antifungal prophylaxis in solid organ transplant recipients: seeking clarity amidst controversy nina...
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Antifungal Prophylaxis in Solid Antifungal Prophylaxis in Solid Organ Transplant Recipients: Organ Transplant Recipients:
Seeking Clarity Amidst ControversySeeking Clarity Amidst Controversy
Nina Singh, M.D.Nina Singh, M.D.
Rationalizing antifungal Rationalizing antifungal prophylaxis and strategiesprophylaxis and strategies
Diversity in the incidence of Diversity in the incidence of fungal infectionsfungal infections
Risk of disseminationRisk of dissemination
Predilection towards specific Predilection towards specific pathogenpathogen
Time of onsetTime of onset
Which solid organ transplant Which solid organ transplant groups should receive groups should receive prophylaxis?prophylaxis?
Who are the high-risk patients?Who are the high-risk patients? Against which pathogens should Against which pathogens should
prophylaxis be directed?prophylaxis be directed? When should prophylaxis be When should prophylaxis be
administered and for how long?administered and for how long?
Frequency of major fungal infections in Frequency of major fungal infections in organ transplant recipientsorgan transplant recipients
Incidence ofIncidence of
invasive fungalinvasive fungal Infections due Infections due Infections due Infections due
infections*infections* to to AspergillusAspergillus to to CandidaCandida
RenalRenal 1.4 - 14%1.4 - 14% 0 - 10%0 - 10% 2.0 - 100%2.0 - 100%
HeartHeart 5 - 21%5 - 21% 77 - 91%77 - 91% 8 - 23%8 - 23%
LiverLiver 7 - 42%7 - 42% 9 - 34%9 - 34% 35 -91%35 -91%
Lung and heart-lungLung and heart-lung 15 - 35%15 - 35% 25 - 50%25 - 50% 43 - 72%43 - 72%
Small-bowelSmall-bowel 40 - 59%40 - 59% 0 - 3.6%0 - 3.6% 80 - 100%80 - 100%
PancreasPancreas 18 - 38%18 - 38% 0 - 3%0 - 3% 97 - 100%97 - 100%
Type ofType of IA ,%IA ,% DisseminatedDisseminated MortalityMortality
transplanttransplant range (mean)range (mean) aspergillosis, %aspergillosis, % rate, %rate, %
LiverLiver 1-8 (2)1-8 (2) 50-6050-60 9292
LungLung 3-14 (6)3-14 (6) 15-2015-20 7474
HeartHeart 1-15 (5.2)1-15 (5.2) 20-3520-35 7878
KidneyKidney 0.9 - 0 4 (.7)0.9 - 0 4 (.7) 9-369-36 7777
PancreasPancreas 1.1 - 2.9 (1.3)1.1 - 2.9 (1.3) NANA 100100
Small bowelSmall bowel 0 - 3.6% (2.2)0 - 3.6% (2.2) NANA 100100
Risk factors for invasive aspergillosis in liver Risk factors for invasive aspergillosis in liver transplant recipentstransplant recipents
Poor allograft functionPoor allograft function
Renal failure, particularly requirement Renal failure, particularly requirement of dialysisof dialysis
Fisher et al., J Antimicrob Chemother, 99Fisher et al., J Antimicrob Chemother, 99
Breigel et al., EJ Clin Micro Infect Dis, 95Breigel et al., EJ Clin Micro Infect Dis, 95
Singh et al., Transplantation, 97Singh et al., Transplantation, 97
Allograft dysfunction in 26/26 patients Allograft dysfunction in 26/26 patients with IA; median serum bilirubin, 21.8 with IA; median serum bilirubin, 21.8 mg/dlmg/dl
Fulminant hepatic failure (21% had IA)Fulminant hepatic failure (21% had IA) Retransplantation (27% of the IA cases)Retransplantation (27% of the IA cases)
Sampathkumar, Transplantation 99Sampathkumar, Transplantation 99
Singh, Transplantation 97Singh, Transplantation 97
54-92% of the patients, with IA have 54-92% of the patients, with IA have been on dialysisbeen on dialysis
Fisher, 99; Singh, 97; Selby 97Fisher, 99; Singh, 97; Selby 97
