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Microbiology > antifungal therapy > Flashcards

antifungal therapy Flashcards

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1
Q

Why should you care about antifungal therapy?

A

The number of immunocompromised patients at risk for invasive fungal infection (IFI) is large
Hematology and oncology patients
Solid organ transplants
Rheumatology, GI patients on biologics

This number is expected to increase acutely in SHR in the near future
Allo-Stem Cell Transplant program
HIV epidemic

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2
Q

What was the antifungal therapy before 1990?

A

AMPHOTERICIN B!!!!!!!!!!! FOR EVERYTHING!!!!!!!!!!!

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3
Q

What is special about amphotericin B? how should you administer it? What are the toxicities of it?

A

Discovered in 1950s
Still broadest spectrum agent available

Almost always administered IV

Toxicities:
Infusion-related = “shake & bake” premedication
Nephrotoxicity, marrow suppression

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4
Q

What type of ampho. B preparations are there?

A

Amphotericin B deoxycholate

Lipid-complexed formulations:

amphotericin B lipid complex
(ABLC /Abelcet)

liposomal amphotericin B
(L-AMB /AmBisome)

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5
Q

What is the mechanism of action of amphotericin B?

A

Binds to ergosterol in the fungal cell membrane

Altered membrane permeability with resulting leakage of cellular components

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6
Q

What is AMPs spectrum of activity?

A
  • candidiasis, cryptococcosis
  • histoplasmosis, coccidioidomycosis, blastomycosis
  • Aspergillosis
  • zygomycosis (mucormycosis)
  • sporotrichosis, trichosporidiosis, fusariosis, phaeohyphomycosis
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7
Q

What are the toxicities of AMB?

A

Nephrotoxicity
Dose dependent
Concomitant agents
Less with lipid formulations

Infusion related
Fever, rigors predominate
Differences between the formulations

With the lipid formulation of AMB. there were less patients with hindered glomerular function.

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8
Q

What are the cost issues with AMB deoxycholate and lipid formulations?

A

Amphotericin B deoxycholate:
Usual dose 40-80 mg/day = $40-60

Lipid formulations: 		
Usual daily dose 5 mg/kg
$ hundreds per day
$800-$1000/day 5 years ago
Dropping significantly due to new alternatives
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9
Q

What are the recommendations for use for Lipid AmB. in saskatoon health region?

A

Invasive fungal infections refractory to conventional AmB

Patient intolerant of conventional AmB

Renal dysfunction
- Pre-existing or developing on AmB

Selected difficult to treat pathogens

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10
Q

What are the marketed systemic antifungal agents?

A

amphtericin B, Azoles, Echinocandins (e.g. caspofungin)

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11
Q

What are the targets of these antifungals?

A 
Membrane ergosterol
Direct damage
     - Polyenes
             - Amphotericin B, Nystatin
Synthesis inhibited
      - Azoles
                 - Keto-, Flu-, Itra-, Vori- and Posaconazole
     - Allylamine
                 - Terbinafine
Cell wall Glucan synthesis
 - Echinocandins
             - Caspo-, Mica- and Anidulafungin
  - Several other targets under investigation
  • Nucleoside analogue
    - Flucytosine (5-FC)
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12
Q

What are invasive mycoses?

A

Invasive candidiasis
Despite safer therapies, significant crude and attributable mortality rates remain

Invasive Aspergillosis
Treatment outcomes poor due to severely immunocompromised patients
Recent emphasis on prophylaxis

Miscellaneous mycoses
Zygomycetes, many uncommon moulds
Cryptococcus neoformans, C. gattii

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13
Q

What still remains to be the easiest stemic antifungal to use in invasive candidiasis? and why, or why not?

A

Fluconazole remains the easiest systemic antifungal to use
Well absorbed orally, IV uncomplicated
Well tolerated, few significant drug interactions
BUT resistance can be an issue

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14
Q

What is fluconazole?

A

Water soluble
Oral tabs, solution
IV

Excellent safety profile

Activity

  • Most yeasts
  • Moulds variable
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15
Q

What are the echinocandins?

A

Semisynthetic derivatives of Echinocandin B, naturally synthesized by A. nidulans

Inhibit β-(1,3)-D-glucan synthase

in vitro and animal activity:
Candida spp. (including azole-resistant strains)
Aspergillus spp.
Not Cryptococcus species

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16
Q

What is caspofungin?

A

Approved in Canada in 2004
Treatment of Invasive Aspergillosis in patients refractory to or intolerant of other therapies

Empirical therapy for presumed fungal infection in febrile, neutropenic patients

Treatment of Invasive Candidiasis
Candidemia, intra-abdominal abscesses, peritonitis, pleural space infections

Treatment of Esophageal Candidiasis

17
Q

What is micafungin?

A

Approved in Canada in 2007:
Candidemia, acute disseminated candidiasis, Candida peritonitis and abscesses (100 mg/d)
Esophageal candidiasis (150 mg/d)
Prophylaxis in patients undergoing hematopoetic stem cell transplantation (50 mg/d)

Major route of elimination is fecal excretion
No adjustments for renal failure, dialysis, mild or moderate liver dysfunction

18
Q

What is anidulafungin?

