Transcript Ontwikkeling en validatie van een hoge druk

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.
 Newly emerging fungi
- Fusarium
- Scedosporium

Endemic geographically restricted
- Blastomyces spp.
- Coccidiodes spp.
- Histoplasma spp.
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
Pathogen
% Isolated
% Mortality
CNS
31.9
21
S aureus
15.7
25
Enterococci
11.1
32
Candida spp.
7.6
38
E. Coli
5.7
24
Klebsiella spp.
5.4
27
Enterobacter spp.
4.5
28
Pseudomonas spp.
4.4
33
Serratia spp.
1.4
26
S. viridans
1.4
23
Hospital acquired pathogens and their associated mortality
Edmond et al. CID 1999; 29:239-44.
Invasive Aspergillosis – Mortality Rate
Review of 1941 Patients from 50 Studies
Case Fatality Rate (%)
100
80
60
40
20
0
Overall (1941)
BMT (285)
Leuk/Lymph (288)
Pulm (1153)
CNS/Dissem (175)
Lin S-J et al, CID 2001; 32:358-66
Risk factors for fungal disease
Candidiasis
Aspergillosis
-Broad
-Granulocytopenia
-Decreased neutrophil number
-Decreased function
-T-cell dysfunction
-Hematologic malignancies
-Organ allograft recipients
-Immunosuppressants
-Corticosteroids
-AIDS
spectrum antibiotics
-Intravascular catheters
-Abdominal surgery
-Neoplastic diseases
-Chemotherapy
-Immunosuppressants
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
To be expected:
Posaconazole
isovuconazole – anidulafungin –
micafungin …
Voriconazole
Caspofungin
Lipid amphotericin
products
Itraconazole
Fluconazole
Ketoconazole
Amphotericin B
1950
1960
Flucytosine
1970
1980
1990
2000
Outline
Product Overview
 Spectrum
 Therapeutic indications
 Recommended dosages
 Pharmacokinetics
 Pharmacokinetic difficulties and problems
Tolerability and safety
Therapeutic drug monitoring?
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
Polyenes
Amphotericin B
Target: 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

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

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
 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 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 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.
Azoles
The azoles
Target: 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
Inhibits also human
CYP450-dependent
enzymes playing an
important role in
human hormone
synthesis or drug
metabolism
DRUG
INTERACTIONS!!!
Fluconazole
Fluconazole
Spectrum, 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:
Candidemia in nonneutropenic patients
Fluco 400 mg + remove IV catheter
! C. glabrata-I: fluco 800 mg
! C. glabrata-R: caspofungin
Invasive candidiasis
(intra-abdominal/
postoperative)
Fluco 400 mg (+ surgical drainage)
Alternative caspofungin 70/50 mg IV
Charlier C. JAC 2006; 57:384-410.
Fluconazole
Pharmacokinetics
 Bio-availability
- > 90%
- not dependent of gastric pH or food: IV-PO switch
possible!
 Distribution
-
 Metabolism
-
 Excretion
-
extensive: Vd 0.7-1.0 L/kg
- protein binding: 11%
- CSF levels: 70% of plasma levels
- good penetration in bone
not metabolised
60-75% glomerular filtration: dose adjustments in
decreased renal clearance
- 8-10% feces
- halflife: 27-34 hrs: OD administration, LD required
- removed by dialysis
Charlier C. JAC 2006; 57:384-410.
Fluconazole
Pharmacokinetics

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

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?

No routine indications for measuring fluco levels
- Predictable fluconazole PK and serum concentrations
Charlier C. JAC 2006; 57:384-410.
Voriconazole
Voriconazole
Spectrum 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
 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
Pharmacokinetics

Bio-availability
96%

Steady state
-

Distribution
-

Metabolism
-
extensive (Vd: 4.6 L/kg)
- CSF concentration: 50% of plasma concentration:
dosage increase by 50%
- protein binding 58%
-

Elimination
5-6 days
loading dose necessary!
CYP2C9, CYP2C19, CYP3A4
major metabolite (72%): N-oxide
-80%
via urine
-20% via feces
Voriconazole
Pharmacokinetics
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
Pharmacokinetics
 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
Pharmacokinetics

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
 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
Safety

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

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?

Complex pharmacokinetics
High inter and intra- individual variability!!

