FUNGAL INFECTIONS AND THE KIDNEY

FUNGAL INFECTIONS AND THE KIDNEY

Prof K L GUPTA,

Department of Internal Medicine,

King Fahd Hospital of University,

AL KOBAR

OBJECTIVES & Parts of TalkOBJECTIVES & 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

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.

Postgraduate Medical Journal (1987) 63, 297-299

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-160012, 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.

Am Journal of Kidney Diseases,Vol 22, No 3(September),1993; pp 393-397

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-160012, India

Renal mycoses : Indian scenePGI,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 1984 - 2004

No.of cases 85 ( 74 M, 11 F )

Age (yrs ) 24.2 ± 18.5

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 6 ( 5%)Cutaneous 20 ( 15%)Renal 18 (14%)

Renal Mucormycosis

*Chakrabarti et al J Infectious Dis 42; 261-266:2001

Case Discussion

• 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 200-250, 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-NormalUS and CT Abdomen:

Course & Management

Hemodialysis, antibiotics,Laparotomy and aspiration of perinephric collectionPus direct smear-Mucor hyphaeCulture-Apophysomyces elegansKidney biopsy: Ischemic necrosis with vessel invasion by mucorAmphotericin B total dose -560mg( 2 weeks)B/L nephrectomyPatient died after two weeks of diagnosisAutopsy: No other organ involvementComments: Isolated renal mucormycosis with

ARF

Sex ratio M:F 22:3Age (yrs. ) 33.1±15.1Presenting features No. %Fever 21 85Flank pain 20 80Luekocytosis 20 80Hematuria 18 72Pyuria 18 72Renal failure* 18 72

* In (95%) pts with bilateral involvement

Renal Mucormycosis: PGI Study (n=25)

Nephrology

Dialysis

Transplantation

Nephrol Dial Transplant (1999) 14: 2720-2725

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

Ultrasonography ( n-24)• Enlarged kidneys 22• Perinephric collection 10

Computerised tomography ( n-12 )

• Enlargement of kidneys 11• Absence of contrast 10• Low attenuated areas 10• Perinephric collection 9

Renal Mucormycosis: Radiological Features

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

Tissue obtained at autopsy 18 at biopsy 7Gross examination ( n-18 )Evidence of infarction 16Hilar vessel thrombosis 14

Microscopic examination ( n-25)Vasculitis 18Cortical & medullary necrosis 18Microabscess & granuloma 17Glomerular invasion 15

Renal Mucormycosis : Renal Pathology

(A fumigatus, A.flavus, A.niger ) Identified by slender,regular,dichtomouslybranching,septate hyphae Invariably associated with debilitated stateUsually part of disseminated disease & rarely isolatedOther organs lungs (94%),GIT (92%),brain (13%) †Clinically: Three patterns

1) Disseminated aspergillosis with renal involvement

2) Aspergillus cast of renal pelvis3) Ascending panurothelial aspergillosis

Renal Aspergillosis

† Wise & Silver (1993)

Sex ratio M:F 23:4Age (yrs. ) 22.6 ± 19.5 Presenting featuresRenal failure 15 (55%)Pathologic findingsMicroabscesses 19Vasculitis 13Papillary necrosis 6Culture identification 6

Aspergillosis: PGI Study (n=27)

Renal Failure, 20(6), 839-843 (1998)

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

Postgraduate Institute of Medical Education and Research, Chandigarh, India.

3Department of Pathology

Postgraduate Institute of Medical Education and Research, Chandigarh, India.

CASE REPORT

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,dysuriaPyuria,hematuria,candiduria,Urinary retention & anuriaProgressive renal failure

Renal candidiasis

† (Wise & Silver, J Urol 1993)

Sex ratio M:F 23:7Age (yrs.) 18.2±18.0Presenting featuresAcute pyelonephritis 21Pyonephrosis 14Renal failure 12* (40%)Pathologic findingsMicroabscesses 24Papillary necrosis 15Vasculitis 5Mixed infectionsRenal 3Extrarenal 5

Candidiasis: PGI Study (n=30)

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

Renal mycoses: incidence of papillary necrosis

Fungal Total RPN %InfectionsCandidiasis 30 15 50Aspergillosis 27 6 22Mucormycosis 25 2 8Cryptococcosis 4 0 -Histoplasmosis 1 0 -

Total 85 23 27

Renal Mycoses: Treatment and Outcome

Fungal Untreated† Treatment Survived

infections (Ampho B )

Candidiasis 20 10‡ 8

Aspergillosis 18 9 5

Mucormycosis 17 8 3*

Cryptococcosis 4 - -

Histoplamsosis 1 - -

)

† Diagnosed postmortem, ‡ Oral fluconazole in 4,*Unilateral involvement , nephrectomy(2

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.

