systemic antifungal agents spectrum indications precautions
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SYSTEMIC ANTIFUNGAL AGENTS
SPECTRUM
INDICATIONS
PRECAUTIONS
DR ALPAY AZAP
Ankara University Medical School
Infectious Diseases and Clinical Microbiology Dept
0
2
4
6
8
10
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14
1950 1960 1970 1980 1990 2000
Nys
tatin
Am
phot
eric
in B
(195
8)
Gris
eofu
lvin
5-FCMiconazole
KetoconazoleFluconazole
Itraconazole
L-AmB ABCD ABLC
Terbinafine
VoriconPosacon
XM
P
Sordarins
Cas
po
fun
gin
MicafunRavucon
Ani
du
lafu
ngi
n
# of Antifungals
AZOLEs
POLYENsECHINOCANDINs
AZOLES
ITRACONAZOLE
KETOCONAZOLE
FLUCONAZOLE
VORICONAZOLE
POSACONAZOLE
RAVUCONAZOLE
POLYENS
NYSTATIN
AMPHOTERICIN B
Deoxycholate
Lipid formulations
ECHINOCANDINS
CASPOFUNGIN
ANIDULAFUNGIN
MICAFUNGIN
ECHINOCANDINS
Candida spp.
Aspergillus spp.
Cryptococcus neoformans
Trichosporon spp.
Fusarium spp.
Zygomycetes
Scedosporium spp.
Pseudoallescheria spp.
SUSCEPTIBLE
INHERENTLY RESISTANT
CASPOFUNGIN
Indications: Invasive candida infections
Esophageal candidiasis
Empirical antifungal tx of FEN
IPA resistant or intolerant to OLAT
Dosing regimen: IV, 70 mg loading dose, 50 mg/day maintenance
Age; 3 months-17 years: 50 mg/m2/day
Dose alteration: No dose alteration in renal dysfunction
In moderate hepatic failure 35 mg/day maintenance
CASPOFUNGIN
Side effects: Fever (>%10), Raised LFTs (%1-10) Hypokalemia (%1-10) Nausea/vomiting (%1-10) Histamine mediated symptoms ?
Drug interactions: No contraindicated concomitant drugs.
Cyclosporine may increase caspo levels and increase LFTs
Rifampicin caspo dose should be 70 mg/kg/day
70 mg/kg/day may be requiredPhenytoin, Carbamazepine, Dexamethasone,Efavirenz, Nevirapine
ANIDULAFUNGIN
Indications: Invasive candidiasis (Non-neutropenic patients)
Esophageal candidiasis
The single candin compared with fluconazole in candidemia
Reboli C et al. New Engl J Med 2007;356:2472-82
Dosing regimen:
Invasive candidiasis: 200 mg/d loading, 100 mg/d maintenance
Esophageal candidiasis: 100 mg/d loading, 50 mg/d maintenance
Not approved for use in children.
Dose alteration: No dose alteration needed in renal/hepatic failure
Side effects: Gastrointestinal (%3-26)
Hypokalaemia (%1-10)
Fever, rash (%1-10)
Raised LFTs (%1-10)
Drug interactions: No contraindicated concomitant drugs.
No need for dose alteration of co-administered drugs
Plasma level monitoring is not recommended
ANIDULAFUNGIN
MICAFUNGIN
Indication: age ≥16 y: Invasive candidiasis Esophageal candidiasis Prophylaxis in Allo HSCT/prolonged neutropenia IPA treatment in non-responsive/intolerant pts.
age<16 y: Treatment of invasive candidiasisProphylaxis in Allo HSCT/prolonged neutropenia
Dosing regimen : IV, therapeutic dose in candidiasis: 100 mg/d prophylaxis: 50 mg/d
Dose alteration: No dose alteration needed in renal/hepatic failure
Side effects: Nausea, vomiting (%1-10)
Hypokalaemia (%1-10)
Fever, rash (%1-10)
Raised LFTs (%1-10)
Anaphylactoid reactions (<%0.1)
Intravascular haemolysis (rare)
MICAFUNGIN
Drug interactions: No contraindicated concomitant drugs.
Plasma level monitoring is not recommended
Increase sirolimus, nifedipine and ıtraconazole levels
AZOLES
Triazoles: Fluconazole
Itraconazole
Voriconazole
Posaconazole
Ravuconazole
IsavuconazoleDifferent antifungal activity / indications for use
Important drug interactions!
Each has different formulations!
