1. Antifungal prophylaxis in liver transplantation
Epidemiology of invasive fungal infection
Risk factor for IFI
Universal prophylaxis vs targeted prophylaxis
Choice of agent-Fluconazole/itaconazole/ voriconazole/Echinocandins/ Liposomal amphotericin B
Guidelines of American Society of Transplantation (AST) and Infectious Diseases Society of America (IDSA)
Take home message

2. Epidemiology of IFI
Liver transplant recipients are susceptible to invasive fungal infection (IFI), with infection rates of 7 %–42 % in historical series
Candidiasis and aspergillosis typically occur early post-transplant
Recent data from the Transplant Associated Infection Network (TRANSNET) reported a 1- year cumulative incidence for the first IFI of 4.7% in liver transplant recipients.
The most commonly reported IFI among liver transplant recipients are
Candidiasis (60% to 80%) and aspergillosis (1%t o 8%)
Candida albicans and Candida glabrata being most commonly isolated

3. Epidemiology of IFI
Historically, survival following IFI has been poor with mortality rates of 71% for invasive candidiasis and 74–92% for invasive aspergillosis
Recent report showed decreased mortality and the 12-month mortality after infection in the TRANSNET cohort was 41% for patients with invasive aspergillosis, 39% for infections due to non-Aspergillus moulds and 36% for invasive candidiasis

4. Risk factors for IFI Retransplantation (30-fold higher risk)
Transplantation for ALF
Receipt of corticosteroids for at least 2 weeks within 4 weeks preceding transplantation
Hospitalization for at least 48 h in ICU at the time of transplantation
Colonization with Candida species at ≥ 2 sites within 4 weeks preceding transplantation
≥ 15 U of intraoperative PRBC transfusions and operative time >6 h
Requirement of any form of RRT at the time or within 7 days of transplantation ( 15- to 25-fold greater risk )
Reexploration
MELD score > 30 ( four fold increase)
Collins et al. J Infect Dis 1994; 170: 644–652. and Saliba et al. Clin Transplant 2013; 27: E454–E461

5. MELD score > 30 was found to be the most influential factor, associated with more than a fourfold increase in relative risk of fungal infection compared with lower scores

9. Systemic antifungal versus placebo/nonabsorbable antifungal
Seven studies- four using fluconazole , one itraconazole , one L-AmB, and one three-arm study comparing placebo, L-AmB and fluconazole
All studies included all liver transplant recipients and therefore represented an approach of universal prophylaxis in the treatment groups.

10. Systemic antifungal prophylaxis resulted in a significant reduction in the odds for proven IFI (OR 0.37, 95% CI 0.19– 0.72, p = 0.003)

11. Prophylaxis also reduced the incidence of suspected and proven IFI, superficial fungal infection and fungal colonization
No difference in the incidence of adverse effects requiring cessation of study drug (OR 1.11,95% CI 0.48–2.55, p= 0.81).
Mortality due to fungal infection was significantly reduced with the use of systematic prophylaxis (OR 0.32, 95% CI 0.10–0.83 p =0.02)

12. Direct comparisons of antifungal agents- Fluconazole
It is the only drug with sufficient data for comparison with placebo in conventional meta-analysis
Fluconazole reduced the incidence of proven IFI (OR 0.24, 95% CI 0.11–0.52, p =0.0003).
Similar reductions were also seen in incidence of suspected IFI, fungal colonization and superficial fungal infections
Mortality due to fungal infection was significantly reduced in patients treated with fluconazole (OR 0.22, 95% CI 0.06–0.75, p = 0.016)

13. Impact of fluconazole on IFI aspergillus
The incidence of Aspergillus IFI was reported in seven studies.
There was no difference in the incidence of Aspergillus IFI in studies comparing any prophylaxis with placebo/nonabsorbable antifungal or in studies comparing fluconazole with placebo/nonabsorbable antifungal

15. Direct comparisons of antifungal agents- Amphotericin B
Only one study compared L-AmB prophylaxis to placebo demonstrating significant reductions in both proven and suspected IFIs with treatment.
Prophylaxis was given for 5 days
Drug was well tolerated
Cost analysis suggested a reduction in overall cost with L-AmB prophylaxis relating to the reduction in cost of treatment of fungal infections.

