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  1. 1. By Dr Faisal Guru
  2. 2. Fungal Infection in Humans = Mycosis • Major Types of Mycoses – superficial – cutaneous – subcutaneous – systemic – opportunistic • Symptoms vary from cosmetic to life threatening
  3. 3. Antifungal Agents • Polyene antibiotic • The polyene antibiotics bind with sterols in the fungal cell membrane, principally ergosterol. This causes the cell's contents to leak out and the cell dies. Animal cells contain cholesterol instead of ergosterol and so they are much less susceptible. – Nystatin – Amphotericin B (may be administered liposomally) – Natamycin – Rimocidin – Filipin – Pimaricin
  4. 4. Antifungal Agents • Imidazole and triazole • The imidazole and triazole groups of antifungal drugs inhibit the enzyme cytochrome P450 14α-demethylase. This enzyme converts lanosterol to ergosterol, and is required in fungal cell membrane synthesis. These drugs also block steroid synthesis in humans. • Imidazoles: • Miconazole Bifonazole • Ketoconazole Butoconazole • Clotrimazole Econazole • Mebendazole Fenticonazole • Isoconazole Oxiconazole • Sertaconazole Sulconazole • Thiabendazole Tiaconazole
  5. 5. Antifungal Agents • The triazoles are newer, and are less toxic and more effective: • Fluconazole • Itraconazole • Ravuconazole • Posaconazole • Voriconazole
  6. 6. Antifungal Agents • Allylamines • Allylamines inhibit the enzyme squalene epoxidase, another enzyme required for ergosterol synthesis: • Terbinafine • Amorolfine • Naftifine • Butenafine
  7. 7. Antifungal Agents • Echinocandin • Echinocandins inhibit the synthesis of glucan in the cell wall, probably via the enzyme 1,3-β glucan synthase: – Anidulafungin – Caspofungin – Micafungin
  8. 8. Antifungal Agents • Others: – Flucytosine is an antimetabolite. – Griseofulvin binds to polymerized microtubules and inhibits fungal mitosis; It is derived from the mold Penicillium griseofulvum. – Fluocinonide – Salicylic Acid (topical) – Tinactin or Tolnaftate – Potassium Iodide
  9. 9. Nystatin: The first antibiotic against fungi • Like many other antimycotics and antibiotics, nystatin is of bacterial origin. It was isolated from Streptomyces noursei in 1950 by Elizabeth Lee Hazen and Rachel Fuller Brown. The soil sample where they discovered nystatin, was from the garden of Hazen's friends called Nourses, therefore the strain was called
  10. 10. Systemic fungal infections - settings • Immunocompromised – Congenital immunodeficiency – HIV – HSCT – Iatrogenic – chemotherapy, BMT, SOT, immunosuppressants for autoimmune – VLBW,ELBW • Intensive Care
  11. 11. Systemic fungal infections – opportunistic • Candida • Aspergillus • Cryptococcus • Fusorium
  12. 12. Systemic fungal infections – Management Principles • Prevention is best • Early treatment – often presumptive is next best – high index of suspicion - • High mortality with delayed treatment
  13. 13. Systemic fungal infections – management principles • Prophylaxis – there is no evidence of fungal infection or colonisation but considered at high risk of fungal infection – hence given prophylaxis – – neutropenia post BMT – Chronic Granulomatous disease – GVHD, refractory leukemia
  14. 14. Systemic fungal infection – management principles • Empirical treatment – Setting of febrile neutropenia with persistent fever for more than 5 days in spite of broad spectrum antibacterial drugs
  15. 15. Systemic fungal infection – management principles • Targeted treatment – based on probable or definitive diagnosis of invasive fungal infection
  16. 16. Systemic fungal infection- drugs • Amphotericin B • Ambisome – Liposomal Amphotericin B • Fluconazole • Itraconazole • Flucytosine
  17. 17. Ergosterol Polyenes (AmB, LFAB) Azoles Fluconazole,Itraconazole Voriconazole Posaconazole Ravuconazole (BMS-207,147) Antifungal Mechanisms of Action: “Newer” Antifungal Agents nucleus Nucleoside Analogs Flucytosine
  18. 18. Amphotericin B • Polyene group – affects fungal cytoplasmic membrane • Broad spectrum – covers almost all candida and aspergillus species • IV, oral suspension and lozenges
  19. 19. Amphotericin B • Not absorbed from gut, skin or mm • IV- highly protein bound • Good penetration into serous cavities • Crosses placenta • Half life 24 hours • Slow renal excretion
  20. 20. Amphotericin B • Dose 0.1 – 1 mg/kg/day IV • Duration – usually 14 days after a documented neg culture • Contraindicated if previous allergic reaction to the drug • Monitoring – U, E, Cr. Cr ^, hypokalemia – CBC weekly • Ensure adequate hydration
