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Pharmacotherapy of antifungal drugs. Isabel Spriet Pharmacy Dpt, UZ Leuven. The fungal ‘players’. Opportunistic fungi Normal flora Candida spp. Ubiquitious in our environment Aspergillus spp. Cryptococcus spp. Mucor spp. Invasive fungal infections - Incidence.

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pharmacotherapy of antifungal drugs

Pharmacotherapy of antifungal drugs

Isabel Spriet

Pharmacy Dpt, UZ Leuven

the fungal players
The fungal ‘players’
  • Opportunistic fungi
    • Normal flora
      • Candida spp.
    • Ubiquitious in our environment
      • Aspergillus spp.
      • Cryptococcus spp.
      • Mucor spp.
invasive fungal infections incidence
Invasive fungal infections - Incidence
  • Solid organ transplant: 5-42%
  • Bone marrow transplant: 15-25%
  • ICU: 17%

Singh N. Clin Infect Dis 2000;31:545-53

Vincent JL. Intens Care Med 1998; 24:206-216

candidemia mortality rate
Candidemia – Mortality rate

Hospital acquired pathogens and their associated mortality

Edmond et al. CID 1999; 29:239-44.

slide5

Invasive Aspergillosis – Mortality Rate

Review of 1941 Patients from 50 Studies

Lin S-J et al, CID 2001; 32:358-66

fungal infections today
Fungal infections today

A major change in the

occurence,

diagnosis and

management

of invasive fungal infections has arisen in the recent years.

licensed antifungals a dynamic drug class
Licensed antifungals: a dynamic drug class

To be expected:

isovuconazole – anidulafungin – micafungin …

Posaconazole

Voriconazole

Caspofungin

Lipid amphotericin products

Itraconazole

Fluconazole

Ketoconazole

Flucytosine

Amphotericin B

1950

1960

1970

1980

1990

2000

outline product overview
OutlineProduct Overview
  • Spectrum
  • Therapeutic indications
  • Recommended dosages
  • Pharmacokinetics
    • Pharmacokinetic difficulties and problems
  • Tolerability and safety
  • Therapeutic drug monitoring?
an ideal antifungal agent has
An ideal antifungal agent has…
  • Broad spectrum of activity (yeasts and moulds)
    • Rapidly and highly fungicidal, stable to resistance
    • Potent in vivo activity (even in neutropenia)
  • Good pharmacokinetics (AUC)
    • Both oral and parenteral formulations
    • Good penetration into all tissue compartments
    • Low toxicity, minimal drug-drug interactions
  • Cost effective
amphotericin b target fungal cell membrane
Amphotericin BTarget: fungal cell membrane
  • Ampho B binds ergosterol in the cell membrane
  • depolarisation: leakage of monovalent and divalent cations
    •  cell death
  • stimulates host immune response
amphotericin b spectrum and recommended dosage
Amphotericin BSpectrum and Recommended dosage
  • Spectrum:
    • very broad range of activity: most Candida and Aspergillus spp.
    • active against most fungi except A. terreus, Fusarium spp.
  • Fungicidal
  • Amphotericin B: 1 mg/kg IV (after a test dose of 1 mg)
  • Lipid-based Amphotericin B
    • amphotericin B Lipid Complex: 5 mg/kg IV
    • liposomal amphotericin B: 3 mg/kg IV
amphotericin b pharmacokinetics
Amphotericin BPharmacokinetics
  • Low oral bioavailability: only IV administration
  • Extensive distribution
    • High concentrations in liver, spleen, bone marrow
  • No metabolism
  • Renal excretion
    • Halflife: about 5 days
amphotericin b tolerability and safety
Amphotericin BTolerability and Safety
  • chills, rigors, fever (during infusion)
  • nausea, vomiting
  • cardio/respiratory reactions
  • phlebitis
    • can be explained by mode of action: ampho B stimulates host immune response with release of inflammatory cytokines
amphotericin b tolerability and safety16
Amphotericin BTolerability and Safety
  • Nephrotoxicity: incidence: 49-65%
  • Hypokalemia

can be explained by mode of action: ampho B binds cholesterol in distal tubular membrane leading to wasting of Na+, K+ and Mg++

amphotericin b tolerability and safety17
Amphotericin BTolerability and Safety
  • Nephrotoxicity has been shown to significantly increase:
    • Length of hospital stay
    • Treatment costs
  • Prevention of nephrotoxicity
    • Fluids: saline, sodium bicarbonate
    • Low-dose vasoconstrictors (e.g. dopamine)
    • Alternate day dosing
    • Infusion rates (conventional ampho B: at least 6 hrs)
    • Lipid formulations

Bates DW. CID 2001; 32: 686-93.