Serum levels correlated with efficacy/safety?
FDA report
- no correlation
Smith. AAC 2006; - 28 patients, random plasma samples
50:1570-2.
- progressive disease in 18 patients with levels < 2.05 µg/ml
Trifilio S. BMT
2007; 40:451-6.
-
Denning D. CID
2002; 34: 56371.
-

71 patients, trough plasma levels
- 6 candidiasis cases in patients with levels < 2 µg/ml
Herbrecht study
- liver failure or liver toxicity in 6 out of 22 patients with levels >
6 µg/ml
Optimal serum levels: 2-6 µg/ml
– Well above MIC of Aspergillus/Candida spp.
Voriconazole
Therapeutic 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 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
Posaconazole
Spectrum, 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

Bio-availability
-52-100%
-Dependent
on dosing frequency and intake with/without
meal
-Saturation in absorption if daily dose > 800 mg

Distribution
-Extensive
(Vd: 2447L)
-Tissue penetration: limited data
- crosses BBB
- distributes into bone and eye
-Protein
binding > 98%

Metabolism
-Primarily
unchanged excretion
-<30% metabolised as glucuronide conjugates (UGT 1A4)

Elimination
-Majority
via feces as unchanged drug
-Minimal renal elimination (14%)
-Halflife 20 hr
Schiller D et al. Clin Ther 2007; 29: 1862-1886
Posaconazole
Pharmacokinetics
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
Pharmacokinetics
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
Pharmacokinetics

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
 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?


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 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.
Caspofungin
The echinocandins
Target: fungal cell wall
Echinocandines inhibit 1,3-beta-glucan synthase
• depletion of glucan polymers: weak cell wall
Caspofungin
Spectrum of activity and indications

Candida spp. (ex. C. parapsilosis) and Aspergillus spp.
 Not Cryptococcus as its cell wall does not contain ßD-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


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

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
Pharmacokinetics
 Bio-availability
<2%: only IV
 Distribution
-Vd
4.5L
- high levels in liver, spleen, kidney
- equal levels in lung tissue
- low levels in heart, skeletal muscle, brain
-distribution
phase determines clearance
-protein binding: 96%: no elimination via IHD
 Metabolism
- hydrolysis and N-acetylation: no active metabolites
- not CYP450 dependent
 Excretion
-via
 PK
linear: 3 phases
urine and faeces (only 2% unchanged)
-distribution phase
-elimination phase of 8 hrs
-additional elimination phase with longer halflife of 27 hrs
Caspofungin
Pharmacokinetics

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
Pharmacokinetics
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
Pharmacokinetics

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

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

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
Anidulafungin - Micafungin
Spectrum, therapeutic indications and
recommended dosage
Anidulafungin
Micafungin
 Spectrum
-Candida spp.
-Aspergillus spp.
-Candida spp.
-Aspergillus spp.
 Indications
-Invasive candidiasis
-Esophageal candidiasis
-Prophylaxis for Candida
infections in HSCT
-Esophageal candidiasis
 Dosage
LD: 200 mg
MD: 100 mg
-prophylaxis: 50 mg OD
-treatment: 150 mg OD
No
 Dose adjustement
in hepatic impairment
No
 Weight based dose
adjustments
No
No
Anidulafungin - Micafungin
Pharmacokinetics
Anidulafungin
Micafungin
 Bioavailability
Low, only IV administration
Low, only IV administration
 Distribution
-Rapid
distribution halflife
-Vd: 0.57 L/kg
-Protein binding: 99%
-No specific tissue distribution
studies done
-Vd:
 Metabolism
-No
hepatic metabolism
-No CYP involvement
-Metabolism by slow nonenzymatic, chemical
degradation
-No
 Elimination
-
Halflife : 24hrs
- Via feces
- Halflife: 13 hrs
- Via feces, > 90% unchanged
 PK
linear
linear
0.39 L/kg
-- Protein binding: 99%
- poor CNS penetration
hepatic metabolism
-No CYP involvement
-Breakdown by arylsulfatase
and COMT
Anidulafungin- Micafungin
Pharmacokinetics
anidulafungin
micafungin
 Dose adjustments in
hepatic insufficiency?
No
Studied in Child A,B,C:
no increase in plasma
levels
No
Not studied in Child C
Dose adjustments in
renal
insufficiency/dialysis?
No
No
No
Small increase in
anidula levels if
combined with
cyclosporine
No
Possibly mild inhibition
of CYP3A with small
increase in cyclosporin,
sirolimus and nifedipin
levels


Drug interactions?
Anidulafungin-Micafungin
Tolerability 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
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 report
CASE I
Man, 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 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 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

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 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 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 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?
Final Remarks
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
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