  21. 21. Amphotericin B • IV infusion – chills, fever, vomiting • Flushing, muscle, joint pains • Test dose recommended – risk of anaphylaxis • Avoid other nephrotoxic drugs • Steroids worsen hypokalemia • Potentiates activity of Flucytosine
  22. 22. Liposomal Amphotericin B (LAMB) • Lipid formulations – ABELCET (ABLC) – Lipid complex – AMPHOTEC (ABCD) colloidal dispersion – AMBISOME – Liposomal amphotericin – Reduced nonspecific binding to cholesterol • Reduced toxic effects to human cells – Fungal lipases release drug at site of infection – Fungi reside in RES cells – Poor CNS penetration • Overall, rates of successful response with standard doses of lipid based AMB preparations and conventional AMB indistinguishable. Walsh et al. NEJM 1999:340:764 • Conventional AMB associated with a higher degree of renal toxicity. White et al. CID 1998;27:296 – CAMB vs. ABCD (51.5% vs 19.6%, p<0.001) – Longer time to nephrotoxicity with lipid-based AMB
  23. 23. Ambisome • Polyene – liposomal amphotericin B • Broad spectrum similar to Ampho B • May be used instead of Ampho B – but expensive • Often reserved for patients who do not tolerate Ampho B, have doubling of creatinine or do not respond to Ampho B
  24. 24. Ambisome • IV use – infuse over one hour • Usual doses 3-6 mg/kg/day • Usual starting dose is 1 mg/kg/day • Highest levels in liver and spleen • Low levels in kidney • Much less side effects and nephrotoxicity • Much longer duration and cumulative dose possible • Contraindications and drug interactions similar to Ampho B
  25. 25. Fluconazole • Azole – • IV, oral suspension, capsule • Spectrum – Ineffective against Aspergillus species – Ineffective against some Candida species such as C.krusei and C.glabrata – Useful against cryptococcus and C.albicans • Used to treat skin, mm and systemic candidal infections and cryptococcal infection • Also used orally in prophylaxis of above
  26. 26. Fluconazole • Ideal pharmacokinetics – Good bioavailability after oral and IV – Good serum concentrations – Low protein binding – Good distribution to all tissues • Ideal side effect profile – well tolerated, nausea – Elevated liver enzymes, skin rash - discontinue
  27. 27. Fluconazole • Drug interactions – All azoles interact with a wide variety of drugs including antiretrovirals – hence important to look in the formulary to become aware of possible interactions in a particular patient
  28. 28. Itraconazole • Azole – • IV, oral solution, capsules • Very broad spectrum – covers aspergillus, candida, cryptococcus and others • Uses – Alternative to ampho b in invasive aspergillus – Prophylaxis against aspergillus and candida – Treat superficial skin mm fungal infections – Prevent relapse of cryptococcal infection in HIV
  29. 29. Itraconazole • Pharmacokinetics – not ideal – Oral absorption not good – Liquid tastes bad – Very highly protein bound – Needs repeated dosing before optimal concentrations are achieved – Poor CSF concentrations, reasonable tissue concentrations
  30. 30. Itraconazole • Precautions – Drug interactions – Liver enzymes – contraindicated in severe liver impairment – IV preparation contraindicated in severe renal impairment (cyclodextrin present is excreted by kidney) – BP^, Hypo K+, nausea , rash
  31. 31. Flucytosine • Pyrimidine – • IV or oral • Narrow spectrum – mainly candida and cryptococcus • Not used as sole drug – used along with ampho – B • Oral absorption good, low protein binding
  32. 32. Flucytosine • Precautions – Monitor CBC, LFT and renal function – Monitor trough levels • Usual side effects – Nausea, vomiting, diarrhoea – Transient rashes
  33. 33. Extended-spectrum triazoles • Voriconazole and posaconazole • They inhibit the 14α-lanosterol methylase, an enzyme critical in the ergosterol pathway. • Net effect is accumulation of ergosterol metabolites leading to inhibition of growth and fungal cell death
  34. 34. Voriconazole • Oral (well absorbed) and IV formulations Given orally on an empty stomach • Available in India • Spectrum of activity: Candida spp, Aspergillus, Fusarium Pseudoallescheria / Scedosporium C. neoformans Not active vs: Zygomycosis, Sporothrix • Therapy of choice: Aspergillus • Increasingly used as prophylaxis and empiric therapy in neutropenia and bone marrow/stem cell transplant – Marty et al. ICAAC 2003; Abstract M985 • Adverse drug effects: hepatotoxicity – follow LFTs!hypokalaemia visual disturbances avoid IV in pts with CrCl < 50 ml/min
