Antifungals

• Fungi have been found on: Mucosal surfaces in the body, Skin

• Exist in varying amounts - Some fungi (eg candida

albicans) reside in the human

gut & form part of their normal

flora.

• Others eg yeasts (eg

malassezzia species) help

consume or degrade various

oils produced by our sebaceous

glands.

human mycobiata

• can spread to other parts of the body

• can be superficial (mucocutaneous) – the most common

• Subcutaneous

• Systemic

• incidence of life-threatening fungal infections has increased because there are more immunocompromised patients

fungal infections

• Saprophytic

• Parasitic eukaryotic

• Many of economic importance - Edible, Useful in manufacturing other

products

funghi

• Round or oval shaped.

• Grow as flat round colonies on culture plates

• unicellular reproduce by budding

yeast

• mycelium

• fuzzy appearance

• multicellular filamentous

  forms or hyphae

mould

• Histoplasma, blastomyces, coccidiodes

• both yeast and mold forms

dimorphic funghi

• dermatophyte fungi

• Feed on keratin in the outer layer of skin, hair & nails

• Typically present as pruritic (itchy) rash & erythema

superficial mycoses

• yeasts

• Less common yeasts causing mucocutaneous infections include

  Malassezia furfur

Mucocutaneous mycoses

• Common chronic condition caused

by Malassezia yeasts (normal skin commensal

organisms)

• Presents with patches of hyperpigmentation or

hypopigmentation.

• Well-demarcated pale or tan macules with fine

scale are usually limited to the upper trunk

• But sometimes the whole trunk, upper arms &

neck (but not face) are affected.

• The macules can coalesce.

• The rash is commonly asymptomatic (but may

be slightly itchy)

• Mainly seen in young adults

Pityriasis versicolor

• a chronic fungal

  infection producing nodules and

  ulcers in the lymph nodes and skin.

Sporotrichosis

• caused by puncture

  wounds contaminated with soil

  fungi

• Dermis, Subcutaneous connective tissue, Muscle.

subcutaneous mycoses

• fungal infections of the internal organs & tissues eg UTIs,

  pneumonia, meningitis, septicaemia.

systemic mycoses

• Fungal infection affecting the lungs and is characterised by symptoms that include

  fever, cough, chest pain, or breathlessness

• can cause asthma and fungal keratitis

Aspergillosis

• Fungal infection caused by inhaling the droppings of birds and bats in humid areas. Primarily affects the lungs but occasionally other organs are affected. If left untreated can be fatal.

histoplasmosis

• Fungal infection of humans and other animals such as dogs and occasionally cats, which presents with flu-like illness with fever, chills, arthralgia, myalgia or a chronic illness that mimics tuberculosis or lung cancer.

  • Can cause hemoptysis

  • can be fatal

Blastomycosis

• fungal cell has

  a cell membrane

  that is comprised of

  a phospholipid

  bilayer

• cell wall - Chitin, a polymer of

  N-acetylglucosamine

• fungal membrane - Ergosterol

fungal cell wall structure

• Amphotericin B specifically binds to ergosterol, a crucial component in fungal cell membranes.

• Once bound, the drug molecules group together to form pores (open channels) through the fungal membrane.

• These pores allow essential internal components—like ions and macromolecules—to leak out, killing the fungal cell (fungicidal action).

• can also bind weakly to human membranes, which causes its significant toxicity due to similaritiy due human cholesterol

• can be delivered inside lipid bubbles (liposomes) to reduce toxicity.

amphotericin b mechanism of action

• molecules clump together on the outside of the membrane into large aggregates.

• aggregates act like a selective sponge that physically pulls (sequesters and extracts) ergosterol straight out of the fungal cell membrane bilayer

• Depriving the fungal membrane of ergosterol destabilizes its structure, leading to cell death.

how amphoterinc B is able to kill the fungus

• Severe systemic fungal infections, eg fungaemia, deep

infections

• Empirical treatment in high-risk febrile neutropenic patients

unresponsive to antibacterials

• Cryptococcal meningitis (with flucytosine)

• Treatment of oral and perioral candidiasis

• Prevention of systemic candidiasis, aspergillosis and

cryptococcosis after liver transplant

• Secondary prevention or suppression of fungal infection in HIV

amphoterinc B indications

• Fever, chills, low blood pressure (hypotension), loss of appetite, nausea, vomiting, headache, malaise, muscle/joint pain, chest pain, and shortness of breath (dyspnoea).

