Transcript fungal infections and the kidney - Department of Internal Medicine

FUNGAL INFECTIONS
AND THE KIDNEY
Prof K L GUPTA,
Department of Internal Medicine,
King Fahd Hospital of University,
AL KOBAR
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
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.
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
Am Journal of Kidney Diseases,Vol 22, No 3(September),1993; pp 393-397
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
1984 - 2004
No.of cases
85 ( 74 M, 11 F )
Age (yrs )
24.2 ± 18.5
Renal Mucormycosis
Rhizopus, Absidia and Mucor
Large, aseptate,irregularly branching hyphae
Clinical syndromes:
Rhinocerebral
Pulmonary
Disseminated
Gastrointestinal
Cutaneous
Renal
PGI Study n=129*
57 (44%)
13(10%)
15 (12%)
6 ( 5%)
20 ( 15%)
18 (14%)
*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-Normal
US and CT Abdomen:
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
Renal Mucormycosis: PGI Study (n=25)
Sex ratio M:F
Age (yrs. )
Presenting features
Fever
Flank pain
Luekocytosis
Hematuria
Pyuria
Renal failure*
22:3
33.1±15.1
No.
21
20
20
18
18
18
* In (95%) pts with bilateral involvement
%
85
80
80
72
72
72
Nephrol Dial Transplant (1999) 14: 2720-2725
Nephrology
Clinical Observations
Dialysis
Transplantation
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
Renal Mucormycosis: Radiological Features
Ultrasonography
• Enlarged kidneys
• Perinephric collection
( n-24)
22
10
Computerised tomography
• Enlargement of kidneys
• Absence of contrast
• Low attenuated areas
• Perinephric collection
( n-12 )
11
10
10
9
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
Renal Mucormycosis : Renal Pathology
Tissue obtained at autopsy
at biopsy
Gross examination
Evidence of infarction
Hilar vessel thrombosis
18
7
( n-18 )
16
14
Microscopic examination
Vasculitis
Cortical & medullary necrosis
Microabscess & granuloma
Glomerular invasion
( n-25)
18
18
17
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)
Aspergillosis: PGI Study (n=27)
Sex ratio M:F
Age (yrs. )
Presenting features
Renal failure
Pathologic findings
Microabscesses
Vasculitis
Papillary necrosis
Culture identification
23:4
22.6 ± 19.5
15 (55%)
19
13
6
6
Renal Failure, 20(6), 839-843 (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
Postgraduate Institute of Medical Education and Research, Chandigarh, India.
3Department
of Pathology
Postgraduate Institute of Medical Education and Research, Chandigarh, India.
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)
Candidiasis: PGI Study (n=30)
Sex ratio M:F
Age (yrs.)
Presenting features
Acute pyelonephritis
Pyonephrosis
Renal failure
Pathologic findings
Microabscesses
Papillary necrosis
Vasculitis
Mixed infections
Renal
Extrarenal
23:7
18.2±18.0
21
14
12* (40%)
24
15
5
3
5
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
Infections
Candidiasis
30
Aspergillosis
27
Mucormycosis
25
Cryptococcosis 4
Histoplasmosis 1
RPN
%
15
6
2
0
0
50
22
8
-
Total
23
27
85
Renal Mycoses:
Treatment and Outcome
Fungal
Untreated†
infections
Treatment
Survived
(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 II
INVASIVE FUNGAL INFECTIONS
FOLLOWING RENAL
TRANSPLANTATION
Introduction
• Increased occurrence of opportunistic infections in solid
organ transplant recipients
• Incidence related to organ transplanted,
immunosuppressive regimen, induction therapy and antifungal 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.
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
Pathologenic Fungi in Tx
Primary / Endemic
Opportunistic Emerging Fungi
Histoplasmosis
Candida
Blastomycosis
Coccididomycosis
Fusarium
Trichosporon
Aspergillus
Cryptococcus Paecilomyces
Scopulariopsis
Mucorales
Malassezia furfur
Dematiaceous molds
Phaeohyphomycosis
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
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 infection
Pts diagnosed Pts surviving
alive & treated with therapy
Candidiasis (n= 32)
Cryptococcosis (n= 23 )
Aspergillosis( n=32)
Mucormycosis (n= 26)
N
18
23
13
9
*Including those diagnosed at autopsy
N (%)
14 (78)
8 (47)
7 (54)
2 (23)
Overall *
Mortality
N (%)
13 (48)
9 ( 53)
16 (70)
18 (80)
Case Discussion



Renal Tx
Donor
Acute Graft Rejection
Admitted on with c/o
Triple drug therapy
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 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 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 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
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 infection
Pulmonary Infections in RTX Pts
(1995-96)*
Pts. with infections
Organism identified by BAL
Pyogenic bacteria
M. tuberculosis
P. carinii
Candida
Aspergillus
CMV
Others
34/81 (42%)
20/28 (71%)
33%
31%
15%
10%
8%
8%
5%
*Kidney International 56(5), 1944-50, 1999.
