Presentation on theme: "FUNGAL INFECTIONS AND THE KIDNEY"— Presentation transcript:
1FUNGAL INFECTIONS AND THE KIDNEY Prof K L GUPTA,Department of Internal Medicine,King Fahd Hospital of University,AL KOBAR
2OBJECTIVES & Parts of Talk PART 1. To discuss the kidney involvement in fungal infectionsPart 2. To discuss the fungal infections following renal transplantationPart 3. To discuss management of invasive fungal infections
3Introduction 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 involvedDiagnosis is often delayed due to co-existing illnesses.Early identification is important in providing timely therapy.
4Disseminated mucormycosis presenting with acute renal failure Postgraduate Medical Journal (1987) 63,Disseminated mucormycosis presenting with acute renal failureK.L.Gupta,1 Kusum Joshi,2 Brian J.G.Pereira1 and Kartar Singh3Departments of 1 Nephrology, 2 Pathology and 3Gastroenterology, Postgraduate Institute ofMedical 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.
5Mucormycosis in patients with renal failure K.L. Gupta, B.D. Radotra, V. Sakhuja, A.K. Banerjee and K.S. ChughDepartments of Nephrology and Pathology,Postgraduate Institute of Medical Education and Research,Chandigarh , IndiaAm Journal of Kidney Diseases,Vol 22, No 3(September),1993; pp
6Renal mycoses : Indian scene PGI,Chandigarh Study Data-source Medical & pathology recordsDiagnostic criteriaHistological demonstration of tissue invasion in H&E,PAS & Silver Methenamine estained sectionsIdentification by characteristic morphlologyIsolation of in fungi culturePeriod of studyNo.of cases ( 74 M, 11 F )Age (yrs ) ± 18.5
7Renal Mucormycosis Rhizopus, Absidia and Mucor Large, aseptate,irregularly branching hyphaeClinical 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
8Case Discussion Examination SJ 17 M Student admitted with Fever, flank pain (Lt.). Vomiting。Haematuria, and doligo-Anuria for 10 daysExaminationPale, febrile, toxic, pt. B/L pedal oedema BP 150/90, Pulse-110/mGeneralised tenderness in abdomen Fullness of C-V anglesInvestigations Hb-80g/L, WBC 23x109/LUrine Prot.++, pus cells , RBC 15-20/HPFUrea 240 mg/dl, Creat.10mg/dl, uric acid 12 mg/dlSugar 100mg/dl ALB. 2.5g/dl, TP 5.1g/dlHIV Neg., T4/T8 Ratio normal,Fungal serology-NormalUS and CT Abdomen:
9Course & Management Hemodialysis, antibiotics, Laparotomy and aspiration of perinephric collectionPus direct smear-Mucor hyphaeCulture-Apophysomyces elegansKidney biopsy: Ischemic necrosis with vesselinvasion 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
10Renal Mucormycosis: PGI Study (n=25) Sex ratio M:F 22:3Age (yrs. ) ±15.1Presenting features No. %FeverFlank painLuekocytosisHematuriaPyuriaRenal failure** In (95%) pts with bilateral involvement
11Renal Zygomycosis: an under-diagnosed cause of acute renal failure Nephrol Dial Transplant (1999) 14:NephrologyDialysisTransplantationClinical ObservationsRenal Zygomycosis: an under-diagnosed cause of acute renal failureKrishan Lal Gupta, Kusum Joshi1, Kamal Sud, Harbir S. Kohli and Vivekanand Jha, Bishan D. Radotra1 and Vinay SakhujaDepartments of Nephrology and 1Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
12Renal Mucormycosis: Radiological Features Ultrasonography ( n-24)Enlarged kidneys 22Perinephric collection 10Computerised tomography ( n-12 )Enlargement of kidneysAbsence of contrast 10Low attenuated areas 10Perinephric collection 9
13Am Journal of Kidney Diseases,Vol 22, No 3(September),1993; pp 393-397 Renal Mucormycosis: Computerized Tomographic Findings and Their Diagnostic SignificanceK.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
