“ Current Concepts in Invasive fungal infection & treatment in Renal Transplanted Patients”

Outline of the Presentation Invasive fungal infections Signs and symptoms of fungal infections in renal transplant recipients. Fungal Pathogens &Fungal infections after transplantation. Invasive Candida Infections Reported in Various Transplant Types Distribution of fungal pathogens causing invasive fungal infections in transplant recipients Incidence of Invasive Fungal Infections Risk Factor Strategies for the Management of Neutropenic Patients at High Risk for Invasive Fungal Infection Management of fungal infections in renal transplant recipients. Renal correction for various antifungal agents

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

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

Fungal Pathogens Candida sp Aspergillus sp Cryptococcus Fusarium Pneumocystis

Fungal infections

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 Pneumonia Histoplasmosis Pneumonia or disseminated disease

Incidence of Invasive Fungal Infections

Invasive Candida Infections Reported in Various Transplant Types 60 50 42 38 40 Prevalence, % 30 The 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. Reference Andes 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. 20 17 12 8 10 Liver Kidney Pancreas Lung Heart *Numbers reflect data collected by TRANSNET from 2001 to 2004. Andes D, et al. ICAAC 2004. Abstract M-1014. 9

Distribution of fungal pathogens causing invasive fungal infections in transplant recipients Ther Adv Infect Dis (2013) 1(3) 85105

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%), and Zygomycosis (2%) IA is a life-threatening complication in patients who undergo solid organ transplantation, having an incidence between 0.5% and 2.2% with a mortality rate of > 70% and a high case-fatality rate of up to 88%

Aspergillosis in SOT Recipients Analysis of interim data from 4110 SOT procedures from 19 centers in the United States from March 2001 to December 2002 Transplant type, n (%) Incidence* Mortality† Heart 3 (0.8) 2 (66.7) Kidney 3 (0.1) Liver 3 (0.3) 1 (33.3) Lung 10 (3.5) 2 (20.0) Other 1 (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. Reference Morgan 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

Indian Prospective Recipients of solid organ transplants have 6–10% incidence of opportunistic fungal infections with a very high mortality of 70– 100% in the Indian subcontinent.

Risk Factor

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 corticostéroïdes Graft failure requiring Hemodialysis Potent immunosuppressive therapy for rejection

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

Invasive Aspergillosis: Risk factors of early IA (1) < 3 months OR (95% CI) p Use of vascular amines > 24h 2.2 (1.2 - 4.1) < 0.0001 Renal failure after SOT 4.9 (2.4 -9.8) Hemodialysis after SOT 3.2 (1.3 - 8.1) 0.014 > 1 episode of bacterial infetion (3.2 - 17.4) < 0.006 CMV disease 2.3 (1.1 - 4.9) < 0.029 Gavaldà J et al, Clin Inf Dis 2005; 41:52-9

Invasive Aspergillosis : Risk factors of late IA (2) > 3 months OR (95% CI) p Age > 50 years 2.5 (1.3 - 5.1) 0.009 Renal failure after SOT 3.9 (1.9 -7.8) < 0.0001 High levels of CNI (1.2 - 5) 0.01 > 1 episode of bacterial infetion 7.5 (3.2 - 17.4) De novo cancer 69.3 (6.4 - 75.3) Chronic graft rejection 5 (1.9 - 13) 0.001 Gavaldà J et al, Clin Inf Dis 2005; 41:52-9

Risk Factor of Renal transplant patients Other risk factors such as: Diabetes Prolonged Pre-transplant dialysis has also shown to promote serious fungal infection.

Diagnosis

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 invasion Positive culture results from a deep tissue specimen such as Blood Cerebrospinal fluid Peritoneal fluid, or a biopsy specimen

Diagnosis of fungal infections in renal transplant recipients Biomarkers 1,3 b-D-glucan (BG) Galactomannan (GM)a Direct Microscopic examinations Culture Results Serological Diagnosis (Antigen Detection Assay) Molecular Methods (PCR Polymerase Chain reactions)

Antifungal Treatment in Renal Transplant Recipients

Goals of Therapy in Renal transplant Recipient Prevention of fungal infections. Individual risk assessment Initiated early in patients with a suspected fungal infection. Optimize the pharmacokinetics of antifungal drugs. Assess for potential side effects.

Strategies for the Management of Neutropenic Patients at High Risk for Invasive Fungal Infection Current Strategies for the management of IFIs includes: Prophylaxis Therapy Empiric therapy Pre Emptive Therapy Targeted Therapy

Antifungal Prophylaxis

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 futile J Clin Med Res. 2015;7(6):371-378

Management of Neutropenic Patients at High Risk for IFI

Management of fungal infections in renal transplant recipients

Management of fungal infections in renal transplant recipients J Clin Med Res. 2015;7(6):371-378

Treatment of fungal infections: Special considerations in renal disease

Renal correction for various antifungal agents Drug Dose for normal GFR > 50 ml/min GFR 10–50 ml/min GFR < 10 ml/min Supplement for dialysis renal function Amphotericin B 0.3–0.5 mg/kg/day 100% None Fluconazole 200–400 mg/da 50 HOMO: Dose after Dialysis Flucytosine 150 mg/kg/d 12 h 25–50 mg/kg 12 h 25–50 mg/kg 12 h 50 mg/kg HEMO: dose after dialysis in 3–4 divided doses Itraconazole 100–200 mg 12 h 50–100% 100 mg 12–24 h VCZ 6 mg/kg 12 hrly 1st day followed by 4 mg/kg/day Orally 200 mg BD No IV Rx J Postgrad Med 2005 Vol 51 Suppl 1

Invasive Fungal Infections in Renal Transplant Recipients: Epidemiology and Risk Factors.

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