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

12

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)