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FUNGAL INFECTIONS AND THE KIDNEY

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1 FUNGAL INFECTIONS AND THE KIDNEY
Prof K L GUPTA, Department of Internal Medicine, King Fahd Hospital of University, AL KOBAR

2 OBJECTIVES & Parts of Talk
PART 1. To discuss the kidney involvement in fungal infections Part 2. To discuss the fungal infections following renal transplantation Part 3. To discuss management of invasive fungal infections

3 Introduction Invasive fungal infections have  recently.
Renal involvement results in increased morbidity and mortality.Similarly fungal infections may complicate the course of renal transplant recipients. Clinical manifestations depend on pathogenic organism. And the organ involved Diagnosis is often delayed due to co-existing illnesses. Early identification is important in providing timely therapy.

4 Disseminated mucormycosis presenting with acute renal failure
Postgraduate Medical Journal (1987) 63, Disseminated mucormycosis presenting with acute renal failure K.L.Gupta,1 Kusum Joshi,2 Brian J.G.Pereira1 and Kartar Singh3 Departments of 1 Nephrology, 2 Pathology and 3Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh , India. Summary : An unusual presentation of disseminated mucormycosis as acute renal failure in a patient without any predisposing condition, is reported. The diagnosis was established at autopsy.

5 Mucormycosis in patients with renal failure
K.L. Gupta, B.D. Radotra, V. Sakhuja, A.K. Banerjee and K.S. Chugh Departments of Nephrology and Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh , India Am Journal of Kidney Diseases,Vol 22, No 3(September),1993; pp

6 Renal mycoses : Indian scene PGI,Chandigarh Study
Data-source Medical & pathology records Diagnostic criteria Histological demonstration of tissue invasion in H&E, PAS & Silver Methenamine estained sections Identification by characteristic morphlology Isolation of in fungi culture Period of study No.of cases ( 74 M, 11 F ) Age (yrs ) ± 18.5

7 Renal Mucormycosis Rhizopus, Absidia and Mucor
Large, aseptate,irregularly branching hyphae Clinical syndromes: PGI Study n=129* Rhinocerebral 57 (44%) Pulmonary 13(10%) Disseminated 15 (12%) Gastrointestinal ( 5%) Cutaneous ( 15%) Renal (14%) *Chakrabarti et al J Infectious Dis 42; :2001

8 Case Discussion Examination
SJ 17 M Student admitted with Fever, flank pain (Lt.). Vomiting。Haematuria, and doligo-Anuria for 10 days Examination Pale, febrile, toxic, pt. B/L pedal oedema BP 150/90, Pulse-110/m Generalised tenderness in abdomen Fullness of C-V angles Investigations Hb-80g/L, WBC 23x109/L Urine Prot.++, pus cells , RBC 15-20/HPF Urea 240 mg/dl, Creat.10mg/dl, uric acid 12 mg/dl Sugar 100mg/dl ALB. 2.5g/dl, TP 5.1g/dl HIV Neg., T4/T8 Ratio normal, Fungal serology-Normal US and CT Abdomen:

9 Course & Management Hemodialysis, antibiotics,
Laparotomy and aspiration of perinephric collection Pus direct smear-Mucor hyphae Culture-Apophysomyces elegans Kidney biopsy: Ischemic necrosis with vessel invasion by mucor Amphotericin B total dose -560mg( 2 weeks) B/L nephrectomy Patient died after two weeks of diagnosis Autopsy: No other organ involvement Comments: Isolated renal mucormycosis with ARF

10 Renal Mucormycosis: PGI Study (n=25)
Sex ratio M:F 22:3 Age (yrs. ) ±15.1 Presenting features No. % Fever Flank pain Luekocytosis Hematuria Pyuria Renal failure* * In (95%) pts with bilateral involvement

11 Renal Zygomycosis: an under-diagnosed cause of acute renal failure
Nephrol Dial Transplant (1999) 14: Nephrology Dialysis Transplantation Clinical Observations Renal Zygomycosis: an under-diagnosed cause of acute renal failure Krishan Lal Gupta, Kusum Joshi1, Kamal Sud, Harbir S. Kohli and Vivekanand Jha, Bishan D. Radotra1 and Vinay Sakhuja Departments of Nephrology and 1Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

