Infectious Disease Seminar I: Antifungal use for invasive fungal infection in ICU

1. Infectious Disease Seminar I:Antifungal use for invasive fungal infection in ICU Dr. Richard Li 23rd March, 2007

2. Drug Targets in Fungi

3. Structure of Fungi • Eukaryotes with the chromosomal material enclosed with nuclear membrane • Most have mitochondria • Cell wall contains glucan & chitin which maintains osmotic stability • Cytoplasmic membrane contained more ergosterol than cholesterol • Sexual stages in life cycle. • Mould & dimorphic fungi has specialised structure for the production of infectious spores

4. Classification of fungi • More than a million species of fungi, ~ 400 species caused disease in human, animal or plants • Yeast: rounded forms: actively dividing and metabolizing form of the fungus. Reproduction via budding. Colonies are moist and mucoid. • Mould: consists of hyphae and forming mycelium mass. Spread by forming metabolic inactive spores • Dimorphic fungi

5. Mycoses • Clinical manifestations: • Invasive/ disseminated infection – blood stream & internal organs • Superficial skin, mucosa or nail infection: tinea, onychomycosis, oral/ vaginal/ perianal or glans penis thrush • Subcutaneous mycoses - mycetoma

6. Systemic mycosis • Pathogenesis: • Invasive moulds: affect paranasal sinuses & lung first by inhalation of spores/ colonization • Originated from skin colonizer, breaching skin barrier through wound infection or catheter-related infection • Hematogenous spread: vascular invasion then causing brain or other viscera dissemination • vascular thrombosis & tissue infarction

7. Antifungals Classification • Azoles • Allylamines • Polypenes • Glucan Synthesis Inhibitors/ Echinocandins • Antimetabolites

8. 1958 1st antifungal, Amphotericin B (iv), Fungizone 1972 5-flurocytosine (iv, po), Alcoban 1981 1st imidazole, Ketoconazole (oral), Nizoral 1990 1st triazole Fluconazole (iv, oral), Diflucan 1992 Itraconazole (iv, oral), Sporanox Amphotericin B lipid complex (Abelcet) in 95’ Amphotericin B cholesteryl sulphate (Amphotec) in 96’ Amphotericin B lipsomal (AmBisome) in 97’ 1995 - 1997 2001 1st echinocandin, Capsofungin (iv), Cancidas 2002 Newest azole, Voriconazole (iv, oral), V-Fend 2005 Latest antifungal, Micafungin (iv), Mycamine

9. Azole Target All azole antifungal agents works principally by inhibition of cytochrome P450 14a-demethylase (P45014DM). This enzyme is in the sterol bio-synthesis pathway that leads from lanosterol to ergosterol Toxic sterols accumulations

10. Imidazoles • Topical azoles - Clotrimazole, Miconazole: preferred treatment vs. keratomycoses due to yeast infection • Ketoconazole (Nizoral) – introduced in 1981, as the only member of this class in treating systemic mycoses • Induced anorexia, menstrual irregularities in women, gynaecomastia & oligospermia in men; and potent anti-thyroid activity • seldom use nowadays because of hepatotoxicity & better drugs available

11. Triazoles • Triazoles - Fluconzole, Itraconazole & Voriconazole have following advantages: • Greater affinity vs. fungal target enzymes than mammalian enzymes • Fewer drug interaction • A broader spectrum • Better distribution into body fluids • Less GI distress and hepatotoxicity

12. Triazoles • Fluconazole – • Potent activity against Candida albicans, also active to non-albicans, especially C. glabata • Candida krusei is resistant • No activity against mould • Absorption is not altered by food or gastric acidity • Widely distributed in most tissues including CSF • Rarely leads to relevant drug interactions

13. Triazoles • Itraconazole – • more active than fluconazole vs. C. albicans, & non-albicans candida • Cross-resistance with fluconzole • Possess activity against Aspergillus and dematiaceous fungi • Absorption of itraconazole capsule is affected by gastric acid; bioavailability improved with food/ coke intake (55%) • Oral suspension is better absorbed, not affected by gastric acid • Very poor CSF penetration < 1%

14. Triazoles • Voriconazole • Broad spectrum antifungal activity • Active to Candida spp., Aspergillus spp, Cryptococcus neoformans • Widely distributed in body including CSF • Possess fungicidal activity vs. Aspergillus terreus (resistant to AmpB); better in vitro fungicidal activity vs. A. fumigatus • Also active vs. dimorphic fungi, Fusarium spp, dematious fungi • Not active vs. Zygomycetes e.g. Mucor, Absida, Rhizopus spp.