15Renal Aspergillosis (A fumigatus, A.flavus, A.niger ) Identified by slender,regular,dichtomouslybranching,septate hyphaeInvariably associated with debilitated stateUsually part of disseminated disease & rarely isolatedOther organs lungs (94%),GIT (92%),brain (13%) †Clinically: Three patterns1) Disseminated aspergillosis with renalinvolvement2) Aspergillus cast of renal pelvis3) Ascending panurothelial aspergillosis† Wise & Silver (1993)
16Aspergillosis: PGI Study (n=27) Sex ratio M:F 23:4Age (yrs. ) ± 19.5Presenting featuresRenal failure 15 (55%)Pathologic findingsMicroabscesses 19Vasculitis 13Papillary necrosisCulture identification 6
17Isolated Bilateral Renal Aspergillosis: Renal Failure, 20(6), (1998)CASE REPORTIsolated Bilateral Renal Aspergillosis:An unusual Presentation in an Immunocompetent HostKamal 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, DM1Department of NephrologyPostgraduate Institute of Medical Education and Research, Chandigarh, India.2Department of Microbiology3Department of Pathology
18Renal 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,dysuriaPyuria,hematuria,candiduria,Urinary retention & anuriaProgressive renal failure† (Wise & Silver, J Urol 1993)
19Candidiasis: PGI Study (n=30) Sex ratio M:F 23:7Age (yrs.) ±18.0Presenting featuresAcute pyelonephritis 21Pyonephrosis 14Renal failure * (40%)Pathologic findingsMicroabscesses 24Papillary necrosis 15Vasculitis 5Mixed infectionsRenal 3Extrarenal 5
20Renal cryptococcosisC.neoformans identified by large clear capsules sorrounding yeast cellsUsually a disseminated disease involvingbrain,lungs,GIT,kidneys,prostate etc.Renal lesions includeSparse lymphocytic infiltrate and rarelyMicroabscesses,granulomas & caseationPapillary necrosis &tubular atrophy.Clinically no significant abnormality
21Renal mycoses: incidence of papillary necrosis Fungal Total RPN %InfectionsCandidiasisAspergillosisMucormycosisCryptococcosisHistoplasmosisTotal
22Renal Mycoses: Treatment and Outcome Fungal Untreated† Treatment Survivedinfections (Ampho B )Candidiasis ‡ 8AspergillosisMucormycosis *CryptococcosisHistoplamsosis)† Diagnosed postmortem, ‡ Oral fluconazole in 4,*Unilateral involvement , nephrectomy(2
23Conclusions Fungal infections have been being increasingly seen in the last decadeRenal involvement occured as disseminated (57%)or isolated form ( 43%)Candidiasis was the commonest renal infection but had alow incidence of renal failure ( 40%)*.Mucormycosis causes most severe lesions. IrreversibleARF occurred in 92% of pts with bilateral renal invlvement.Aspergillus is less angioinvasive. ARF occurred in 55% pts.
24Conclusions (contd.) Most fungal infection occurred in presence of predisposing conditions. However 68% of pts. withmucormycosis had no apparent underlying disease.Renal mycoses has a very high mortality ( 80% ).Diagnosis is usually made at autopsy. Disease wasrecognised in life only in 1/3rd of pts.A high index of suspicion is required to identify renal mycoses.Imaging techniques combined with interventionsincluding kidney biopsy may clinch the diagnosis andhelp in initiating antifungal therapy.
25PART II INVASIVE FUNGAL INFECTIONS FOLLOWING RENAL TRANSPLANTATION
26IntroductionIncreased occurrence of opportunistic infections in solid organ transplant recipientsIncidence related to organ transplanted, immunosuppressive regimen, induction therapy and anti-fungal prophylaxisDiagnosis often difficult and delayed because ofPaucity of rapid diagnostic testsConcomitant infections (90% have Bacteria, CMV and P car)Presence of comorbid conditionsHigh index of suspicion is thus necessary to provide timely therapy.
