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Flashcards in Antifungals Deck (71):
1

Characteristics of fungi

Eurkaryotic. Asexual or sexual reproduction. Cell wall containing chitin and glucan and cell membrane containing ergosterol.

2

Different ways of living for fungi

Saphrophtyic = on dead, organic matter. Parasitic = at the cost of a living organism. Symbiotic = in a relationship with another living organism.

3

Classification of fungi

Yeasts/blastophores. Yeast-like fungi that produce mycelium/hyphae/filamentous like structure. Filamentous fungi with true mycelium/hyphae. Dimorphic fungi which can grow as yeast or filamentous fungi with hyphae/mycelium.

4

Types of fungi infections

Cutaneous = Trichophyton e.g tinea pedis ir Candida albicans ausing oral and vaginal candidosis. Subcutaneous = implantation of fungi beneath skin by animal or tree scratch e.g. Sporotrichosis by Sporothrix schenckii. Systemic fungal infections = opportunistic or true infections, invasive. e.g. Systemic candidosis, Aspergillosis by Aspergillus fumigatus.

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Diagnosis of fungal infections

Microscopy and culture

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Diagnosis of Candidosis

Culture = white colonies. Microscopy = not very useful, shows dimorphic. Matrix assisted Laser Desorption Ionisation Time of Flight Spectroscopy.

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Spread of subcutaneous fungal infection

E.g. Sporotrichosis from Sporothrix ischenckii associated with sphagnum moss. Spreads up lymph system emerging at intervals to give symptoms.

8

Systemic Candidosis Infection

Commonly Candidaemia (in blood). Also infect peritoneum, meninges, heart, eye and brain.

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Risk factors for systemic candidosis

IV drug use (heroin low pH and candida likes low pH). Central venous catheters, gut sugery, antibiotics, immune suppression, premature, diabetes, cancer.

10

Why are Abx a risk factor for fungal infections

Broad-spec kill commune micro-flora which compete with fungus for resources in body.

11

Types of Aspergillosis infections

Allergic Bronchopulmonary Aspergillosis (RF=asthma or CF). Severe asthma with fungal sensitisation. Aspergilloma (in old TB cavity). Aspergillus sinusitis. Chronic pulmonary aspergillosis (RF=lung pathology e.g. COPD). Invasive Aspergillosis.

12

Invasive Aspergillosis

RF=immunocompromised esp neutropenic leukaemia. Primary infection is pulmonary aspergillosis then spreads via lung vessels to become systemic and invasive. Active tissue and blood vessel invasion. Common organs include brain, skiin and kidney. High mortality.

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Diagnosis of invasive aspergillosis in immunocompromised

Chest X-ray and CT - HALO sign, culture bronchoscopy alveolar lavage, antigen test, PCR test for DNA, biopsy.

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Diagnosis of invasive aspergillosis in immune competent.

chest x-ray and CT. Culture sputum. antibody test.

15

Most common pathogen for invasive aspergillosis

Aspergillus fumigatus.

16

Mucoromycosis

pathogen = mucormycetes moulds e.g. Mucor or Lichtheimia. Rhino-cerbral or pulmonary (if immunocompromised or poor DM control) infection. Rapid progressing, difficult diagnosis, rare.

17

Cryptococcosis

Pathogen = Cryptococcus neoformans yeast. Infects pulmonary system and meningitis. RF = immunocompromised. Diagnosis = India ink staining of culture. Antigen test

18

Histoplasmosis

An example of a true invasive infection. Pathogen = Histoplasma capsulatum, dimorphic fungus as mould in environment and yeast inside human. Principally a pulmonary infection as Conidia inhaled from bird or bat roost shredding. Diagnosis = CXR, culture and microscopy.

19

5 classes of antifungal treatment

Pyrimidine, Polyenes, Allyamine, Azoles, Echinocandins.