Renal failure and OKT3 use were Renal failure and OKT3 use were independently significant risk factorsindependently significant risk factors
Kusne, 92Kusne, 92
OKT3 use no longer a significant risk OKT3 use no longer a significant risk factorfactor
1981-1990, 70% of IA patients 1981-1990, 70% of IA patients received OKT3received OKT3
1990-1996, 8% of IA patients 1990-1996, 8% of IA patients received OKT3 received OKT3
CMV not a risk factorCMV not a risk factor
Patel 98, Singh 97Patel 98, Singh 97
Liposomal AmB for ProphylaxisLiposomal AmB for Prophylaxis
No prophylaxisNo prophylaxis Prophylaxis Prophylaxis
(dialyzed cohort(dialyzed cohort (Dialyzed (Dialyzed
before 1997)before 1997) cohort since cohort since
1997)1997)
Invasive fungalInvasive fungal 36% (8/22)36% (8/22) 0% (0/11)0% (0/11)
infectionsinfections
p = .03, prophylaxis independently protective (p = .017)p = .03, prophylaxis independently protective (p = .017)
Singh et al, Transplantation 01Singh et al, Transplantation 01
Retransplantation,dialysis, prophylaxis for SBP, CMV Retransplantation,dialysis, prophylaxis for SBP, CMV viremia, and return to surgeryviremia, and return to surgery
Risk with <1 factor present 10.3% (0.R. , 1.0)Risk with <1 factor present 10.3% (0.R. , 1.0)
Risk with 1 factors present 25% (O.R., 2.9)Risk with 1 factors present 25% (O.R., 2.9)
Risk with 2 factors present 61.1% (O.R., 136)Risk with 2 factors present 61.1% (O.R., 136)
Risk with 3 factors present 87.5%(O.R., 60.7)Risk with 3 factors present 87.5%(O.R., 60.7)
Risk with 4 factors present 100%Risk with 4 factors present 100%
Chi-square for trend p = .001Chi-square for trend p = .001
Hussain et al, ICAAC 01Hussain et al, ICAAC 01
Thrombocytopenia and Infections after Thrombocytopenia and Infections after Liver TransplantationLiver Transplantation
NadirNadir Nadir Nadir
<< 30x10 30x1033/cmm/cmm >30x10>30x1033/cmm/cmm
Early major infectionsEarly major infections 43%43% 17%17% p =.046 p =.046
CMV infectionCMV infection 14%14% 10%10% p > .1 p > .1
Bacterial infectionsBacterial infections 38%38% 21% 21% p > .1 p > .1
Fungal infectionsFungal infections 15%15% 0% 0% p = .06 p = .06
Chang, et al., Transplantation, 2000Chang, et al., Transplantation, 2000
AspergillusAspergillus Infections after Infections after Liver TransplantationLiver Transplantation
Median time to onset 15 - 17 daysMedian time to onset 15 - 17 days
81 - 100% of the patients still in ICU81 - 100% of the patients still in ICU
Selby, 97; Fisher, 99Selby, 97; Fisher, 99
Extrapulmonary Spread of Extrapulmonary Spread of AspergillusAspergillus
Liver transplant recipientsLiver transplant recipients 92% (11/12)92% (11/12)
Hematologic patientsHematologic patients 30% (6/16)30% (6/16)
Non-liver transplantNon-liver transplant 45% (9/20)45% (9/20)
recipientsrecipients
p < 0.02p < 0.02
Boon, et al., J Clin Pathol, 90Boon, et al., J Clin Pathol, 90
Aspergillus Aspergillus Infections in Lung Transplant Infections in Lung Transplant Recipients: Unique CharacteristicsRecipients: Unique Characteristics
Transplanted organ is in direct Transplanted organ is in direct communication with the communication with the environmentenvironment
Bronchial anastomosis uniquely Bronchial anastomosis uniquely susceptible to infection with susceptible to infection with AspergillusAspergillus
Frequency of Frequency of AspergillusAspergillus Colonization and InfectionColonization and Infection