  35. 35. • Not yet been formally tested in neonates due to the visual adverse events reported in adults and children. There is a major concern over its effect on the developing retina. • Recently a case series of safe voriconazole use in critically ill newborn with cardiac disease has been reported from India. No significant drug interaction despite use of severalcardiac drugs or any side effect was observed
  36. 36. Posaconazole • Currenty only an oral formulation, iv in the works. • Excellent bioavailability, and it improves with food • Dose 200 mg po QID (acute) or 400 mg po BID (maintenance) • CYP3A4 inhibitor – Known drug interactions: ↑ levels of cyclosporine and tacrolimus • Very well tolerated in critically ill patients. • Side effects: N/V, diarrhea, abdominal pain. – Most are mild – Very occasional elevation in LFTs. not yet commercially available in India
  37. 37. Posaconazole (2) • VERY BROAD spectrum: – Candida spp, Aspergillus, Zygomycetes, hyahyphomycetes, Fusarium, endemic fungi • CSF penetration poor, but case reports and series suggest activity against CNS infections. • Currently approved indications based on clinical trials: – Antifungal prophylaxis: • patients with HCST and severe GVHD • Patients with hematologic malignancies and profound neutropenia secondary to chemotherapy • Other unapproved uses: salvage therapy of Zygomycosis and other mould infections Herbrecht et al. Int J Clin Pract 2004;58:612
  38. 38. • Ravuconazole. • derivative of fluconazole with potent activity against Candida spp., Aspergillus spp., C. neoformans, H. capsulatum and C. immitis • fungicidal, long half-life of approximately 100h. • Activity against Fusarium and Scedosporium is less than that of voriconazole
  39. 39. • No activity against Rhizopus orMucor spp. • Unfortunately, no pediatric data is available on the safety and tolerability
  40. 40. • BAL-8557. • water-soluble pro-drug that gets cleaved to BAL-4815 (isavuconazole). • very high (98%) plasma protein binding in humans and has potent in vitro activity against Aspergillus spp. including A. fumigatus, A. flavus, A. terreus and A. niger. Several randomized clinical trials are evaluating the safety and efficacy of this drug for the treatment of invasive Candida infections
  41. 41. • Additional triazoles such as albaconazole are undergoing early clinical evaluation and their future is uncertain.
  42. 42. B. ECHINOCANDINS • new class of antifungal agents which exert their activity by noncompetitive inhibition of 1, 3-β-D-glucan, an essential fungal cell wall polysaccharide. • fungi static (due to blockade of cell wall synthesis) against Aspergillus and fungicidal (due to loss of cell wall integrity) against Candida activities. • fewer side effects as cell walls are lacking in human cell, possibility of successful combination with agents acting on cell membrane as combination therapy. • poor bioavailability and have to be administered intravenously
  43. 43. Caspofungin. • Prototype and best studied echinocandin. – Others: micafungin, anidulafungin. • Spectrum of activity  Candida and Aspergillus: – Excellent coverage vs. Candida spp – Fungistatic against Aspergillus spp! • Adverse Effects – FEW and RARE Elevated LFTs, N/V, itching
  44. 44. • Used in adults for empiric therapy of presumed fungal infections in febrile neutropenic patients, for the treatment of candidemia and esophageal candidiasis, and for treatment of refractory invasive aspergillosis. • As of July 2008 FDA approval for pediatric use. alternative therapy for neonatal candidiasis refractory to conventional antifungal therapy.
  45. 45. • Micafungin and Anidulafungin. – are echinocandins with spectra of activity similar to caspofungin. – not available in India. – achieve highest concentration in lung, liver, spleen, and kidney. • approved by FDA in 2005 for therapy of esophageal candidiasis and for prophylaxis of Candida infection in HSCT.
  46. 46. • Micafungin in combination with second antifungal agent in pediatric and adult bone marrow transplant
  47. 47. • Aminocandin (HMR3270). This is a semi- synthetic fermentation product from Aspergillus sydowi, and is similar in structure to the other members of the echinocandin class. • activity against both Candida and Aspergillus spp.(including itraconazole resistant strains) but not active against Scedosporium spp.Fusarium spp. and the Zygomycetes).
