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Chemotherapy BMSC2210 > Lecture 11 Pyrimidine and Polyenes > Flashcards

Lecture 11 Pyrimidine and Polyenes Flashcards

1
Q

Name the one example of a pyrimidine

A

5-fluorocytosine

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2
Q

By which enzyme is 5-flurocytosine taken up by fungi?

A

Cytosine permease

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3
Q

Explain the mode of action of 5-flyrocytosine

A

inhibits 2 of the following pathways:
5-fluorocytosine → Fluorouridine monophosphate (FUMP) → fluorouridine triphosphate (FUTP) → incorporation in RNA → disrupts translocation

5-fluorocytosine → fluorodeoxyuridine monophosphate (FdUMP) → inhibition of thymidylate synthetase → inhibition of DNA synthesis

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4
Q

Which fungi is 5-fluorocytosine active against?

A

Generally yeast: Cryptococcus neoformans, most candida, some dematiaceous (brown) molds

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5
Q

Which fungi is 5-fluorocytosine inactive against?

A

Candida krusei
Aspergillus spp.
Histoplasma capsulatum
Most molds

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6
Q

Why is 5-fluorocytosine used in combination with amphotericin B/fluconazole?

A

Risk of resistance developing quickly in monotherapy

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7
Q

What uses is 5-fluorocytosine licensed for?

A

Treatment of systemic fungal infections caused by candidosis, cryptococcosis and chromoblastomycosis (brown mold)
Main use with amphotericin B in cryptococcal meningitis

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8
Q

Describe the study that explains the efficacy of amphotericin B and fluorocytosine by Bennett et al, (1979)

A

27 patients treated with amphotericin B alone and 24 treated with amphotericin B + fluorocytosine
Mortality rate found to be similar
Combination therapy showed: more rapid CFS sterilization, a lower rate of relapse.

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9
Q

Describe the study that explains the efficacy of fluorocytosine monotherapy vs combined by Day et al, (2013)

A

Cryptococcal meningitis in HIV-AIDS
3 groups: Amp B only, Amp B + fluorocytosine, Amp B + fluconazole
Mortality at 2 weeks as follows:
Amp B 25%, Amp B + fluorocytosine 15%, Amp B + fluconazole 22%
Therefore combination therapies were more effective

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10
Q

Explain the absorption of 5-fluorocytosine

A

readily absorbed
wide distribution in tissues and body fluids e.g. almost the same levels in CFS as in the blood
Minimally absorbed by gut flora due to lack of deaminase

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11
Q

What is the half-life of 5-fluorocytosine?

A

3-6 hours

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12
Q

What is the normal dose of 5-fluorocytosine given?

A

3-4 doses a day

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13
Q

How is 5-fluorocytosine excreted?

A

mainly via urine

Therefore a good choice for UTIs as a monotherapy - though there is still a risk of resistance

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14
Q

What are the side effects associated with 5-fluorocytosine?

A

> 100mg/L for 2 weeks = risk of bone marrow suppression - leucopenia, thrombocytopenia, aplastic anemia
Rare: allergic reactions, liver toxicity

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15
Q

What drugs are known to interact with 5-fluorocytosine?

A

Brivudine (antiviral) - inhibits dihydropyrimidine dehydrogenase (DPD) which normally degrades fluorouracil = can lead to fluorouracil toxicity

Phenytoin - higher levels of phenytoin may occur

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16
Q

Which fungi are particularly vulnerable to developing resistance to 5-fluorocytosine?

A

Candida sp. and Cryptococcus

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17
Q

Explain the mechanism of action of resistance to 5-fluorocytosine

A

1) Most mutations occur to the uracil phosphoribosyltransferase (UPRT) → inhibition of protein synthesis.
2) Mutations also occur to the cytosine permease and cytosine deaminase →inhibition of thymidylate
synthetase ∴ disruption of DNA synthesis

18
Q

What are the 2 examples of polyene antifungals?

A

Nystatin

Amphotericin B

19
Q

Where is the source of polyene antifungals?

A

natural products of Streptomyces species

20
Q

What is the mode of action of polyene antifungals?

