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Medical Microbiology > Fungal infection & anti-fungal resistance > Flashcards

Fungal infection & anti-fungal resistance Flashcards

1
Q

Describe fungi

A

Eukaryotes
Kingdom = fungi
Separate from plants, animals and bacteria
Ubiquitous (found everywhere), mainly soil

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2
Q

How are fungi classified?

A
  • Yeasts
  • Moulds
  • Dimorphic
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3
Q

Describe yeasts

A

Unicellular
Reproduce by budding
eg. Cryptococci, Candida, Pnuemocystis

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4
Q

Describe moulds

A

Also called filamentous fungi
Grow as filaments (hyphae) which may intertwine to form a mass (mycelium)
eg. Aspergillus

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5
Q

Describe dimorphic fungi

A

Grow as moulds in the environment and as yeasts in the body
eg. Histoplasma, Coccidioides

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6
Q

What are the 3 types of fungal infection?

A

Superficial
Subcutaneous
Systemic

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7
Q

Describe superficial infection

A

Affect mucous membranes (yeasts)
Keratinised tissue - skin, nail, hair (dermatophytes)

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8
Q

Describe subcutaneous infection

A

Inoculation into deeper skin tissue (usually traumatic)
Local disease, tissue destruction and sinus formation

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9
Q

Describe systemic infection

A

Haematogenous spread (via bloodstream) to any organ (esp eyes, liver, kidneys, spleen, lungs)
Often severe infections with high mortality
Opportunistic

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10
Q

What is candida?

A

Yeast
Normal gut (vaginal) flora
Can cause thrush in mouth or vagina
At risk - ICU patients

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11
Q

What is aspergillus?

A

Mould
Ubiquitous
Present in environment
Causes infection by inhalation
Causes localised infection, semi-invasive, invasive aspergillosis
At risk - transplant patients, ICU, haematology patients

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12
Q

What is cryptococcus?

A

Yeast
Ubiquitous
Present in environment
Inhaled
Causes pneumonia, meningoencephalitis
At risk - HIV groups, patients with solid organ transplant e.g. lung

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13
Q

What is pneumocystis?

A

Yeast
Coloniser of human lung
Causes pneumonia in HIV CD4<200

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14
Q

What is the innate predisposing factors to fungi?

A

Neutropenia (low neutrophils)
Diabetes mellitus (phagocytosis)

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15
Q

What is the acquired immune impairments to fungi?

A

HIV/AIDS
Chemotherapy for leukaemia/lymphoma
Organ transplant - BMT, SOT
Immunosuppressant drugs - steroids, tacrolimus, biologics (anti-TNF Abs)
Immaturity - premature birth, neonates

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16
Q

What are some other risk factors of Candida?

A

Prosthetic material - e.g. intravascular device, catheters
Broad spec antibiotic use
Mucosal breach - burns, mucositis, abdominal surgery

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17
Q

How are fungi emerging as a cause of human disease?

A

Increasing host susceptibility - cancer, autoimmune disease
Widespread use of broad spectrum antibiotics
Maybe global warming

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18
Q

What are the classes of antifungals?

A
  • Azoles
  • Echinocandins
  • Polyenes
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19
Q

Name some examples of azoles

A

Fluconazole
Voriconazole
Posaconazole

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20
Q

How are azoles administered?

A

Orally

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21
Q

Name some examples of polyenes

A

Amphotericin B (intravenous)
Nystatin

22
Q

Name some examples of echinocandins

A

Caspofungin
Micafungin
Anidulafungin

23
Q

How are echinocandins adminstered?

A

Intravenously

24
Q

What is another antifungal not in any of the other 3 classes?

A

5-Flucytosine a pyrimidine analogue

25
Q

What do azoles target?

A

Inhibit synthesis of ergosterol in fungi via binding to sterol 14 alpha demethylase (CYP51)

26
Q

What do the polyenes target?

A

Bind to ergosterol in plasma membrane of fungi
Forming aqueous pores that promote leakage of intracellular ions and disrupt active transport mechanisms

27
Q

What do echinocandins target?