• Pre-medicate with antihistamines or paracetamol, or slow down the IV infusion rate.

• increased serum creatinine, low potassium (hypokalaemia), and low magnesium (hypomagnesaemia).

• Leads to anuria or oliguria (reduced urine production, indicating impaired kidney filtration

• Blood pressure changes (hypo/hypertension) and neurological effects (e.g., seizures, confusion, blurred vision, hearing loss, tinnitus)

• Anaphylactoid (severe allergic-like) reactions.

• Hyperkalaemia (high potassium levels).

adverse effects of amphoternic B

• Poorly absorbed from the gastrointestinal (GI) tract. Oral forms stay inside the gut lumen to treat local fungal infections (like thrush/oesophageal candidiasis) and cannot treat systemic infections.

• Widely distributed throughout most body tissues. However, brain penetration across the blood-brain barrier (BBB) is low, reaching only 2–3% of blood levels in cerebrospinal fluid (CSF).

• Mostly metabolised, with some excreted slowly in urine over several days. It has a very long half-life

• Liver or kidney impairment has little impact on overall drug concentrations, so dose adjustment is generally not required.

amphoterminc B

• Before starting, check kidney (renal) function. Monitor renal function, electrolytes, complete blood count (CBC), and liver function at least twice weekly during treatment and until stable after stopping.

• Fungal resistance to Amphotericin B is uncommon.

• Depends on infection site, patient comorbidities, and clinical response.

• oral lozenges - : Used for oral candidiasis (oral thrush). Suck one 10 mg lozenge 4 times daily (QID) for 7–14 days. Take best after eating or drinking. Continue taking for several days after symptoms (Sx) have completely resolved.

counselling point for amphotermic B

• Administered orally (also topically) but is not absorbed through

  mucous membranes or skin, and its use is mainly limited to

  Candida infections of the skin, mucous membranes and the GIT

• effective treatment for minor

  oral fungal infections but Tx with oral itraconazole

  or fluconazole is often required in

  immunocompromised people

nystatin

• Oropharyngeal candidiasis

• Treatment and suppression of intestinal candidiasis

• Vulvovaginal candidiasis

indication for nystatin

• nausea, vomiting, diarrhoea

nystatin adverse effects

• Use oral liquid after (rather than before) a meal or drink.

   Swish the liquid around the mouth for as long as

  comfortable before swallowing

   Continue for several days after Sx disappear

nystatin counselling

• synthetic azoles

• imidazoles and triazoles

azoles

• Inhibit C14α-demethylase, which is

  responsible for converting lanosterol

  to ergosterol, the main sterol in the

  fungal cell membrane.

  • Depletion of ergosterol

  • Alters fluidity of the membrane

   Interferes with the action of

  membrane-associated enzymes

   Inhibits replication.

   Azoles also inhibit the transformation

  of candida yeast cells into hyphae

azoles mechanism of action

• Fluconazole, isavuconazle & voriconazole are better absorbed orally than

  itraconazole

   Miconazole is poorly absorbed after oral administration

   Posaconazole’s absorption from the oral liquid is slow, unpredictable & depends

  on the presence of food (is more reliable from the tablet)

comparision with oral administered azoles

• Best ocular & CSF penetration/ high concs in the urine

   Suitable Tx option for ocular & CNS Candida infections & symptomatic candiduria.

   Preferred to itraconazole to prevent relapse of cryptococcal disease.

