Pharmacotherapy of antifungal drugs

1
Pharmacotherapy of antifungal drugs

• Isabel Spriet
• Pharmacy Dpt, UZ Leuven

2
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.
3
Invasive fungal infections - Incidence

• Solid organ transplant 5-42
• Bone marrow transplant 15-25
• ICU 17

Singh N. Clin Infect Dis 200031545-53 Vincent
JL. Intens Care Med 1998 24206-216
4
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 29239-44.
5
Invasive Aspergillosis Mortality Rate
Review of 1941 Patients from 50 Studies
Lin S-J et al, CID 2001 32358-66
6
Risk factors for fungal disease
Candidiasis Aspergillosis
Broad spectrum antibiotics Intravascular catheters Abdominal surgery Neoplastic diseases Chemotherapy Immunosuppressants -Granulocytopenia Decreased neutrophil number Decreased function T-cell dysfunction Hematologic malignancies Organ allograft recipients Immunosuppressants Corticosteroids AIDS
7
Fungal infections today

• A major change in the
• occurence,
• diagnosis and
• management
• of invasive fungal infections has arisen in the
  recent years.

8
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
9
OutlineProduct Overview

• Spectrum
• Therapeutic indications
• Recommended dosages
• Pharmacokinetics
• Pharmacokinetic difficulties and problems
• Tolerability and safety
• Therapeutic drug monitoring?

10
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

11
Polyenes
12
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

13
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

14
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

15
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

16
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

17
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.
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Azoles
19
The azolesTarget fungal cell membrane

• Azoles inhibit ergosterol synthesis by inhibiting
  14-a-demethylase
• toxic sterol intermediates accumulate in the
  cell membrane leading to enhanced cellular
  permeability and inhibition of fungal growth

20
(No Transcript)
21
Fluconazole
22
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

Candidemia in non-neutropenic 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 57384-410.
23
FluconazolePharmacokinetics
? Bio-availability - gt 90 - not dependent of gastric pH or food IV-PO switch possible!
? Distribution extensive Vd 0.7-1.0 L/kg protein binding 11 CSF levels 70 of plasma levels good penetration in bone
? Metabolism not metabolised
? Excretion 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 57384-410.
24
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 57384-410.
25
FluconazoleTolerability and Safety

• Generally very well tolerated no adverse events
• Side effects only occur in high doses (gt400
  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 gt 1200 mg/day),
• prolongation of the QT interval

Charlier C. JAC 2006 57384-410.
26
FluconazoleTherapeutic drug monitoring?

• No routine indications for measuring fluco levels
• Predictable fluconazole PK and serum
  concentrations

Charlier C. JAC 2006 57384-410.
27
Voriconazole
28
VoriconazoleSpectrum of activity

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

Mashmeyer G et al. Future Microbiol 2006 1
365-85.
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VoriconazoleRecommended dosage

• Loading dose 2 x 6mg/kg
• Maintenance dose 2 x 4 mg/kg
• Infusion over 1hr
• Adult Patients lt 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

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VoriconazolePharmacokinetics
Bio-availability 96
Steady state 5-6 days loading dose necessary!
Distribution extensive (Vd 4.6 L/kg) CSF concentration 50 of plasma concentration dosage increase by 50 protein binding 58
Metabolism CYP2C9, CYP2C19, CYP3A4 major metabolite (72) N-oxide
Elimination 80 via urine 20 via feces
31
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 462546-53.
32
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

33
VoriconazolePharmacokinetics

• Oral bio-availability affected if taken with food
• reduction oral bio-availability with gt 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
34
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

35
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 41755-63
36
VoriconazoleTolerability and Safety

• Nephrotoxicity of SBECD
• IV vials contain SBECD, a solubilizer
• in patients with moderate to severe renal failure
  (CrCl lt 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 66
37
VoriconazoleTherapeutic drug monitoring?

• Complex pharmacokinetics
• High inter and intra- individual variability!!
• Serum levels correlated with efficacy/safety?
• Optimal serum levels 2-6 µg/ml

FDA report - no correlation
Smith. AAC 2006 501570-2. 28 patients, random plasma samples progressive disease in 18 patients with levels lt 2.05 µg/ml
Trifilio S. BMT 2007 40451-6. 71 patients, trough plasma levels 6 candidiasis cases in patients with levels lt 2 µg/ml
Denning D. CID 2002 34 563-71. Herbrecht study liver failure or liver toxicity in 6 out of 22 patients with levels gt 6 µg/ml
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VoriconazoleTherapeutic drug monitoring?

• TDM voriconazole
• 52 adult patients 181 samples
• 25 levels lt 1mg/L
• Correlated with oral therapy
• Lack of response more frequent in this group
• 31 levels gt 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 200846201-211.
39
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
40
Posaconazole
41
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

42
PosaconazolePharmacokinetics
Bio-availability 52-100 Dependent on dosing frequency and intake with/without meal Saturation in absorption if daily dose gt 800 mg
Distribution Extensive (Vd 2447L) Tissue penetration limited data crosses BBB distributes into bone and eye Protein binding gt 98
Metabolism Primarily unchanged excretion lt30 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
43
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.
44
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.
45
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.
46
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.
47
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 lt
  0.7 µg/ml
• Proven (1.8) or probable (0) IFI if levels gt
  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.
48
PosaconazoleTherapeutic drug monitoring?

• TDM in patients with
• Progressive disease
• Suspected poor oral absorption (nausea, vomiting,
  mucositis, compliance)
• Levels gt 1.25 mg/L

Goodwin M et al. JAC 2007. Epub.
49
Caspofungin
50
The echinocandinsTarget fungal cell wall

• Echinocandines inhibit 1,3-beta-glucan synthase
• depletion of glucan polymers weak cell wall

51
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

52
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

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CaspofunginRecommended dosage

• Loading dose 70 mg
• Maintenance dose 50 mg
• Patients gt 80 kg 70 mg
• Child B liver cirrhosis
• Loading dose 70 mg
• Maintenance dose 35 mg

Mistry GC. J Clin Pharmacol 2007 47 951.
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CaspofunginPharmacokinetics
? Bio-availability lt2 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 urine and faeces (only 2 unchanged)
? PK linear 3 phases distribution phase elimination phase of 8 hrs additional elimination phase with longer halflife of 27 hrs
55
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.
56
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

57
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

58
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
• lt 5-fold ULN

59
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 (lt 75 kg)
• Higher in patients with albumin concentration gt
  23.6 g/L
• ! Patients body weight varied from 48 108 kg
  gtlt every patient got LD 70 mg/ MD 50 mg!

Nguyen TH et al. JAC 2007 60100-106.
60
Anidulafungin - Micafungin
61
Anidulafungin - MicafunginSpectrum, 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
? Dose adjustement in hepatic impairment No No
? Weight based dose adjustments No No
62
Anidulafungin - MicafunginPharmacokinetics
Anidulafungin Micafungin
? Bio-availability 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 0.39 L/kg - Protein binding 99 poor CNS penetration
? Metabolism No hepatic metabolism No CYP involvement Metabolism by slow non-enzymatic, chemical degradation No hepatic metabolism No CYP involvement Breakdown by arylsulfatase and COMT
? Elimination Halflife 24hrs Via feces - Halflife 13 hrs - Via feces, gt 90 unchanged
? PK linear linear
63
Anidulafungin- MicafunginPharmacokinetics
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
Drug interactions? 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
64
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 lt 3-fold ULN

65
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/myca
mine/H-734-PI-en.pdf
66
Case report
67
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

68
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

69
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

70
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

71
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)

72
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

73
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?

74
Final Remarks
75
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

76
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