5. Yeasts causing Invasive fungal infections:
Invasive Candidiasis
⢠Largely a disease of medical progress
⢠Reflecting advances in health care technology
⢠Risk factors:
â Use of broad spectrum antibiotics
â Central Venous catheter
â Parentral nutrition
â Renal replacement therapy
â Neutropenia
â Implantable prosthetic agents
â Immunosuppresant agents
â Glucocorticosteroids
â Chemotherapy
â 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:
â Prologed neutropenia
â Advanced HIV infection
â Allogenic hematopoietic stem cell transplantation
â Lung transplantation
8. Diagnosis of invasive fungal infections
a. probable, b. possible, c. definite
⢠Host factors
â Neutropenia > 10 days
â Persistent fever > 96 hours
â History of immunosuppresive drugs
â HIV +ve
â Signs of GVHD
⢠Microbiologic criteria
â Positive culture of mold from BAL or sinus aspirate
â Blood culture for candida
â 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
â Amph B Lipid
Complex
Abelcet IV 1995
â Amph B Choleteryl
sulfate
Amphotec IV 1996
â Amph B liposomal AmBisome IV 1997
Pyrimidine Flucytosine Ancoban Oral 1972
Azole (5) Ketoconazole Nizoral Oral 1981
â Fluconazole Diflucan IV, Oral, Susp 1990
â Itraconazole Sporonax Oral, IV, Susp 1992
â Voriconazole Vfend Oral, IV 2002
â Posaconazole Noxafil Oral 2006
Echinocandin Caspofungin Cancidas IV 2001
â Anadulafungin Eraxis IV 2006
â Micafungin Mycamine IV 2007
12. Polyene Antifungal
Amphotericin B (Fungisone)
⢠Spectrum of activity:
â 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:
â oral suspension 100 mg/ml
â lozenge 10 mg
â powder for injection 50 mg per vial
⢠Pharmacokinetics:
â no mucosal or cutaneous absorption
â minimal absorption from GI tract
â extensively bound to plasma lipoproteins
â enters serous cavities
â crosses placental barrier
â plasma half-life 24 h
â renal excretion very slow
15. ⢠Dosage:
â 0.5â1.0 mg/kg per day i.v. for 10â14 days
â up to 1.5 mg/kg per day for disseminated infections
⢠Precautions:
â to avoid precipitation do not reconstitute or dilute with saline, do
not mix with other drugs
â renal function and serum potassium concentrations should be
closely monitored
â maintain high fluid and sodium intake
â potassium supplements may be required to compensate for urinary
losses
â dosage must be reduced if renal function deteriorates substantially,
particularly
â if serum creatinine levels rise by more than 50%
â infusion of an osmotic diuretic such as mannitol may then be of
value
â 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)
22. Fluconazole
⢠Spectrum of activity:
â Limited in vitro activity, Fungistatic
â Candida species
⢠(reduced activity against C. glabrata, virtually no
activity against C. krusei)
â Cryptococcus neoformans
â ineffective against Aspergillus species
23. ⢠Uses: Excellent in vivo activity
â mucosal and cutaneous candidosis
â recalcitrant oropharyngeal candidosis in HIV-positive patients
â deep forms of candidosis in non-neutropenic patients
â acute cryptococcal meningitis in AIDS
â in combination with amphotericin B in treatment of
cryptococcosis and deep forms of candidosis (urinary tract and
peritoneum)
â maintenance treatment to prevent relapse of cryptococcosis in
patients with AIDS
â prophylaxis against candidosis;
â ineffective against aspergillosis
24. ⢠Pharmaceutics:
â Tablets: either 50 mg, 150 mg, or 200 mg
â powder for oral suspension available as 50 mg, 100 mg, or 200 mg
in 5 ml and 35 ml packs
â intravenous infusion : 2 mg/ml in 0.9% sodium chloride solution
⢠Dosage:
â oropharyngeal candidosis, 50â100 mg per day for 1â2 weeks
â esophageal and mucocutaneous candidosis, 100â200 mg per day
for 2â4 weeks
â lower urinary tract candidosis, 50â100 mg per day for 14â30 days
â cryptococcosis, 200â400 mg per day for 6â8 weeks
â systemic candidosis, 200â400 mg per day for 6â8 weeks
25. ⢠Pharmacokinetics: Excellent
â rapid and almost complete absorption after oral administration
â identical serum concentrations attained after both oral and
parenteral administration
â blood concentrations increase in proportion to dosage over wide
range of dose levels
â serum concentrations in the region of 1 mg/l achieved 2 h after
single 50 mg oral dose
â after repeated dosing, serum level increases to 2â3 mg/l
â administration with food does not affect absorption
â rapid and widespread distribution after both oral and parenteral
administration
â protein binding low
â elimination by renal excretion in active form
â serum half-life 20â30 h, prolonged in renal failure
â removed during hemodialysis
26. ⢠Drug Interaction: Extensive Cyp P 450 enzyme
â hepatic metabolism of cyclosporine, phenytoin, sulfonylureas,
theophylline, and warfarin is inhibited
â rifampicin accelerates clearance of fluconazole
â concomitant administration of terfenadine should be avoided, since
it has been associated with serious, sometimes fatal, cardiac
dysrhythmias
â fluconazole prolongs serum half-life of chlorpropamide,
glibenclamide, glipizide, and tolbutamide
â prothrombin time in patients receiving concomitant treatment with
fluconazole and anticoagulants should be monitored
â fluconazole increases plasma zidovudine concentrations
â fluconazole increases plasma rifabutin concentrations
28. Voriconazole
⢠Spectrum of activity:
â broad spectrum of activity :
⢠fungicidal against aspergillus, fungistatic against candida
â Candida species
â Cryptococcus neoformans
â Aspergillus species
â Fusarium species