• narrow specturm

fluconazoles

• Also good ocular & CSF penetration/ inadequate concs in urine

   Not suitable for candiduria.

voriconazole

• Only used topically as an oral gel for cutaneous candidiasis

miconazole

• First oral azole but oral ketoconazole withdrawn from market

   Severe hepatotoxicity

   SAS → liver function tests

   Used topically

   Acidic stomach pH

   Antacids

• PPI - decrease absorption

ketoconazole

• All imidazoles are used topically

   Fungal infections where other antifungals have failed or are

  inappropriate

   Fungal skin infections eg

   Tinea

   Cutaneous candidiasis

   Pityriasis versicolor

   Seborrhoeic dermatitis (ketoconazole, miconazole)

imdiazoles

• Cryptococcosis: consolidation and suppression after

induction treatment of meningitis or disseminated

disease; treatment of mild pulmonary disease

• Acute or recurrent mucocutaneous candidiasis

• Vulvovaginal candidiasis where topical therapy has failed

• Primary and secondary prevention of candidal infection

in immunocompromised people

• Tinea corporis, cruris or pedis resistant to topical

therapy

• Onychomycosis (if alternatives have failed or are not

tolerated)

dose - Oral/Oesophageal Candidiasis (Thrush): 50–400 mg taken once daily for 7 to 14 days.

• Uncomplicated Vaginal Thrush (Vulvovaginal Candidiasis): A single 150 mg oral dose.

Fluconazole indications

• Common: Nausea, vomiting, diarrhea (N, V, D), and headaches.

• Infrequent: Loss of appetite (anorexia) and tiredness (fatigue).

• Rare: Reduced urine output (oliguria) and low blood potassium (hypokalaemia).

• prolonged QT interval

Fluconazole adverse effects

• Invasive aspergillosis

• Mucormycosis where amphotericin B is inappropriate

Isavuconazole indications

• Precautions

   Risk factors for shortened QT interval

   CI if Tx with strong inducers of CYP3A4 (eg St John’s wort, rifampicin – strong

   Adverse effects

   Common - hypokalaemia, infusion reactions (eg dyspnoea, hypotension,

  paraesthesia)

   Infrequent - shortened QT interval (clinical significance unclear)

   Heart failure

   Cystic fibrosis, immunocompromised

   Decreased gastric acidity

   Adverse effects

   Common: Dyspepsia, anorexia, fatigue, itch

   Infrequent: Insomnia, somnolence, gynaecomastia, impotence

   Rare: Hypertension (high dose), peripheral oedema, pulmonary oedema, heart failure

isavucanzole adverse effects

• Skin & Yeast Infections: Superficial dermatophyte, Candida, or pityriasis versicolor infections that haven't responded to topical creams.

• Vaginal Thrush: Severe or recurring vulvovaginal candidiasis after topical therapy has failed.

• Fungal Nail Infections: Onychomycosis (pictured in the bottom right corner).

• Mouth & Throat Infections

• Oral/Oesophageal Thrush: Oropharyngeal or oesophageal candidiasis in immunocompromised patients, or when other standard treatments aren't suitable.

isavucanzole indication

• absorb significantly better than standard 100 mg capsules (e.g., Itracap®, Itranox®).

• One 50 mg Lozanoc® capsule provides the same effective drug amount as one 100 mg Itracap® or Itranox® capsule.

• Standard 100 mg capsules require an acidic environment in the stomach to dissolve and absorb properly.

• Take with a full meal (though avoid a purely rice-based meal) to maximize stomach acid and absorption.

• Avoid Antacids: Do not take antacids within 2 hours of taking 100 mg capsules, as reducing stomach acid prevents the drug from absorbing.

counselling for Itraconazole

• Has the broadest spectrum

• Serious fungal infections (eg invasive

aspergillosis) where other antifungals have

failed or are inappropriate

• Oropharyngeal candidiasis in the

immunocompromised (including failure with

fluconazole or itraconazole)

• Prevention of invasive fungal infections in

people at risk, eg prolonged neutropenia,

haemopoietic stem cell recipients

posaconazole indications

• CI with various drugs eg

atorvastatin, fluvastatin,

simvastatin

• Malabsorption

• ↑ gastric pH eg PPI

precaution for posaconazole

• Common: Neutropenia, fever,

thrombophlebitis

• Infrequent: Hypokalaemia,

respiratory insufficiency,

oedema

• Rare: Tongue or facial oedema;

neurotoxicity

posaconazole adverse effects

• better: On an empty stomach, tablets are absorbed nearly 4 times better than the oral liquid.

• Absorption from the oral liquid varies more and is heavily influenced by food.