12 Renal Mucormycosis: Radiological Features
Ultrasonography ( n-24) Enlarged kidneys 22 Perinephric collection 10 Computerised tomography ( n-12 ) Enlargement of kidneys Absence of contrast 10 Low attenuated areas 10 Perinephric collection 9

13 Am Journal of Kidney Diseases,Vol 22, No 3(September),1993; pp 393-397
Renal Mucormycosis: Computerized Tomographic Findings and Their Diagnostic Significance K.S.Chugh, MD, FACP, V.Sakhuja, MD, DM, FAMS, K.L.Gupta, MD, DM, V.Jha, MD, DM, A.Chakravarty, MD, N.Malik, MD, P.Kathuria, MD, N.Pahwa, MD, and O.P.Kalra, MD

14 Renal Mucormycosis : Renal Pathology
Tissue obtained at autopsy at biopsy 7 Gross examination ( n-18 ) Evidence of infarction Hilar vessel thrombosis Microscopic examination ( n-25) Vasculitis 18 Cortical & medullary necrosis 18 Microabscess & granuloma Glomerular invasion 15

15 Renal Aspergillosis (A fumigatus, A.flavus, A.niger )
Identified by slender,regular,dichtomously branching,septate hyphae Invariably associated with debilitated state Usually part of disseminated disease & rarely isolated Other organs lungs (94%),GIT (92%),brain (13%) † Clinically: Three patterns 1) Disseminated aspergillosis with renal involvement 2) Aspergillus cast of renal pelvis 3) Ascending panurothelial aspergillosis † Wise & Silver (1993)

16 Aspergillosis: PGI Study (n=27)
Sex ratio M:F 23:4 Age (yrs. ) ± 19.5 Presenting features Renal failure 15 (55%) Pathologic findings Microabscesses 19 Vasculitis 13 Papillary necrosis Culture identification 6

17 Isolated Bilateral Renal Aspergillosis:
Renal Failure, 20(6), (1998) CASE REPORT Isolated Bilateral Renal Aspergillosis: An unusual Presentation in an Immunocompetent Host Kamal Sud, 1MD, DM, Sanjay D’Cruz, 1 MD, DM, Harbir S Kohli, 1 MD, DM, Vivekanand Jha, 1 MD, DM, Krishan L Gupta, 1 MD, DM, Arunaloke Chakrabarti, 2MD, Kusum Joshi, 3MD, and Vinay Sakhuja, 1 MD, DM 1Department of Nephrology Postgraduate Institute of Medical Education and Research, Chandigarh, India. 2Department of Microbiology 3Department of Pathology

18 Renal candidiasis Pathogens C. albicans, C.tropicalis,C.glabrata
Exist as Yeast or Filaments (hyphal phase) Disseminated candidiasis involves Kidney (82%) GIT (66%) lungs (61%),heart (51%),spleen (50%)† Renal presentations: Fever,abdominal or loin pain,dysuria Pyuria,hematuria,candiduria, Urinary retention & anuria Progressive renal failure † (Wise & Silver, J Urol 1993)

19 Candidiasis: PGI Study (n=30)
Sex ratio M:F 23:7 Age (yrs.) ±18.0 Presenting features Acute pyelonephritis 21 Pyonephrosis 14 Renal failure * (40%) Pathologic findings Microabscesses 24 Papillary necrosis 15 Vasculitis 5 Mixed infections Renal 3 Extrarenal 5

20 Renal cryptococcosis C.neoformans identified by large clear capsules sorrounding yeast cells Usually a disseminated disease involving brain,lungs,GIT,kidneys,prostate etc. Renal lesions include Sparse lymphocytic infiltrate and rarely Microabscesses,granulomas & caseation Papillary necrosis &tubular atrophy. Clinically no significant abnormality

21 Renal mycoses: incidence of papillary necrosis
Fungal Total RPN % Infections Candidiasis Aspergillosis Mucormycosis Cryptococcosis Histoplasmosis Total