Isolation ofIsolation of Aspergillus Aspergillus in in 29% (580/2,001),29% (580/2,001),
respiratory samplesrespiratory samples range 9-68%range 9-68%
AspergilluAspergillus airways airway 23% (219/969)23% (219/969)
colonizationcolonization
Isolated tracheobronchitisIsolated tracheobronchitis 4% (35/615)4% (35/615)
Invasive aspergillosisInvasive aspergillosis 6% (85/1,542)6% (85/1,542)
AspergillusAspergillus colonization portends a colonization portends a higher risk for subsequent infectionhigher risk for subsequent infection
17% (3/18) vs. 1.5% (2/133), p < .05 17% (3/18) vs. 1.5% (2/133), p < .05
Cahill, Chest 97Cahill, Chest 97
29% (4/14) vs. 1.7% (1/57), p = .00429% (4/14) vs. 1.7% (1/57), p = .004
Husni, Clin Infect Dis 98Husni, Clin Infect Dis 98
Invasive disease almost exclusively due Invasive disease almost exclusively due to to Aspergillus fumigatusAspergillus fumigatus
Cahill, Chest 97Cahill, Chest 97
Other Risk FactorsOther Risk Factors
CMV InfectionCMV Infection
Obliterative bronchitisObliterative bronchitis
Rejection and augmented Rejection and augmented immunosuppressionimmunosuppression
Paradowski, 97; Husni 98; Scott 91; Tazelaar 89Paradowski, 97; Husni 98; Scott 91; Tazelaar 89
Median time to onsetMedian time to onset 120 days120 days
Infections within 3 monthsInfections within 3 months 49%49%
Infections within 6 monthsInfections within 6 months 68%68%
Infections within 9 monthsInfections within 9 months 79%79%
Aspergillus Infections in Other Solid Aspergillus Infections in Other Solid Organ Transplant RecipientsOrgan Transplant Recipients
Heart transplants, overall Heart transplants, overall frequency 5.2% (102/1,948), frequency 5.2% (102/1,948), range 1 to 15%range 1 to 15%
Rare in kidney and pancreas Rare in kidney and pancreas transplant recipientstransplant recipients
Risk factors for Invasive Risk factors for Invasive CandidiasisCandidiasis
Odds ratio (95% C.I.)Odds ratio (95% C.I.) P-valueP-value
CMV infectionCMV infection 3.0 (1.2 - 7.32)3.0 (1.2 - 7.32) .03.03
Prophylaxis for SBPProphylaxis for SBP 11.0 (3.0 - 33.8)11.0 (3.0 - 33.8) .007.007
RetransplantationRetransplantation 11.0 (3.2 - 36.4)11.0 (3.2 - 36.4) .0003.0003
Posttransplant dialysisPosttransplant dialysis 8.0 (3.1 - 20.0)8.0 (3.1 - 20.0) .0001.0001
Hussain et al, ICAAC 01Hussain et al, ICAAC 01
Invasive Candidiasis in Liver Transplant Invasive Candidiasis in Liver Transplant Recipients in the Current EraRecipients in the Current Era
Over one-third of the infections due to non-Over one-third of the infections due to non-albicansalbicans CandidaCandida spp. spp.
Prior antifungal prophylaxis the only risk-Prior antifungal prophylaxis the only risk-factor for non-factor for non-albicansalbicans CandidaCandida
Mortality 25 fold higher for cases than for Mortality 25 fold higher for cases than for controls (p = .0002); 58% for non-controls (p = .0002); 58% for non-albicansalbicans, and , and 22.7% for 22.7% for albicans albicans infectionsinfections
Husain et al, ICAAC 01Husain et al, ICAAC 01
AspergillusAspergillus in respiratory samples is in respiratory samples is virtually always indicative of invasive virtually always indicative of invasive disease.disease.
Prophylactic antifungal agent must Prophylactic antifungal agent must rapidly be able to achieve systemic rapidly be able to achieve systemic drug levels considered adequate for drug levels considered adequate for activity against activity against Aspergillus.Aspergillus.