16. Fluconazole vs L-AmB
Three studies (202 patients) compared fluconazole and L-AmB in high-risk patients, demonstrating no difference in the risk of proven IFI (OR 1.02, 95% CI 0.46–2.23, p= 0.97)
Perrella et al showed a significantly higher risk of bacterial infection and longer intensive treatment unit (ITU) stay in the fluconazole group, and also greater variability in calcineurin inhibitor (CNI) exposure in this group
Perrella A, et al. Role of liposomal amphotericin B prophylaxis after liver transplantation compared with fluconazole for high-risk patients, impact on infections and mortality within one year. Transplant Proc 2012; 44: 1977–1981

17. Direct comparisons of antifungal agents-Itraconazole
Evidence – is limited (one study comparing a prolonged course of prophylaxis to placebo in unselected liver recipients .
Significant reduction in the incidence of fungal infection requiring treatment in the prophylaxis arm, with no difference in mortality or adverse events.
Two studies compared fluconazole with itraconazole
Winston et al demonstrated no difference between the two prophylactic strategies
Cai et al demonstrated a significant increase in the rate of fungal infection (clinical diagnosis,no tissue or mirobiological confirmation) with fluconazole when compared with itraconazole

19. Both L-AmB (OR 0. 21, 95% credible interval 0. 05–0
Both L-AmB (OR 0.21, 95% credible interval 0.05–0.71) and fluconazole (OR 0.21, 95% credible interval 0.06–0.57) significantly reduce the odds of IFI compared to placebo/no treatment
No statistically significant difference is seen between these two treatments, or between itraconazole and any other treatment/placebo

20. First study to report the efficacy and tolerability of VORI as prophylaxis in LT recipients
Less expensive than echinocandins and lipid amphotericin B formulations and
Oral administration
Less nephrotoxic than amphotericin B products
Broader -spectrum activity than FLU (covering moulds) or echinocandins (covering C. neoformans and certain non-Aspergillus moulds

21. Concerns are
Hepatotoxicity
Significant interactions with calcineurin inhibitors
Variable pharmacokinetics
Discontinued in three patients due to suspected hepatotoxicity, and in a single patient due to an interaction with tacrolimus.
Our study does not suggest that VORI is superior to any other prophylactic agent but can be used as prohphylaxis

22. Echinocandins
Echinocandins are antifungal drugs that inhibit the synthesis of glucan in the cell wall, via noncompetitive inhibition of the enzyme 1,3-β glucan synthase and are thus called "penicillin of antifungals
Caspofungin (Cancidas, by Merck)
Micafungin (Mycamine, by Astellas Pharma.)
Anidulafungin ( Eraxis, by Pfizer)

23. Broad efficacy against Candida species including those resistant to fluconazole, have a favorable safety profile and a low potential for drug interactions and are established first-line treatments for invasive candidiasis
Anidulafungin is unique among echinocandins in that it is eliminated almost exclusively via biotransformation by nonenzymatic degradation in the blood without hepatic or renal elimination

24. Micafungin vs fluconazole/L-AmB
The multicenter TENPIN study reported by Saliba et al
Randomized 347 high-risk recipients to micafungin 100 mg/day IV or standard care, which could be one of fluconazole, L-AmB or caspofungin, for 21 days
Study duration from 15 December 2009 to 3 May 2012 at 37 European centers

25. The full analysis set comprised 344 patients (172 micafungin; 172 standard care).
48.0% had a MELD score ≥20.
At EOP (mean treatment duration, 17 days), clinical success was 98.6% for micafungin and 99.3% for standard care in the per protocol set and 96.5% and 93.6%, respectively in the full analysis set.
Incidences of drug-related adverse events for micafungin and standard care were 11.6% and 16.3%, leading to discontinuation in 6.4% and 11.6% of cases, respectively