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Drugs which act on DNA and protein synthesis

Pyrimidine .e.g. 5 fluorocytosine

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Antifungal acting on plasma membrane

Polyene e.g. amphotericin B

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Anti fungal acting on ergosterol biosynthesus

Allyamine and Azole e.g. terbinafine and fluconazole

23

Antifungal acting on beta 1-3, glucan synthesis of cell wall

Echinocandins e.g. caspofungin

24

Active Pyrimidines

5-Fluorocytosine is taken up by a fungal-cell specific cytosine permeate. It is converted to a false nucleotide: 5-fluorouracil by fungal deaminase (also in bacteria). Phosphorylated to either fluorouridine triphosphate or fluorodeoxyuridine monophosphate.

25

Action of pyrimidines

Inhibit DNA and RNA synthesis. Monophosphate form decreases raw materials for DNA synthesis by inhibition of thymidylate synthetase. Triphisphate form is incooperated into RNA strand and prevents RNA translation.

26

Use of pyrimidines

Used in severe systemic infections and meningitis due to fungi.

27

Selective toxicity of pyrimidines

Humans lack deaminase to form active form. As bacteria have enzyme can kill gut microflora but only at low level.

28

Pharmacokinetics of pyrimidines and ADR

Water soluble, readily absorbed and wide distribution, short half life, urine excretion, IV administration. ADR: bone marrow suppression, GI upset.

29

Drug interactions of pyrimidines

Brivudine (antiviral) as this inhibts the enzyme needed to degrade 5-fluorouracil. - dihydropyrimidine dehydrogenase. Anti-epileptic: Phenytoin

30

Resistance of 5-fluorocysosine

Mutations in enzyme Uracil phophoribosyl transferase which creates active 5-fluorouracil. Also in permease and deaminase involved in uptake and deamination of drug.

31

Polyene antifungals

Amphotericin B and Nystatin

32

Mode of action of polyenes

large macrolide doughnut shaped molecule. Inserts into fungal cell membrane and acts as ion channel pore, increasing permeability and disturbing membrane potentials esp potassium. De-stabilise cell membrane. Also cause oxidative damage through auto-oxidation of amphotercin B

33

Selectivity of polyenes

Bind to ergosterol in membrane of fungi membranes, has some ABx activity.

34

Use of polyenes

Amphotericin B = Broad spec of activity. Rx for Aspergillus and Candida. In any suspected fungal infection in immunocompromised. Studies of use in febrile neutropenia and prophylaxis in risk patients. Nystatin = oral and vaginal Candida infections (topical)

35

Admnistration of Amphotericin B

As Liposomal Ambisome lipid formulation to prevent nephrotixicity.

36

resistance of polyenes

As ergosterol is not a protein resistance is rare as mutation is not as simple a process as for protein targets. ERG2 gene coding for isomerase in ergosterol synthesis is route of C.glabrata resistance. Less ergosterol in membrane is C.lusitaniae resistance.

37

Pharmokinetics of Amphotericin B and ADR

Protein bound, long half life, most bile excretion unchanged. ADR: acute infusion related toxicity (fever, chills, rigours, vomiting, hypotension), nephrotoxicity but lipid formula decrease these.

38

Drug interactions of Amphotericin B

Nephrotoxic agents increase nephrotoxicity. Corticosteroids and diuretics increase hypokalemia. Muscle relaxants increase in effect. Flucytosine clearance reduced increase bone marrow suppression.

39

Examples of echinocandins

Caspofungin, Anidulafungin, Micafungin

40

Mode of action of enchinocandins

Bind to Fks1p subunit of beta1,3-D-synthase. inhibit glucan synthesis. Leaky, more permeable unstable membrane. Fungalcidal.

41

Clinical use of Echinocandins

Caspofungin - invasive candidosis in adults, Intolerant Aspergillosis, Presumed fungal infections in at risk patients. Anidulafungin - Invasive candidosis in adults. Micafungin - Invasive candidosis in children and adults.

42

Pharmacokinetics of Echinocandins

IV only. Travel protein bound. Excreted in faeces. Not metabolised in liver but in tissue and blood, no CYP involvement.

43

Drug interactions of Echinocandins

Caspofungin - immunosuppressants, steroids and some ABx. Micafungin - immunosuppressants.

