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Chemotherapy intercalation > Lecture 11 Pyrimidine and Polyenes > Flashcards

Lecture 11 Pyrimidine and Polyenes Flashcards

1
Q

Name the one example of a pyrimidine

A

5-flurocytosine

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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-flurocytosine → Flurouridine monophosphate (FUMP) → flurouridine triphosphate (FUTP) → incorporation in RNA → disrupts translocation

5-flurocytosine → flurodeoxyuridine monophosphate → inhibition of thymidylate synthetase → inhibition of DNA synthesis

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4
Q

Which fungi is 5-flurocytosine active against?

A

Generally yeast: cryptococcus neoformans, most candida, some dematiaceous (brown) moulds

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5
Q

Which fungi is 5-flurocytosine inactive against?

A

Candida krusei
Aspergillus spp.
Histoplama capulatum
Most moulds

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6
Q

Why is 5-flurocytosine used in combination with amphotericin B/fluconozole?

A

Risk of resistance developing quickly in monotherapy

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7
Q

What uses is 5-flurocytosine licenced for?

A

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

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8
Q

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

A

27 patients treated with either amphotericin B alone and 24 treated with amphotericin B + flurocytosine
Mortality rate found to be similar
Combination therapy showed: more rapid CFS sterilisation, lower rate of relapse

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9
Q

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

A

Cyptococcal meningitis in HIV-AIDS
3 groups: Amp B only, Amp B + flurocytosine, Amp B + fluconozole
Mortality at 2 weeks as follows:
Amp B only 25/99, Amp B + flurocytosine 15/100, Amp B + fluconozole 22/99
Therefore combination therapies were more effective

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10
Q

Explain the absorption of 5-flurocytosine

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-flurocytosine?

A

3-6 hours

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12
Q

What is the normal dose of 5-flurocytosine given?

A

3-4 doses a day

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13
Q

How is 5-flurocytosine excreted?

A

mainly via urine

Therefore 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-flurocytosine?

A

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

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15
Q

What drugs are known to interact with 5-flurocytosine?

A

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

Phenytoin - higher levels of phenytoin may occur

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16
Q

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

A

can develop quickly for candida and cryptococcus

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17
Q

Explain the mechanism of action of resistance to 5-flurocytosine

A

Most mutations occur to the uracil phosphoribosyltransferase - therefore probably the more important pathway during drug activation
Most mutations also occur to the cytosine permease and cytosine deaminase (see slide for pathway)

18
Q

What are the 2 examples of polyene antifugals?

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 hydrophobic side of macrolide rings = distortion of membrane bilayers = pore for leakage to occur
Also theory of damage through auto-oxidation of amphotericin B though the exact mechanism is unknown

21
Q

Explain the spectrum of activity for amphotericin B

A

Broad spectrum
Most yeasts/moulds are sensitive
The parasite Leishmania
Exceptions: Aspergillus terreus, most scedosporium and lomentospora are resistant

22
Q

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

A

Deoxylate was associated with infusion related kidney toxicity - now rarely used
Ambisome produced - a lipid based formulation that has less side effects (see slide for structure of molecule)

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
Occassional 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 empirical treatment?

A

Neuropenia

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 a amphotericin B for persistant febrile neutropenia despite antibacterial therapy - 50% had leukaemia
Amphotericin B deoxylate = 49.4% success
Ambisome 50.1% success

Therefore no difference in success but less side effects with Ambisome

29
Q

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

A

Ambisome vs virconazole:
Ambisome = 30.6% success
Virconazole = 26% success

Ambisome vs caspofungin:
Ambisome = 33.7%
Caspofungin = 33.9%

30
Q

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

A

355 acute lymphocytic leukaemia 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 lunch and kidney, low in heart and brain

32
Q

What is the half life of abisome?

A

initially 24h

later up to 15 days

33
Q

How is abisome eliminated?

A

43% in bile

21% in urine

34
Q

Does abisome 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 deoxylate?

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 effects of muscle relaxants
Flurocytosine: nephrotoxicity may reduce flurocytosine 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 high minimum inhibitory concentrations
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

Due to the main target of the drug being 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 invoved in ergosterol synthesis = increase in minimum inhibitory concentration
Increased catalase activity may reduce oxidative damage caused

Chemotherapy intercalation (14 decks)

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