Your SlideShare is downloading. ×
×

Introducing the official SlideShare app

Stunning, full-screen experience for iPhone and Android

Text the download link to your phone

Standard text messaging rates apply

Antifungal drugs 2010

3,993
views

Published on

Choosing antifungal for treatment of invasive fungal infections

Choosing antifungal for treatment of invasive fungal infections

Published in: Technology, Health & Medicine

0 Comments
3 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
3,993
On Slideshare
0
From Embeds
0
Number of Embeds
1
Actions
Shares
0
Downloads
671
Comments
0
Likes
3
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
No notes for slide

Transcript

  • 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
    • 25 º C Dimorphic Fungi 37 º C
          • Blastomycosis
          • Histoplasmosis
          • Coccidioidomycosis
          • Para coccidioidomycosis
          • 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 4 th 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 2007 IV Mycamine Micafungin “ 2006 IV Eraxis Anadulafungin “ 2001 IV Cancidas Caspofungin Echinocandin 2006 Oral Noxafil Posaconazole “ 2002 Oral, IV Vfend Voriconazole “ 1992 Oral, IV, Susp Sporonax Itraconazole “ 1990 IV, Oral, Susp Diflucan Fluconazole “ 1981 Oral Nizoral Ketoconazole Azole (5) 1972 Oral Ancoban Flucytosine Pyrimidine 1997 IV AmBisome Amph B liposomal “ 1996 IV Amphotec Amph B Choleteryl sulfate “ 1995 IV Abelcet Amph B Lipid Complex “ 1958 IV, Oral Fungizone Amphotericin B Polyene (4) Year of first approval Available as Brand name Generic name Class
  • 10. Mechanism of action
  • 11.  
  • 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 173.4 34 2nd phase 235 3rd phase 23 2nd phase h Half-life (elimination) 2286 111 553 25.9 l Volume of distribution 211 40.2 28.4 22.2 ml/h/kg Clearance 9.5 34.2 56.8 423 μg/ml/h AUC 1.7 3.6 2.5 29 μg/ml Peak blood level 5 1 1 .5 3 mg/kg Dose ABLC Amp B ABCD AmBisome
  • 19. Azole
    • Ketoconazole
    • Itraconazole
    • Posaconazole
  • 20. Azole Fluconazole
          • Voriconazole
  • 21.  
  • 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
  • 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
  • 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
  • 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
  • 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 S S S S 5 C. tropicalis S S S S 20 C. parapsilosis S to I R S S 4 C. krusei S to I S DD to R S S 15 C.glabrata S S S S 50 C. albicans Vori Flu Caspo Amp B %
  • 49. Treatment of adults with invasive candiadiasis Voriconazole or CAB Caspofungin Or Liposomal Amp B Candidiasis with known risk factors for azole resis Caspofungin or Voriconazole Fluconzaole Candidiemia 6mg/kg bid IV load, 4mg/kg bid IV Voriconazole 70 mg IV load & 50 mg IV / day 3-5 mg/kg IV Caspofungin or Liposomal Amp B Candida spp unknown,unstable, neutropenic, risk factors azole R 70 mg load, IV Caspofungin or Voriconazole or Liposomal Amp B 400 mg (6 – 12 mg/kg) day IV or oral Fluconazole Candida spp unknown, not haemodynamically unstable, not neutropenic, no risk for azole Resis Dose Alternative Dose Therapy Clinical setting
  • 50.  
  • 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)