Unconvincing Efficacy ForUnconvincing Efficacy For
ItraconazoleItraconazole
Low-dose amphotericin BLow-dose amphotericin B
(.1 to .5 mg/kg/d)(.1 to .5 mg/kg/d)
Itraconazole Cyclodextrin for Prophylaxis in Itraconazole Cyclodextrin for Prophylaxis in Liver Transplant RecipientsLiver Transplant Recipients
Itraconazole Itraconazole
SolutionSolution PlaceboPlacebo
(n = 24)(n = 24) (n = 37)(n = 37)
Invasive candidiasisInvasive candidiasis 4% (1/24)4% (1/24) 24% (9/37) 24% (9/37)
p = .049p = .049
Invasive aspergillosisInvasive aspergillosis 0/240/24 0/370/37
Colby et al., ICAAC, 99Colby et al., ICAAC, 99
Nephrotoxicity of Amphotericin B in Nephrotoxicity of Amphotericin B in Solid Organ Transplant RecipientsSolid Organ Transplant Recipients
Increase in creatinineIncrease in creatinine 36% (15/42)36% (15/42)
to >2.5 mg/dLto >2.5 mg/dL
Dialysis requiredDialysis required 18% (10/55)18% (10/55)
Wingard et al, Clin Infect Dis ,1999Wingard et al, Clin Infect Dis ,1999
CostCost LAmB > ABLC > ABCD > AmBLAmB > ABLC > ABCD > AmB
($698) ($231) ($194) ($6)($698) ($231) ($194) ($6)
Infusion Infusion ABCD > ABLC > LAmBABCD > ABLC > LAmB
relatedrelated
toxicitytoxicity
Ambisome (1 mg/kg/d for 7 days)Ambisome (1 mg/kg/d for 7 days)
Invasive fungal infectionsInvasive fungal infections 7% (4/58)7% (4/58)
Invasive aspergillosisInvasive aspergillosis 33
Invasive candidiasisInvasive candidiasis 11
Lorf et al, Mycoses, 99Lorf et al, Mycoses, 99
Recommendations for prophylaxis for Recommendations for prophylaxis for aspergillosis in liver transplant recipientsaspergillosis in liver transplant recipients
ApproachApproach TargetedTargeted High-riskHigh-risk Poorly functioning allograft,Poorly functioning allograft,
populationpopulation e.g., PNF, fulminant e.g., PNF, fulminant
hepatic failure, retransplanthepatic failure, retransplant
recipients, dialysisrecipients, dialysis
Suggested Suggested Liposomal preparation ofLiposomal preparation of
antifungal agentsantifungal agents AmB (3-5 mg/Kg/d)AmB (3-5 mg/Kg/d)
Proposed durationProposed duration 4 weeks4 weeks
Less nephrotoxicLess nephrotoxic
Equivalent or superior efficacy against invasive mycelial Equivalent or superior efficacy against invasive mycelial infectionsinfections(Leenders, B J Hem 98, White, Clin Infect Dis 97, Linden, (Leenders, B J Hem 98, White, Clin Infect Dis 97, Linden, Transplantation 99)Transplantation 99)
Higher achievable tissue concentrations (17 to 78 times Higher achievable tissue concentrations (17 to 78 times higher lung concentration) with ABLChigher lung concentration) with ABLC
(Williams, Transplantation 99)(Williams, Transplantation 99)
Animal data supportive of decreased dissemination and Animal data supportive of decreased dissemination and increased survivalincreased survival
(Leenders, J Antimicrob Chemother 96)(Leenders, J Antimicrob Chemother 96)
Aerosolized AmB for fungal infections in Aerosolized AmB for fungal infections in lung, heart-lung, and heart transplantslung, heart-lung, and heart transplants
Incidence ofIncidence of Incidence ofIncidence of
aspergillosis aspergillosis aspergillosisaspergillosis
(3 months)(3 months) (12 months) (12 months)
AmB (126)AmB (126) 00 2%2%
Control (101)Control (101) 11%11% 12%12%
p < .05p < .05 p < .005p < .005
Reichenspurner, Transplant Proceed 97Reichenspurner, Transplant Proceed 97
Recommendations for prophylaxis for Recommendations for prophylaxis for lung transplant recipientslung transplant recipients
ApproachApproach TargetedTargeted
