Transcript Infections in Liver Transplant Recipients

Antifungal Prophylaxis in Solid
Organ Transplant Recipients:
Seeking Clarity Amidst Controversy
Nina Singh, M.D.
Rationalizing antifungal
prophylaxis and strategies
 Diversity
in the incidence of
fungal infections
 Risk
of dissemination
 Predilection
towards specific
pathogen
 Time
of onset
 Which
solid organ transplant
groups should receive
prophylaxis?
 Who are the high-risk patients?
 Against which pathogens should
prophylaxis be directed?
 When should prophylaxis be
administered and for how long?
Frequency of major fungal infections in
organ transplant recipients
Renal
Heart
Liver
Lung and heart-lung
Small-bowel
Pancreas
Incidence of
invasive fungal Infections due
infections*
to Aspergillus
Infections due
to Candida
1.4 - 14%
5 - 21%
7 - 42%
15 - 35%
40 - 59%
18 - 38%
2.0 - 100%
8 - 23%
35 -91%
43 - 72%
80 - 100%
97 - 100%
0 - 10%
77 - 91%
9 - 34%
25 - 50%
0 - 3.6%
0 - 3%
Type of
transplant
IA ,%
range (mean)
Disseminated
aspergillosis, %
Mortality
rate, %
Liver
1-8 (2)
50-60
92
Lung
3-14 (6)
15-20
74
Heart
1-15 (5.2)
20-35
78
Kidney
0.9 - 0 4 (.7)
9-36
77
Pancreas
1.1 - 2.9 (1.3)
NA
100
Small bowel
0 - 3.6% (2.2)
NA
100
Risk factors for invasive aspergillosis in liver
transplant recipents

Poor allograft function

Renal failure, particularly requirement
of dialysis
Fisher et al., J Antimicrob Chemother, 99
Breigel et al., EJ Clin Micro Infect Dis, 95
Singh et al., Transplantation, 97



Allograft dysfunction in 26/26 patients
with IA; median serum bilirubin, 21.8
mg/dl
Fulminant hepatic failure (21% had IA)
Retransplantation (27% of the IA cases)
Sampathkumar, Transplantation 99
Singh, Transplantation 97

54-92% of the patients, with IA have
been on dialysis
Fisher, 99; Singh, 97; Selby 97

Renal failure and OKT3 use were
independently significant risk factors
Kusne, 92

OKT3 use no longer a significant risk
factor
1981-1990, 70% of IA patients
received OKT3
1990-1996, 8% of IA patients
received OKT3

CMV not a risk factor
Patel 98, Singh 97
Liposomal AmB for Prophylaxis
Invasive fungal
infections
No prophylaxis
Prophylaxis
(dialyzed cohort
before 1997)
(Dialyzed
cohort since
1997)
36% (8/22)
0% (0/11)
p = .03, prophylaxis independently protective (p = .017)
Singh et al, Transplantation 01

Retransplantation,dialysis, prophylaxis for SBP, CMV
viremia, and return to surgery

Risk with <1 factor present 10.3% (0.R. , 1.0)
Risk with 1 factors present 25% (O.R., 2.9)
Risk with 2 factors present 61.1% (O.R., 136)
Risk with 3 factors present 87.5%(O.R., 60.7)
Risk with 4 factors present 100%
Chi-square for trend p = .001
Hussain et al, ICAAC 01
Thrombocytopenia and Infections after
Liver Transplantation
Nadir
< 30x103/cmm
Nadir
>30x103/cmm
Early major infections
43%
17%
p =.046
CMV infection
14%
10%
p > .1
Bacterial infections
38%
21%
p > .1
Fungal infections
15%
0%
p = .06
Chang, et al., Transplantation, 2000
Aspergillus Infections after
Liver Transplantation

Median time to onset 15 - 17 days

81 - 100% of the patients still in ICU
Selby, 97; Fisher, 99
Extrapulmonary Spread of
Aspergillus
Liver transplant recipients
92% (11/12)
Hematologic patients
30% (6/16)
Non-liver transplant
recipients
p < 0.02
45% (9/20)
Boon, et al., J Clin Pathol, 90
Aspergillus Infections in Lung Transplant
Recipients: Unique Characteristics
 Transplanted
organ is in direct
communication with the
environment
 Bronchial
anastomosis uniquely
susceptible to infection with
Aspergillus
Frequency of Aspergillus
Colonization and Infection

Isolation of Aspergillus in
respiratory samples
29% (580/2,001),
range 9-68%

Aspergillus airway
colonization
23% (219/969)

Isolated tracheobronchitis
4% (35/615)

Invasive aspergillosis
6% (85/1,542)
Aspergillus colonization portends a
higher risk for subsequent infection

17% (3/18) vs. 1.5% (2/133), p < .05
Cahill, Chest 97

29% (4/14) vs. 1.7% (1/57), p = .004
Husni, Clin Infect Dis 98

Invasive disease almost exclusively due
to Aspergillus fumigatus
Cahill, Chest 97
Other Risk Factors

CMV Infection

Obliterative bronchitis

Rejection and augmented
immunosuppression
Paradowski, 97; Husni 98; Scott 91; Tazelaar 89
Median time to onset
120 days
Infections within 3 months 49%
Infections within 6 months 68%
Infections within 9 months 79%
Aspergillus Infections in Other Solid
Organ Transplant Recipients