  48. 48. CHARACTERISTICS OF NEW ANTIFUNGAL AGENTS • Drug Antifungal activity Route Can Crypto Asper Other hyalomyces Zygom. • Voriconazole + + + + /- – iv/po • Posaconazole + + + + /- +/– po • Ravuconazole + + + +/ - +/– iv/po • Caspofungin + - + – - iv • Anidulafungin + - + – - iv • Micafungin + - + - - iv
  49. 49. Invasive candidiasis (IC) and candidemia • Candidemia is a leading nosocomial blood stream infection. • Traditional practice has been to use amphotericin B and/or fluconazole. • There is an increasing incidence of: – Non-albicans isolates – Fluconazole-resistant isolates. • While amphotericin B remains an active drug, the toxicity and inconvenience argue for different treatment options.
  50. 50. Is caspofungin as good as amphotericin B in the treatment of invasive candidiasis? Blinded prospective randomized trial 224 non-neutropenic pts Mora-Duarte et al. NEJM 2002;347:2020-9 Outcome (%) Caspo AMB p Success (Modified intent-to treat) 73.4 61.7 Success (evaluable patients) 87% 75% <.05 Adverse effects requiring withdrawal of therapy 2.6% 23.2% 0.003 Nephrotoxicity 8.4% 24.8% .02 Mortality 34% 30% NS Persistent candidemia 8% 9% NS
  51. 51. Voriconazole in the treatment of candidemia • Prospective, doubled blinded randomized trial of non- neutropenic patients with candidemia • Patients were randomized 2:1 to voriconazole or amphotericin B + fluconazole • Primary outcome: successful response to therapy – Mycological eradication – Clinical cure or improvement at 12 weeks Kullberg BJ et al. Lancet 2005;366:1435-42
  52. 52. Voriconazole vs. amphotericin B + fluconazole in candidemia Kullberg BJ et al. Lancet 2005;366:1435-42 Species Vori (272) Ampho/ Flu (131) p C. albicans 107 (43%) 63 (51%) Non-albicans Candida 150 (61%) 61 (50%) All cause adverse events Hepatic 63 (23%) 32 (24%) 0.78 Renal 22 (8%) 28 (21%) 0.0002 Visual 11 (4%) 1(1%) 0.07 Outcomes Successful response 101 (41%) 50 (41%) 0.96 Mortality 88 (36%) 51 (42%) 0.23
  53. 53. Invasive aspergillosis. • First described in 1953 • 14-fold increase in incidence since 1992 Groll et al. J infect 1996;33:23 • Overall, response to amphotericin B 10 - 40% Denning et al. CID 1996;23:608 • No evidence that lipid-based amphotericins are more effective than traditional preparations. Patterson TF et al. Medicine (Baltimore) 2000;791:250
  54. 54. What is the role of caspofungin and voriconazole in the treatment of IC? Dismukes, WE. CID 2006; 42:1289-96 Guidelines for treatment of candidiasis. CID 2004;38:16:161-89. Spanakis EA et al. CID 2006;43:1060-9 •Pending further trials and a direct head-to-head comparison, current guidelines recommend: Caspofungin: Primary therapy of candidemia in both non-neutropenic and neutropenic adults. (along with ampho B and fluconazole) Alternative in endocarditis, oropharyngitis and esophagitis and maybe in other forms of IC. Voriconazole An option for step down to oral therapy in cases of candidemia secondary to FLU-resistant isolates. An option in esophagitis that fails to respond to fluconazole.
  55. 55. Primary therapy of invasive aspergillosis with voriconazole (1).• Open randomized trial of voriconazole (N=144) vs. ampho B (N=133) Herbrecht et al NEJM 2002;6:408 102 (70.8%) 343 30 (20.8%) 46 (31.9%) 77 (57.9%) 421 22 (16.5%) 20 (15.0%) 0 100 200 300 400 500 Survival at 12 weeks Adverse Events Partial Response Complete Response Ampho B Vori Overall Successful responses: Voriconazole 52.8% Ampho B 31.6%
  56. 56. Invasive aspergillosis. Should we use combination therapy? (1) • Animal models suggest an additive effect with the combination of an echinocandin & azole Petroitis et al. JID 2003; 1834. McCallum et al. AAC 2005; 3697. • Salvage therapy with vori/caspo was associated with decreased mortality compared to voriconazole alone in a retrospective review of patients with hematologic malignancies (p=0.08). Marr et al. CID 2004;39:797. • In a prospective open trial in 87 SOT recipients, primary therapy with vori/caspo was not associated with increased survival compared to historical controls treated with ampho B. (p=0.0177). Singh et al. Transplantation 2006;81:320 – However, combination therapy in patients with renal failure (p=0.022) and with infection with A. fumigatus (p=0.019) was associated with increased survival.