Cagnoni PJ. J Clin Oncol 2000; 18: 2476-83.

Greenberg RN. J Med Economics 2002; 2: 109-18.

the azoles target fungal cell membrane
The azolesTarget: fungal cell membrane
  • Azoles inhibit ergosterol synthesis by inhibiting 14-α-demethylase
  • toxic sterol intermediates accumulate in the cell membrane leading to enhanced cellular permeability and inhibition of fungal growth
slide20

Inhibits also human CYP450-dependent enzymes playing an important role in human hormone synthesis or drug metabolism

DRUG INTERACTIONS!!!

fluconazole spectrum therapeutic indications dosage
FluconazoleSpectrum, therapeutic indications, dosage
  • Spectrum: Candida spp. except C. krusei (C. glabrata: reduced susceptibility), Cryptococcus spp.
  • Indications and dosage:
    • Prophylaxis in neutropenic patients: fluco 200 mg
    • Treatment of Candida-infections:

Charlier C. JAC 2006; 57:384-410.

fluconazole pharmacokinetics
FluconazolePharmacokinetics

Charlier C. JAC 2006; 57:384-410.

fluconazole pharmacokinetics24
FluconazolePharmacokinetics
  • Pharmacokinetic problems?
    • Majority unchanged renal excretion

 glomerular filtration+ tubular reabsorption

      • Dose adjustments in severe renal failure
      • Removed by dialysis: 100 mg extra dose after IHD
    • Drug interactions:
      • Inhibits CYP2C9, CYP2C19 and CYP3A4
        • cyclosporin – nephrotoxicity: TDM
        • midazolam: excessive sedation
        • phenytoin: TDM
        • tacrolimus – nephrotoxicity, neurotoxicity: TDM
        • warfarin: INR
      • Rifampicin induces fluconazole metabolism:
        • increase fluco dose with 25%

Charlier C. JAC 2006; 57:384-410.

fluconazole tolerability and safety
FluconazoleTolerability and Safety
  • Generally very well tolerated: no adverse events
  • Side effects only occur in high doses (>400 mg/day)
    • Common: headache, nausea, abdominal pain
    • Elevated AST/ALT levels: generally mild
      • Reported in 10% of leukemia patients with fluco prophylaxis
      • Reported in 20% of ICU patients with fluco prophylaxis
    • Rare: case reports of fulminant hepatitis
    • Very rare:
      • neurotoxicity (high doses > 1200 mg/day),
      • prolongation of the QT interval

Charlier C. JAC 2006; 57:384-410.

fluconazole therapeutic drug monitoring
FluconazoleTherapeutic drug monitoring?
  • No routine indications for measuring fluco levels
    • Predictable fluconazole PK and serum concentrations

Charlier C. JAC 2006; 57:384-410.

voriconazole spectrum of activity
VoriconazoleSpectrum of activity
  • Invasive aspergillosis
    • fungicidal activity as great as ampho B
  • Invasive candidiasis
    • C. glabrata?
  • Fusarium, Penicillium, Scedosporium
  • Cryptococcus
    • in vitro activity > flucytosine or fluconazole
  • ! Zygomycetes: resistant to voriconazole
    • Breakthrough infections

Mashmeyer G et al. Future Microbiol 2006; 1: 365-85.

voriconazole recommended dosage
VoriconazoleRecommended dosage
  • Loading dose: 2 x 6mg/kg
  • Maintenance dose: 2 x 4 mg/kg
    • Infusion over 1hr
  • Adult Patients < 40 kg
    • Loading dose idem
    • Maintenance dose: 2 x 2 mg/kg or 2 x 100 mg
  • Child A and B cirrhosis (Child C: no data)
    • Loading dose idem
    • Maintenance dose: 2 x 2 mg/kg or 2 x 100 mg
  • Children (2-12 yrs)
    • 2 x 7 mg/kg
voriconazole pharmacokinetics31
VoriconazolePharmacokinetics

Voriconazole serum levels: high interindividual variability!

!Difficult pharmacokinetics!