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.

PART IIINVASIVE FUNGAL INFECTIONS

FOLLOWING RENAL TRANSPLANTATION

PART IIINVASIVE FUNGAL INFECTIONS

FOLLOWING RENAL TRANSPLANTATION

IntroductionIntroduction• 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 testsConcomitant infections (90% have Bacteria, CMV and P car) Presence of comorbid conditions

• High index of suspicion is thus necessary to provide timely therapy.

ISSUES IN MANAGEMENT OF INVASIVE FUNGAL INFECTIONSISSUES 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

Pathologenic Fungi in TxPathologenic Fungi in Tx

Primary / Endemic Opportunistic Emerging Fungi

Histoplasmosis

Blastomycosis

Coccididomycosis

Candida

Aspergillus

Cryptococcus

Mucorales

FusariumTrichosporonPaecilomycesScopulariopsisMalassezia furfurDematiaceous molds Phaeohyphomycosis

a) Epidemiological exposureb) 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

Risk factors in Tx recipients

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)

Time-table of Post-Tx Fungal Infections

Fungal Infections following renal Transplantation Therapy and Outcome

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) 18 14 (78) 13 (48)

Cryptococcosis (n= 23 ) 23 8 (47) 9 ( 53)

Aspergillosis( n=32) 13 7 (54) 16 (70)Mucormycosis (n= 26) 9 2 (23) 18 (80)

*Including those diagnosed at autopsy

Case DiscussionCase Discussion

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

Clinical features suggesting IFI 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

Laboratory Diagnosis OF IFISLaboratory 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

Immunological /DNA assays for IFISImmunological /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

Radiological diagnosis of IFISRadiological diagnosis of IFISPlain 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

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

Imaging in P carinii infectionImaging in P carinii infection

Pulmonary Infections in RTX Pts (1995-96)*

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 8%

CMV 8%

Others 5%

*Kidney International 56(5), 1944-50, 1999.

Specimen: BALStain: GM Sx1000

BAL;Stain: Fungi-Fluor x400

Lung specimen x 1000 Parenthesis or comma like internal dots surrounded by cyst walls. ( Dx 2 cysts reqd)

P. jirovecii : USRDS 2009P. 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,

o Expanded criteria donoro Donation after cardiac deatho Concomitant viral , HCVo Prednisone ≥ 16 mg for > eight weekso Combination immunosupression

Tacrolimus and sirolimus Neoral and MMF Sirolimus and MMF

(Analysis of USRDS: July 2009 - 88 - 135-141)

Part III

Advances in Management of Invasive Fungal

Infections

Part III

Advances in Management of Invasive Fungal

Infections

Advances in TreatmentAdvances in Treatment

Antifungal therapy: Lipid associated amphotericin preparations

Echinocandins Newer triazoles (Vori; Posa) Surgical intervention Immuno-modulatory therapy:

- INF Gamma- Hematopoietic growth factors

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

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

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

What are the targets for antifungal therapy?

Cell membraneFungi use principally ergosterol instead of cholesterol

Cell WallUnlike mammalian cells, fungi have a cell wall

DNA SynthesisSome compounds may be selectively activated by fungi, arresting DNA synthesis.

Atlas of fungal Infections, Richard Diamond Ed. 1999Introduction to Medical Mycology. Merck and Co. 2001

Polyenes

Candins

Azoles

Azole Antifungals for Systemic Infections

• Ketoconazole• Itraconazole • Fluconazole• Voriconazole• Posaconazole,

Imidazole

Triazoles

“2nd generationtriazole”

• Isavuconazole• Revuconazole• Albuconazole

EmergingTriazoles

DoseIV 6 mg/kg X 2 doses, then 3 to 4 mg/kg every 12

HrsPO > 40 kg—200-300 mg PO every 12 hours < 40 kg—100-150 mg PO every 12 hoursCirrhosis: 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 hoursRenal impairment:

If CrCl<50 ml/min, use oral formulation to avoid accumulation of cyclodextrin solubilizer

Voriconazole ; Dosing schedule

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

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.