BAL;Stain: Fungi-Fluor x400
Lung specimen x 1000 Parenthesis or
comma like internal dots surrounded
by cyst walls. ( Dx 2 cysts reqd)
Specimen: BALStain: GM Sx1000
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,
o Expanded criteria donor
o Donation after cardiac death
o Concomitant viral , HCV
o Prednisone ≥ 16 mg for > eight weeks
o 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
Advances 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--Dglucan 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 membrane
Fungi use principally ergosterol
instead of cholesterol
Polyenes
DNA Synthesis
Some compounds may be
selectively activated by fungi,
arresting DNA synthesis.
Azoles
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
Azole Antifungals for Systemic Infections
•
•
•
•
•
Ketoconazole
Itraconazole
Fluconazole
Voriconazole
Posaconazole,
•Isavuconazole
•Revuconazole
•Albuconazole
Imidazole
Triazoles
“2nd generation
triazole”
Emerging
Triazoles
Voriconazole ; Dosing schedule
Dose
IV 6 mg/kg X 2 doses, then 3 to 4 mg/kg every 12 Hrs
PO > 40 kg—200-300 mg PO every 12 hours
< 40 kg—100-150 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
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%
? Therapeutic drug monitoring needed
Asians
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
Number of IFIs
30
P = .074
25
P = .004
20
22
27
P = .006
P = .001
17
15
21
16
10
5
7
7
3
0
All IFIs
Invasive
Aspergillosis
While on treatment
Posaconazole
All IFIs
Invasive
Aspergillosis
Primary time period
112 days after randomization
Fluconazole
Ullmann AJ et al. NEJM 2007.
The Fungal Cell Wall
mannoproteins
b1,3
b1,6
glucans
Cell
membrane
b1,3 glucan
synthase
chitin
ergosterol
Atlas of fungal Infections, Richard Diamond Ed. 1999
Introduction 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 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 - 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
Abelcet ® ABLC
Ribbon-like particles
Carrier lipids: DMPC,
DMPG
Particle size (µm): 1.6-11
Amphotec ® ABCD
Disk-like particles
Carrier lipids: Cholesteryl
sulfate
Particle size (µm): 0.12-0.14
DMPC-Dimyristoyl phospitidylcholine
DMPG- Dimyristoyl phospitidylcglycerol
Ambisome ® L-AMB
Unilaminar liposome
Carrier lipids: HSPC,
DSPG, cholesterol
Particle size (µm) : 0.08
HSPC-Hydrogenated soy phosphatidylcholine
DSPG-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
Author
Year
N=
Org
Combination
Resp
Kotoyiannis
2003
2003
2004
2004
2006
48
30
16
30
17
IA
IA
IA
IA
Any
Caspo+LAmB
”
Caspo+ Voric
Caspo+ either
Caspo + any
42%
60%
65%
57%
71%
Aliff
Marr
Maartens
Nivoix
• IA=invasive aspergillosis
Combination treatment –2:
• Multi-institutional, retrospective
Event
L-AmB
Sample size
90 day survival
Renal failure
A fumigatus
47
67.5%
-
Caspo+
Voricon
40
51%
-
HR
P=
0.58
0.32
0.38
0.117
0.022
0.019
Singh, 2006
Combination: Mycograb
• Monoclonal antibody to Hsp90
• Phase III RCT in culture positive,
disseminated candida (n= 117)
Event
Complete response
Clinical response
Attributable mortality
L-AmB +
Mycograb
84%
86%
4%
L-AmB +
placebo
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
Voriconazole
Posaconazole
Itraconazole,
Caspofungin
Amphotericin
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. Cytokines
3. Adoptive T-cell transfer
4. Monoclonal antibodies?
5. Antifungal peptides? (cationic AMP)
Pathogen-targeting agents
(immunotherapeutics)
1. Monoclonal antibodies
2. Antifungal peptides
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 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 :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 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
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.
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.