
toxicity, lipid formulations were developed. This makes this formulation more
expensive than conventional amphotericin b.
 Lipid complex formulations: This is a formulation made by mixing amphotericin b
with two lipids in a 1:1 ratio so as to form a ribbon-like structure.
 Oral amphotericin b: This formulation is not widely available due to its low
solubility and its low bioavailability. Thus, when dealing with throat fungal infections
other drugs such as nystatin and fluconazole are preferred.

Distribution of Amphotericin B in the body.

After it is administered intravenously, it is distributed widely in the body so as to reach the

paces of infection. The concentration of amphotericin b may vary in different organs and
tissues of the body. It may accumulate in different organs in the body which leads to higher
concentrations of the drug and a longer exposure to the drug. In a case such as invasive
pulmonary aspergillosis, amphotericin b

accumulates in the lung tissue and is able to penetrate the fungal biofilm thus treating the
infection. Amphotericin b may penetrate the blood brain barrier and accumulate in the
cerebrospinal fluid thus able to tread CNS fungal infections such as cryptococcal meningitis.

Amphotericin B is actively removed from the body primarily through the kidneys in urine,
but some small amounts may be removed through the faeces. The elimination half-life of
amphotericin b is relatively long ranging from several days to weeks depending on - the
patients kidney function competence. This relatively long half-life of amphotericin b allows
for less frequent dosing e.g.. once daily.

It is important to monitor the patients that are taking amphotericin b so as to look out for any
potential adverse effects which may occur due to drug distributions in the body which are not
being eliminated.

Spectrum of activity of amphotericin b

It has a wide range of action against numerous finals such as-candidiasis, cryptococcosis,
histoplasmosis, blastomycosis, Para coccidioidomycosis, coccidioidomycosis, aspergillosis,

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extracutaneous sporotrichosis and mucormycosis, and some cases of hyalohyphomycosis and
phaeohyphomycosis. Some species such as candida species may develop a resistance to the
drug during the course of treatment.

Drug interactions combination therapy

 Azole antifungal drugs

 Medications that affect the kidney
 Anti-cancer drugs

The toxicity of amphoteric B may be minimized by reducing the dose and using combination
therapy with other antifungals to expose synergy of drugs to treat the fungal infection.

Routes of administration.

 Oral
 Intravenous

Adverse reactions of intravenously infused Amphotericin B.

 Fever
 Chills
 Headache
 Hypotension.
 Increased urination
 Irregular heartbeat
 Nausea
 Muscle cramps
 weakness
 Vomiting.

With spinally injected amphotericin B

 Blurred or double vision

 convulsions (seizures)
 numbness, tingling, pain, or weakness in hands or feet

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  shortness of breath, troubled breathing, wheezing, or tightness in chest
 skin rash or itching
 sore throat and fever
 unusual bleeding or bruising

Adverse reactions of conventional Amphotericin B

 Infusion related reactions-mediated by cytokine release from monocytes such as

Electrolyte disturbances in the host body
 Hypokalemia this is where there is dangerously low levels of potassium in the body
 Nephrotoxicity-This is kidney damage that is characterized by a decrease in the rate
of glomerular filtration, a decrease in the renal plasma flow and a decrease in the rate
of creatinine removal or clearance.

2. FLUCYTOSINE

Flucytosine, also known as 5-fluorocytosine (5-FC), is an antifungal medication that fights

infections caused by fungus. It is used to treat serious fungal infections of the blood, lungs,
heart, central nervous system, and urinary tract. Flucytosine is sometimes given with another
medicine called amphotericin B for serious Candida infections and cryptococcosis.

Mechanism of Action

Antimycotic activity of 5-FC results from is rapid conversion into 5-fluorouracil (5-FU) by
the enzyme cytosine deaminase, within susceptible cells. There are two mechanisms involved
by which 5-fluorouracil exerts its antifungal activity.

• The first mechanism includes the conversion of 5-fluorouracil through 5-fluorouridine

monophosphate (FUMP) and 5-fluorouridine diphosphate (FUDP) into 5-fluorouridine
triphosphate (FUTP). FUTP is further incorporated into fungal RNA in place of uridylic acid,

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this alters the amino acylation of tRNA, disturbs the amino acid pool and inhibits protein
synthesis.