A

damage to cells by increasing cell permeability = K+ release
Bind to ergosterol via the hydrophobic side of macrolide rings → distortion of membrane bilayers = leakage
Also theory of damage through auto-oxidation of amphotericin B but the exact mechanism is unknown

21
Q

Explain the spectrum of activity for amphotericin B

A

Broad spectrum
Most yeasts/molds are sensitive
Visceral Leishmania
Exceptions: Aspergillus terreus, most Scedosporium, and Lomentospora are resistant

22
Q

What was the problem associated with amphotericin B deoxycholate and how was this overcome?

A

Deoxycholate was associated with infusion-related kidney toxicity - now rarely used
Ambisome produced - a lipid-based formulation that has fewer side effects

23
Q

In what form is nystatin given?

A

topical
not orally absorbed
too toxic for IV

24
Q

What is Amphotericin B indicated for?

A

Empirical treatment for suspected fungal infections in immunocompromised patients
Treatment of a wide range of fungal infections including candidosis, aspergillosis, zygomycosis, and cryptococcosis
Treatment of visceral leishmaniasis
Occasional topical use e.g. eyes, mouth, ears

25
Q

What is Nystatin indicated for?

A

treatment of oral or vaginal candidosis

26
Q

What signs/symptoms would a patient present with that would prompt a clinician to give amphotericin B as an empirical treatment?

A

Neutropenia

Pyrexia

27
Q

Explain the evidence for the use of amphotericin B as empirical therapy

A

early studies comparing amphotericin and placebo
Improvement in survival from fungal infections
No overall increase in survival from empirical therapy
Many problems regarding side effects seen

28
Q

Explain the study that compares Ambisome and amphotericin deoxycholate by Walsh et al, 1999

A

687 patients on either Ambisome or an amphotericin B for persistent febrile neutropenia despite antibacterial therapy - 50% had leukemia
Amphotericin B deoxycholate = 49.4% success
Ambisome 50.1% success

Therefore no difference in success but fewer side effects with Ambisome

29
Q

Explain the study that compares Ambisome and other agents for empirical therapy

A

Ambisome vs virconazole:
Ambisome = 31% success
Virconazole = 26% success

Ambisome vs caspofungin:
Ambisome = 34%
Caspofungin = 34%

30
Q

Explain the study that looks into the use of amphotericin as a prophylactic drug

A 
355 acute lymphocytic leukemia patients 
Ambisome vs placebo
Rates of invasive fungal disease (change not significant):
Placebo = 45%
Ambisome = 48%

Therefore no evidence for efficacy as prophylaxis

31
Q

Explain the tissue distribution of Ambisome

A

95% protein bound

High accumulation in liver and spleen, medium in lung and kidney, low in heart and brain

32
Q

What is the half-life of ambisome?

A

initially 24h

later up to 15 days

33
Q

How is ambisome eliminated?

A

43% in bile

21% in urine

34
Q

Does ambisome need drug monitoring?

A

No

35
Q

What are the adverse effects of ambisome use?

A

Acute infusion-related toxicity: fever, chills and rigors, nausea, vomiting, headaches, hypotension
Nephrotoxicity: raised serum creatinine levels, hypokalemia

36
Q

Which side effects have significantly reduced from the use of ambisome compared to amphotericin B deoxycholate?

A

Fever, chills and rigors, vomiting, hypotension

raised creatinine levels

37
Q

What drugs does Amphotericin B interact with?

A

Other nephrotoxic agents: ciclosporin, aminoglycosides, antibiotics, some anti-neoplastic agents
Corticosteroids, diuretics: increases risk of hypokalaemia
Skeletal muscle relaxants - effects of hypokalaemia may heighten the effects of muscle relaxants
Fluorocytosine: nephrotoxicity may reduce fluorocytosine clearance and result in high serum levels = bone marrow suppression

38
Q

Name species that are resistant to Amphotericin B

A

Candida krusei and C. glabrata may have a high minimum inhibitory concentration
C. lusitaniae can develop resistance in vitro
Aspergillus terreus intrinsically resistant
Scedosporium, Lomentospora, and Fusarium are often resistant

39
Q

Explain why there is not a simple mutation-resistance relationship

A

Because the main target of the drug is ergosterol which is not a protein.

40
Q

Explain the mechanisms of action of resistance to Amphotericin B

A

C. lusitaniae - reduced ergosterol content of membranes (Peyron et al, 2002)
C. glabrata - mutation in the ERG2 gene coding for an isomerase involved in ergosterol synthesis = increase in minimum inhibitory concentration
Increased catalase activity may reduce oxidative damage

Chemotherapy BMSC2210 (14 decks)

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