Choosing antifungal for treatment of invasive fungal infections

1. Choosing the appropriate
Anti-Fungal agent in present era
for invasive infections
Dr Ashok Rattan,
Chief Executive,
Fortis Clinical Research Ltd

2. Fungus
Morphotypes
25º C Dimorphic Fungi 37º C
1. Blastomycosis
2. Histoplasmosis
3. Coccidioidomycosis
4. Para coccidioidomycosis
5. Sporotrichiosis
MOLD YEAST

3. Fungal infections
Classification
• Anatomical location
– Muco-cutaneous
• Morbidity high
• Mortality low or nil
– Invasive infections
• Morbidity high
• Mortality very high
• Epidemiology
– Endemic
• Acquired from
environment in certain
locations
• Inhalation route
– Opportunistic
• Acquired ubiquitously
• Colonized mucous
membranes

4. Invasive Fungal Infections
• Yeast:
– Candida spp.
– Cryptococcus neoformans
• Molds (Filamentous)
– Aspergillus spp.
– Fusarium spp.
– Scedosporium spp.
– Zygomycetes

5. Yeasts causing Invasive fungal infections:
Invasive Candidiasis
• Largely a disease of medical progress
• Reflecting advances in health care technology
• Risk factors:
– Use of broad spectrum antibiotics
– Central Venous catheter
– Parentral nutrition
– Renal replacement therapy
– Neutropenia
– Implantable prosthetic agents
– Immunosuppresant agents
– Glucocorticosteroids
– Chemotherapy
– Immunomodulators

6. • Candida is 4th most common cause of nosocomial
blood stream infection
• Non albicans are becoming common
• 47% attributable cause of mortality

7. Moulds causing invasive fungal infections:
Aspergillus
• Emerged as important cause of life threatening
infections in immunocompromised patients
• A. fumigatous is the most common species
• A. flavus, A. niger, A. terreus are next in frequency
• Risk factors:
– Prologed neutropenia
– Advanced HIV infection
– Allogenic hematopoietic stem cell transplantation
– Lung transplantation

8. Diagnosis of invasive fungal infections
a. probable, b. possible, c. definite
• Host factors
– Neutropenia > 10 days
– Persistent fever > 96 hours
– History of immunosuppresive drugs
– HIV +ve
– Signs of GVHD
• Microbiologic criteria
– Positive culture of mold from BAL or sinus aspirate
– Blood culture for candida
– Antigen for aspergillus (GM-EIA) or cryptococcus: blood, urine, CSF
• Clinical Criteria

9. Drugs for treatment of invasive fungal infections
Class Generic name Brand name Available as Year of first
approval
Polyene (4) Amphotericin B Fungizone IV, Oral 1958
“ Amph B Lipid
Complex
Abelcet IV 1995
“ Amph B Choleteryl
sulfate
Amphotec IV 1996
“ Amph B liposomal AmBisome IV 1997
Pyrimidine Flucytosine Ancoban Oral 1972
Azole (5) Ketoconazole Nizoral Oral 1981
“ Fluconazole Diflucan IV, Oral, Susp 1990
“ Itraconazole Sporonax Oral, IV, Susp 1992
“ Voriconazole Vfend Oral, IV 2002
“ Posaconazole Noxafil Oral 2006
Echinocandin Caspofungin Cancidas IV 2001
“ Anadulafungin Eraxis IV 2006
“ Micafungin Mycamine IV 2007

10. Mechanism of action

12. Polyene Antifungal
Amphotericin B (Fungisone)
• Spectrum of activity:
– Broad, fungicidal
• Aspergillus species
• Blastomyces dermatitidis
• Candida species
• Coccidioides immitis
• Cryptococcus neoformans
• Fusarium species
• Sporothrix shenckii
• Histoplasma capsulatum
• Paracoccidioides brasiliensis
• ineffective against Scedosporium and Trichosporon

13. Uses
• aspergillosis
• candidosis
• blastomycosis
• coccidioidomycosis
• cryptococcosis
• fusariosis
• histoplasmosis
• paracoccidioidomycosis
• sporotrichosis
• certain forms of mucormycosis, hyalohyphomycosis and
phaeohyphomycosis
• reduced effectiveness in aspergillosis and candidosis in
neutropenic patients

14. • Pharmaceutics:
– oral suspension 100 mg/ml
– lozenge 10 mg
– powder for injection 50 mg per vial
• Pharmacokinetics:
– no mucosal or cutaneous absorption
– minimal absorption from GI tract
– extensively bound to plasma lipoproteins
– enters serous cavities
– crosses placental barrier
– plasma half-life 24 h
– renal excretion very slow