30. At EOP, liver function tests were similar but creatinine clearance was higher in micafungin- vs standard care–treated patients.
Micafungin was demonstrated to be noninferior to standard care for antifungal prophylaxis in liver transplant patients at high risk of IFI, with a similar overall safety profile but associated with better renal function throughout prophylaxis than standard care.
Micafungin also provides an additional prophylactic option, especially in patients with a high risk of infection by species resistant to current standard care, patients at risk of drug–drug interactions, or patients with renal impairment or receiving RRT

31. Anidulafungin Versus Fluconazole

32. Study period between February 2010 and November 2011.
Liver transplant patients ≥18 years of age who had one or more of the risk factors for IFI
Anidulafungin mg iv loading dose followed by 100 mg iv daily.
No adjustment of the anidulafungin dosage for renal failure.
Fluconazole mg intravenously daily.
The fluconazole dosage was adjusted for renal failure
The study contiued for 21 days
In patients with ongoing need for renal replacement therapy, persistent liver allograft dysfunction, continued ICU stay, or increased immunosuppression for rejection in the previous 21 days, study drug could be continued beyond 21 days for a maximum of 42 days.

33. 200 high-risk liver transplant recipients (100 patients per group) received either anidulafungin or fluconazole for antifungal prophylaxis.
Randomization was stratified by MELD >30 and receipt of a pretransplant antifungal agent.
The overall incidence of IFI was similar for the anidulafungin (5.1%) and the fluconazole groups (8.0%) (OR 0.61, 95% CI 0.19–1.94, p = 0.40).
Anidulafungin prophylaxis was associated with less Aspergillus colonization or infection (3% vs. 9%, p =0.08), lower breakthrough IFIs among patients who had received pretransplant fluconazole (0% vs. 27%, p =0.07), and fewer cases of antifungal resistance (no cases vs. 5 cases).

34. No significant difference in breakthrough IFIs among patients not receiving a systemic antifungal agent prior to transplantation (2 in 84 anidulafungin patients or 2.4% vs. 2 in 88 fluconazole patients or 2.3%, p = 0.96).
None of these IFIs were fatal, and there were no adverse effects of antifungal therapy
Both drugs were well-tolerated.
Fungal isolates (Candida species 8, Aspergillus species 1) from nine patients (fluconazole 6, anidulafungin 3) with IFIs were sensitive to anidulafungin
Three anidulafungin patients, who developed candidemia after completing days of prophylactic anidulafungin, had Candida isolates still sensitive to anidulafungin

36. Graft rejection, fungal-free survival, and mortality were similar for both groups
Adverse events leading to discontinuation of the study drug occurred in 1 (1%) of 98 patients in the anidulafungin group (prolonged QT interval) and in none of the 99 fluconazole patients (p = 0.99)
There were no deaths due to an IFI.
So , anidulafungin and fluconazole have similar efficacy for antifungal prophylaxis in most liver transplant recipients.
Anidulafungin may be beneficial if the patient has an increased risk for Aspergillus infection or received fluconazole before transplantation.

37. Caspofungin prophylaxis in 71 patients for 21 days achieved a successful treatment outcome (absence of proven IFI in the first 100 days posttransplant) in 88.7% of high-risk recipients.
No participants experienced clinical side effects
6 of the 71 patients developed drug related liver dysfunction requiring cessation of caspofungin

38. Two patients developed IFI: a Mucor and a Candida albicans surgical wound infections, respectively.
Eight patients died, six during caspofungin administration and two during follow-up period, but none were attributed to IFI or caspofungin toxicity.
These results show that caspofungin could be considered an efficacious and well-tolerated drug as antifungal prophylaxis in high-risk liver transplant recipients.

39. The efficacy and safety of targeted prophylaxis with micafungin or amphotericin B lipid complex (ABLC) in cohort of high-risk patients (posttransplantation dialysis, retransplantation, or reoperation) and compared with those without high risk who did not receive prophylaxis.
Invasive fungal infections developed in 11.1% (2 of 18) of micafungin recipients, 8.3% (2 of 24) of ABLC recipients, and 3% (7 of 234) of patients without high risks (P=0.12).