• Giving the oral liquid through a nasogastric tube can reduce blood levels of the drug.

• Best option: Take during or immediately after a high-fat meal.

• Second best option: Take with any food or nutritional drink (the more food, the better the absorption).

• If unable to eat: Take with an acidic, carbonated drink (like cola) or split the daily dose into smaller, more frequent doses.

• Avoid stomach-acid reducers: Avoid medications that raise stomach pH (like proton pump inhibitors / PPIs) because acid helps absorption.

• Oral Liquid: Take with or right after a high-fat meal.

• Tablets: Swallow whole with food; do not crush or chew.

posaconazole counselling points

• Invasive aspergillosis

• Serious infections due to susceptible fungi

Voriconazole indications

• Sodium restriction

• Risk factors for skin cancer

• CI with other drugs eg rifampicin, carbamazepine, St John’s wort – may

decrease voriconazole concentrations significantly

causes visual problems and prolonged QT interval

voriconazole precautions

• Common: Temporary vision changes, skin reactions, low blood pressure (hypotension), and injection/infusion site reactions.

• Infrequent: Sudden kidney failure (acute renal failure), irregular heartbeats (arrhythmias), and pancreas inflammation (pancreatitis).

• Prolonged QT interval, dangerous heart rhythms (torsades de pointes), kidney tissue damage (renal tubular necrosis), swollen lymph nodes (lymphadenopathy), and nerve/brain effects

• Oral bioavailability (how much drug enters the bloodstream when taken by mouth) is very high in adults, but noticeably lower in children.

• Can cause blurred vision or sensitivity to bright light (often within 30 minutes of taking a dose). Patients affected should avoid driving or operating machinery.

• Increases skin sensitivity to sunlight. Advise patients to avoid direct sun, wear a broad-brimmed hat, and apply SPF 30 or 50+ broad-spectrum sunscreen.

• Take at least 1 hour before or 1 hour after meals to ensure proper absorption.

adverse effects of voriconazole

• Azoles slow down the liver enzyme CYP3A4, which breaks down many common medications.

  • Strong Inhibitors: Itraconazole, ketoconazole, posaconazole, and voriconazole.

  • Moderate Inhibitors: Fluconazole and isavuconazole.

• azoles block CYP3A4 (and several other CYP enzymes), they slow the clearance of other drugs processed by the liver. This raises the concentrations of those drugs in the blood, increasing both their therapeutic effects and potential side effects.

• block P-gp, a transporter protein that pumps drugs out of cells.

• creams or ointments applied to the skin are unlikely to cause significant drug interactions because very little drug enters the bloodstream (though occasionally enough can be absorbed).

• a single dose (e.g., for vaginal thrush) is unlikely to affect the levels of other medications long enough to cause problems.

azole drug interactions

• Inhibits fungal ergosterol synthesis by inhibiting squalene

epoxidase, leading to membrane disruption and cell death

• Fungicidal against dermatophytes & some other organisms

• Fungistatic against C. albicans

allyamines mechanism of action

• Onychomycosis (tinea unguium)

• Dermatophyte infection of skin, groin, feet, when topical

treatment is ineffective or inappropriate

• Fungal skin infections

allyamines indications

• Common (>1%): Nausea, vomiting, diarrhea (N, V, D), stomach pain, skin rash, itchiness, hives (urticaria), temporary rises in liver enzymes, joint pain (arthralgia), muscle pain (myalgia), and headaches.

• Infrequent (0.1–1%): Changes in taste (altered or lost taste, usually temporary).

• Rare (<0.1%): Liver inflammation (hepatitis) or failure, and serious blood cell drops (low white blood cells, low platelets, or overall blood cell depletion/anaemia).

allyamines adverse effects

• Dosing (Oral 250 mg Once Daily)

  • Fungal Nail Infections (Onychomycosis / Tinea unguium):

    • Fingernails: 6 weeks.

    • Toenails: 12 weeks (or longer).

  • Other Skin Fungal Infections:

    • Jock itch (tinea cruris): 2 to 4 weeks.

    • Athlete's foot (tinea pedis): Up to 6 weeks.