• The second mechanism is the metabolism of 5-FU into 5-fluorodeoxyuridine

monophosphate (FdUMP) by uridine monophosphate pyro phosphorylase. FdUMP is a potent
inhibitor of thymidylate synthase, which is a key enzyme involved in DNA synthesis and
nuclear division. Thus, 5-FC acts by interfering with pyrimidine metabolism and protein
synthesis in the fungal cell. These activity result in cell lysis and death.

Spectrum of antifungal activity

Flucytosine is most active against yeasts, including Candida, Torulopsis and Cryptococcus
spp., and against the dematiaceous fungi causing chromomycosis (Phialophora and
Cladosporium spp.) and Aspergillus spp. The mode of action of 5-FC and the essential role
of cytosine deaminase have been proven in Saccharomyces cerevisiae and C. albicans and are
probably also valid for other sensitive fungi. However, specific research in this field is
lacking.

Adverse effects

The adverse reactions which have occurred during treatment with flucytosine are grouped
according to organ system affected.

 Cardiovascular: Cardiac arrest, myocardial toxicity, ventricular dysfunction.

 Respiratory: Respiratory arrest, chest pain, dyspnea.
 Dermatologic: Rash, pruritus, urticaria, photosensitivity.
 Gastrointestinal: Nausea, emesis, abdominal pain, diarrhea, anorexia, dry mouth,
duodenal ulcer, gastrointestinal hemorrhage, acute hepatic injury including hepatic
necrosis with possible fatal outcome in debilitated patients, hepatic dysfunction,
jaundice, ulcerative colitis, enterocolitis, bilirubin elevation, increased hepatic
enzymes.
 Genitourinary: Azotemia, creatinine and BUN elevation, crystalluria, renal failure.
 Hematologic: Anemia, agranulocytosis, aplastic anemia, eosinophilia, leukopenia,
pancytopenia, thrombocytopenia, and fatal cases of bone marrow aplasia.

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  Neurologic: Ataxia, hearing loss, headache, paresthesia, parkinsonism, peripheral
neuropathy, pyrexia, vertigo, sedation, convulsions.
 Psychiatric: Confusion, hallucinations, psychosis.
 Miscellaneous: Fatigue, hypoglycemia, hypokalemia, weakness, allergic reactions,
Lyell's syndrome.

Drug interactions

Cytosine arabinoside, a cytostatic agent, has been reported to inactivate the antifungal activity
of flucytosine by competitive inhibition. Drugs which impair glomerular filtration may
prolong the biological half-life of flucytosine.

Flucytosine has serious interactions with the following drugs:

 bacitracin
 deferiprone
 ropeginterferon alfa 2b
 Saccharomyces boulardii

Flucytosine has moderate interactions with the following drugs:

 dichlorphenami
 hydroxyurea
 ifosfamide
 lomustine
 peramivir
 tenofovir DF
 tobramycin inhaled
 voclosporin

Flucytosine has minor interactions with the following drugs:

 amphotericin B deoxycholate
 fluconazole
 ganciclovir
 itraconazole
 valganciclovir

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  zidovudine

Flucytosine has minor interactions with the following drugs:

 amphotericin B deoxycholate
 fluconazole
 ganciclovir
 itraconazole
 valganciclovir
 zidovudine

Dosage

 The current standard daily dose of flucytosine is 100 mg/kg daily given in four
divided doses in persons with normal renal function. Doses ranging between 50 and
150 mg/kg daily have been utilized successfully among patients with established
fungal infection, but the 150 mg/kg daily dose is often associated with serious side
effects
 Induction phase with liposomal amphotericin B (3 mg/kg/day) and flucytosine
(100 mg/kg/ day in four divided doses) for at least 2 weeks and up to 6 weeks
depending on host and clinical/mycological response to therapy.
 Consolidation phase with fluconazole (400– 800 mg/day) for 8–10 weeks. We and
others suggest using fluconazole (FCZ) at a dose of 800 mg/day in non-HIV patients
and in HIV patients until cART introduction.
 A maintenance phase is indicated and depends on host immunity. Maintenance phase
should begin after microbiological assessment in CSF at week 10. A minimum of 6–
12 months of FCZ (200–400 mg/day) is required.

Distribution of the disease

• Cryptococcus neoformans is a fungus that lives in the environment throughout the world.
People can become infected with C. neoformans after breathing in the microscopic fungus,
although most people who are exposed to the fungus never get sick from it.