15. Triazoles • Posaconazole • A new extended spectrum triazole • In vitro activity to Aspergillus spp., at least as good as or better than voriconazole • Good activity v.s. Zygomycetes

16. Triazoles – drug precautions • Elimination route of fluconzaole: via renal, need reduce dose • Elimination route of voriconazole/ itraconazole: hepatic; suggest half maintanence dose in Child’s A,B patients • Triazoles inhibit cytochrome P450 enzymes - markedly increase serum cyclosporin, tacrolimus and omerprazole level • Voriconazole level would be affected by CYP 450 inducer (e.g. phenytoin, carbamazepine & rifampicin)

17. Triazoles - drug precautions • preparation of voriconazole is solubilized in sulfobutylether-β-cyclodextrin (SBECD), which is cleared via renal route. • very limited animal/ renal insufficiency patients’ toxicology data regarding the accumulation of SBECD in the blood-stream  • Voriconazole: potential of QT prolongation (avoid concomitant use of terfenadine, macrolides, cisapride or quinidine)

18. Glucan Synthesis inhibition Caspofungin blocks the synthesis of a major fungal cell wall component, 1-3-beta-D-glucan. The lack of glucan synthesis enzymes in mammalian tissue makes this an attractive target for antifungal activity

19. Echinocandins • Caspofungin & Micafungin • Against most Candida spp (fungicidal), Aspergillus (fungistatic); and dimorphic Moulds • Not active against Crpyotococcus, Trichosporon beigelii, dematiaceous mould, Zygomycetes, Fusarium • No evidence of cross resistance to antifungal triazoles

20. Antimetabolite Target Antimetabolite inhibits fungal protein synthesis by - replace uracil with 5-flurouracil in fungal RNA. - inhibit thymidylate synthetase via 5-FU monophosphate and thus interferes with fungal DNA synthesis

21. Antimetabolite • 5-Flurocytosine, as flourine analogue of cytosine • Noncompetitive inhibitor of thymidylate synthetase • Seldom used as single drug; mostly combinated with Amphotericin B in treating candidiasis or cryptococcosis

22. Antimetabolite • Indication of 5-fluorocytosine: • Serious cryptocoocal meningitis • Neonates candidal infection involving CNS • Adults severe candidal infections including endocarditis & meningitis • Toxicity toward bone marrow & GI tract

23. Polypenes Target Amphotericin B binds to primary fungal cell membrane ergosterol. disrupts osmotic integrity of the fungal membrane: leakage of intracellular K, Mg, sugars/metabolites -> cellular death.

24. Amphotericin B • A polypene agent • First isolated by Gold et al. from Streptomyces nodosus in 1955 • Lipophilic drug; insoluble at physiological pH • Four preparations in market/ clinical use • No need to protect the infusion bottle from light • hydrophilic polyhydroxyl chain along one side • lipophilic polyene hydrocarbon chain on the other

25. Coverage • Amphotericin B has a very broad range of activity and is active against most pathogenic fungi. • Notable exceptions include Trichosporon beigeli, Aspergillus terreus, Pseudallescheria boydii, Malassezia furfur, and Fusarium spp. • Among the Candida spp., isolates of C. albicans, C. guilliermondii, C. lipolytica, C. lusitaniae, C. norvegensis, C. tropicalis, C. glabrata, and C. krusei have been reported to be relatively resistant to amphotericin B

26. Preparations • Amphotericin B deoxycholate • Amphotericin B Colloidal dispersion - ABCD; Amphocil™ or Amphotec™ • Amphotericin B Lipid complex – ABLC; Abelcet™ • Liposomal Amphotericin B - L-AMB; Ambisome™ (only one in liposome form)

27. IRAE • most commonly infusion-related adverse effects (IRAE) of amphotericin B: fever, nausea, vomiting, chills, myalgia, thrombophlebitis (71%) • Common practice: premedication with piriton +/- paracetamol; or hydrocortisone, heparin – No evidence that this practice can reduce the IRAE • Instead, IRAE can be significantly reduced with infusion over 12 – 24 hours • Amphotericin B preparations should be diluted & infused with 5% dextrose