  • Non-linear kinetics: saturable metabolism!
    • Disproportional increase in plasma levels if dosage increased
    • Half-life = dose dependent
    • In children: linear pharmacokinetics: higher metabolising capacity
      • Dosage 7 mg/kg bid
  • Genetic polymorphism CYP2C19
    • 3 genotypes: extensive metabolizers, heterozygous extensive metabolizers, poor metabolizers
    • PM especially in Asian population: 18-23%
    • PM in Caucasion population: 3-5%
    • Plasma levels up to 2-fold (HEM) or 4- fold (PM) higher!

Purkins L et al. AAC 2002; 46:2546-53.

voriconazole pharmacokinetics32
VoriconazolePharmacokinetics
  • Extensive CYP-metabolism: drug interactions!
    • Other drugs affecting voriconazole plasma levels
      • Contra-indicated with potent inducers
        • Rifampicin, ritonavir, carbamazepine, phenobarbital
      • Dose adjustments needed if combined with phenytoin (5 mg/kg bid)
    • Voriconazole affecting plasma levels of others (inhibition)
      • Contra-indicated with sirolimus, terfenadines, astemizole, cisapride, …
      • Dose adjustments needed if combined with
        • Cyclosporin (- 50% ): if not, risk of nephrotoxicity
        • Tacrolimus (- 66%): if not, risk of nephrotoxicity
voriconazole pharmacokinetics33
VoriconazolePharmacokinetics
  • Oral bio-availability affected if taken with food
    • reduction oral bio-availability with > 20%!
    • no studies if administered with enteral feeding on ICU
      • Stop enteral feeding 1hr before up to 2 hrs after administration
      • Administration 2x daily: 6 hrs without calory intake!

Purkins L et al. Br J Clin Pharmacol 2003; 56 (S1): 17-23

voriconazole safety
VoriconazoleSafety
  • Visual disturbances: (20%)
    • Altered perception of light, photophobia, blurred vision, color vision changes: mechanism unknown
    • transient, infusion related
    • more in patients with higher levels - how to assess in sedated patients?
  • Hepatotoxicity (13%)
    • AST, ALT, alkaline phosphatase, bilirubin elevations
      • AST, ALP and BILI abnormalities correlating with higher vorico plasma levels
  • Phototoxicity (6%): erythema, Steven-Johnson syndrome, toxic epidermal necrolysis
  • Neurological changes: confusion and hallucinations
voriconazole safety35
VoriconazoleSafety
  • Adverse effects of voriconazole
    • French pharmacovigilance database
      • 4 year registration period
      • detailed registration of cases
      • causality assessment
      • Results
        • LFT abnormalities in 23% patients
        • Visual disturbances in 18% of patients
        • Skin rashes in 17% of patients
        • Cardiovascular events (10%), hematologic disorders (8%) renal disturbances (4%)

Eiden C. Ann Pharmacother 2007; 41:755-63

voriconazole tolerability and safety
VoriconazoleTolerability and Safety
  • Nephrotoxicity of SBECD
    • IV vials contain SBECD, a solubilizer
      • in patients with moderate to severe renal failure (CrCl < 50 ml/min): accumulation of SBECD with potential nephrotoxicity (vacuolization of urinary epithelium)
      • frequent problem in ICU patients: switch to oral formulation? Or other product?

Von Mach MA et al. BMC Clin Pharamacol 2006; 6:6

voriconazole therapeutic drug monitoring
VoriconazoleTherapeutic drug monitoring?
  • Complex pharmacokinetics

High inter and intra- individual variability!!

  • Serum levels correlated with efficacy/safety?
  • Optimal serum levels: 2-6 µg/ml
    • Well above MIC of Aspergillus/Candida spp.
voriconazole therapeutic drug monitoring38
VoriconazoleTherapeutic drug monitoring?
  • TDM voriconazole
    • 52 adult patients: 181 samples
    • 25%: levels < 1mg/L
      • Correlated with oral therapy
      • Lack of response more frequent in this group
    • 31%: levels > 5.5 mg/L
      • Correlated with omeprazole comedication
      • 5 patients with neurotoxicity
        • 4 of 5 treated intravenously
    • TDM improves efficacy and safety
    • Proposed therapeutic interval 1-5.5 µg/ml
  • Pascual A. CID 2008;46:201-211.
voriconazole therapeutic drug monitoring39
VoriconazoleTherapeutic drug monitoring?
  • TDM …
    • in all patients?
      • in patients with progressive disease?
      • in patients exhibiting significant visual or hepatic toxicity?
    • in patients at risk of fluctuating plasma levels?
      • drug interactions?
      • changing hepatic and renal function?
      • treated by mouth?
      • ICU?
    • daily (cost-effectiveness)?
    • method?
    • dose adjustments?
      • non-lineair kinetics!