A

Approved in Canada in 2008 for:
Treatment of invasive candidiasis/candidemia in adult non-neutropenic patients

Chemical degredation
No renal clearance or hepatic metabolism
No adjustments, no CYP interactions

19
Q

What is the word then on invasive candidiasis?

A

Fluconazole remains the easiest systemic antifungal to use
Well absorbed orally, IV uncomplicated
Well tolerated, few significant drug interactions
BUT resistance can be an issue

Echinocandins
As safe as FLU
Cover most FLU resistant strains
might be more effective even for susceptible strains
Cost is dropping (competition)
20
Q

What is invasive aspergillosis/?

A 
Invasive aspergillosis
~ 60% case-fatality rate
1990’s US hospital discharge data:
10,000 hospitalizations, 2000 deaths, $633M
Cumulative 12 mo. incidence @ 12 centers
Auto SCT				0.5%
Matched, related allo		2.3% 
Mismatched, related allo	3.2%
Unrelated donor SCT		3.9%

New procedures likely will increase risk
Nonmyeloablative conditioning, T-cell depletion

21
Q

What is the treatment of choice for invasive aspergillosis?

A

Voriconazole

considered to be the treatment of choice for proven or probable IA

22
Q

What is voriconazole?

A

aka Vfend
Twice daily dosing, IV and oral forms

Variable po bioavailability

Most metabolized: CYP2C19
No renal failure adjustment
Voriconazole IV solubilizer accumulates in renal failure

Transient ocular symptoms at time of peak levels

23
Q

what is voriconazole used for?

A

Spectrum (in vitro, animals):
Candida spp., including many flu-resistant
Cryptococcus and Aspergillus species
Dimorphic fungi

“Difficult” filamentous organisms
Fusarium spp.
Trichosporon spp.
Pseudallescheria boydii
Scedosporium prolificans
24
Q

What are some indications for use of variconazole?

A

Canadian approval in 2005:
Invasive aspergillosis

Candidemia in non-neutropenic patients

Invasive candidiasis involving other sites
Dissemination involving skin
Abdomen, kidney, bladder wall, wounds

25
Q

So what are the guidelines of invasive aspergillosis?

A

Primary
“Most pts”: Voriconazole; IV initially if seriously ill
“Alternative in some pts”: Liposomal AMB (L-AMB)
Combination therapy not routinely recommended

Alternatives
L-AMB 3-5 mg/kg/d
ABLC 5 mg/kg/d 
Caspo 70      50 mg/d
Micafungin 100-150 mg/d
Posaconazole 200 mg po qid       400 mg po bid

Duration “not well defined”
Minimum of 6 to 12 weeks
In immunosuppressed patients:
“…therapy should be continued throughout the period of immunosuppression and until lesions have resolved.”
Resume therapy if immunosuppression is required after successful IA treatment

26
Q

So what is considered still to be the treatment of choice for proven or probable invasive aspergillosis?

A

Voriconazole
Considered to be the treatment of choice for proven or probable IA
However, IA mortality rate remains high, prompting:
Evaluation of relationship between drug levels and outcomes for patients on oral VORI
Search for earlier diagnostic signals
Investigation of mould-active prophylaxis

27
Q

What are challenges to voriconazole ?

A

Challenges:
Oral bioavailability unpredictable
Nonlinear pharmacokinetics
Variability in metabolism rates

Many published references indicate:
Trough levels < 1 μg/ml assoc with failure
Trough > 5μg/ml assoc with hepatotoxicity

We send to the Mayo Clinic

28
Q

What are some predisposing conditions for zygomycosis?

A

Predisposing conditions
DM (36%), malignancy (17%) SOT (7%), IVDU (5%), BMT (4%), prematurity (3%), HIV (2%)

zygomycosis is increasing

29
Q

What is the survival like for zygomycosis and what are the sites of infection and the survival based on that?

A

Survival:
surgery + antifungals = 70%, no therapy = 3%
AmB alone = 61%, Surgery alone = 57%

Sites of infection	   	     Survival
Sinus* 	 	    (39%) 	    	54%
Pulmonary 	    (24%)		37%			
Disseminated     (23%)		4%
Cutaneous 	    (19%)		85% 
Gastrointestinal   (5%)		15%
30
Q

What is the therapy for zygomycosis?

A

Combined medical & surgical often recommended

Previously, only Amphotericin B preparations

Posaconazole active in vitro, in animal models; some successful outcomes reported in human cases

Investigational agents (e.g. Isavuconazole) look promising

31
Q

efficacy, tolerability, and cost convenience is best for what antifungals?

A

AmB + - +-
Lipid AmB + +/- - -
Fluconazole +/- + + +

echinocandins + + +/- -
vori + + +/- +/-
posa (prophylaxis) + + - +

32
Q

What are some other agents?

A

Nystatin

  • Polyene currently used topically
    - Oropharyngeal, vaginal candidiasis

Flucytosine

  • Cytosine analogue, inhibits RNA synthesis
  • Usually combined with AMB

Terbinafine

  • Inhibits lanosterol synthesis
  • Topical, oral; often used for dermatophytes

Microbiology (13 decks)

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