Prophylactic therapy ; Incidence of Proven/Probable IFIs

0

5

10

15

20

25

30

Posaconazole Fluconazole

Nu

mb

er

of

IFIs

All IFIs Invasive Aspergillosis

P = .004

P = .001

While on treatment

7

22

3

17

All IFIs Invasive Aspergillosis

P = .074

P = .006

Primary time period112 days after randomization

27

16

7

21

Ullmann AJ et al. NEJM 2007.

The Fungal Cell Wall

mannoproteins

b1,6glucans

b1,3

chitin

ergosterol

b1,3 glucansynthase

Cellmembrane

Atlas of fungal Infections, Richard Diamond Ed. 1999Introduction to Medical Mycology. Merck and Co. 2001

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 fragilitySpectrum:• Candida species including non-albicans isolates resistant to fluconazole• Aspergillus spp. but not activity against other moulds (Fusarium, Zygomycosis)• No coverage of Cryptococcus neoformansDose and modification• Water soluble available only in IV form • Dose - 70 mg day 1 and 50 mg afterwards• Dosage adjustment in hepatic insufficiency• Metabolites excreted by kidneys and GI tract

Emerging ECHDN Aminococandin

Echinocandins act at the apical tips of Aspergillus hyphae

DiBAC

Bowman et al. Antimicrob Agent Chemother 2002;46:3001-12

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

Antiviral Drug Products Advisory Committee, January 10, 2001- www.FDA.gov

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

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

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

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.

Lipid Amphotericin B Formulations

Ribbon-like particlesCarrier lipids: DMPC, DMPGParticle size (µm): 1.6-11

Abelcet ® ABLC Amphotec ® ABCD Ambisome ® L-AMB

Disk-like particlesCarrier lipids: Cholesteryl sulfateParticle size (µm): 0.12-0.14

Unilaminar liposomeCarrier lipids: HSPC, DSPG, cholesterolParticle size (µm) : 0.08

DMPC-Dimyristoyl phospitidylcholineDMPG- Dimyristoyl phospitidylcglycerol

HSPC-Hydrogenated soy phosphatidylcholineDSPG-Distearoyl phosphitidylcholine

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

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

Combination treatment

• IA=invasive aspergillosis

Author Year N= Org Combination Resp

Kotoyiannis

AliffMarrMaartensNivoix

20032003200420042006

4830163017

IAIAIAIAAny

Caspo+LAmB ”Caspo+ VoricCaspo+ eitherCaspo + any

42%60%65%57%71%

Combination treatment –2:

• Multi-institutional, retrospective

Event L-AmB Caspo+ Voricon

HR P=

Sample size90 day survivalRenal failureA fumigatus

47 67.5% - -

40 51% - -

0.580.320.38

0.1170.0220.019

Singh, 2006

Combination: Mycograb

• Monoclonal antibody to Hsp90• Phase III RCT in culture positive,

disseminated candida (n= 117)

Event L-AmB + Mycograb

L-AmB + placebo

Complete responseClinical response Attributable mortality

84%86%4%

48%52%18%

Matthews, 15 ECCMID 2005

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

VoriconazolePosaconazole

Itraconazole, CaspofunginAmphotericin

Cryptococcus neoformans

Amphotericin B ± Flucytosine followed by Fluconazole

Itraconazole or Amphotericin B

Histoplasma capsulatum

Itraconazole or Amphotericin B

Fluconazole

Mucomycosis Amphotericin B Posaconazole

Antifungal Immunotherapy and Immunomodulation

Host-targeting agents (immunomodulators)

1. Vaccines 2. Cytokines3. Adoptive T-cell transfer4. Monoclonal antibodies?5. Antifungal peptides? (cationic AMP)Pathogen-targeting agents

(immunotherapeutics) 6. Monoclonal antibodies 7. Antifungal peptides

Antifungal Prophylaxis in SOT RecipientsAntifungal 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 0.57-1.44). 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.).

Antifungal Prophylaxis :IndicationsAntifungal 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

Antifungal Prophylaxis: Drug RegimensAntifungal 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

1. Fluconazole (200 to 400 mg [3 to 6 mg/kg] daily) OR

2. 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

ConclusionsIncidence 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.

ConclusionsIncidence 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.