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

2. 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

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

5. Fungal Pathogens Candida sp Aspergillus sp Cryptococcus Fusarium
Pneumocystis

6. Fungal infections

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 Pneumonia
Histoplasmosis Pneumonia or disseminated disease

8. Incidence of Invasive Fungal Infections

9. Invasive Candida Infections Reported in Various Transplant Types60 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 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%), 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%

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 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

13. 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.

14. Risk Factor

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 corticostéroïdes
Graft failure requiring Hemodialysis
Potent 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 months
OR (95% CI) p
Use of vascular amines > 24h
2.2
( )
<
Renal failure after SOT
4.9
( )
Hemodialysis after SOT
3.2
( )
0.014
> 1 episode of bacterial infetion
( )
< 0.006
CMV disease
2.3
( )
< 0.029
Gavaldà J et al, Clin Inf Dis 2005; 41:52-9

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

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

20. Diagnosis

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

22. 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)

23. Antifungal Treatment in Renal Transplant Recipients

24. 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.

25. 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

26. Antifungal Prophylaxis

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 futile
J 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
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

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

34. Thank you