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• Infection with the fungus Cryptococcus (either C. neoformans or C. gattii) is called
cryptococcosis. Cryptococcosis usually affects the lungs or the central nervous system (the
brain and spinal cord), but it can also affect other parts of the body. Brain infections due to
the fungus Cryptococcus are called cryptococcal meningitis.

• C. neoformans infections are rare in people who are otherwise healthy. Most cases of C.
neoformans infection occur in people who have weakened immune systems, particularly
those who have advanced HIV/AIDS

3. NYSTATIN

Nystatin is an antifugal medication of bacterial origin. It was isolated from Streptomyces

noursei in 1950 by Elizabeth Lee Hazen and Rachel Fuller Brown, who were doing research
for the Division of Laboratories and Research of the New York State Department of Health.

Mechanism of action

Nystatin acts by binding to sterols in the plasma membranes of fungi causing the cells to
leak, eventually leading to fungal cell death. Nystatin is a channel-forming ionophore, which
means it works by creating a membrane-spanning pore in the fungus plasma membrane.The
creation of this hole changes the permeability of the membrane, allowing for the escape of
intracellular contents and the consequent disturbance of electrochemical gradients required
for normal cell function. 8,2 The preference for fungal cells over mammalian cells is due to
nystatin's higher binding affinity for ergosterol, a crucial sterol present in fungi cell walls, as
opposed to cholesterol, its mammalian equivalent.

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Spectrum of activity

Nystatin has a spectrum of activity slightly narrower than that of other antifungals but is
nevertheless active against a number of species of Candida, Histoplasma, Cryptococcus,
Blastomyces, and the dermatophytes Epidermophyton, Trichophyton, and Microsporum.

Distribution in body

Nystatin is not absorbed into the systemic circulation and thus does not undergo distribution.
Since nystatin is not absorbed into the systemic circulation it is therefore not subject to
plasma protein binding. Because nystatin undergoes little-to-no systemic absorption it is not
metabolized to any appreciable extent.

Adverse effects

 diarrhea
 nausea
 stomach bloating or pain
 irritation or burning of the mouth.
 hives
 rash or itching
 difficulty breathing or swallowing

Drug combinations

Nystatin can be combined with a number of other antifungal drugs in order to treat a wide
array of fungal infections without displacing any negative interactions.

Routes of administration

This medicine is to be taken by mouth even if it comes in a dropper bottle. If it does come in
a dropper bottle, use the specially marked dropper to measure each dose accurately. Take this
medicine by placing one-half of the dose in each side of your mouth.

4. AZOLES

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Azoles are a class of five-membered heterocyclic compounds containing a nitrogen atom and
at least one other non-carbon atom as part of the ring. Their names originate from the
Hantzsch–Widman nomenclature. The first report on the antifungal activity of an azole
compound was presented by Woolley in 1944 a ground breaking discovery that declared the
antimycotic effect of benzimidazole moiety for the first time

Mechanism of action

The azoles exert their main antifungal action by inhibiting a fungus cytochrome P-450
enzyme involved in the synthesis of ergosterol, the predominant sterol in the fungal cell
membrane. On a molecular level, binding of the free azole nitrogen with the heme moiety of
fungal C-14a demethylase blocks lanosterol demethylation, denying the cell of ergosterol and
permitting the buildup of different 14a methylsterols. Therefore, the usual structure and
function of the cell membrane are disrupted, eventually inhibiting cell development and
morphogenesis. At therapeutically attainable concentrations, azoles are widely known as
fungistatic agents. Recent in vitro experiments with itraconazole and voriconazole, on the
other hand, showed fungicidal action against conidial suspensions of Aspergillus fumigatus
and several other Aspergillus species at concentrations lower than those obtained with
suggested doses.

Spectrum of activity

As a class, azoles have a wide range of action against most fungal pathogens involved with
systemic infections. Among the Candida species, medications are most efficacious against C.
albicans, C. parapsilosis, C. tropicalis, C. lusitaniae, and sC. dubliniensis. Triazoles, except
for voriconazole, are usually ineffective against C. krusei. Although fluconazole has been
shown to be active against some species of C. glabrata, MICs are greater, and tolerance is
prevalent. Few C. glabrata isolates that have developed fluconazole tolerance are still
vulnerable to second-generation triazoles.

Distribution in body

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Flucytosine and azoles penetrate into most of relevant tissues. It accumulates in the liver and
in the spleen. Its concentrations in lung and kidney are intermediate and relatively low
myocardium and brain. Tissue distribution of echinocandins is similar to that of
amphotericin.