High-riskHigh-risk Positive Positive AspergillusAspergillus airway culture, airway culture,
populationpopulation particularly in patients with rejection, particularly in patients with rejection,
obliterative bronchitis and CMVobliterative bronchitis and CMV
AntifungalAntifungal Itraconazole, with or withoutItraconazole, with or without
agentagent aerosolized amphotericin B aerosolized amphotericin B
SuggestedSuggested 4 to 6 months (or until bronchial4 to 6 months (or until bronchial
durationduration anastomosis has healed)anastomosis has healed)
Fluconazole in liver transplant Fluconazole in liver transplant recipientsrecipients
FluconazoleFluconazole
400 mg/dx10 wks400 mg/dx10 wks PlaceboPlacebo
(n = 108)(n = 108) (n = 104)(n = 104)
Fungal infectionsFungal infections 9%9% 43%43%
Invasive fungalInvasive fungal 6%6% 23%23% infectionsinfections
Invasive candidiasisInvasive candidiasis 5.5%5.5% 19%19%
Winston et al, Ann Intern Med 99Winston et al, Ann Intern Med 99
Recommendations for invasive Recommendations for invasive candidiasis in transplant recipientscandidiasis in transplant recipients
Type of organType of organ Liver Liver PancreasPancreas
transplanttransplant
ApproachApproach TargetedTargeted TargetedTargeted
High-risk groupHigh-risk group RetransplantationRetransplantation Enteric Enteric drainage,drainage, dialysis, dialysis, retroperitonealretroperitoneal
SBP prophylaxisSBP prophylaxis graft graft placement,placement,
OR time > 8 OR time > 8 hours hours
Suggested durationSuggested duration 4 weeks4 weeks 4 weeks4 weeks
Principles of ProphylaxisPrinciples of Prophylaxis
Antifungal strategies should be targeted Antifungal strategies should be targeted towardstowards high-risk patients and should not be high-risk patients and should not be universaluniversal
All modifiable risk factors should be corrected All modifiable risk factors should be corrected before considering prophylaxisbefore considering prophylaxis
Must limit the duration of prophylaxisMust limit the duration of prophylaxis
Identify specific markers that predict infectionIdentify specific markers that predict infection
DialyzedDialyzed All otherAll other
patientspatients patientspatients
(n=22)(n=22) (n=126) (n=126)
Fungal Fungal 36% (8/22)36% (8/22) 7% (9/126)7% (9/126) p p = .0007= .0007
infectionsinfections
Invasive Invasive 14% (3/22)14% (3/22) 2% (2/126)2% (2/126) p = .02p = .02
aspergillosisaspergillosis
Singh et al, ICAAC 00Singh et al, ICAAC 00
DialyzedDialyzed All otherAll other
patientspatients patientspatients
(n=22)(n=22) (n=126) (n=126)
Fungal Fungal 36% (8/22)36% (8/22) 7% (9/126)7% (9/126) p p = .0007= .0007
infectionsinfections
Invasive Invasive 14% (3/22)14% (3/22) 2% (2/126)2% (2/126) p = .02p = .02
aspergillosisaspergillosis
Singh et al, Transplantation 01Singh et al, Transplantation 01
Dialyzed cohortDialyzed cohort
Dialyzed cohortDialyzed cohort since 1997 since 1997
prior to 1997prior to 1997 (antifungal(antifungal
(no prophylaxis)(no prophylaxis) prophylaxis) prophylaxis)
Invasive Invasive 36% (8/22)36% (8/22) 0% (0/11)0% (0/11) p = .03p = .03
fungalfungal
infectionsinfections
Antifungal prophylaxis was independently protective from fungal Antifungal prophylaxis was independently protective from fungal infection (p=.017) (infection (p=.017) (Singh et al, Transplantation 01Singh et al, Transplantation 01))
Singh.pptSingh.ppt
file: Prophylaxisfile: Prophylaxis
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