  57. 57. Voriconazole vs L-AMB in prolonged fever and neutropenia Walsh et al. NEJM 2002;346:225 Prospective randomization Non-inferiority trial N=837 Voriconazole N= 415 (49.6%) L-AMB N= 422 (50.4 %) Success (%) 108 (26) 129 (30.6) NS Breakthrough infections (%) 8 (1.9) 21 (5) 0.02 Survival 7 d after treatment (%) 382 (92) 397 (94.1) NS Therapy stopped due to lack of efficacy (%) 22 (5.3)* 5 (1.2) 0.002 Discontinuation due to persistent fever 14 2 0.002
  58. 58. • Voriconazole did not fullfill criteria for non-inferiority – Vori 95% CI (-10.6 to 1.6) • It was almost there! (missed by 0.6 percentage points) • Voriconazole was better than L-AMB at preventing breakthrough infections, particularly in high risk patients • Higher discontinuation due to “lack of efficacy” in patients receiving voriconazole – But most of these were due to fever – None of these fevers were due to fungal infections – Low comfort level with a new drug? Voriconazole vs L-AMB in prolonged fever and neutropenia Walsh et al. NEJM 2002;346:225
  59. 59. Caspofungin vs L-AMB in prolonged fever and neutropenia Walsh et al. NEJM 2004;351:1391 Prospective randomization & non-inferiority trial N=1095 Caspofungin N= 556 (50.7%) L-AMB N= 539 (49.3%) Success (%) 190 (33.9) 181 (33.7) NS Success in patients with baseline fungal infections 14/27 (51.9) 7/27 (25.9) 0.04 Breakthrough infections (%) 29 (2.6) 24 (4.4) NS Survival 7 d after treatment (%) 512 (92.6) 481 (89.2) 0.05 D/C therapy due to lack of efficacy (%) 30 (5.4) 34 (6.3) NS
  60. 60. Caspofungin vs. L-AMB in prolonged fever and neutropenia Walsh et al. NEJM 2004;351:1391 • Overall, caspofungin was at least as effective as L- AMB. • Caspofungin was significantly less nephrotoxic and had a lower rate of infusion-related events compared to L-AMB (p<0.001 for both) • There was a survival advantage to caspofungin on longer follow up (p=0.04)
  61. 61. Empirical antifungal therapy of prolonged fever and neutropenia • “One size fits does not fit all” Spanakis EK. CID 2006;1060-8. • There are no clear guidelines. • A possible approach is to choose based on the risk of a mould infection: – Low risk. Caspofungin is a proven and safer alternative to AMB – High risk. Voriconazole may be preferable Spanakis EK. CID 2006;1060-8. • Role of L-AMB and AMB: – Great coverage but again, very toxic – Still primary therapy in some centers – On its way to being the second-line agent?
  62. 62. • NEW ANTIFUNGAL AGENTS • TREATMENT OPTIONS FOR INVASIVE FUNGAL INFECTIONS • Clinical Condition Underlying diseas DOC AD • Prophylaxis for IFI a Neutropenic patient Posaconazole Itraconazole fluconazole • with malignancy/HSCT • Empiric therapy for IFI Neutropenic patient with Caspofungin LAmB • malignancy/HSCT and headache • clinical and/or radiological • hematological signs of IFI • laboratory evidence, • Possible IAb • Preemptive/targeted Neutropenic patient with, Voriconazole iv LAmB • therapy for IFI malignancy/HSCT and clinical, • signs of IFI with laboratory • evidence of fungal infection; • Probable or proven IAc • Prophylactic therapy Neutropenic Fluconazolee • for candidiasis in the patients • ICU • Empiric/targeted Neutropenic/ Caspofungin LAmB • treatment for invasive HSCT • candidiasis • Non-neutropenic/ Echinocandin LAmB • ICU patients
  63. 63. Conclusions • Caspofungin – Effective as primary therapy of candidemia and systemic candidiasis and as salvage therapy of aspergillosis. – Reasonable agent in neutropenic fever in patients at low risk of mould infections – Potential role in antifungal prophylaxis, but not well defined yet. • Voriconazole – Primary therapy of aspergillosis and a first line agent in Fusarium – Alternative therapy in cases of candidiasis – Increasingly used in prophylaxis, but studies pending. • Combination therapy with vori/caspo an option in salvage treatment in Aspergillosis, but not supported yet by data
  64. 64. Conclusions • Posaconazole – Approved for prophylaxis in pts with HCST and GVHD (although studies not published yet!) – Primary therapy of Zygomycosis? – Salvage therapy of other mould infections • Role of Amphotericin B compounds limited • Studied needed to define subsets of high-risk populations and to better target prophylaxis and therapy.
  65. 65. http://www.criticalpediatrics.org/ www.dnbpediatrics.com

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