15. • Dosage:
– 0.5–1.0 mg/kg per day i.v. for 10–14 days
– up to 1.5 mg/kg per day for disseminated infections
• Precautions:
– to avoid precipitation do not reconstitute or dilute with saline, do
not mix with other drugs
– renal function and serum potassium concentrations should be
closely monitored
– maintain high fluid and sodium intake
– potassium supplements may be required to compensate for urinary
losses
– dosage must be reduced if renal function deteriorates substantially,
particularly
– if serum creatinine levels rise by more than 50%
– infusion of an osmotic diuretic such as mannitol may then be of
value
– monitor blood count at weekly intervals

16. Adverse effects of Amphotericin B
• progressive normochromic anemia is
indicative of bone marrow depression

17. Lipid formulations
• Liposomal Amphotericin B (LAB)
• Amphotericin B Lipid Complex (ABLC)
• Amphotericin B Colloidal Dispersion (ABCD)

18. Comparative Pharmacokinetics
AmBisome ABCD Amp B ABLC
Dose mg/kg 3 1 .5 1 5
Peak blood
level
μg/ml 29 2.5 3.6 1.7
AUC μg/ml/h 423 56.8 34.2 9.5
Clearance ml/h/kg 22.2 28.4 40.2 211
Volume of
distribution
l 25.9 553 111 2286
Half-life
(elimination)
h 23
2nd phase
235
3rd phase
34
2nd phase
173.4

19. Azole
• Ketoconazole
• Itraconazole
• Posaconazole
N
N
H3C
O
O
O
O
Cl
N
N
Cl
H
N
N
N
N
N
O
CH3
H3C
O
O
O
Cl
N
N
N
Cl
H
N
N
N
N
N
O
H3C
O
O
F
N
N
N
F
H
HO
H3C

20. Azole
N
N
N
F
F
OH
N
N N
Fluconazole
N
N
N
N
N
C
H
3
F
O
H
F
F
Voriconazole

21. TERB

22. Fluconazole
• Spectrum of activity:
– Limited in vitro activity, Fungistatic
– Candida species
• (reduced activity against C. glabrata, virtually no
activity against C. krusei)
– Cryptococcus neoformans
– ineffective against Aspergillus species

23. • Uses: Excellent in vivo activity
– mucosal and cutaneous candidosis
– recalcitrant oropharyngeal candidosis in HIV-positive patients
– deep forms of candidosis in non-neutropenic patients
– acute cryptococcal meningitis in AIDS
– in combination with amphotericin B in treatment of
cryptococcosis and deep forms of candidosis (urinary tract and
peritoneum)
– maintenance treatment to prevent relapse of cryptococcosis in
patients with AIDS
– prophylaxis against candidosis;
– ineffective against aspergillosis

24. • Pharmaceutics:
– Tablets: either 50 mg, 150 mg, or 200 mg
– powder for oral suspension available as 50 mg, 100 mg, or 200 mg
in 5 ml and 35 ml packs
– intravenous infusion : 2 mg/ml in 0.9% sodium chloride solution
• Dosage:
– oropharyngeal candidosis, 50–100 mg per day for 1–2 weeks
– esophageal and mucocutaneous candidosis, 100–200 mg per day
for 2–4 weeks
– lower urinary tract candidosis, 50–100 mg per day for 14–30 days
– cryptococcosis, 200–400 mg per day for 6–8 weeks
– systemic candidosis, 200–400 mg per day for 6–8 weeks

25. • Pharmacokinetics: Excellent
– rapid and almost complete absorption after oral administration
– identical serum concentrations attained after both oral and
parenteral administration
– blood concentrations increase in proportion to dosage over wide
range of dose levels
– serum concentrations in the region of 1 mg/l achieved 2 h after
single 50 mg oral dose
– after repeated dosing, serum level increases to 2–3 mg/l
– administration with food does not affect absorption
– rapid and widespread distribution after both oral and parenteral
administration
– protein binding low
– elimination by renal excretion in active form
– serum half-life 20–30 h, prolonged in renal failure
– removed during hemodialysis

26. • Drug Interaction: Extensive Cyp P 450 enzyme
– hepatic metabolism of cyclosporine, phenytoin, sulfonylureas,
theophylline, and warfarin is inhibited
– rifampicin accelerates clearance of fluconazole
– concomitant administration of terfenadine should be avoided, since
it has been associated with serious, sometimes fatal, cardiac
dysrhythmias
– fluconazole prolongs serum half-life of chlorpropamide,
glibenclamide, glipizide, and tolbutamide
– prothrombin time in patients receiving concomitant treatment with
fluconazole and anticoagulants should be monitored
– fluconazole increases plasma zidovudine concentrations
– fluconazole increases plasma rifabutin concentrations