22 Renal Mycoses: Treatment and Outcome
Fungal Untreated† Treatment Survived infections (Ampho B ) Candidiasis ‡ 8 Aspergillosis Mucormycosis * Cryptococcosis Histoplamsosis ) † Diagnosed postmortem, ‡ Oral fluconazole in 4, *Unilateral involvement , nephrectomy(2

23 Conclusions Fungal infections have been being increasingly seen in
the last decade Renal involvement occured as disseminated (57%) or isolated form ( 43%) Candidiasis was the commonest renal infection but had a low incidence of renal failure ( 40%)*. Mucormycosis causes most severe lesions. Irreversible ARF occurred in 92% of pts with bilateral renal invlvement. Aspergillus is less angioinvasive. ARF occurred in 55% pts.

24 Conclusions (contd.) Most fungal infection occurred in presence of
predisposing conditions. However 68% of pts. with mucormycosis had no apparent underlying disease. Renal mycoses has a very high mortality ( 80% ). Diagnosis is usually made at autopsy. Disease was recognised in life only in 1/3rd of pts. A high index of suspicion is required to identify renal mycoses. Imaging techniques combined with interventions including kidney biopsy may clinch the diagnosis and help in initiating antifungal therapy.

25 PART II INVASIVE FUNGAL INFECTIONS FOLLOWING RENAL TRANSPLANTATION

26 Introduction Increased occurrence of opportunistic infections in solid organ transplant recipients Incidence related to organ transplanted, immunosuppressive regimen, induction therapy and anti-fungal prophylaxis Diagnosis often difficult and delayed because of Paucity of rapid diagnostic tests Concomitant infections (90% have Bacteria, CMV and P car) Presence of comorbid conditions High index of suspicion is thus necessary to provide timely therapy.

27 ISSUES IN MANAGEMENT OF INVASIVE FUNGAL INFECTIONS
Discussion points: Epiedemiology of IFIS and its Risk factors Local experience of IFIS Clinical and Laboratory Diagnosis of IFIS Advances in management of IFIS Triazoles, Echinos. Ampho-B and its formulations Role of combination therapy Summarized managemet of IFIS Role of prophylaxis therapy

28 Pathologenic Fungi in Tx
Primary / Endemic Opportunistic Emerging Fungi Histoplasmosis Blastomycosis Coccididomycosis Candida Aspergillus Cryptococcus Mucorales Fusarium Trichosporon Paecilomyces Scopulariopsis Malassezia furfur Dematiaceous molds Phaeohyphomycosis

29 Risk factors in Tx recipients
a) Epidemiological exposure b) Net state of immunosuppression Immunosuppressive therapy Integrity of muco-cutaneous barrier Devitalised tissues, fluid collection Metabolic factors ; uremia and diabetes Immuno-modulating viruses: CMV, EBV, HBV Hospital exposures/adjacent construction Selected agricultural, occupational, and recreational activities

30 Immunosuppressants and Fungi
Calcineurin inhibitors Antifungal activity of the CNIs is mediated through inhibition of Calcineurin phosphatase. Mycophenolic acid MPA activity against P jiroveci (Inhibition of IMPDH) Sirolimus TOR kinases promote cell proliferation in fungi. SRL on fungi with TOR activity ALA Both for induction and anti-rejection therapy Corticosteroids Medications with myelosuppressive properties (miscellaneous)

31 Time-table of Post-Tx Fungal Infections

32 Fungal Infections following renal Transplantation Therapy and Outcome
Fungal infection Pts diagnosed Pts surviving Overall * alive & treated with therapy Mortality N N (%) N (%) Candidiasis (n= 32) (78) 13 (48) Cryptococcosis (n= 23 ) (47) 9 ( 53) Aspergillosis( n=32) (54) 16 (70) Mucormycosis (n= 26) (23) 18 (80) *Including those diagnosed at autopsy

33 Case Discussion Renal Tx Donor Triple drug therapy
Acute Graft Rejection Admitted on with c/o

34 Clinical features suggesting IFI
Fever resistant to BSA ± severe neutropenia S/S of resistant or progressive LRI or URI Periorbital or Maxillary swelling / tenderness Palatal necrosis or perforation Focal neurological or meningeal irritation S/S Unexplained mental changes with fever Papular or nodular skin lesions