    • Ringworm on body (tinea corporis): 4 weeks.

allyamines dose

• severe, chronic or active hepatic disease

contraindications allyamines

• Well absorbed orally

   Extensively metabolised in liver (F = 40%)

   Accumulates in skin, nails & fat

   Excreted mainly in urine

   Initial t 1/2 = 17 hours (extends to 200-400 hours at ss)

terbinafine adsorption

• Terbinafine is a strong inhibitor of CYP2D6

• Potential to ↑ [amitriptyline], [imipramine], [nortriptyline]

• Rifampicin ↓ plasma concentrations (↑ metabolism of terbinafine)

• Terbinafine inhibits metabolism of tramadol to its active

metabolites which may decrease its analgesic effect. Combination should be avoided.

• Potential to interact may last for months

terbinafine drug interactions

• Inhibit 1,3-beta-D-

  glucan synthase, which

  inhibits synthesis of 1,3-

  β-D-glucan, a glucose

  polymer that is

  necessary for

  maintaining the structure

  of fungal cell walls.

Echinocandins mechanism of action

• Invasive candidiasis, including candidaemia

Echinocandins indications

• N, V, D, rash, hypokalaemia, increased liver enzymes, injection site

  reaction

• Anaphylaxis

Echinocandins adverse effects

• Active against most Candida spp., including strains resistant to azoles and

amphotericin B.

• active against Aspergillus spp

specturm of activity of Echinocandins

• Invasive candidiasis, including candidaemia

   Adult dose: IV infusion 200 mg on day 1, then 100 mg once daily

  (injection site reactions are uncommon)

   Reconstituted solution for IV infusion should be diluted with NaCl

  0.9% or glucose 5%

   Baseline liver fn; monitor during Tx

   No liver metabolism or renal excretion of active drug occurs / no 

Anidulafungin

 hyperkalaemia, thrombocytopenia

 hypomagnesaemia

Anidulafungin adverse effects

•  Invasive candidiasis, including candidaemia

   Oesophageal candidiasis

   Invasive aspergillosis (second line)

   Empiric treatment of fungal infection (eg Candida 

Caspofungin indications

• Can cause liver dysfunction (rare - ↓ dose in moderate impairment)

Precautions - Caspofungin

• Adult dose: Administered IV - 70 mg on the first day, then 50 mg once

   Reconstituted solution for IV infusion should be diluted with NaCl 0.9%

  (caspofungin is unstable in glucose)

   Common SE: ↑ urine proteins, eosinophilia, anaemia, headache

   Rare SE: hepatic dysfunction

Caspofungin dose

•  Indications

   Invasive candidiasis, including candidaemia

   Oesophageal candidiasis

   Prophylaxis of candidal infection 

Micafungin indications

• Fluorinated pyrimidine related to fluorouracil (5-fluorouracil or 5-FU).

   Synthetic orally active antifungal agent that is effective against a limited range (mainly

  yeasts) of systemic fungal infections.

   Has a narrow spectrum of activity

   If given alone, drug resistance commonly occurs during treatment

   Usually given with amphotericin for severe systemic infections eg cryptococcal infections

   Capsules - excellent bioavailability (orally) & is absorbed rapidly from the GIT.

Flucytosine

• Common or infrequent: N, V, D, anaemia, leucopenia, thrombocytopenia.

   Infrequent or rare: hepatic necrosis, agranulocytosis, GI haemorrhage

• be kept at 15-25°C

Flucytosine - adverse effects

• Flucytosine is transported by cytosine permease into the fungal cell, where it is

  deaminated to 5FU by cytosine deaminase

• 5FU is converted to 5FUMP (5-fluorouridine monophosphate) by PRT (phosphoribosyl pyrophosphate).

• 5FUMP is converted to 5FUTP (5-fluorouridine triphosphate).

• 5FUTP gets incorporated into fungal RNA, halting fungal protein synthesis.

• 5FUMP is converted by ribonucleotide reductase into 5FdUMP (5-fluorodeoxyuridine monophosphate).

• 5FdUMP potently inhibits thymidylate synthase, preventing the conversion of dUMP to dTMP.

• Blocking dTMP depletes essential thymine building blocks, stopping fungal DNA synthesis.