A

Target fungal cell wall
Inhibit synthesis of beta(1, 3)-D-glucan synthase

28
Q

What are the uses of antifungals?

A

Prophylaxis - azoles
Empirical - AmB, echinocandins, azoles
Pre-emptive treatment - AmB, echinocandins, azoles
Targeted treatment -

29
Q

What are reasons for failure of antifungal therapy?

A
  • Host immune system unable to clear infection (immunosuppression)
  • Poor patient adherence to treatment
  • Source control - failure to remove a device that infection is on eg. biofilm on catheters, lines, artificial heart valves
  • Inadequate doses or penetration of drugs to site of infection
  • Antifungal resistance - intrinsic or acquired
30
Q

How is antifungal susceptibility assessed?

A

Using measurement of minimum inhibitory concentration (MIC) using E-test or broth micro-dilution

31
Q

What are the types of antifungal resistance?

A

Primary (intrinsic)
Secondary (acquired)

32
Q

What is primary resistance?

A

When all known isolates of a species are resistant to an antifungal
e.g. Candida krusei to azoles

33
Q

What is secondary resistance?

A

Develops when susceptible strains are exposed to antifungal agents
Dependent on altered gene expression
e.g. Candida glabrata to echinocandins or Aspergillus fumigatus to azoles

34
Q

What are the most common mechanisms of antifungal resistance?

A

Target alteration
Drug efflux

35
Q

What are drivers of antifungal resistance?

A

Agricultural use of antifungals and widespread use in humans

36
Q

What are azoles?

A

Ergosterol synthesis inhibitors - block cytochrome P450 enzyme 14alpha-demethylase (converts lanosterol to ergosterol

37
Q

What is the 14 alpha demethylase enzyme encoded by?

A

ERG11 gene in Candida/Cryptococcus
Cyp51 in moulds

38
Q

Define fungistatic

A

Inhibit the growth of fungi without destroying them

39
Q

Define fungicidal

A

Destroys the fungi altogether

40
Q

How do azoles work against fungi?

A

Fungistatic in yeasts
Fungicidal in moulds

41
Q

What are azoles used to treat?

A

Candidiasis
Cryptococcosis
Aspergillosis

42
Q

What are mechanisms of azole resistance?

A

Efflux pumps
Target site mutation
Increased expression of target
Genomic plasticity

43
Q

How do efflux pumps act as a mechanism of azole resistance?

A

They can pump out antimicrobial agents from the cell which will prevent them from working

44
Q

What are efflux pumps encoded by?

A

ABD and MFS genes
e.g. CDR1 in Candida, AFR1 in Cryptococcus

45
Q

How do target site mutations act as a mechanism of azole resistance?

A

Point mutations in ERG11 (yeasts), CYP51A (moulds) and FKS in Candida

46
Q

What is increased expression of target as a mechanism of azole resistance?

A

Gain of function mutation in transcription factor UPC2 for ERG11 in C. albicans

47
Q

How does genome plasticity work as a mechanism of azole resistance?

A

Duplication of entire chromosomes or regions in response to drug pressure-increased expression of target/pump
e.g. C. albicans, C. neoformans

48
Q

How do polyenes function?

A

Bind to sterols (ergosterol preferentially) in cell membrane, forming channels
Results in leakage and disruption
Primary resistance

49
Q

What is the mechanism of polyenes?

A

Reduction in ergosterol content
ERG mutations e.g. ERG3 loss of function mutation

50
Q

How do echinocandins work?

A

Bind to and inhibits beta(1, 3) glucan synthase, causing cell lysis
Enzyme encoded by FKS gene

51
Q

How do echinocandins work?

A

Active against Candida - fungicidal
Aspergillus - fungistatic

52
Q

What is the mechanism of echinocandins?

A

Target site modification - FKS1 and FKS2 (encode 1,3 B-D glucan synthase)

Medical Microbiology (23 decks)

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