Goodwin M et al. JAC 2007. Epub

posaconazole spectrum therapeutic indication and dosage
PosaconazoleSpectrum, therapeutic indication and dosage
  • Spectrum: Candida spp. (less active C. glabrata), Aspergillus spp., C. neoformans, H. capsulatum, Zygomycetes
  • Indications:
    • Prophylaxis of invasive fungal infections in high-risk patients (SCTx – GvHD, AML-MDS)
    • Treatment of IA, fusariosis, chromoblastosis, mycetoma, coccidiomycosis refractory to ampho B or itra
  • Dosage: 200 mg 3 - 4x/day
    • Only available as oral suspension
posaconazole pharmacokinetics
PosaconazolePharmacokinetics

Schiller D et al. Clin Ther 2007; 29: 1862-1886

posaconazole pharmacokinetics43
PosaconazolePharmacokinetics

Posaconazole levels: high interindividual variability!

!Difficult pharmacokinetics!

  • Absorption
    • 2.6-4-fold higher if taken with a meal
    • High-fat meals enhance absorption
    • Cimetidine: gastric pH: 40% decrease in posaconazole AUC and Cmax
      • Avoid concomitant use of histamine 2-blockers or PPIs!
    • Mucositis?

Schiller D et al. Clin Ther 2007; 29: 1862-1886

Goodwin M et al. JAC 2007. Epub.

posaconazole pharmacokinetics44
PosaconazolePharmacokinetics
  • Drug interactions
    • Posaconazole inhibits CYP3A4 (not a substrate of CYP3A4)
      • Tacrolimus: dose reduction with 66%
      • Cyclosporine: dose reduction with 25%
      • Increase in serum concentrations of benzodiazepines, calcium channel blockers, statines, TCA, nevirapine…
    • Posaconazole is substrate of UGT 1A4
      • Induction by phenytoin: contra-indicated!
      • Induction by rifabutin: contra-indicated!

Schiller D et al. Clin Ther 2007; 29: 1862-1886

Goodwin M et al. JAC 2007. Epub.

posaconazole pharmacokinetics45
PosaconazolePharmacokinetics
  • Dosing in patients with hepatic impairment?
    • posaconazole should be used with caution
    • not studied using Child score
  • Dosing in patients with renal impairment?
    • Dose adjustment not necessary
    • Use with caution in severe renal failure

Schiller D et al. Clin Ther 2007; 29: 1862-1886

Goodwin M et al. JAC 2007. Epub.

posaconazole tolerability and safety
Posaconazole Tolerability and Safety
  • Gastro-intestinal side effects
    • Abdominal pain, diarrhea, vomiting: 3-7%
  • Elevated liver function tests
  • Rash

- Not correlated with elevated posa serum levels

Schiller D et al. Clin Ther 2007; 29: 1862-1886

Goodwin M et al. JAC 2007. Epub.

posaconazole therapeutic drug monitoring
PosaconazoleTherapeutic drug monitoring?
  • Limited data available
  • FDA approved product information:
    • association between posa levels and efficacy
      • Proven (6%) or probable (3.8%) IFI if levels < 0.7 µg/ml
      • Proven (1.8%) or probable (0%) IFI if levels > 0.7 µg/ml

 lower concentrations correlate with treatment failure

    • recommendations:
      • ensurance of adequate plasma levels:
        • Administration of posaconazole with a meal
        • Avoidance of drug inducing agents
        • Monitoring for breakthrough infections

Goodwin M et al. JAC 2007. Epub.

posaconazole therapeutic drug monitoring48
PosaconazoleTherapeutic drug monitoring?
  • TDM in patients with:
    • Progressive disease
    • Suspected poor oral absorption (nausea, vomiting, mucositis, compliance)
    • Levels > 1.25 mg/L

Goodwin M et al. JAC 2007. Epub.