35 Laboratory Diagnosis OF IFIS
Histopathologic diagnosis:  Using special stains like Periodic acid-Schiff, Grocott-Gomori methenamine silver and Gridley fungal stains.  Demonstration of the Yeast cells or hyphae in FNAC or Bx of infected tissue Culture on solid media  Blood culture may not detect all IFIS (50% yield)  Other fluids like urine,CSF, BAL etc may be cultured  Growth of any mould from biopsies by sterile technique is always very significant

36 Immunological /DNA assays for IFIS
Detection of fungal cell wall components and antigens Antigen detection e.g. Double sandwich ELISA for candidal antigen and Galactomannan ELISA for Asper and Cryptococcal antigen by RIA Detection of 1, 3-β-D-Glucan synthetase Molecular diagnosis, like PCR for DNA assay Nucleic acid probes

37 Radiological diagnosis of IFIS
Plain chest X-ray Normal in upto 29% of Pulmonary IFIS Findings include segmental or subsegmental consolidation, patchy infiltrates, nodules (single or multiple), nodular infiltrates and cavitation CT Scans HRCT should be undertaken with 1 mm slices “Early” CT findings in IFI are single or multiple nodules or mass like infiltrates and the “Halo sign” “Late” signs are cavitation, with or without the air “crescent sign” , which correspond to the CXR findings

38 Pneumocystis jirovecii (P Carinii)
Universal seropositive status by age two Usually air-borne transmission Diffuse alveolar damage, impaired gas exchange, and respiratory failure (More in Non-HIV) Usually occurs with 6-12 mon but sometimes late Presents with fever, nonproductive cough Tachypnoea, cyanosis, hypoxemia Diffuse crepitations BAL and lung biopsy help in confirming Dx Radiology : B/L ground glass opacities, homogenous and diffuse; HRCT- more sensitive

39 Imaging in P carinii infection

40 Pulmonary Infections in RTX Pts (1995-96)*
Pts. with infections 34/81 (42%) Organism identified by BAL 20/28 (71%) Pyogenic bacteria 33% M. tuberculosis 31% P. carinii 15% Candida 10% Aspergillus % CMV 8% Others % *Kidney International 56(5), , 1999.

41 BAL;Stain: Fungi-Fluor x400
Lung specimen x Parenthesis or comma like internal dots surrounded by cyst walls. ( Dx 2 cysts reqd) Specimen: BALStain: GM Sx1000

42 P. jirovecii : USRDS 2009 No series available from India, limited cases included 4% of opportunistic infections in HIV patients USEDS - 32,757 renal TX recorded 142 (04% ) PCP Cases Median post-tx time was 0.80±0.95 yrs Risk factors in Transplant patients, Expanded criteria donor Donation after cardiac death Concomitant viral , HCV Prednisone ≥ 16 mg for > eight weeks Combination immunosupression Tacrolimus and sirolimus Neoral and MMF Sirolimus and MMF (Analysis of USRDS: July )

43 Part III Advances in Management of Invasive Fungal Infections

44 Advances in Treatment Antifungal therapy: Echinocandins
Lipid associated amphotericin preparations Echinocandins Newer triazoles (Vori; Posa) Surgical intervention Immuno-modulatory therapy: - INF Gamma - Hematopoietic growth factors

45 Why we need new antigumgal ?
Several new antifungal drugs licensed in last 5 yrs ; Intrinsic or acquired antifungal resistance, Organ dysfunction preventing use of some agents Poor penetrabilty into sanctuary sites (eye /urinine) Drug interactions and considerable adverse events Still some patients remain difficult to treat

46 Wish List for an Antifungal Drug
Broad spectrum fungicidal Nontoxic even with prolonged use Can be administered parenterally and orally Favorable pharmacokinetic properties, Minimal drug interactions Minimal genetic variation in metabolism

47 Mechanisms of Action Cell Wall Synthesis: Echinocandins inhibit glucan synthesis via inhibition of 1,3--D-glucan synthase, blocking chitin synthesis fungal cell lysis. Inhibition of Cell Membrane Function: Polyenes bind to ergosterol, principal sterol in fungal cell membrane causing cell wall disruption, loss of integrity of the cell membrane, and cell death. Ergosterol Synthesis: Azoles inhibit 14-demethylation of lanosterol by binding to fungal cytochrome P450 enzymes, thus preventing the synthesis of ergosterol

