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1 “ Current Concepts in Invasive fungal infection & treatment in Renal Transplanted Patients”
2 Outline of the Presentation Invasive fungal infectionsSigns and symptoms of fungal infections in renal transplant recipients.Fungal Pathogens &Fungal infections after transplantation.Invasive Candida Infections Reported in Various Transplant TypesDistribution of fungal pathogens causing invasive fungal infections in transplant recipientsIncidence of Invasive Fungal InfectionsRisk FactorStrategies for the Management of Neutropenic Patients at High Risk for Invasive Fungal InfectionManagement of fungal infections in renal transplant recipients.Renal correction for various antifungal agents
3 Invasive fungal infections Invasive fungal infections are a significant and often lethal problem in transplant patients.They are at risk for these infections as a result of their general health status, technical complications of surgery, and immunosuppression.Journal de Mycologie Médical (2013) 23, 255—260
4 Signs and symptoms of fungal infections in renal transplant recipients Fungal infections in renal transplant recipients can manifest in 2 forms:Cutaneous or Subcutaneous,Systemic
7 Fungal infections after transplantation Candidiasis: Mucocutaneous, disseminated, UTI,Cryptococcosis: Central nervous system (CNS), pulmonary, dematologic, skeletal, and organ-specific disease.Aspergillosis: Pneumonia, genitourinary, CNS, rhinocerebral, gastrointestinal, and skin.Zycomocoses Rhizopus and Mucor species Pneumocystis PneumoniaHistoplasmosis Pneumonia or disseminated disease
9 Invasive Candida Infections Reported in Various Transplant Types 6050423840Prevalence, %30The prevalence of an invasive Candida infection varies based on the type of transplant. Eighty percent of invasive Candida infections occur in liver and kidney transplant recipients.This was a study of 19,237 hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients from 25 US transplant centers (TRANSNET) conducted from March 2001 to December 2003.Invasive Candida infections developed in 2.6% of SOT recipients during the study period.Overall mortality in patients with invasive candidiasis was 40% for both populations of transplant recipients. Investigator-determined mortality attributable to invasive candidiasis was 24% for both populations of transplant recipients.ReferenceAndes D, Safdar N, Hadley S, et al. Epidemiology of invasive Candida infections in solid and hematologic transplantation: prospective surveillance results from the TRANSNET database. Abstract presented at: 44th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; October 30-November 2, 2004; Washington, DC. Abstract M-1014.201712810LiverKidneyPancreasLungHeart*Numbers reflect data collected by TRANSNET from 2001 to 2004.Andes D, et al. ICAAC Abstract M-1014.9
10 Distribution of fungal pathogens causing invasive fungal infections in transplant recipients Ther Adv Infect Dis (2013) 1(3) 85105
11 Incidence of Invasive Fungal Infections The Transplant-Associated Infection Surveillance Network conducted a 5-year prospective study among 1,063 organ transplant recipients.One thousand two hundred eight were diagnosed with IFI.The most common IFIs were:Invasive candidiasis (53%),Invasive aspergillosis (IA) (19%),Cryptococcosis (8%),Non-Aspergillus molds (8%),Endemic fungi (5%), andZygomycosis (2%)IA is a life-threatening complication in patients who undergo solid organ transplantation, having an incidence between0.5% and 2.2% with a mortality rate of > 70% and a high case-fatality rate of up to 88%
12 Aspergillosis in SOT Recipients Analysis of interim data from 4110 SOT procedures from 19 centers in the United States from March 2001 to December 2002Transplant type, n (%)Incidence*Mortality†Heart3 (0.8)2 (66.7)Kidney3 (0.1)Liver3 (0.3)1 (33.3)Lung10 (3.5)2 (20.0)Other1 (0.4)Although the incidence of invasive aspergillosis in this patient population is low, mortality rates were high. It is important to note that the cause of death was not necessarily attributable to invasive aspergillosis.These interim results of a prospective multicenter surveillance program were collected from the TRANSNET database from 4110 solid organ transplant procedures at 19 centers in the United States over a 22-month period from March 2001 to December 2002.It is important to note that the incidence of fungal infections were calculated from data limited to the 12 months following transplantation. In addition, patients may have received antifungal treatment, both of these circumstances may have contributed to the low incidence of invasive aspergillosis found in this study.ReferenceMorgan J, Wannemuehler KA, Marr KA, et al. Incidence of invasive aspergillosis following hematopoietic stem cell and solid organ transplantation: interim results of a prospective multicenter surveillance program. Med Mycol. 2005;43(suppl 1):S49-S58.*Weighted aggregate incidence after 12 months.†Three months after diagnosis of aspergillosis.SOT indicates solid organ transplant.Morgan J, et al. Med Mycol. 2005;43(suppl 1):S49-S58.12
13 Indian ProspectiveRecipients of solid organ transplants have 6–10% incidence of opportunistic fungal infections with a very high mortality of 70– 100% in the Indian subcontinent.