the echinocandins target fungal cell wall
The echinocandinsTarget: fungal cell wall
  • Echinocandines inhibit 1,3-beta-glucan synthase
    • depletion of glucan polymers: weak cell wall
caspofungin spectrum of activity and indications
CaspofunginSpectrum of activity and indications
  • Candida spp. (ex. C. parapsilosis) and Aspergillus spp.
    • Not Cryptococcus as its cell wall does not contain ß-D-glucan
    • Not Fusarium spp., Zygomycetes
  • Empirical therapy for presumed fungal infections in febrile, neutropenic patients
  • Candidemia, intra-abdominal abscess, peritonitis
  • Invasive aspergillosis if refractory or intolerant to other therapies
caspofungin52
Caspofungin
  • Measurement of in vitro activity?
    • Candida spp.: minimal inhibitory concentration (MIC)
      • Macroscopic growth inhibition
      • Lowest concentration of the drug that results in inhibiting growth in 24 hours
    • Aspergillus spp.: minimal effective concentration (MEC)
      • Microscopic endpoint
      • Lowest concentration of the drug that results in formation of aberrantly growing hyphal tips
caspofungin recommended dosage
CaspofunginRecommended dosage
  • Loading dose: 70 mg
  • Maintenance dose: 50 mg
    • Patients > 80 kg: 70 mg
  • Child B liver cirrhosis
    • Loading dose: 70 mg
    • Maintenance dose: 35 mg
  • Mistry GC. J Clin Pharmacol 2007; 47: 951.
caspofungin pharmacokinetics55
CaspofunginPharmacokinetics
  • Pharmacokinetic problems?
    • Elimination based on tissue distribution
      • No dose adjustments in renal insufficiency
      • No CYP-mediated metabolism
        • No CYP-mediated drug interactions
        • No genetic polymorphisms
    • Uptake via hepatic transporter: OATP
      • OATP= organic anion transporting polypeptide
      • Reduced uptake in patients with hepatic insufficiency
        • Dose reduction in Child B liver cirrhosis
        • No recommendations in Child C
      • Drug interactions mediated by OATP?

Sandhu P et al. DMD 2005; 33: 676-82.

caspofungin pharmacokinetics56
CaspofunginPharmacokinetics
  • OATP = organic anion transporting polypeptide
  • drug uptake transporter
  • Basolateral membrane of hepatocytes
  • Contributes to overall elimination of caspofungin
  • Cyclosporin and rifampicin are also substrates for OATP1B1
caspofungin pharmacokinetics57
CaspofunginPharmacokinetics
  • Co-administration with cyclosporin
    • AUC caspo + 25%
    • Competitive inhibition at OATP?
  • Co-administration with rifampicin
    • Inhibition and induction effect on caspo
    • First days: rifa blocks OATP
    • After continued dosing: rifa induces OATP

 Net effect: AUC caspo ↓: increase MD to 70mg/day

  • Other inducers: efavirenz, nevirapine, dexamethasone, phenytoin, carbamazepin
    • Increase MD to 70 mg/day
caspofungin tolerability and safety
CaspofunginTolerability and Safety
  • Excellent safety and tolerability
    • can be explained by mode of action: human cells do not have a cell wall
  • Adverse events = unspecific drug reactions
    • Histamine-mediated: headache, fever, nausea
    • Elevation of hepatic enzyme levels
      • AST, ALT and ALP
      • < 5-fold ULN
caspofungin tdm in critically ill patients
CaspofunginTDM in critically ill patients
  • Caspofungin plasma concentrations in surgical intensive care units
    • C24hr concentrations
    • 40 SICU patients
      • Altered drug plasma concentrations due to altered PK?
    • Results:
      • Trough levels: 0.52-4.08 µg/ml
      • Literature (Stone studies): 1.12-1.78 µg/ml
    • Higher in patients with low body weight (< 75 kg)
    • Higher in patients with albumin concentration > 23.6 g/L

! Patients’ body weight varied from 48 – 108 kg >< every patient got LD 70 mg/ MD 50 mg!

Nguyen TH et al. JAC 2007; 60:100-106.

anidulafungin micafungin tolerability and safety
Anidulafungin-MicafunginTolerability and Safety
  • Adverse reactions = mild
    • Infusion (histamine-mediated) related reactions (especially at high infusion rates): flushing, pruritis, rash, urticaria
    • Coagulopathy
    • Diarrhoea, vomiting, nausea
    • Hepatic enzyme elevation: ALT, ALP, bilirubin
      • In 5-10% of patients
      • Usually < 3-fold ULN
micafungin
Micafungin
  • Warning EMEA – risk hepatocellular tumour formation
    • discontinuation if persistent elevation ALT/AST
    • consider alternative in patients with severe liver function impairment or chronic liver diseases or concomitant hepatotoxic therapy

