Antifungals & Antivirals Flashcards
recap of fungal infection :
- Epidemiology
– Incidence increasing / Opportunistic infections - Clinical presentation
– In immunosuppressed patients may present insidiously
– Leading to poor response to treatment - Diagnosis
– May take > 3 days to grow & some difficult to identify - Treatment
– Source control: drainage / debridement / device removal
– Successful outcome more likely if effective agent available
fungi are—
* Unlike bacteria they have similar
cellular structure to — cells
* Therefore, greater challenges in
developing effective antifungal
agents that are not also toxic to
human cells
* So the mechanisms of action aim
to target specific fungal structures
/ process
* Needs to be – but also — !
eukaryotes
human
effective n specific
anti fungal mechanism:
1. Act on —
– Disrupts or inhibits production of —
– Leads to — cell —
– Polyenes, azoles, terbinafine
2. Act on fungal —
– Interferes with —
– Echinocandins (the “-fungins”)
3. Interfere with – & – synthesis
– 5-flucytosine
4. Interfere with — metabolism
– Co-trimoxazole/TMP-SMX (also an antibacterial) used to treat Pneumocystis jirovecii
cell membrane
ergosterol ( so basically any anti fungal that ends w azole )
increased cell permeability
cell wall
beta-1,3 glucan synthesis ( as enchinocandins : caspofungin n andiulofungin )
dna and rna synthesis ( as flucoytsoine )
folate
polyenes:
1. Commonly used agents
– Amphotericin B & Nystatin
2. Mechanism of action
– Disrupts — in –
– Increased —
3. Spectrum
– – activity: — and —
– Aspergillus spp, Mucorales
spp
4. Route
– Amphotericin: —
(IV only)
– Nystatin: —
(mouthwash, drops)
5. Toxicity
– — toxicity, –
– – formulation fewer
side effects (liposomal
amphotericin = Ambisome)
6. Resistance
– –
– – lusitaniae
ergosterol in cell membrane
increased cell permeability
broad
easy n mould
systemic
topical
renal , rigors
lipid
rare
candida
azaloles :
1. Commonly used agents
– Fluconazole
– Voriconazole
– Posaconazole
– Isavuconazole
– Miconazole
2. Mechanism of action
– Affects —
– Inhibits an – necessary for –
biosynthesis
3. Spectrum
– Fluconazole: no activity
against — e.g. Aspergillus sp.
– Voriconazole has — and –
activity
4. Route
– Topical: miconazole
– Systemic: (PO & IV):
* Fluconazole
* Voriconazole
* Posaconazole
* Isavuconazole
5. Toxicity
– —
– — interactions
– Rash (esp. — )
– – disturbances or —
(—)
6. Resistance
– C. krusei intrinsically
resistant to —
– C. albicans usually
susceptible to — but can acquire resistance
– C. auris (emerging spp.)
more resistant to –
* Variable resistance to others
* Can be — resistant
cell membrane
enzyme
erogesterol
miould
mould n candida
heptaptixty
CYP450.
rash especially voriconzole
visual ditrusbances n hallucination ( voriconazole)
fluroconzole
fluroconzole
fluroconzole
multi drug
enchinocandins:
1. Commonly used agents
– Caspofungin
– Anidulafungin
2. Mechanism of action
– Interferes with —
synthesis in —
3. Spectrum
– Often — , esp for— infections
– Can be used for some – but not 1st line
4. Route
– – only
5. Toxicity
– Most well —
– — (rare)
6. Resistance
– Many fungi are
intrinsically resistant
– Resistance in Candida
sp. is rarer but can
occur e.g. C. auris
glucan in cell wall
1st line
systemic candida
mould
iv only
well tolerated
heptaoxity
terbinafine :
. Commonly used agents
– Terbinafine
2. Mechanism of action
– Disrupts — biosynthesis
3. Spectrum
– For treatment of:
* Tinea ( – )
* Onychomycoses (fungal –
infections)
4. Route
– Topical or PO
5. Toxicity
– Very well –
topically
– If PO, monitor LFTs
* Can cause —
6. Resistance
– — resistance
becoming an issue
* Particularly in India
ergosterol
ringworm
nail
well tolerated
heptaotxity
dermatophyte
5-flucytosine:
1. Commonly used agents
– Flucytosine
2. Mechanism of action
– Inhibits — synthesis
3. Spectrum
– Not used as— usually
– Mostly —
* Cryptococcus
* Candida
4. Route
– IV or PO
5. Toxicity
– —-
suppression
– – / — dysfunction
– — toxicity
– —
6. Resistance
– Variable particularly
among Candida spp.