27. RESISTANCE TO FLUCONAZOLE
PRIMARY C. krusei
C. glabrata
Aspergillus
SECONDARY C. albicans
C. dubliniensis

28. Voriconazole
• Spectrum of activity:
– broad spectrum of activity :
• fungicidal against aspergillus, fungistatic against candida
– Candida species
– Cryptococcus neoformans
– Aspergillus species
– Fusarium species
– Penicillium marneffei
– Scedosporium apiospermum
– Blastomyces dermatitidis
– Coccidioides immitis
– Histoplasma capsulatum
– dermatophyte species
– dematiaceous fungi
N N
N N
N
CH3
F
OH
F
F

29. • Uses:
– treatment of serious fungal infection in immunocompromised
patients
– acute invasive aspergillosis – in USA approved as first-line
treatment. 53% complete or partial response
– invasive candidosis due to fluconazole-resistant Candida species
(including Candida krusei): 71% complete or partial response
– infections due to Fusarium and Scedosporium – in USA approved
for salvage treatment
– cryptococcosis: variable response
– Fusarium infections: 43% response

30. • Pharmaceutics:
– supplied for i.v. administration in lyophilized form in 200
mg amounts
– reconstitute in 19 ml sterile water to give an extractable
volume of 20 ml concentrated solution containing 10
mg/ml voriconazole
– dilute further with 5% dextrose or 0.9% sodium chloride
– can be stored at refrigerator temperature for maximum of
24 h
– Oral tablets: 50 mg and 200 mg

31. • Pharmacokinetics:
– oral administration leads to rapid and almost complete absorption
– 2 h after single 400 mg dose, serum concentrations of ~2 mg achieved
– but variable levels seen in certain demographic groups
– disproportionate increase in blood levels with increasing oral and parenteral
dosage
– non-linear pharmacokinetics in high-risk patients: may indicate monitoring
levels
– mean time to maximum plasma concentration: 1–2 h post-dose
– bioavailability >96%
– best when not administered within 1 h of food intake
– widely distributed throughout tissues
– protein binding 58%
– large volume of distribution: 4.6 l/kg
– elimination by metabolic clearance
– extensively metabolized by cytochrome P450 isoenzymes: may affect delivery
across intestinal mucosa
– elimination half-life is dose-dependent: 6–9 h after a 3 mg/kg parenteral dose or
200 mg oral dose

32. • Dosage:
– loading dose: i.v. formulation 6 mg/kg every 12 h for two doses:
steady state reached
– infusion rate: maximum 3 mg/kg/h over a 1–2 h period
– infusion concentration should not exceed 5 mg/ml
– maintenance dose: 4 mg/kg every 12 h
– oral therapy:
• 200 mg every 12 h >40 kg
• 100 mg every 12 h <40kg
• if patient response inadequate, increase to 300 mg every 12h (or 150 mg
every 12 h for patients <40 kg)
– 1 h before or 1 h following a meal
– no adjustment required in patients with abnormal liver function
tests (up to 5-fold upper limit of normal) but continued monitoring
is recommended
– no adjustment of oral dose required for patients with renal
impairment
– hemodialysis (4 h session) does not remove a sufficient amount of
drug – no dosage adjustment required

33. • Adverse Effects:
– >30% transient visual disturbances, but no anatomical
correlates of the disturbances
– headache
– gastrointestinal upset
– rare cases of severe exfoliative cutaneous reactions, eg.
Stevens–Johnson syndrome
– elevation in liver function tests in ~13% patients

34. Echinocandidin
• Caspofungin
• Anadulafungin
• Micafungin N
O
NH
O
HO
HO
NH
O
OH
H
N
H2N
OH
H2N
O
OH
HN
OH
H
H
H H
NH O
H
CH3
OH
O
N
H
O
H3C
CH3 CH3

35. Caspofungin
Potent fungicidal activity against:
• Candida albicans
• C. tropicalis
• C. glabrata
• C. krusei (less susceptible)
• C. parapsilosis (less susceptible)
• C. dubliniensis
• C. lusitaniae
No activity against:
• Cryptococcus neoformans
• Trichosporon beigelii
• Fusarium species
• Agents of zygomycosis
• Dermatophytes
Variable activity against:
• Aspergillus species
• Histoplasma
• Histoplasma capsulatum
• Blastomyces dermatitidis
• Coccidioides immitis
• Sporothrix schenckii
• dematiaceous fungi

36. • Uses
– invasive forms of candidosis – comparable activity
compared with amphotericin B:
• intraperitoneal abscesses, peritonitis, pleural space infections.
• Not studied in endocarditis, osteomyelitis or meningitis due to
Candida
– candidemia
– invasive aspergillosis – in patients who have failed to
respond to, or who are intolerant to, other antifungal
agents. Has not been studied as initial therapy for
invasive aspergillosis