44

ADR of echinocandins

Few mostly mediated via histamine. Can cause abnormal LFTs. Anidulafungin and Micafungin can cause headache and nausea. Caspofungin can cause hypokalaemia, chills and fever.

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Resistance of echinocandins

Rare, mutations in Fks1 gene at codon 645 can cause resistance in Candida species. Crytococcus are intrinsically resistant.

46

Allyamine example

Terbinafine

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Action of Terbinafine

Inhibit squalene epoxidase, prevent ergosterol synthesis.

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Use of terbinafine

Dermatophyte nail and skin infections and skin yeast infection and Candida albicans.

49

Pharmacokinetics of terbinafine

Oral but poorly absorbed. Topical cream or spray. Slow elimination via kidneys. Extensively metabolised by CYP enzymes. Deposits in skin, nails and fat.

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Drug interactions and ADR of terbinafine.

Liver dysfunction, GI upset, altered taste perception. Interact with drugs acting on CYP

51

Azoles examples

Imidazoles - clotrimazole, Econazole, Ketoconazole, Miconazole. Trizoles - Fluconazole, Itraconazole, Voriconazole, Posaconazole, Isavuconazole.

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Mode of action of Azoles

Bind to enzyme which turns lanosterol to ergosterol - lanosterol 14-alpha-demethylase. Toxic methyl sterol precursors build up. Unstable cell membrane and toxic.

53

General use of Azoles (see slide for specifics)

Candida, Aspergillus (except Fluconazole and ketoconazole), Crytococcus, Dimorphic fungi (except Clotrimazole)

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Use of imidazoles

topical only for superficial infections.

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Pharmacokinetics of azoles

Protein bound, metabolised in liver by CYP enzymes, kidney excretion.

56

ADR of fluconazole

Headache, nausea, vomitting, diarrhoea, abnormal LFTS

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Itraconazole ADRs

Headache, nausea, vomiting, diarrhoea, rash, abnormal LFTs, SOB.

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Voriconazole ADR

Headache, nausea, vomitting, diarrhoea, abnormal LFTs, peripheral oedema, visual abnormalities, rash.

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Posaconazole ADR

Headache, nausea, vomitting, diarrhoea, abnormal LFTs, rash

60

Drug interactions of azoles

Drugs which effect or are effected by CYP enzymes as azoles inhibit them. Need therapeutic monitoring! E.g. warfarin, phenytoin, tolbutamide.

61

Resistance of Candida to azoles

efflux pump. ATP binding cassette family at CDR gene or major facilitator family at MDR gene. Later only gives resistance to fluconazole and voriconazole.

62

resistance in C.albicans to azoles

Mutation in lanosterol 14-alpha -demethylase. Decrease affinity for drug and target. Also target up regulation to decrease efficacy

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Resistance in A.fumigatus

Mutation in target of drugs

64

Example of a synergistic drug administration

Amphotericin B and 5-Flucytosine. AmpB increases permeability of cell to 5-Flucytosine so it can act more

65

Use of fluconazle

Prophylatically to reduce fungal infections in bone marrow transplant patients.

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Antifungals for systemic or subcutaneous infections

Amphotericin B (polyene), Flucyosine (pyrimidines), Azoles (Itraconazole) and Echinocandins (anidulafungin).

67

Antifingals for cutaneous infections

Nystatin (polyene), Terbinafine (allymine), Azoles (miconazole)

68

Selective toxicity of terbinafine

Human squalene epoxidase needs much higher drug concentrations to be inhibited compared to fungal enzyme

69

Paradoxic effect of echinocandins

Seen esp in Caspofungin treating Candida. Low drug concs inhibit growth but at higher drug concs the fungal growth continues.

70

Paper on efficacy of Anidulafungin

Use a prophylactic medicine compared to fluconazole in liver transplant patients. The randomised double-blind trial saw that the incidence of fungal infections was similar but anidulafungin treatment caused less invasive Aspergillus infections.

71

Difference between Imidazoles and Triazoles

Imidazoles discovered first, mostly topical use but also systemic fungal infection treatment. Triazoles discovered in 1990s with broader spec of activity and better safety e.g. Fluconazole and Itraconazole.