ITRACONAZOLE
Indications:
Alternative option in treatment of IPA
Alternative option in treatment of candidiasis (neutropenic host)
Alternative option in treatment of oral/esophageal candidiasis
First line treatment of ABPA and allergic aspergillus sinusitis
First line treatment of chronic cavitary pulmonary aspergillosis
Prophylaxis in neutropenic/allogeneic HSCT patients
Dosing regimen: oral capsule, oral solution, IV solution
Mucocutaneous candidiasis: 200mg/d oral solution
Treatment or prophylaxis in Aspergillosis:
2x 200mg for first 2 days, 200mg/d maintenance
Plasma level should be monitored weekly (target: >500ng/ml)
Side effects: Nausea, vomiting (%10-28)
Hypokalaemia (%1-10)
Fever, rash (%1-10)
Raised LFTs (%1-10)
ITRACONAZOLE
Drug interactions: Use with;
Quinidine, dofetilide, pimozide, nidazolam, triazolam,
cisapride, lovastatine, simvastatine is CONTRAINDICATED
Raised Tacrolimus, sirolimus, cyclosporine levels!
Macrolide antibiotics, indinavir, ritonavir increase ITRA levels
VORICONAZOLE
Indications:
First line treatment of IPA
Treatment of candidiasis (fluconazole resistant strains)
Tx of Scedosporium apiospermum and Fusarium spp
Dosing regimen: IV, oral tablets, oral suspension
IV: 2 x 6 mg/kg first day, 2 x 4 mg/kg maintenance
Oral: 2 x 400 mg first day, 2 x 200 mg maintenance
Children: IV: 2 x 7mg/kg, oral: 2 x 200 mg
Dose alteration:
Renal failure: No need for oral formulations
IV formulation should not be given to pts
with a creatinine clearence <50 ml/min
Hepatic failure: Mild-moderate impairment one half maintenance dose
Use not recommended in severe impairment
VORICONAZOLE
Side effects: Transient visual disturbance: Photopsy (%20-30)
Rash, photosensitivity (%7)
Raised LFTs (%1-10) (should be monitored every 2 weeks)
Headache, vomiting, diarrhoea, abdominal pain (%1-10)
Hallucination (%5)
Drug interactions: Use with;
Carbamazepine, phenobarbital, sirolimus, rifampicin, ritonavir,
terfenadine, astemizole, cisapride, pimozide, quinidine, ergot alkaloids
is CONTRAINDICATED
VORICONAZOLE
Plasma level monitoring:
In selected pts (serious and/or unresponsive IFI )
Target levels: 2-6 mg/L
Cyclosporine dose should be reduced to one half and its serum
levels monitored
Omeprazole dose should be reduced to one half
Tacrolimus and methadone will require dose reduction
If co-administered with phenytoin vori maintenance dose: 2 x 5 mg/kg
POSACONAZOLE
Indications:
Prophylaxis in AML/MDS pts receiving chemotherapy
Prophylaxis in Allo HSCT pts with GVHD
Treatment of severe oropharyngeal candidiasis
Dosing regimen: Oral suspension
Prophylaxis: 3 x 200 mg with meals
Salvage therapy: 2 x 400 mg or 4 x 200 mg with meals
Children: should not be used in age <18 y (EU)
can be used in age >13 y (USA)
Salvage therapy for IPA (EU)
Alternative option in tx of IPA (IDSA)
POSACONAZOLE
Dose alterations:
Renal failure: No dose adjustment, bevare of “breakthrough” infections
Hepatic failure: Limited data available. Use with caution!
Side effects: Nausea, vomiting, diarrhoea (%1-10)
QT/QTc prolongation (%1-10)
Headache, rash (%1-10)
Hypokalaemia (%1-10)
Drug interactions: Use with;
Terfenadine, astemizole, cisapride, pimozide,
quinidine, ergot alkaloids is CONTRAINDICATED.
Cyclosporine dose should be reduced to 3/4, Tacrolimus to 1/3,
and drug levels should be monitored.
Rifabutin, midazolam, phenytoin, vincristine levels are increased
Cimetidine, rifabutin and phenytoin decrease POSA levels.
POSACONAZOLE
Plasma level monitoring:
Needed in selected pts (serious and/or unresponsive pts)
Target levels: >1.5 mg/L (after 7 days therapy)
Clin Infect Dis, 2008; 46:1401–8
271 pts, 407 neutropenic episodes, Placebo vs Liposomal Ampho B
2,5 ml of a 5 mg/ml solution 30 minutes inhaled, two consecutive days
Halolite AAD veya ProDose AAD; Romedic/Medic-Aid.
Particule size: 1.9 mikron
L-AmfoB: 6 /139 (4%) IPA
Placebo: 18 /132 (14%) IPA (p=.005)
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