Adverse effects

The most common patient complaints about azole drugs are directed at the GI tract and
consist primarily of anorexia, nausea, vomiting, diarrhea, and abdominal pain. These side
effects appear most common with Itraconazole.

Another shared adverse effect is the potential of antifungal azoles to cause disturbances in
hepatic function. All available azoles may reversibly increase transaminase levels; therefore,
baseline and periodic monitoring of hepatic enzymes is warranted in any patient receiving an
azole for more than a few days.

Drug combinations

Co-administration of drugs such as phenytoin, phenobarbital, carbamazepine, rifampicin,

isoniazid, ritonavir, efavirenz, and others can induce the metabolism of azole antifungals.
This in turn can result in failure of antifungal treatment.

Routes of administration

 Eye drops
 intraocular injections
 ointments
 impregnated bone cement
 endobronchial
 intrathecal administration.

5. TERBINAFINE

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Terbinafine (TRB) is an allylamine anti-fungal agent that has been available for more than a
decade. It is now used for the treatment of dermatophytic infections and onychomycosis.
Despite several studies having demonstrated the efficacy of terbinafine against
nondermatophytic infections including azalea-resistant candidiasis, invasive aspergillosis,
disseminated fusariosis and scedosporiosis, the role of TRB in the management of these
infections remains greatly underappreciated. A brief review of pharmacodynamic,
pharmacokinetic, in vitro and in vivo data and published case reports provides insight into the
use of terbinafine as a potential adjunct in combination with azoles, polyenes or
echinocandins in the management of severe drug-resistant or refractory mycoses. Despite the
lack of intrinsic fungicidal activity against several nondermatophytes, when used in
combination, particularly with azoles, TRB has demonstrated good anti-fungal efficacy that
could be exploited in clinical practice. As comprehensive human clinical studies are not
feasible with the rare occurrence of these mycoses, experiments using animal models are
essential to evaluate the in vivo efficacy of drug combinations. In summary, terbinafine has
established itself as a drug of choice for dermatophytic infections; it must be considered in
combination with other anti-fungal agents for the management of nondermatophytic
refractory or resistant yeast/mold infections as well.

Mechanism of action.

Terbinafine inhibits the enzyme squalene monooxygenase (also called squalene epoxidase),
preventing the conversion of squalene to 2,3-oxydosqualene, a step in the synthesis of
ergosterol. This inhibition leads to decreased ergosterol, which would normally be
incorporated into the cell wall, and accumulation of squalene.

Generation of a large number of squalene containing vesicles in the cytoplasm may leach
other lipids away from, and further weaken, the cell wall. Terbinafine interferes specifically
with fungal sterol biosynthesis at an early stage. This leads to a deficiency in ergosterol and

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to an intracellular accumulation of squalene, resulting in fungal cell death. Terbinafine acts
by inhibition of squalene epoxidase in the fungal cell membrane.

Interactions with other drugs

Some products that may interact with this drug include: warfarin, drugs affecting liver
enzymes that remove terbinafine from your body (such as amiodarone, cimetidine, rifampin,
azole antifungals such as fluconazole/ketoconazole), drugs removed from your body by
certain liver enzymes (such as tricyclic antidepressants,

Dosage

The dose of this medicine will be different for different patients.

Usual Adult Dose for Onychomycosis - Fingernail

Tablets: 250 mg orally once a day

Duration of therapy:

Fingernail onychomycosis: 6 weeks

Toenail onychomycosis: 12 weeks

6. ECHINOCANDINS

Echinocandins are large lipopeptide compounds that block beta-(1,3)-glucan synthesis,

causing fungus cell walls to be damaged. Echinocandins are quickly fungicidal against most
Candida spp. and fungistatic against Aspergillus spp. in vitro and in vivo. The family has

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been named the "penicillin of antifungals," along with the related papulacandins, because
their mode of action in microbes is similar to that of penicillin -glucans are carbohydrate
polymers that are cross-linked with other fungus cell wall components; they are the fungi
counterpart of peptidoglycan in bacteria. Because of their solubility, antifungal spectrum, and
pharmacokinetic characteristics, caspofungin, micafungin, and anidulafungin are
semisynthetic echinocandin compounds with restricted therapeutic use.