http://www.emea.europa.eu/humandocs/PDFs/EPAR/mycamine/H-734-PI-en.pdf

case i man 49 yrs old 65 kg
CASE IMan, 49 yrs old, 65 kg
  • Medical history:
    • diabetes, insuline dependent
    • abuse: nicotine, ethyl (10 U/day)
    • weight loss: - 25 kg/2 months
  • Admitted because of
    • hyperglycemia
    • fever, hypotension, leucopenia, thrombopenia
      • Rx thorax: bilateral infiltrates
      • Diagnosis: CAP: start Cefuroxim – amikacin
    • Elevated liver function tests (bili: 3.38 mg/dL): cirrhosis?
    • On day 8: high fever: switch AB into meropenem – fluconazol
    • Transfer UZ Leuven
case i man 49 yrs old 65 kg68
CASE IMan, 49 yrs old, 65 kg
  • Admitted upon ICU
    • high fever, severe hypotension, respiratory distress:
      • Intubation + mechanical ventilation
      • Fluid resuscitation, noradrenalin, antibiotics
      • New cultures
        • Day 10 and 11: BA Aspergillus +
        • Day 12: BAL Aspergillus +/ galactoBAL: 8.3
        • Serum galactomannan day 11: 3.2
          • Diagnosis: Invasive aspergillosis
          • start Vfend IV LD 400 mg on day 11
          • Stop Diflucan
case i man 49 yrs old 65 kg69
CASE IMan, 49 yrs old, 65 kg
  • At the same day:
    • Decrease of renal function: start CVVH
        • ! Vfend IV: accumulation of SBECD: switch PO?
    • Auramin stain: + : tuberculosis!
      • Start TB therapy: ethambutol, pyrazinamid, moxifloxacin and rifampicin
        • ! Vfend + Rifampicin = contra-indicated!
        • Switch Cancidas
        • Interaction with rifampicin!
        • Dosage: LD 70 mg – MD 70 mg
case ii female 49 yrs old 80 kg
CASE IIFemale, 49 yrs old, 80 kg
  • Medical history:
    • Henoch-Schönlein vasculitis

R/ Medrol 64 mg during 1 month

  • Hospital admission because of
    • anorexia, chills, sputa, respiratory insufficiency
      • Suspicion of pneumonia: Augmentin
      • CRP ↑: switch to Tazocin
      • BAL: A. fumigatus/ serum GM 4.8:

R/ Vfend tablets 2x400mg LD, 200 mg PO

      • IHD - terminal renal insufficiency
case ii female 49 yrs old 80 kg71
CASE IIFemale, 49 yrs old, 80 kg
  • Day 6: Transfer to UZ Leuven - MICU
    • Serum GM: 0.7/BA: fungi
    • CT brain: cerebral aspergillosis – multiple lesions
    • Ocular Aspergillus invasion

Diagnosis: Pulmonary, cerebral, ocular IA

    • Switch Vfend PO → IV + increase dose based on body weight: 2 x 320 mg
    • Vfend intravitreal injection
    • Switch Tazocin into Meronem (follow up GM)
case ii female 49 yrs old 80 kg72
CASE IIFemale, 49 yrs old, 80 kg
  • Day 12:
    • switch Vfend IV → PO (suspension)
    • Association of L-AmB high dose: 5 mg/kg
  • Day 14:
    • serum GM: 0.1
    • CT brain: worsening cerebral lesions
case ii female 49 yrs old 80 kg73
CASE IIFemale, 49 yrs old, 80 kg
  • Discussion
    • CNS aspergillosis
      • Voriconazole = first line – standard dose or higher dose (penetration 50%)?
      • Combination with L-AmB?
    • Initial Vfend dose: too low?
      • Tablets vs. oral suspension (weight based dosing)?
    • Vfend IV vs. PO?
      • PO ↔ critically ill patient, enteral feeding: absorption?
      • IV ↔ accumulation of SBECD in patient with IHD
        • Encephalopathy due to brain accumulation of SBECD?
        • Encephalopathy due to high vorico levels?
how to choose
How to choose?
  • Spectrum
    • Likely or documented pathogen
  • Site of infection
  • Patient-specific factors
    • Concomitant diseases
    • Hepatic/renal function
    • Toxicities
    • Drug interactions with concomitant therapy
    • IV/PO
  • Cost/ Reimbursement criteria
conclusion
Conclusion
  • Despite development of new antifungals during last decade

 mortality of IFI remains very high

    • optimalisation of diagnostics
    • improvement of knowledge on pharmacokinetics – role of TDM?

 avoid toxicity

 warrant effective drug concentrations