40. In nondialyzed patients, ABLC versus micafungin recipients had significantly higher serum creatinine on day 14 (P=0.04)
Renal and hepatic function, rejection, graft loss, and mortality did not differ for the two groups on day 90.
Targeted prophylaxis with micafungin or ABLC decreased the risk of mycoses in high-risk recipients compared with that in low-risk recipients
Compared with ABLC, however, micafungin appeared to be associated with lower early-renal dysfunction and no additional risk of hepatic dysfunction

41. Choice of Antifungal

42. Choice of antifungal- Fluconazole
Inhibit the cytochrome P450 system
Result in elevated levels of CNIs often requiring dose alteration
Dose dependent interaction
In two study doses of 100 or 200 mg did not affect CNI levels
Other two studies using mg fluconazole reported increases in levels of both cyclosporine and tacrolimus
To monitor CNI levels carefully and adjust doses accordingly
Fluconazole exhibits less activity against Aspergillus species
In a multicenter study by Neofytos et al, transplant recipients who received antifungal prophylaxis were more likely to be infected with triazole-resistant nonalbicans Candida species such as C.glabrata or C. krusei

43. Ampotericin B Does not have this interaction with CNIs,
Broader spectrum of activity with greater efficacy against Aspergillus species than fluconazole.
Nephrotoxicity and requires intravenous administration
Expensive when compared with fluconazole
Voriconazole- hepatotoxcity and drug interaction but oral,cheaper and broad spectrum

44. Echinocandins
Micafungin - in patients with a high risk of infection by species resistant to current standard care, patients at risk of drug–drug interactions, or patients with renal impairment or receiving RRT
Caspofungin - an efficacious and but drug related liver dysfunction is kept in mind
Anidulafungin similar efficacy as fluconazole and beneficial if the patient has an increased risk for Aspergillus infection or received fluconazole before transplantation.

45. Universal vs targeted prophylaxis
An increase in Candida krusei and Candida glabrata infections due to prophylactic fluconazole in some studies
Increasing number of reports of echinocandin resistant Candida infections
What should be antifungal prophylaxis in transplant recipients ?

48. Antifungal prophylaxis protocol
The universal prophylaxis group consisted of patients transplanted between November 1, and October 31, 2010, during which the standard practice was VORI 200 mg oral twice daily for all patients.
VORI was started within 1 day of transplant and continued for the duration of the immediate posttransplant ICU stay.
In November 2010, policy changed to targeted approach to antifungal prophylaxis .
The targeted prophylaxis group consisted of patients transplanted between November 1, 2010 and December 1, 2012.

49. a retrospective study of LT recipients who received targeted prophylaxis (n = 145; voriconazole [VORI; 54%], fluconazole [8%], no antifungal [38%]) versus universal VORI prophylaxis (n = 237).
Median durations of targeted and universal prophylaxis were and days, respectively(p < ).
The incidence of invasive fungal infections (IFIs) in targeted and universal groups was 6.9% and 4.2% (p =0.34).
Overall, intra-abdominal candidiasis (73%) was the most common IFI.
Posttransplant bile leaks (p = 0.001) and living donor transplants (p = 0.04) were independent risk factors for IFI.

51. IFIs occurred in 6% of high-risk transplants who received prophylaxis and 4% of low-risk transplants who did not receive prophylaxis (p = 1.0).
Mortality rates (100 days) were 10% (targeted) and 7% (universal) (p = 0.26); attributable mortality due to IFI was 10%
Compliance with prophylaxis recommendations was 97%.
Prophylaxis was discontinued for toxicity in 2% of patients.

52. Short course antifungal therapy -efficacious
The efficacy of short-course antifungal therapy in our universal prophylaxis group suggests that a duration of 30 days is unnecessary for a large proportion of patients.
We currently advocate an individualized approach, with antifungal regimens discontinued upon discharge from the ICU (as a marker of medical stability) and resolution of ongoing surgical complications.