Heart transplants, overall
frequency 5.2% (102/1,948),
range 1 to 15%

Rare in kidney and pancreas
transplant recipients
Risk factors for Invasive
Candidiasis
Odds ratio (95% C.I.)
P-value
CMV infection
3.0 (1.2 - 7.32)
.03
Prophylaxis for SBP
11.0 (3.0 - 33.8)
.007
Retransplantation
11.0 (3.2 - 36.4)
.0003
Posttransplant dialysis 8.0 (3.1 - 20.0)
Hussain et al, ICAAC 01
.0001
Invasive Candidiasis in Liver Transplant
Recipients in the Current Era



Over one-third of the infections due to nonalbicans Candida spp.
Prior antifungal prophylaxis the only riskfactor for non-albicans Candida
Mortality 25 fold higher for cases than for
controls (p = .0002); 58% for non-albicans, and
22.7% for albicans infections
Husain et al, ICAAC 01

Aspergillus in respiratory samples is
virtually always indicative of invasive
disease.

Prophylactic antifungal agent must
rapidly be able to achieve systemic
drug levels considered adequate for
activity against Aspergillus.
Unconvincing Efficacy For
 Itraconazole
 Low-dose
amphotericin B
(.1 to .5 mg/kg/d)
Itraconazole Cyclodextrin for Prophylaxis in
Liver Transplant Recipients
Itraconazole
Solution
(n = 24)
Invasive candidiasis
Invasive aspergillosis
Colby et al., ICAAC, 99
4% (1/24)
p = .049
0/24
Placebo
(n = 37)
24% (9/37)
0/37
Nephrotoxicity of Amphotericin B in
Solid Organ Transplant Recipients
Increase in creatinine
to >2.5 mg/dL
36% (15/42)
Dialysis required
18% (10/55)
Wingard et al, Clin Infect Dis ,1999
Cost
LAmB > ABLC > ABCD > AmB
($698) ($231) ($194) ($6)
Infusion ABCD > ABLC > LAmB
related
toxicity
Ambisome (1 mg/kg/d for 7 days)
Invasive fungal infections
Invasive aspergillosis
Invasive candidiasis
Lorf et al, Mycoses, 99
7% (4/58)
3
1
Recommendations for prophylaxis for
aspergillosis in liver transplant recipients
Approach
High-risk
population
Targeted
Poorly functioning allograft,
e.g., PNF, fulminant
hepatic failure, retransplant
recipients, dialysis

Suggested
antifungal agents
Liposomal preparation of
AmB (3-5 mg/Kg/d)

Proposed duration
4 weeks



Less nephrotoxic

Equivalent or superior efficacy against invasive
mycelial infections
(Leenders, B J Hem 98, White, Clin Infect Dis 97, Linden,
Transplantation 99)

Higher achievable tissue concentrations (17 to 78 times
higher lung concentration) with ABLC
(Williams, Transplantation 99)

Animal data supportive of decreased dissemination and
increased survival
(Leenders, J Antimicrob Chemother 96)
Aerosolized AmB for fungal infections in
lung, heart-lung, and heart transplants
Incidence of
aspergillosis
(3 months)
Incidence of
aspergillosis
(12 months)
AmB (126)
0
2%
Control (101)
11%
p < .05
12%
p < .005
Reichenspurner, Transplant Proceed 97
Recommendations for prophylaxis for
lung transplant recipients

Approach
Targeted

High-risk
population
Positive Aspergillus airway culture,
particularly in patients with rejection,
obliterative bronchitis and CMV

Antifungal
agent
Itraconazole, with or without
aerosolized amphotericin B

Suggested
duration
4 to 6 months (or until bronchial
anastomosis has healed)
Fluconazole in liver transplant
recipients
Fluconazole
400 mg/dx10 wks
(n = 108)
Placebo
(n = 104)
Fungal infections
9%
43%
Invasive fungal
infections
6%
23%
Invasive candidiasis
5.5%
19%
Winston et al, Ann Intern Med 99
Recommendations for invasive
candidiasis in transplant recipients

Type of organ
transplant
Liver
Pancreas

Approach
Targeted
Targeted

High-risk group
Retransplantation Enteric drainage,
dialysis,
retroperitoneal
SBP prophylaxis
graft placement,
OR time > 8 hours

Suggested duration 4 weeks
4 weeks
Principles of Prophylaxis

Antifungal strategies should be targeted
towards high-risk patients and should not be
universal

All modifiable risk factors should be corrected
before considering prophylaxis

Must limit the duration of prophylaxis

Identify specific markers that predict infection
Dialyzed
patients
(n=22)
All other
patients
(n=126)
36% (8/22)
7% (9/126)
p = .0007
Invasive
14% (3/22)
aspergillosis
2% (2/126)
p = .02
Fungal
infections
Singh et al, ICAAC 00
Dialyzed
patients
(n=22)
All other
patients
(n=126)
36% (8/22)
7% (9/126)
p = .0007
Invasive
14% (3/22)
aspergillosis
2% (2/126)
p = .02
Fungal
infections
Singh et al, Transplantation 01
Dialyzed cohort
Invasive
fungal
infections
Dialyzed cohort
prior to 1997
since 1997
(antifungal
(no prophylaxis)
prophylaxis)
36% (8/22)
0% (0/11)
p = .03
Antifungal prophylaxis was independently protective from fungal
infection (p=.017) (Singh et al, Transplantation 01)
Singh.ppt
file: Prophylaxis
1/28/02