– Not used as — due to
development of
resistance
rna and dna
monotherpau
yeast
bone marrow
liver n renal
gi
neurotoxity
monotherpay
choice of agents:
Superficial Mycoses:
* — infections:
– — for 1-4 wks
* Extensive – / –
infections:
– PO for 2-10 wks
* Onychomycosis:
– Duration until — grows out
– Terbinafine: 6-12 wks
– Itraconazole: 1 wk/mo x 3
mos.
* Candidiasis:
– Topical — or —
+/- PO agent
Systemic Mycoses:
* — — fungal infection
(empiric therapy):
– Liposomal amphotericin B
*— infection due to Candida spp:
– Caspofungin (empiric)
– Fluconazole
* Invasive —- :
– Voriconazole
* Cryptococcal —-:
– Liposomal amphotericin B +
flucytosine
* P. jiroveci (carinii) infection:
– Co-trimoxazole, high dose IV
* Drug of choice
– Adjunctive corticosteroids
superficial
topical
skin n nail
nail
topical zones pr polynes
unknown invasive
invasive infection
invasive aspergillosis
anti fungal prophylaxis:
HIV+ patients:
* low — & — viral load
* NB: Pts on HAART with viral
suppression do not need
long-term prophylaxis
* anti-Candida: —
* anti-PJP PO —
* Following treatment for
cryptococcosis: —
HaemOnc & Transplant:
* — for >10 days due to
disease or chemotherapy
* — (solid organ or stem-
cell)
* anti-Candida: —
* anti-aspergillus (for at-risk pts) – –also protects
against Candida
summary :
* More new antifungal agents being developed than for bacteria
* Superficial infections treated with — agents
* Systemic infections require – or –
* Fluconazole has a — spectrum
* Liposomal amphotericin B or caspofungin for initial empiric treatment if patient very ill
* Co-trimoxazole for —
* Certain patient groups receive prophylaxis
low cd4 , high
fluconazole
co trimoxazole
fluconazole
neutropenia
transplant
fluconazole
posaconzole
topical
po OR iv
narrow
penumocytis
anti virals:
* Most viral infections are — & specific agents are — as : Common cold & norovirus
* Challenges in developing anti-viral agents include:
– — vs – pathogens
– —
* Dormant for – : herpes viruses (HSV, VZV, CMV, EBV)
– Lack of – systems for some viruses
– Uncertainty regarding many viral — functions & — properties
* — for the development of new agents
– HIV/AIDS: we know more about immune system & viral pathogenesis
– — -related viral infections: e.g. Herpes viruses
– New & emerging — threats: e.g. COVID-19, Ebola, Avian influenza
self limiting
unnecessary
intra celular vs extra
latency
years
culture
genetic function n pathogenic properties
stimulus
transplant
viral
anti viral mechanism of action 1:
Virucides = — inactivation of intact viruses
* — , hence importance of hand hygiene with the — & –
* – inactivation
– Safety issues!
* — , – or — for treatment of – and —-
anti viral mechanism of action 2: — / Modification of – Response
* These — deficient host immune responses &/or enhance endogenous ones as: Immunomodulatory
* Immunoglobulin (high titre) — exposure:
– Varicella zoster immunoglobulin (VZIG)
– Also immunoglobulin for:
* CMV, ex. – mismatch
* Rabies, ex. —
* Hep B, ex.— stick injury
* Interferon (ex. — )
3rd mechanism includes inhibition of — such as:
1. Aciclovir
2. Valaciclovir
3. Ganciclovir
4. Valganiciclovir
5. Foscarnet (non-nucleoside
polymerase inhibitor)
6. Cidofovir
7. Anti-influenza agents
direct
detergent
common cold and influenza
uv light
cryotherapy
laser
podophyllin
warts and gential warts
augmentation
host response
replace
after
transplant
animal bite
needle
hepatitis
viral replications ( we will focus on 1 3 6 7 )
aciclovir:
Mechanism of action
* Analogue of —
– Needs to be — to achieve
antiviral effect
* Initial — step by viral
—- activated drug
* Phosphorylated to —
(active form) within infected cell
* Incorporated into growing — chain
* Leads to chain —
* Also a direct inhibitor of viral —
- spectrum:
* Active against – & – , —
* Drug of choice for — infections
