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Chemotherapy > Antifungals > Flashcards

Antifungals Flashcards

1
Q

Characteristics of fungi

A

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

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2
Q

Different ways of living for fungi

A

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

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3
Q

Classification of fungi

A

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.

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4
Q

Types of fungi infections

A

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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5
Q

Diagnosis of fungal infections

A

Microscopy and culture

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6
Q

Diagnosis of Candidosis

A

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

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7
Q

Spread of subcutaneous fungal infection

A

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

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8
Q

Systemic Candidosis Infection

A

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

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9
Q

Risk factors for systemic candidosis

A

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

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10
Q

Why are Abx a risk factor for fungal infections

A

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

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11
Q

Types of Aspergillosis infections

A

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.

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12
Q

Invasive Aspergillosis

A

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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13
Q

Diagnosis of invasive aspergillosis in immunocompromised

A

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

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14
Q

Diagnosis of invasive aspergillosis in immune competent.

A

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

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15
Q

Most common pathogen for invasive aspergillosis

A

Aspergillus fumigatus.

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16
Q

Mucoromycosis

A

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

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17
Q

Cryptococcosis

A

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

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18
Q

Histoplasmosis

A

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.

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19
Q

5 classes of antifungal treatment

A

Pyrimidine, Polyenes, Allyamine, Azoles, Echinocandins.

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20
Q

Drugs which act on DNA and protein synthesis

A

Pyrimidine .e.g. 5 fluorocytosine

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21
Q

Antifungal acting on plasma membrane

A

Polyene e.g. amphotericin B

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22
Q

Anti fungal acting on ergosterol biosynthesus

A

Allyamine and Azole e.g. terbinafine and fluconazole

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23
Q

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

A

Echinocandins e.g. caspofungin

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24
Q

Active Pyrimidines

A

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.

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25
Q

Action of pyrimidines

A

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.

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26
Q

Use of pyrimidines

A

Used in severe systemic infections and meningitis due to fungi.

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27
Q

Selective toxicity of pyrimidines

A

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

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28
Q

Pharmacokinetics of pyrimidines and ADR

A

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

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29
Q

Drug interactions of pyrimidines

A

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

30
Q

Resistance of 5-fluorocysosine

A

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

31
Q

Polyene antifungals

A

Amphotericin B and Nystatin

32
Q

Mode of action of polyenes

A

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
Q

Selectivity of polyenes

A

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

34
Q

Use of polyenes

A

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
Q

Admnistration of Amphotericin B

A

As Liposomal Ambisome lipid formulation to prevent nephrotixicity.

36
Q

resistance of polyenes

A

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
Q

Pharmokinetics of Amphotericin B and ADR

A

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
Q

Drug interactions of Amphotericin B

A

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

39
Q

Examples of echinocandins

A

Caspofungin, Anidulafungin, Micafungin

40
Q

Mode of action of enchinocandins

A

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

41
Q

Clinical use of Echinocandins

A

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
Q

Pharmacokinetics of Echinocandins

A

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

43
Q

Drug interactions of Echinocandins

A

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

44
Q

ADR of echinocandins

A

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

45
Q

Resistance of echinocandins

A

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

46
Q

Allyamine example

A

Terbinafine

47
Q

Action of Terbinafine

A

Inhibit squalene epoxidase, prevent ergosterol synthesis.

48
Q

Use of terbinafine

A

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

49
Q

Pharmacokinetics of terbinafine

A

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

50
Q

Drug interactions and ADR of terbinafine.

A

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

51
Q

Azoles examples

A

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

52
Q

Mode of action of Azoles

A

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

53
Q

General use of Azoles (see slide for specifics)

A

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

54
Q

Use of imidazoles

A

topical only for superficial infections.

55
Q

Pharmacokinetics of azoles

A

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

56
Q

ADR of fluconazole

A

Headache, nausea, vomitting, diarrhoea, abnormal LFTS

57
Q

Itraconazole ADRs

A

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

58
Q

Voriconazole ADR

A

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

59
Q

Posaconazole ADR

A

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

60
Q

Drug interactions of azoles

A

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

61
Q

Resistance of Candida to azoles

A

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
Q

resistance in C.albicans to azoles

A

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

63
Q

Resistance in A.fumigatus

A

Mutation in target of drugs

64
Q

Example of a synergistic drug administration

A

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

65
Q

Use of fluconazle

A

Prophylatically to reduce fungal infections in bone marrow transplant patients.

66
Q

Antifungals for systemic or subcutaneous infections

A

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

67
Q

Antifingals for cutaneous infections

A

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

68
Q

Selective toxicity of terbinafine

A

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

69
Q

Paradoxic effect of echinocandins

A

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

70
Q

Paper on efficacy of Anidulafungin

A

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
Q

Difference between Imidazoles and Triazoles

A

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.

Chemotherapy (6 decks)

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