53. Conclusion of the study
Targeted antifungal prophylaxis in LT recipients was feasible and safe, effectively prevented IFIs and reduced the number of patients exposed to antifun gals.
Bile leaks and living donor transplants should be considered high-risk indications for prophylaxis.

54. American Society of Transplantation (AST) and Infectious Diseases Society of America (IDSA)
Antifungal prophylaxis against Candida should be given to all adult liver transplant recipients at high risk for development of invasive candidiasis; i.e. those with ≥ 2 of the following risk factors:
Prolonged or repeat operation;
Retransplantation
Renal failure
High transfusion requirement, i.e.,transfusion of ≥ 40 units of cellular blood products includ ing platelets, packed red blood cells and auto transfusion;
Choledocho -jejunostomy
Candida colonization in the peri-operative period

55. American Society of Transplantation (AST) and Infectious Diseases Society of America (IDSA)
Does not recommend the use of systemic antifungal prophylaxis in low-risk recipients
Duration of prophylaxis is not clearly determined, and has ranged from 5 days to 10 weeks in clinical trials.
Duration of up to 4 weeks, or for the duration of persistent risk factors, seems reasonable

56. American Society of Transplantation (AST) and Infectious Diseases Society of America (IDSA)
Recommended drugs are-fluconazole and amphotericin B
Liver transplant recipients at risk for both candidiasis and aspergillosis should receive an agent with anti-Aspergillus activity.
Pappas et al . Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009; 48: 503–535

57. Survey of Antifungal prophylaxis in USA centers
Singh et al received responses from 67 of 106 centers in the USA
91% of whom used antifungal prophylaxis (28% of these centers - universal prophylaxis for all recipients, 72% -targeted prophylaxis to high-risk recipients
Fluconazole - most commonly used for universal and targeted prophylaxis.
The leading choice for mold-active agents for antifungal prophylaxis was the echinocandins.
Combination therapy was used as primary therapy for invasive aspergillosis in 47%, and as salvage in 80%
Duration of prophylaxis ranged from 2 weeks to 6 months.
Singh N et al . Antifungal management practices in liver transplant recipients. Am J Transplant 2008; 8: 426–431.

58. Survey of Antifungal prophylaxis in European centers
Vandecasteele et al received responses from 61 of 128 European centers enrolled in the ELITA group
88% used prophylaxis
35% as universal therapy
53% targeted to high-risk recipients
These surveys suggest that there is variation in the strategy of prophylaxis with respect to patient selection and duration
Vandecasteele et al. Antimicrobial prophylaxis in liver transplant patients—A multicenter survey endorsed by the European Liver and Intestine Transplant Association. Transpl Int 2010; 23: 182–190.

59. Antifungal Protocol
Fluconazole 400 mg OD universal prophylaxis x 14 days
Caspofungin for *high risk patients
Liposomal Amphotericin B for presumed Infection

60. High risk in our Protocal
Post transplantation re-exploration
Received steroids for more than 14 days within the 4 weeks preceding transplant
Needing ICU care for greater than 48 hours before the transplantation
Colonization with Candida species within 4 weeks preceding transplantation
Requirement of 15 or more units of packed red cell transfusions
Operative time > 14 hrs
Patient referred from other hospitals
Ventilated patient
ALF
If the patient has received multiple antibiotics before LT or need for IV antibiotics for >1week before LT
Exposure to carbapenems or azoles in the 2 weeks prior to LT
Retransplantation
Renal replacement therapy

61. Take home Message
Antifungal prophylaxis reduces the risk of IFI and mortality from fungal infection in liver transplant recipients
Targeted prohylaxis in high risk group
L-AmB and fluconazole recommended drugs by ATS and IDSA
Fluconazole is the most commonly used drugs
Echinocandins are new group of drugs used in prophlaxix
MELD>30 , Bile leak and LDLT are newly identified high risk group for IFI
Duration of prophylaxix-variable