37. • Pharmaceutics:
– only available for parenteral administration
– supplied in lyophilized form in 50 and 70 mg amounts
– reconstituted in 10.5 ml 0.9% sodium chloride
– reconstituted drug solution further diluted by adding 10
ml to 250 ml 0.9% sodium chloride
– use infusion solution within 24 h, store at <25°C

38. • Pharmacokinetics:
– dose-proportional pharmacokinetics
– poor oral bioavailability
– excretion by hepatic and renal routes
– serum concentrations of ~10 mg/l reached after single 70 mg parenteral dose,
administered over 1 h
– 70 mg/day maintains trough plasma levels above MIC of most susceptible fungi
– blood concentrations increase in proportion to dosage
– less than 10% of dose remains in blood 36–48 h after administration
– protein binding >96%
– about 92% of dose distributed to tissues – highest concentration in liver
– CSF level negligible
– little excretion or metabolism during first 30 h after administration
– initial half-life ~9–11 h
– elimination half-life 40–50 h
– not cleared by hemodialysis

39. • Dosage:
– invasive aspergillosis
• once-daily dosing
• 70 mg on day 1 followed by
• 50 mg daily infusion over 1 h period
• duration patient dependent
– systemic candidosis, including candidemia
• i.v. loading dose 70 mg then
• 50 mg/day infusion over 1 h period
– esophageal candidosis: HIV infected adults:
• 70 and 50 mg/day: 14 days
• caspofungin: 85.1% response
• amphotericin B: 66.7% response

40. Esophageal candidasis
Effect of oral cancidas

41. Fluorinated Pyrimidine
N
H
N
F
NH2
O
Flucytosine

42. • Uses:
– seldom used as single drug
– used in combination with amphotericin B for
cryptococcosis
• Pharmacokinetics:
– Oral dose: 25mg/kg, Cmax 30 – 40 mg/L
– Tmax 2.5 to 5 hrs, longer in renal failure
– Rapid and complete absorption
– Low protein binding (12%)
– Wide distribution, including CSF
– Excreted unchanged in urine (90%)

43. in vitro activity of anti fungal agents & Gaps therein

44. Comparative pharmacokinetics of antifungal agents
PK/PD predicator of success:
Trizole : Concentration dependent killing
Fluconazole AUC/MIC > 25 for systemic candida infections
Polyene : Concentration dependent killing
ABLC Cmax/MIC > 4 - 10 for systemic aspergillus infections
Pyrimidine: time dependent killing
Flucytosine t / MIC > 40% of dosing interval
Echinocandin : Concentration dependent killing
Caspofungin Cmax/MIC > 4
Micafungin AUC/MIC > 250

45. Comparative toxicities of antifungal agents
Dose modifications for antifungal agents, by type of organ dysfunction

47. Response to anti fungal therapy
• HOST
Immune status
Site of infection
Severity of infection
Foreign devices
Noncompliance with drug
regimen
• FUNGUS
Initial MIC
Cell type: Yeast/hyphae..
Genomic stability
Biofilm production
Population bottlenecks
• DRUG
Fungistatic nature
Dosing
Pharmacokinetics
Drug-drug interactions

48. In vitro Susceptibility of Candida species
causing invasive infections
% Amp B Caspo Flu Vori
C. albicans 50 S S S S
C.glabrata 15 S S S DD to
R
S to I
C. krusei 4 S S R S to I
C. parapsilosis 20 S S S S
C. tropicalis 5 S S S S

49. Treatment of adults with invasive candiadiasis
Clinical setting Therapy Dose Alternative Dose
Candida spp
unknown, not
haemodynamically
unstable, not
neutropenic, no risk
for azole Resis
Fluconazole 400 mg (6 – 12
mg/kg) day
IV or oral
Caspofungin or
Voriconazole or
Liposomal Amp B
70 mg load, IV
Candida spp
unknown,unstable,
neutropenic, risk
factors azole R
Caspofungin
or
Liposomal
Amp B
70 mg IV load &
50 mg IV / day
3-5 mg/kg IV
Voriconazole 6mg/kg bid IV
load, 4mg/kg
bid IV
Candidiemia Fluconzaole Caspofungin or
Voriconazole
Candidiasis with
known risk factors
for azole resis
Caspofungin
Or
Liposomal
Amp B
Voriconazole
or
CAB

51. Treatment of definitive, probable & possible
invasive aspergillosis
• Invasive Pulmonary aspergillosis:
– First line:
• Voriconazole IV 6mg/kg BID for 24 hrs, then
4mg/kg IV BID or 200mg PO BID
– Alternate:
• Liposomal Amp B 3 – 5 mg/kg IV or
• ABLC 5 mg/ kg IV or
• Caspofungin 70 mg/day loading day 1 IV then 50
mg / day IV or
• Itraconazole (dose depends upon formulation)