48 What are the targets for antifungal therapy?
Cell membrane Fungi use principally ergosterol instead of cholesterol Polyenes DNA Synthesis Some compounds may be selectively activated by fungi, arresting DNA synthesis. Azoles There are key differences between mammalian and fungal eukaryotic cells. This is the basis of drug selectivity. Cell Wall Unlike mammalian cells, fungi have a cell wall Candins Atlas of fungal Infections, Richard Diamond Ed. 1999 Introduction to Medical Mycology. Merck and Co. 2001

49 Azole Antifungals for Systemic Infections
Ketoconazole Itraconazole Fluconazole Voriconazole Posaconazole, Imidazole Triazoles “2nd generation triazole” The azoles are a very large group of synthetic agents, which includes drugs used in bacterial and parasitic as well as fungal infections. The majority are used as a topical treatment. The drugs listed here are the few which are suitable for systemic administration. The azoles are widely used because of their broad therapeutic window, wide spectrum of activity, and low toxicity. Members of the azole group have either an imidazole or triazole ring with N carbon substitution. Imidazole ring: five-membered ring structure containing two nitrogen atoms. Triazole ring: five-membered ring structure containing three nitrogen atoms. While ketoconazole was more widely used before the development of newer, less toxic, and more effective triazole compounds, fluconazole and itraconazole, its use has now been limited. Unfortunately, azoles are generally fungistatic (especially in Candida) and resistance to fluconazole is emerging in several fungal pathogens. Isavuconazole Revuconazole Albuconazole Emerging Triazoles

50 Voriconazole ; Dosing schedule
Dose IV 6 mg/kg X 2 doses, then 3 to 4 mg/kg every 12 Hrs PO > 40 kg— mg PO every 12 hours < 40 kg— mg PO every 12 hours Cirrhosis: IV  6 mg/kg X 2 doses, then 2 mg/kg every 12 Hrs PO > 40 kg—100 mg PO every 12 hours < 40 kg— 50 mg PO every 12 hours Renal impairment: If CrCl<50 ml/min, use oral formulation to avoid accumulation of cyclodextrin solubilizer

51 VORICONAZOLE : TOXICITY Visual hallucinations Hepatotoxicity
Drug interactions – via CYP 3A4. Rifampin, LA-barbiturates,carbamazepine  vori conc. Vori interferes in metabolism of SRL and better avoided  dose of immsupps drugs TAC, CSA Metabolised by CYP 2C19 Polymorphism : 3% whites; 15 –20% Asians ? Therapeutic drug monitoring needed

52 Posaconazole: Dosing schedule
Spectrum: Zygo, Asper, Fusarium and candida Dosing (only available PO admn with food supplement) Prophylaxis of invasive Aspergillus and Candida species 200 mg 3 times/day Treatment of oropharyngeal candidiasis 100 mg twice daily for 1 day, then 100 mg once daily for 13 days Treatment or refractory oropharyngeal candidiasis 400 mg twice daily Treatment of refractory invasive fungal infections 800 mg/day in divided doses Drug Interactions Moderate inhibitor of CYP3A4 (AVOID coadmPPI & H2 Blocker) Adverse Reactions Hepatotoxicity, GI: Diarrhea. QTc prolongation SAFE in Ren Insuff.

53 Prophylactic therapy ; Incidence of Proven/Probable IFIs
30 P = .074 27 25 P = .004 P = .006 22 20 P = .001 21 Number of IFIs 17 15 16 10 7 7 5 3 All IFIs Invasive Aspergillosis All IFIs Invasive Aspergillosis While on treatment Primary time period 112 days after randomization Posaconazole Fluconazole Ullmann AJ et al. NEJM 2007.