28. Itraconzole vs. Amphotericin B in neutropenic fever patients (RCT) Ann Intern Med 2001;135: 412-422

29. Nephrotoxicity • Nephrotoxicity can be reduced or delayed by routine saline pre-loading with 0.5-1L NS before each dose of amphotericin • Associated with hypokalemia & hypomagnesemia Itraconzole vs. Amphotericin B in neutropenic fever patients (RCT) Ann Intern Med 2001;135: 412-422

30. Nephrotoxicity • Lipid formulations of Amphotericin B are less nephrotoxic comparing to AmpB deoxycholate • More information from AmBisome than Abelcet and Amphocil • They has reduced affinity for cholesterol and lower concentration (10-folds less) in the kidney • Not to mix intralipid with Amphotericin B; risk of fat embolism by forming small particles

31. Lipid formulations of AmpB • In vitro: liposomal ampB is as effective as conventional one vs. Candida & aspergillosis; ABCD is less active vs. Asepergillus fumigatus and A. niger • Animal study: higher dose liposomal amphotericin B (5mg/kg) is more effective than low dose (1mg/kg) • Human study: ABLC is equally active to invasive candidiasis • Higher response rate for AmBisome than conventional group (61% vs. 32%) in pts’ without neutrophil recovery; • But no change in response rate (50% vs 49%); survival at day 7 (93% vs 90%); resolution of fever (58% equal)

32. Cost of Antifungals

33. Lipid formulations indications • Potential indications (adapted from IDSA guidelines) • Second line therapy of systemic mycosis patients who are intolerant/ refractory to conventional AmpB • Development of renal impairment during treatment (Cr > 220mmol/L) • Severe/ persistent infusion related adverse events despite premedication with antihistamine +/- steroid

34. Lipid formation indications • Disease progression after >500mg total dose of conventional amphotericin B • Initial therapy of neutropenic patient who has persistent fever, despite broad spectrum antibiotic treatment & who are in high risk of nephrotoxicity • Initial therapy of proven systemic mould disease but have preexisting renal impairment (Cr > 220mmol/L)

35. Common invasive Fungal Infection in ICU • Yeast: Candidiasis • Yeast: Cryptococcosis • Mould: Aspergillosis • Dimorphic Fungi

36. Courtesy from www.doctorfungus.com

37. Invasive Candidiasis • Candidemia • most commonly catheter related; Rx: removal of infected cath. • antifungal speed clearance of any local infection • assist with clearance of undetected foci of hematogenous spread • Acute disseminated candidiasis • Chronic disseminated candidiasis • occurred exclusively in leukaemia/ marrow suppressed hosts with • Hepatosplenic candidiasis +/- renal; characteristic lucencies in these organs; blood C/ST rarely positive • Deep organ candidiasis • multi-organ involvement, distinguished from chronic one clinically

38. Systemic candidiasis • Cathether infection/ CAPD peritonitis: Candida parapsilosis • Invasive candidiasis - • Candida albicans (tendency to attack eye, kidney, suppurative granulomata in hepatosplenic candidiasis) • Candida tropicalis in immunosuppresive hosts • Candida dubliniensis in AIDS • Candida glabata & krusei are resistant to fluconazole

39. Systemic candidiasis • Frequency of systemic candidiasis in oncology patients (n=1591): • Group I: Candida albicans (46%), Candida tropicalis (25%); most virulent in terms of mortality rate, endophthalmitis & fungal bruden in kidneys • Group II: Candida glabrata (8%) • Group III: Candida parapsilosis (7%), Candia krusei (4%)

40. Treatment of systemic candidiasis • Empirical therapy in febrile non-neutropenic/ neutropenic patients • Amphotericin B deoxycholate (0.6mg/kg per day) is conventional therapy (AII) • Adjuct flucytosine if case is refractory • Liposomal amphotericin B (3 mg/kg per day) showed similar overall clinical efficacy but superior safety, less breakthrough fungal infections, particularly in BMT recipients (A-I) • Itraconazole (200 mg iv q12h for 2/7, 200 mg iv daily for 12/7, and then 400-mg solution daily) similar breakthrough fungal infection rates and mortality but significantly less toxicity (A-I) IDSA Guideline for treatment of Candidiasis Clin Infect Dis 04;38:161-189