Flucytosine mechanism of action

• Active against numerous dermatophytes,

• Skin (tinea corporis)

   Scalp and hair (tinea capitis)

   Nails (tinea unguium)

   Feet (tinea pedis)

   Groin (tinea cruris)

Griseofluvin indications

• Is deposited in keratin precursor cells of

the skin, hair, and nails, where it disrupts

microtubule function and inhibits the

mitosis of susceptible dermatophytes.

• The infected cells are gradually exfoliated

and replaced by noninfected tissue

Griseofluvin mechanism of action

• Lupus erythematosus

  • Severe liver failure

  • May affect sperm so men should not father a child during,

  and for 6 months after, Tx.

  • Women should use additional non-hormonal contraception

  while taking and for 1 month after stopping Tx

Griseofluvin contraindications

• Common: Nausea (N), headache, diarrhoea, loss of appetite (anorexia).

• Infrequent: Sensitivity to sunlight (photosensitivity), blurred vision, confusion, changes in taste, rash.

• Rare: Severe peeling/blistering skin reaction (toxic epidermal necrolysis), triggering or worsening of lupus (an autoimmune condition).

• Skin, Hair, or Groin Infections: 500 mg daily for 4–6 weeks.

• Foot or Nail Infections: 1 g daily for up to 12 months (nails take much longer because the drug must work through thick keratin layers).

griseolfluvin adverse effects and dose

• Take with food or milk to increase absorption.

   May cause dizziness

   Avoid driving or operating machinery if you are affected.

   Very occasionally effects such as increased heart rate & skin flushing may occur with alcohol

   Avoid sun exposure, wear protective clothing and use sunscreen

   Contraceptive pill less effective

counselling for griseofluvin

• Blocks the production of essential sterols needed to build and maintain fungal cell membranes.

• Used to treat fungal nail infections (onychomycoses).

• Deeply penetrates the nail structure and remains active there for several weeks.

• Applied once or twice weekly until healthy nail completely regrows.

• Treatment Duration: Typically takes 6 months for fingernails and 12 months or longer for toenails.

• Preparation: File down and clean the affected nail before the initial application.

• Method: Paint the lacquer over the entire surface of affected nails and let it dry.

Precautions

• Avoid: Do not use cosmetic nail polish, artificial/fake nails, or occlusive dressings during the course of treatment.

Amorolfine

• Binds (chelates) iron, resulting in fungistatic or fungicidal action against a broad spectrum of fungi; also possesses anti-inflammatory activity.

• indicated for fungal nail infections (onychomycoses).

• Skin Reactions: Localised irritation such as itch, burning, rash, and redness (erythema).

• Frequency: Applied once daily until healthy nail completely regrows.

• Duration: Typically takes 6 months for fingernails and 12 months or longer for toenails.

• Preparation: Wash and dry affected nails prior to application (no filing required).

• Technique: Paint over the entire nail surface, $5\text{ mm}$ of surrounding skin, and under the free edge of the nail.

• Drying & Retention: Allow to dry; leave on for at least 6 hours (preferably overnight) before rinsing off with water.

• Precautions: Avoid contact with eyes, and do not use cosmetic polishes or artificial nails during treatment.

Ciclopirox

• Mechanism: Exact mode of action is unknown, but it distorts fungal hyphae and stunts mycelial growth.

• Spectrum: Inhibits dermatophytes and Malassezia furfur, but is inactive against Candida species.

• Indication: Indicated for tinea infections.

Patient Counselling

• Preparation: Wash and thoroughly dry affected areas before applying.

• Application Frequency: Apply to clean, dry skin 2–3 times daily.

• Duration: Continue using for 2 weeks after symptoms disappear to prevent the infection from returning (repeat treatments may be required).

• Footwear Care: Spray regularly into socks and shoes to help prevent reinfection.

Practice Points

• Prophylaxis

Tolnaftate

• Amphotericin B

• Nystatin

Polyenes drugs

• Terbinafine

Allylamines

• end in fungin

Echinocandins classification

• Bifonazole

• Clotrimazole

• Econazole

• Miconazole

• Ketoconazole

Imidazoles classification

• Fluconazole

• Isavuconazole

• Itraconazole

• Posaconazole

• Voriconazole

Triazoles