54 The Fungal Cell Wall chitin ergosterol mannoproteins b1,3 b1,6 glucans
synthase Cell membrane The most overt distinction between fungal and mammalian cells is the cell wall of fungi. The uniqueness of this structure makes it a premier target of antifungal drugs. Although the cell wall was initially considered an almost inert cellular structure that protected the cell against osmotic offense, more recent studies have demonstrated that it is a dynamic organelle. The major components of the cell wall are glucan and chitin, which are associated with structural rigidity, and mannoproteins. Biosynthesis of β (1-3) glucans is under the control of a membrane protein complex, the glucan synthase. There are at least two subunits of this enzyme, one a catalytic subunit in the plasma membrane, the other a GTP-binding subunit that activates the catalytic subunit. In the periplasmic space, neosynthesized β 1-3 glucans are modified and associated to the other cell wall polysaccharides (chitin, galactomannan and β 1-3, 1-4 glucan) to produce the rigid three-dimensional network characteristic of the cell wall. Atlas of fungal Infections, Richard Diamond Ed. 1999 Introduction to Medical Mycology. Merck and Co. 2001

55 Echinocandins: Capso,Mica,Anidula-fungin
Mechanism of Action Cyclic lipopeptide antibiotics that interfere with fungal cell wall synthesis by inhibition of ß-(1,3) D-glucan synthase Loss of cell wall glucan results in osmotic fragility Spectrum: Candida species including non-albicans isolates resistant to fluconazole Aspergillus spp. but not activity against other moulds (Fusarium, Zygomycosis) No coverage of Cryptococcus neoformans Dose and modification Water soluble available only in IV form Dose mg day 1 and 50 mg afterwards Dosage adjustment in hepatic insufficiency Metabolites excreted by kidneys and GI tract The echinocandins are a recently-developed class of antifungal agents that interfere with fungal cell wall synthesis through the inhibition of glucan synthesis. The lack of glucan synthesis enzymes in mammalian tissue makes this an attractive target for antifungal activity. The mode of action of the echinocandins means they possess an unusual extended spectrum of activity. They are not active at all against Cryptococcus neoformans, since this pathogen has little or no β(1,3)-D-glucan synthase enzyme. On the other hand, they are very active against Pneumocystis carinii. (unlike other antifungal agents) because the wall of the ‘cyst’ form of this fungus contains β(1,3)-D-glucan synthase. They have a fungicidal action. There are currently three such agents at present, 1) Caspofungin 2) Micafungin 3) Anidulafungin Cilofungin, the first member of the group, reached clinical trials but was abandoned because of side effects associated with the carrier used for the parenteral formulation. A major breakthrough in antifungal therapy occurred in January 2001 with FDA fast track approval for the marketing of caspofungin (Cancidas ®), The unique action of this particular class of drug is very useful for 2 reasons: The echinocandins are active against Candida spp. isolates that are resistant to the azoles and amphotericin B. 2) Since their activity is specific to fungal cell walls, it bodes well for minimal toxicity. Emerging ECHDN Aminococandin

56 Echinocandins act at the apical tips of Aspergillus hyphae
Caspofungin is the drug of choice for invasive aspergillosis which is unresponsive to other antifungal drugs. High-magnification photomicrographs of caspofungin treated, DiBAC-stained A. fumigatus from a study by Bowman et al 2002. Previous to this study, it was known that caspofungin caused cell death in yeasts and dimorphic fungi such as Candida albicans, but its effects on Aspergillus fumigatus remained unclear. Bowden et al used the fluorescent dyes CFDA and DiBAC, which stain live and dead cells, respectively, to further characterise the anti-fungal activity of caspofungin. They observed a differential effect of the drug as a function of cell position. 88% of apical cells and 61% of sub-apical branching cells failed to stain with the viable dye CFDA, but only 24% of subapical cells were unstained. Complementary results were seen with DiBAC staining. The dye staining patterns illustrate that the cells at the active centres for new cell wall synthesis within the growing A. fumigatus hyphae are more susceptible to lysis after caspofungin treatment, compared to subapical cells with mature cell walls. This antifungal activity occurring at actively growing tips and branching points of Aspergillus hyphae, leads to formation of flattening and swelling tips. DiBAC Bowman et al. Antimicrob Agent Chemother 2002;46:

57 Caspofungin - Adverse effects
Most common AEs are infusion related: Intravenous site irritation (15-20%) Mild to moderate infusion-related AE including fever, headache, flushing, erythema, rash (5-20%) Symptoms consistent with histamine release (2%) Most AEs were mild and did not require treatment discontinuation Most common laboratory AE Asymptomatic  of serum transaminases (10-15%) Clinical experience to date suggests that these drugs are extremely well-tolerated Caspofungin administration is associated with possible histamine-mediated symptoms including reports of rash, facial swelling, pruritus, and warmth sensations. These side effects are minimal. Antiviral Drug Products Advisory Committee, January 10,

58 Amphotericin B Polyene, Fermentation product of Streptomyces nodusus
Long time gold standard in treatment of serious fungal infection with Broad spectrum activity Highly insoluble. Exists in micellar mixture with deoxycholate No oral bioavailability; intravenous formulation Relatively poor penetration of urinary tract, CNS

59 Amphotericin B is active in vitro against
Candida spp. (including azole-resistant species) Aspergillus spp. Cryptococcus neoformans Mucor spp. Blastomyces dermatitidis Coccidioides immitis Histoplasma capsulatum Paracoccidioides brasiliensis

60 Toxicities of Amphotericin B
“Don’t look cross-eyed at it” -- comes out of micellar mixture with contact with blood, potassium, saline, etc. anaphylactoid reaction “Cytokine storm” -- Fever and chills; TNF, IL-1, IL-6. Patient usually becomes tachyphylactic Renal toxicity -- RTA; K+ and Mg++ wasting, S cr . Dose Related.  renal toxicity in hypovolemia in and those receiving other nephrotoxic drugs. Amphotericin B - Drug Interactions Uncommon except with high doses: Liver toxicity; bone marrow toxicity

61 Lipid Formulations of Amphotericin B
All three approved for “rescue therapy” (failure of previous therapy or toxicity) Liposomal amphotericin successful for empiric therapy in febrile neutropenia Less nephrotoxicity and cytokine storms Lipid preparations are thus preferred for inhalation delivery Lipid firms distributes mostly in reticular endothelial tissue (liver, spleen, lung), but less in kidney. Hypothesis: By encapsulating ampho-B in liposomal vesicles or binding it to other lipid carriers, protect kidneys and achieve higher concentrations in liver and spleen and RE system.

62 Lipid Amphotericin B Formulations
Abelcet ® ABLC Amphotec ® ABCD Ambisome ® L-AMB Ribbon-like particles Carrier lipids: DMPC, DMPG Particle size (µm): Disk-like particles Carrier lipids: Cholesteryl sulfate Particle size (µm): Unilaminar liposome Carrier lipids: HSPC, DSPG, cholesterol Particle size (µm) : 0.08 DMPC-Dimyristoyl phospitidylcholine DMPG- Dimyristoyl phospitidylcglycerol HSPC-Hydrogenated soy phosphatidylcholine DSPG-Distearoyl phosphitidylcholine

63 Lipid AMB Formulations-Summary
Efficacy Lipid formulation > AMB-deoxy Nephrotoxicity L-AMB < ABLC < ABCD << AMB-deoxy Infusion related toxicity L-AMB < ABLC < ABCD < AMB-deoxy Product cost (AWP) L-AMB > ABLC > ABCD > AMB-deoxy

64 Combination Anti-fungal Therapy
Potential benefits Enhanced potency of antifungal efficacy, Reduced selection of resistant organisms and Reduced toxicities due to lower dosing. Evidence of benefit Rx cryptococcal meningitis, AmB-D and Flucytosine Amphotericin B plus Fluconazole However few large studies in IA

65 Combination treatment
IA=invasive aspergillosis Author Year N= Org Combination Resp Kotoyiannis Aliff Marr Maartens Nivoix 2003 2004 2006 48 30 16 17 IA Any Caspo+LAmB Caspo+ Voric Caspo+ either Caspo + any 42% 60% 65% 57% 71%

66 Combination treatment –2:
Multi-institutional, retrospective Event L-AmB Caspo+ Voricon HR P= Sample size 90 day survival Renal failure A fumigatus 47 67.5% - 40 51% 0.58 0.32 0.38 0.117 0.022 0.019 Singh, 2006