41. Treatment of systemic candidiasis • Itraconazole (iv) has an adequate antifungal spectrum of activity; equivalent to amphotericin B • Fluconazole: inappropriate because of prior exposure and its limited spectrum. • Voriconazole reserved to high-risk patients (e.g., BMT recipients and leukemia) for prevention of breakthrough infection • caspofungin and other echinocandin: uncertain • appropriate in neutropenic patients having persistent unexplained fever, after 4-7 days of appropriate antibiotics; continued until resolution of neutropenia IDSA Guideline for treatment of Candidiasis Clin Infect Dis 04;38:161-189

42. Cryptococcosis • Found in soil, infected by spore inhalation • divided to C. neoformans vars neoformans (serotype A,D), and C. neoformans vars gatti (serotype B,C) • Attack immuocomprimised host/ AIDS patients as opportunistic infection • Occasionally in immunocompetent hosts • Tendency to attack CNS; or pulmonary cryptococcosis

43. CNS Cryptoccocosis • Longer prodromal symptoms up to several months prior to diagnosis • Present with s/s of meningoencephalitis * • Fever, lethargy, headache, coma, personality changes, memory loss over 2-4 weeks time • May present with severe headache for few days, intermittent headache for months or without a headache • Papilloedema, cranial nerve involvement, visual loss, and hydrocephalus • Rarely cryptococcoma

44. Treatment: CNS disease • From Mycoses Study group Cryptococcus subproject (US): • Amphotericin + flucytosine: sterilize CSF within 2 wks. in 60%-90% of patients • Most patients will be treated sucessfully within 6 weeks • Extra-polated from HIV+ve cases series: 2 wks of AmpB+Flucytosine (induction) + 10wks fluconazole (consolidation) • LP is required 2 weeks after induction therapy to prove CSF sterilization • Repeated positive C/ST needs a longer induction therapy period • Large accessible CNS lesion (>3cm) require surgery Practical guidelines for the Mx.of cryptococcosis Clin Infect Dis 2000; 30:710-718.

45. Pulmonary Cryptococcosis • Pulmonary cryptococcosis: active pulmonary infection with • positive C/ST from BAL, blood or CSF • organism in lung biopsy specimen • detection of cryptococcal Ag in blood or CSF • Acute infection: can present as ARDS in HIV +ve. Patients • Most cases are chronic pulmonary infections: present as nodules or masses (usually in the upper lobes), cavities, airspace lesion, or pleural effusion, or lymphadenopathy

46. Treatment: pulmonary & non-CNS diseases • LP is needed to rule out concomitant CNS disease • many immunocompetent patients with positive sputum cultures have done well without therapy*: observe or fluconazole 3-6 months • with mild –moderate chest symptoms: fluconazole 200-400mg daily x 6-12 months • Itraconazole is acceptable alternatives; ketoconazole is ineffective • Severe disease/ not able to take oral azoles: AmpB:0.4-0.7mg/kg/day for a total dose 1000-2000mg • Solid organ transplants recipient should receive early aggressive treatment Practical guidelines for the Mx.of cryptococcosis Clin Infect Dis 2000; 30:710-718.

47. Mould

48. Aspergillosis • Second common recovered fungus in opportunistic mycosis; caused by over 20 species of aspergillus • Most common: Asepergillus fumigatus, followed with A. flavus and A. niger • Local colonizer in pervious destroy lung e.g. old TB, bronchiectasis, pneumoconiosis • Invasive aspergillosis: tendency to invade or obstruct blood vessels, causing hemorrhage, infarction or tissue ischaemia • Mortality of invasive aspergillosis: 50 – 100%

49. Aspergillosis • Paranasal sinus and lung are the most common site of 1’ invasive disease • allergic bronchopulmonary aspergillosis, • pulmonary aspergilloma • invasive aspergillosis (today’s presentation concern) • Risk factor: neutropenic, chronic immunosuppression • CNS is the most common secondary invasive site • But most common presentation is unremitting fever in the absence of complaint & failed to respond to broad-spectrum antibiotic

50. Aspergillosis • Direct microscopy of sputum/ BAL; 80-90% +ve. predictive value in neutropenic patients • Can be indistinguishable with pseudallescheria boydii or fusarium • Distinguished features of aspergillus hyphae: acute angle branching, septated nonpigmented hyphae 2-4mm in width • Culture can be taken > 4 weeks