â Penicillium marneffei
â Scedosporium apiospermum
â Blastomyces dermatitidis
â Coccidioides immitis
â Histoplasma capsulatum
â dermatophyte species
â dematiaceous fungi
N N
N N
N
CH3
F
OH
F
F
29. ⢠Uses:
â treatment of serious fungal infection in immunocompromised
patients
â acute invasive aspergillosis â in USA approved as first-line
treatment. 53% complete or partial response
â invasive candidosis due to fluconazole-resistant Candida species
(including Candida krusei): 71% complete or partial response
â infections due to Fusarium and Scedosporium â in USA approved
for salvage treatment
â cryptococcosis: variable response
â Fusarium infections: 43% response
30. ⢠Pharmaceutics:
â supplied for i.v. administration in lyophilized form in 200
mg amounts
â reconstitute in 19 ml sterile water to give an extractable
volume of 20 ml concentrated solution containing 10
mg/ml voriconazole
â dilute further with 5% dextrose or 0.9% sodium chloride
â can be stored at refrigerator temperature for maximum of
24 h
â Oral tablets: 50 mg and 200 mg
31. ⢠Pharmacokinetics:
â oral administration leads to rapid and almost complete absorption
â 2 h after single 400 mg dose, serum concentrations of ~2 mg achieved
â but variable levels seen in certain demographic groups
â disproportionate increase in blood levels with increasing oral and parenteral
dosage
â non-linear pharmacokinetics in high-risk patients: may indicate monitoring
levels
â mean time to maximum plasma concentration: 1â2 h post-dose
â bioavailability >96%
â best when not administered within 1 h of food intake
â widely distributed throughout tissues
â protein binding 58%
â large volume of distribution: 4.6 l/kg
â elimination by metabolic clearance
â extensively metabolized by cytochrome P450 isoenzymes: may affect delivery
across intestinal mucosa
â elimination half-life is dose-dependent: 6â9 h after a 3 mg/kg parenteral dose or
200 mg oral dose
32. ⢠Dosage:
â loading dose: i.v. formulation 6 mg/kg every 12 h for two doses:
steady state reached
â infusion rate: maximum 3 mg/kg/h over a 1â2 h period
â infusion concentration should not exceed 5 mg/ml
â maintenance dose: 4 mg/kg every 12 h
â 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)
â 1 h before or 1 h following a meal
â no adjustment required in patients with abnormal liver function
tests (up to 5-fold upper limit of normal) but continued monitoring
is recommended
â no adjustment of oral dose required for patients with renal
impairment
â hemodialysis (4 h session) does not remove a sufficient amount of
drug â no dosage adjustment required
33. ⢠Adverse Effects:
â >30% transient visual disturbances, but no anatomical
correlates of the disturbances
â headache
â gastrointestinal upset
â rare cases of severe exfoliative cutaneous reactions, eg.
StevensâJohnson syndrome
â elevation in liver function tests in ~13% patients
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
â invasive forms of candidosis â comparable activity
compared with amphotericin B:
⢠intraperitoneal abscesses, peritonitis, pleural space infections.
⢠Not studied in endocarditis, osteomyelitis or meningitis due to
Candida
â candidemia
â invasive aspergillosis â 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:
â only available for parenteral administration
â supplied in lyophilized form in 50 and 70 mg amounts
â reconstituted in 10.5 ml 0.9% sodium chloride
â reconstituted drug solution further diluted by adding 10
ml to 250 ml 0.9% sodium chloride
â use infusion solution within 24 h, store at <25°C
38. ⢠Pharmacokinetics:
â dose-proportional pharmacokinetics
â poor oral bioavailability
â excretion by hepatic and renal routes
â serum concentrations of ~10 mg/l reached after single 70 mg parenteral dose,
administered over 1 h
â 70 mg/day maintains trough plasma levels above MIC of most susceptible fungi
â blood concentrations increase in proportion to dosage
â less than 10% of dose remains in blood 36â48 h after administration
â protein binding >96%
â about 92% of dose distributed to tissues â highest concentration in liver
â CSF level negligible
â little excretion or metabolism during first 30 h after administration
â initial half-life ~9â11 h
â elimination half-life 40â50 h
â not cleared by hemodialysis
39. ⢠Dosage:
â invasive aspergillosis
⢠once-daily dosing
⢠70 mg on day 1 followed by
⢠50 mg daily infusion over 1 h period
⢠duration patient dependent
â systemic candidosis, including candidemia
⢠i.v. loading dose 70 mg then
⢠50 mg/day infusion over 1 h period
â esophageal candidosis: HIV infected adults:
⢠70 and 50 mg/day: 14 days
⢠caspofungin: 85.1% response
⢠amphotericin B: 66.7% response
42. ⢠Uses:
â seldom used as single drug
â used in combination with amphotericin B for
cryptococcosis
⢠Pharmacokinetics:
â Oral dose: 25mg/kg, Cmax 30 â 40 mg/L
â Tmax 2.5 to 5 hrs, longer in renal failure
â Rapid and complete absorption
â Low protein binding (12%)
â Wide distribution, including CSF
â Excreted unchanged in urine (90%)
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
46.
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 â 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
50.
51. Treatment of definitive, probable & possible
invasive aspergillosis
⢠Invasive Pulmonary aspergillosis:
â First line:
⢠Voriconazole IV 6mg/kg BID for 24 hrs, then
4mg/kg IV BID or 200mg PO BID
â Alternate:
⢠Liposomal Amp B 3 â 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)