67 Combination: Mycograb
Monoclonal antibody to Hsp90 Phase III RCT in culture positive, disseminated candida (n= 117) Event L-AmB + Mycograb L-AmB + placebo Complete response Clinical response Attributable mortality 84% 86% 4% 48% 52% 18% Matthews, 15 ECCMID 2005

68 SUMMARY OF FUNGAL THERAPY
Pathogen Primary Secondary Candida albicans Fluconazole Amphotericin B Caspofungin Posaconazole Anidulafungin Voriconazole, Itraconazole Cryptococcus neoformans Amphotericin B ± Flucytosine followed by Fluconazole Itraconazole or Amphotericin B Aspergillus fumigatus Voriconazole Posaconazole Itraconazole, Caspofungin Amphotericin Histoplasma capsulatum Fluconazole Mucomycosis Amphotericin B

69 Antifungal Immunotherapy and Immunomodulation
Host-targeting agents (immunomodulators) Vaccines Cytokines Adoptive T-cell transfer Monoclonal antibodies? Antifungal peptides? (cationic AMP) Pathogen-targeting agents (immunotherapeutics) Monoclonal antibodies Antifungal peptides

70 Antifungal Prophylaxis in SOT Recipients
Prophylaxis reasonable given the high incidence/ mortality However In 14 RCT with 1497 participants AFP did not  mortality ( [RR] 0.90, 95% CI ). Current data supports limited benefit (Aspergillus in liver/ lung and Candida in liver, bowel, and pancreas tx recipients. Fluc significantly  early IFIs in liver tx with no  mortality. Assuming 10%, 14 pts require prophylaxis to prevent 1 IFI. Less data are available for other agents/transplants. Drug interactions and toxicities must be considered Interscience Conference on Antimicrobial Agents and Chemotherapy (43rd: 2003: Chicago, Ill.).

71 Antifungal Prophylaxis :Indications
High risk patents with: Renal and hepatic dysfunction Large blood transfusion requirements Prolonged ICU stays Additional surgery post transplant including laparotomy and re-transplantation Known fungal colonization pretransplantation Prior (broad-spectrum) antimicrobial use

72 Antifungal Prophylaxis: Drug Regimens
None is ideal for all of the indications for post-tx prophylaxis Fluconazole — Safe ,no hepatotox in liver tx used only for Candida Itraconazole — Poor bioavailability unreliable for AFP Use in lung tx ? Voriconazole  — Offers  filamentous mold activity > Flucon or Itracon but not against the zygo. However, no prophylactic studies. Posaconazole — Its use in SOT AFP have not yet been defined. Ampho- B  —  Failure of low-dose regimens as AFP . Few studies suggested aerosolized forms benefitted in lung tx against Asper Echinocandins — No trials of SOT AFP have been performed to date. Choice of drug — The 2009 Infectious Diseases Society of America Fluconazole (200 to 400 mg [3 to 6 mg/kg] daily) OR Liposomal Ampho- B (1 to 2 mg/kg IV/d) for 7 to 14 days as AFP for liver, pancreas, and small bowel transplant recipients at of IFIs

73 Conclusions Incidence of IFI in Transplant recipients is increasing partcularly that of angio-invasive filamentous fungi with  morbidity and mortality Diagnosis depends on understanding of  Risk factors and incidence rates,  Significance of different clinical presentation and  Timely use of mycological and radiological investigations. Antifungal Therapy Empirical use should be discouraged. Azoles hold Good Promise but all IFI do not respond (Except Posa)  Lowest toxicity seen with caspo and L-Ampho B Prophylaxis of IFI should be confined to high risk patients and drugs of choice are itraconazole and posaconazole.

74 Conclusions Incidence of IFI in Transplant recipients is increasing partcularly that of angio- invasive filamentous fungi with  morbidity and mortality Diagnosis depends on understanding of  Risk factors and incidence rates,  Significance of different clinical presentation and  Timely use of mycological and radiological investigations. Antifungal Therapy Empirical use should be discouraged. Azoles Hold Good Promise but all IFI do not respond (Exception Posa)  Lowest toxicity seen with caspo and L-Ampho B Prophylaxis of IFI should be confined to high risk patients and drugs of choice are itraconazole and posaconazole.

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