27ISSUES IN MANAGEMENT OF INVASIVE FUNGAL INFECTIONS Discussion points:Epiedemiology of IFIS and its Risk factorsLocal experience of IFISClinical and Laboratory Diagnosis of IFISAdvances in management of IFISTriazoles, Echinos. Ampho-B and its formulationsRole of combination therapySummarized managemet of IFISRole of prophylaxis therapy
28Pathologenic Fungi in Tx Primary / EndemicOpportunisticEmerging FungiHistoplasmosisBlastomycosisCoccididomycosisCandidaAspergillusCryptococcusMucoralesFusariumTrichosporonPaecilomycesScopulariopsisMalassezia furfurDematiaceous moldsPhaeohyphomycosis
29Risk factors in Tx recipients a) Epidemiological exposureb) Net state of immunosuppressionImmunosuppressive therapyIntegrity of muco-cutaneous barrierDevitalised tissues, fluid collectionMetabolic factors ; uremia and diabetesImmuno-modulating viruses: CMV, EBV, HBVHospital exposures/adjacent constructionSelected agricultural, occupational, and recreational activities
30Immunosuppressants and Fungi Calcineurin inhibitorsAntifungal activity of the CNIs is mediated through inhibition of Calcineurin phosphatase.Mycophenolic acidMPA activity against P jiroveci (Inhibition of IMPDH)SirolimusTOR kinases promote cell proliferation in fungi. SRL on fungi with TOR activityALA Both for induction and anti-rejection therapyCorticosteroidsMedications with myelosuppressive properties (miscellaneous)
32Fungal Infections following renal Transplantation Therapy and Outcome Fungal infection Pts diagnosed Pts surviving Overall *alive & treated with therapy MortalityN 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
33Case Discussion Renal Tx Donor Triple drug therapy Acute Graft RejectionAdmitted on with c/o
34Clinical features suggesting IFI Fever resistant to BSA ± severe neutropeniaS/S of resistant or progressive LRI or URIPeriorbital or Maxillary swelling / tendernessPalatal necrosis or perforationFocal neurological or meningeal irritation S/SUnexplained mental changes with feverPapular or nodular skin lesions
35Laboratory 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 tissueCulture 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
36Immunological /DNA assays for IFIS Detection of fungal cell wall components and antigensAntigen detection e.g. Double sandwich ELISA for candidal antigen and Galactomannan ELISA for Asper and Cryptococcal antigen by RIADetection of 1, 3-β-D-Glucan synthetaseMolecular diagnosis, like PCR for DNA assayNucleic acid probes
37Radiological diagnosis of IFIS Plain chest X-rayNormal in upto 29% of Pulmonary IFISFindings include segmental or subsegmentalconsolidation, patchy infiltrates, nodules (single or multiple), nodular infiltrates and cavitationCT ScansHRCT 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
38Pneumocystis jirovecii (P Carinii) Universal seropositive status by age twoUsually air-borne transmissionDiffuse alveolar damage, impaired gas exchange, and respiratory failure (More in Non-HIV)Usually occurs with 6-12 mon but sometimes latePresents with fever, nonproductive coughTachypnoea, cyanosis, hypoxemia Diffuse crepitationsBAL and lung biopsy help in confirming DxRadiology : B/L ground glass opacities, homogenous and diffuse; HRCT- more sensitive
40Pulmonary 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.