– HSV encephalitis
– Neonatal HSV
– Disseminated HSV
– Disseminated VZV
– Severe varicella pneumonia
route : iv or po
limited toxicity:
* As active form only present
in virally infected cells
* – can occur
clinical use:
* Recurrent — infection
* — HSV infection
* — (— )
* Prophylaxis of — in immunocompromised
patients
guanosine
activated
phosphorylation
viral thymidine kinase
triphosphate
dna chain
termination
dna oolymerase
HSV1 , 2 VZA
serious
nephrotoxity
genital HSV
orolabial
zoster shingles
hsv
variations of aciclovir:
Valaciclovir:
* A —
– Valyl – of aciclovir
* — absorbed from –
* 1st pass – & — hydrolysis yields
complete conversion to —
mainly used for —- , —
Ganciclovir
* Derivative of aciclovir
* 1st antiviral agent
with activity vs –
* IV administration for:
– –
– –
– –
used for:
– Primarily impaired — -
mediated immunity
* Ex. – , post —
– CMV pneumonia, colitis,
encephalitis, retinitis
– Side effects:
* —
* —
pro drug
ester
rapidly
GIT
intestinal and heptatic
acicilovir
HSV and VZV
CMV
HSV 1 ,2
VZV
CMV
used for:
cell mediated immunity as HIV and post transplant
neuropenia and thrombocytopenia
foscarnet:
Mechanism of action
* — analogue
* Forms complexes with — inhibiting
further —
Route
* IV. Poor PO bioavailability
Spectrum + Clinical uses
* Ganciclovir-resistant —
* CMV—
*—–resistant mucocutaneous HSV or VZV
Toxicity limits widespread
use
* Side effects:
– —
– –
– — abnormalities
– — & —
– Infusion-related –
Pyrophosphate
dna polymerase
dna sythesis
cmv
retinitis
acicolvir
side effects:
– Nephrotoxicity
– Seizures
– Metabolic abnormalities
– Anaemia & neutropenia
– Infusion-related nausea
cidofovir:
Mechanism of action
* — active form
* — inhibitor of viral—
Spectrum
* — spectrum anti- — activity
* Developed primarily as a — agent
Clinical uses
* Resistant CMV
– Ganciclovir & foscarnet
* Resistant HSV
* CMV retinitis
* Adenovirus infection in stem
cell transplant recipients
Toxicity
* — dependent
* — , –
triphosphate
competitive inhibitor of viral dna polymerase
broad
anti herpesvirus
anti cmv
dose
nephrotoxity , nerupenis
anti influenza agents:
1- Oseltamivir (Tamiflu)
Mechanism of action
* —- (NA) inhibitor
* Specific for influenza A & B NA
* Some resistance has emerged, though not yet a widespread problem
Route: – formulation, well tolerated
Clinical uses
* Give within — of symptom onset to patients at risk of severe infection
– Reduces — & – of symptoms
* Can also be given as – to exposed ‘at-risk’
patients
2- Zanamivir
Mechanism of action: – inhibitor
Route
* — agent via — & also — formulation
* Contraindicated in:
– – patients
– Children <–
* Used much – than
oseltamivir
Neuraminidase
oral
48 hours
duration n severity
prophylaxis
NA
inhaled via inhaler
iv
COPD
<7
less
ANTI-SARS-COV-2 AGENTS:
PaxlovidTM: PF-07321332
(Nirmatrelvir)/Ritonovir
PO x 5 days
* Available since April 2022
* Recommended for those
at risk of severe disease:
unvaccinated, vaccinated
>75yoa or >65yoa with
risk factors
* To be given within 5 days
of symptom onset in
confirmed COVID-19
Remdesivir IV x 3 days
* Unvaccinated >18yoa at
risk of progression to
severe COVID-19
* To be given within 7
days of symptom onset
and within 4 days of a
confirmed COVID-19
diagnosis
other anti viral agents:
- Nucleo(t)ide analogues
- Pegylated interferon α (PEGIFNα)
- …to be covered in Year 2 GIHEP Module
(Viral Hepatitis)
summary :
* Most viral infections are —
* Many antivirals in clinical use inhibit – at the — level or augment – response
* Antivirals against herpes, influenza & hepatitis viruses are the — clinically used
– Excluding anti-HIV agents
* Major recent changes in the treatment of Hepatitis C make the virtual eradication of Hep C possible
* — for post-exposure prophylaxis
self limiting
clinical
cellular level
host
most
immunoglobin