Mechanism of action

The echinocandins have a unique mechanism of action, inhibiting beta-(1,3)-D-glucan

synthase, an enzyme that is necessary for the synthesis of an essential component of the cell
wall of several fungi. The echinocandins display fungistatic activity against Aspergillus
spp.The echinocandins act as non competitive inhibitors of β - (1, 3) - D-glucan synthase, an
essential component of the fungal cell wall that is not present in mammals. Inability of the
organism to synthesize β - (1, 3) - D-glucan leads to osmotic instability and cell death.

Drug Interaction

At clinically relevant concentrations, anidulafungin is not a clinically significant substrate,

inducer, or inhibitor of key human cytochrome P450 isoforms, nor is it an inhibitor of P-
glycoprotein. Formal interaction tests showed that when anidulafungin is co-administered
with cyclosporine A, tacrolimus, voriconazole, liposomal amphotericin B, or rifampin, no
dose modification of either medication is required. There was no indication that the presence
of rifampin or metabolic substrates, inhibitors, or inducers of cytochrome p450 affected
anidulafungin clearance in a big population-based pharmacokinetic study.

Side Effects

Infusion related reactions (facial flushing, swelling, rash, pruritis, and fever) have been
reported with all the echinocandins. They usually occur immediately after infusion and
respond well to antihistamines. The drug need not be withdrawn but the rate of infusion
should be decreased. Thrombophlebits may occur with all the three drugs. Overall, the
infusion-related events seem to be much fewer than those due to amphotericin

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B.Derangement of hepatic transaminases has been observed in almost all the studies of
adverse events of the echinocandins.Liver function should be monitored, especially in case of
caspofungin. However, the gross disturbance in creatinine clearance, as observed with
amphotericin B, is not seen and these drugs are probably safer than amphotericin B in case of
renal impairment. Overall, the tolerability profile of echinocandins seems to be comparable to
that of fluconazole and better than that of amphotericin B.

Spectrum of activity

Fungicidal activity against Candida species and fungistatic activity against Aspergillus
species is demonstrated by echinocandins. Most isolates of Candida species, including those
that are amphotericin B-resistant or fluconazole- and itraconazole-resistant, appear to have
adequate antifungal action in vitro for anidulafungin, caspofungin, and micafungin. The
echinocandins have less action against Candida parapsilosis and Candida guilliermondii, as
well as no activity against fungus with no -glucan in their cell walls, such as Cryptococcus
neoformans, Trichosporon species, and Zygomycetes organisms. Echinocandin doses
currently suggested show little or no action against dimorphic fungi. The susceptibility of
Fusarium and Scedosporium species to echinocandins in vitro varies greatly between species.

Dosage And Administration

Echinocandins are only available as intravenous preparations due to their large molecular
structure and poor bioavailability.

Caspofungin is available in vials containing 50 or 70 mg of caspofungin acetate as a sterile,

lyophilized powder, which should be reconstituted with 0.9% sodium chloride injection,
sterile water for injection, bacteriostatic water for injection with methylparaben and
propylparaben, or bacteriostatic water for injection with 0.9% benzyl alcohol.

The reconstituted solution should then be added to an i.v. bag containing 250 mL of 0.9%,
0.45%, or 0.225% sodium chloride injection or lactated Ringer's injection. This infusion
solution must be used within 24 hours if stored at 77°F or below and within 48 hours if stored
at 36- 46°F. The diluted solution should be infused over approximately 1 hour.

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REFERENCES

 Kauffman, C. A., Pappas, P. G., Sobel, J. D., & Dismukes, W. E. (2011). Essentials of
Clinical Mycology. Springer Science & Business Media.
 Presterl, E. (2018). Clinically Relevant Mycoses : a Practical Approach.
 Lemke, A., Kiderlen, A. F., & Kayser, O. (2005). Amphotericin b. Applied
microbiology and biotechnology, 68, 151-162.
 Gallis, H. A., Drew, R. H., & Pickard, W. W. (1990). Amphotericin B: 30 years of
clinical experience. Reviews of infectious diseases, 12(2), 308-329.
 Chandra, J., Mohammad, S., Ghannoum, M.A. (2009). Flucytosine: Site of Action,
Mechanism of Resistance and Use in Combination Therapy. In: Mayers, D.L. (eds)
Antimicrobial Drug Resistance. Infectious Disease. Humana Press.
 Echinocandins in the Management of Invasive Fungal Infections, Part 1. (n.d.).
Medscape.

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