41BAL;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
42P. jirovecii : USRDS 2009No series available from India, limited cases included4% of opportunistic infections in HIV patientsUSEDS - 32,757 renal TX recorded 142 (04% ) PCP CasesMedian post-tx time was 0.80±0.95 yrsRisk factors in Transplant patients,Expanded criteria donorDonation after cardiac deathConcomitant viral , HCVPrednisone ≥ 16 mg for > eight weeksCombination immunosupressionTacrolimus and sirolimusNeoral and MMFSirolimus and MMF(Analysis of USRDS: July )
43Part III Advances in Management of Invasive Fungal Infections
45Why we need new antigumgal ? Several new antifungal drugs licensed in last 5 yrs ;Intrinsic or acquired antifungal resistance,Organ dysfunction preventing use of some agentsPoor penetrabilty into sanctuary sites (eye /urinine)Drug interactions and considerable adverse eventsStill some patients remain difficult to treat
46Wish List for an Antifungal Drug Broad spectrum fungicidalNontoxic even with prolonged useCan be administered parenterally and orallyFavorable pharmacokinetic properties,Minimal drug interactionsMinimal genetic variation in metabolism
47Mechanisms of ActionCell 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
48What are the targets for antifungal therapy? Cell membraneFungi use principally ergosterol instead of cholesterolPolyenesDNA SynthesisSome compounds may be selectively activated by fungi, arresting DNA synthesis.AzolesThere are key differences between mammalian and fungal eukaryotic cells. This is the basis of drug selectivity.Cell WallUnlike mammalian cells, fungi have a cell wallCandinsAtlas of fungal Infections, Richard Diamond Ed. 1999Introduction to Medical Mycology. Merck and Co. 2001
49Azole Antifungals for Systemic Infections KetoconazoleItraconazoleFluconazoleVoriconazolePosaconazole,ImidazoleTriazoles“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.IsavuconazoleRevuconazoleAlbuconazoleEmergingTriazoles
50Voriconazole ; Dosing schedule DoseIV 6 mg/kg X 2 doses, then 3 to 4 mg/kg every 12 HrsPO > 40 kg— mg PO every 12 hours< 40 kg— mg PO every 12 hoursCirrhosis:IV 6 mg/kg X 2 doses, then 2 mg/kg every 12 HrsPO > 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
51VORICONAZOLE : 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, CSAMetabolised by CYP 2C19Polymorphism : 3% whites; 15 –20% Asians? Therapeutic drug monitoring needed
52Posaconazole: Dosing schedule Spectrum: Zygo, Asper, Fusarium and candidaDosing (only available PO admn with food supplement)Prophylaxis of invasive Aspergillus and Candida species200 mg 3 times/dayTreatment of oropharyngeal candidiasis100 mg twice daily for 1 day, then 100 mg once daily for 13 daysTreatment or refractory oropharyngeal candidiasis400 mg twice dailyTreatment of refractory invasive fungal infections800 mg/day in divided dosesDrug InteractionsModerate inhibitor of CYP3A4 (AVOID coadmPPI & H2 Blocker)Adverse ReactionsHepatotoxicity, GI: Diarrhea. QTc prolongation SAFE in Ren Insuff.
53Prophylactic therapy ; Incidence of Proven/Probable IFIs 30P = .0742725P = .004P = .0062220P = .00121Number of IFIs171516107753All IFIsInvasive AspergillosisAll IFIsInvasive AspergillosisWhile on treatmentPrimary time period112 days after randomizationPosaconazoleFluconazoleUllmann AJ et al. NEJM 2007.
54The Fungal Cell Wall chitin ergosterol mannoproteins b1,3 b1,6 glucans synthaseCellmembraneThe 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. 1999Introduction to Medical Mycology. Merck and Co. 2001
55Echinocandins: Capso,Mica,Anidula-fungin Mechanism of ActionCyclic lipopeptide antibiotics that interfere with fungal cell wall synthesisby inhibition of ß-(1,3) D-glucan synthaseLoss of cell wall glucan results in osmotic fragilitySpectrum:Candida species including non-albicans isolates resistant to fluconazoleAspergillus spp. but not activity against other moulds (Fusarium, Zygomycosis)No coverage of Cryptococcus neoformansDose and modificationWater soluble available only in IV formDose mg day 1 and 50 mg afterwardsDosage adjustment in hepatic insufficiencyMetabolites excreted by kidneys and GI tractThe 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) Caspofungin2) Micafungin3) AnidulafunginCilofungin, 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
56Echinocandins 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.DiBACBowman et al. Antimicrob Agent Chemother 2002;46:
57Caspofungin - 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 discontinuationMost common laboratory AEAsymptomatic of serum transaminases (10-15%)Clinical experience to date suggests that these drugs are extremely well-toleratedCaspofungin 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,
58Amphotericin B Polyene, Fermentation product of Streptomyces nodusus Long time gold standard in treatment of serious fungal infection with Broad spectrum activityHighly insoluble. Exists in micellar mixture with deoxycholateNo oral bioavailability; intravenous formulationRelatively poor penetration of urinary tract, CNS
59Amphotericin B is active in vitro against Candida spp.(including azole-resistant species)Aspergillus spp.Cryptococcus neoformansMucor spp.Blastomyces dermatitidisCoccidioides immitisHistoplasma capsulatumParacoccidioides brasiliensis
60Toxicities 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 tachyphylacticRenal toxicity -- RTA; K+ and Mg++ wasting, S cr . Dose Related. renal toxicity in hypovolemia in and those receiving other nephrotoxic drugs.Amphotericin B - Drug InteractionsUncommon except with high doses: Liver toxicity; bone marrow toxicity
61Lipid Formulations of Amphotericin B All three approved for “rescue therapy” (failure of previous therapy or toxicity)Liposomal amphotericin successful for empiric therapy in febrile neutropeniaLess nephrotoxicity and cytokine stormsLipid preparations are thus preferred for inhalation deliveryLipid 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.