15 Risk Factor of Renal transplant patients Aspergillus spores are ubiquitous in the environment.Hospital constructions or at adjacent sites predispose the hospital ventilation systems to become concentrated with Aspergillus spores and may serve as the source micro- epidemics of aspergillosis.High doses or prolonged duration of corticostéroïdesGraft failure requiring HemodialysisPotent immunosuppressive therapy for rejection
16 Risk Factor of Renal transplant patients In Retrospective case-control study on 156 transplant cases, early-onset IA (i.e., occurred during the first 90 days after transplantation) was identified.57% cases and 43% cases had late-onset infections (i.e., occurred after 90 days period).This bimodal pattern of infection is suggestive of different risk factors between early- and late-onset cases
17 Invasive Aspergillosis: Risk factors of early IA (1) < 3 monthsOR (95% CI)pUse of vascular amines > 24h2.2( )<Renal failure after SOT4.9( )Hemodialysis after SOT3.2( )0.014> 1 episode of bacterial infetion( )< 0.006CMV disease2.3( )< 0.029Gavaldà J et al, Clin Inf Dis 2005; 41:52-9
18 Invasive Aspergillosis : Risk factors of late IA (2) > 3 monthsOR (95% CI)pAge > 50 years2.5( )0.009Renal failure after SOT3.9( )<High levels of CNI( )0.01> 1 episode of bacterial infetion7.5( )De novo cancer69.3( )Chronic graft rejection5( )0.001Gavaldà J et al, Clin Inf Dis 2005; 41:52-9
19 Risk Factor of Renal transplant patients Other risk factors such as:DiabetesProlonged Pre-transplant dialysis has also shown to promote serious fungal infection.
21 Diagnosis of fungal infections in renal transplant recipients Fungal infections in renal transplant recipients are diagnosed on the basis of:Clinical and radiologic signs and symptoms that include:Tissue invasionPositive culture results from a deep tissue specimen such asBloodCerebrospinal fluidPeritoneal fluid, or a biopsy specimen
23 Antifungal Treatment in Renal Transplant Recipients
24 Goals of Therapy in Renal transplant Recipient Prevention of fungal infections.Individual risk assessmentInitiated early in patients with a suspected fungal infection.Optimize the pharmacokinetics of antifungal drugs.Assess for potential side effects.
25 Strategies for the Management of Neutropenic Patients at High Risk for Invasive Fungal Infection Current Strategies for the management of IFIs includes:Prophylaxis TherapyEmpiric therapyPre Emptive TherapyTargeted Therapy
27 Antifungal Prophylaxis in in renal transplant recipients Fluconazole prophylaxis (400 mg/day) has been shown to reduce the incidence and severity of Candida infections.Itraconzole (2.5 mg/kg twice daily)Amphotericin B (both regular and lipid formulations) can be used for the prevention of invasive fungal infections. However, low dose amphoteracin B regimens as a prophylaxis for IA have been futileJ Clin Med Res. 2015;7(6):
28 Management of Neutropenic Patients at High Risk for IFI
29 Management of fungal infections in renal transplant recipients
30 Management of fungal infections in renal transplant recipients J Clin Med Res. 2015;7(6):
31 Treatment of fungal infections: Special considerations in renal disease
32 Renal correction for various antifungal agents DrugDose for normalGFR > 50 ml/minGFR 10–50 ml/minGFR < 10 ml/minSupplement for dialysis renal functionAmphotericin B0.3–0.5 mg/kg/day100%NoneFluconazole200–400 mg/da50HOMO: Dose after DialysisFlucytosine150 mg/kg/d 12 h25–50 mg/kg12 h 25–50 mg/kg12 h 50 mg/kgHEMO: dose after dialysis in 3–4 divided dosesItraconazole100–200 mg 12 h50–100%100 mg 12–24 hVCZ6 mg/kg 12 hrly 1st day followed by 4 mg/kg/day Orally 200 mg BDNo IV RxJ Postgrad Med 2005 Vol 51 Suppl 1
33 Invasive Fungal Infections in Renal Transplant Recipients: Epidemiology and Risk Factors.