64Combination Anti-fungal Therapy Potential benefitsEnhanced potency of antifungal efficacy,Reduced selection of resistant organisms andReduced toxicities due to lower dosing.Evidence of benefit Rx cryptococcal meningitis,AmB-D and FlucytosineAmphotericin B plus FluconazoleHowever few large studies in IA
67Combination: Mycograb Monoclonal antibody to Hsp90Phase III RCT in culture positive, disseminated candida (n= 117)EventL-AmB + MycograbL-AmB + placeboComplete responseClinical responseAttributable mortality84%86%4%48%52%18%Matthews, 15 ECCMID 2005
68SUMMARY OF FUNGAL THERAPY PathogenPrimarySecondaryCandida albicansFluconazole Amphotericin B Caspofungin Posaconazole AnidulafunginVoriconazole, ItraconazoleCryptococcus neoformansAmphotericin B ± Flucytosine followed by FluconazoleItraconazole or Amphotericin BAspergillus fumigatusVoriconazolePosaconazoleItraconazole, CaspofunginAmphotericinHistoplasma capsulatumFluconazoleMucomycosisAmphotericin B
70Antifungal Prophylaxis in SOT Recipients Prophylaxis reasonable given the high incidence/ mortalityHowever 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 consideredInterscience Conference on Antimicrobial Agents and Chemotherapy (43rd: 2003: Chicago, Ill.).
71Antifungal Prophylaxis :Indications High risk patents with:Renal and hepatic dysfunctionLarge blood transfusion requirementsProlonged ICU staysAdditional surgery post transplant including laparotomy and re-transplantationKnown fungal colonization pretransplantationPrior (broad-spectrum) antimicrobial use
72Antifungal Prophylaxis: Drug Regimens None is ideal for all of the indications for post-tx prophylaxisFluconazole — Safe ,no hepatotox in liver tx used only for CandidaItraconazole — 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 AsperEchinocandins — No trials of SOT AFP have been performed to date.Choice of drug — The 2009 Infectious Diseases Society of AmericaFluconazole (200 to 400 mg [3 to 6 mg/kg] daily) ORLiposomal 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
73ConclusionsIncidence of IFI in Transplant recipients is increasing partcularly that of angio-invasive filamentous fungi with morbidity and mortalityDiagnosis depends on understanding of Risk factors and incidence rates, Significance of different clinical presentation and Timely use of mycological and radiological investigations.Antifungal TherapyEmpirical use should be discouraged.Azoles hold Good Promise but all IFI do not respond (Except Posa) Lowest toxicity seen with caspo and L-Ampho BProphylaxis of IFI should be confined to high risk patients and drugs of choice are itraconazole and posaconazole.
74ConclusionsIncidence of IFI in Transplant recipients is increasing partcularly that of angio- invasive filamentous fungi with morbidity and mortalityDiagnosis depends on understanding of Risk factors and incidence rates, Significance of different clinical presentation and Timely use of mycological and radiological investigations.Antifungal TherapyEmpirical use should be discouraged.Azoles Hold Good Promise but all IFI do not respond (Exception Posa) Lowest toxicity seen with caspo and L-Ampho BProphylaxis of IFI should be confined to high risk patients and drugs of choice are itraconazole and posaconazole.