Effect of Sirolimus on Infection Incidence in LiverTransplant Recipients

Adrian Fisher, Joseph M. Seguel, Andrew N. de la Torre, Dorian Wilson,Anand Merchant, Rakesh K. Arora, and Baburao Koneru

Sirolimus is a new immunosuppressive agent that lacksthe nephrotoxicity and neurotoxicity associated with cal-cineurin inhibitors.1–3 The addition of sirolimus toimmunosuppressive protocols may thus allow sparing ofcalcineurin inhibitors and reduction or elimination ofassociated toxicities.1,6 Between January 2000 and July2001, sirolimus was administered to 55 of 116 consecutiveliver recipients. The remaining 61 patients served as thecomparison group in the retrospective analysis. In thesirolimus group, perioperative steroids were reduced, andcalcineurin inhibitor initiation was delayed. All infectiousepisodes that occurred within 60 days of liver transplan-tation were evaluated but were limited to 1 per patient forstatistical analysis of sepsis. Demographic variables werecomparable between groups. Patients receiving sirolimusexperienced more infection (47.2% vs. 18.03%,P<0.001), and this effect persisted across high and lowdosage ranges and sirolimus levels. A trend towardincreased length of stay was noted (P�0.07). No differ-ence between groups was found in acute rejection rates(17.5% vs. 22.5%), 1-year graft (81% vs. 89%), patientsurvival (86% vs. 89%), or hepatic artery thrombosis. Inconclusion, despite reduction of other immunosuppres-sants, patients receiving even low doses of sirolimus expe-rienced increased sepsis rates. This agent may have greaterusefulness for patients with threatened renal function orpatients with chronic rejection after wound healing hasoccurred. (Liver Transpl 2004;10:193–198.)

Introduction

The availability of new immunosuppressant agentsover the last several years has allowed the consid-

eration of calcineurin inhibitor (CI) and steroid sparingor avoidance in liver transplant recipients. AlthoughCI’s are very effective in preventing rejection, theseagents continue to cause serious nephrotoxicity andneurotoxicity in many patients. Other CI adverseeffects include diabetes, gastrointestinal toxicity, hyper-lipidemia, and, occasionally, hepatotoxicity. Steroidcomplications are well described and include osteopo-rosis, hypertension, mood changes, diabetes, obesity,and inhibition of wound healing.

Sirolimus is a new immunosuppressive agent with adifferent mechanism of action than CI, steroids, myco-phenolate mofetil (MMF), or azathioprine.1–3 Siroli-mus lacks the neurotoxicity and nephrotoxicity associ-ated with CI use.1,2,4,5 It also appears to actsynergistically with CI.1,6 After sirolimus demonstratedefficacy in renal transplantation, we reasoned that intro-

ducing it immediately after liver transplantation (LTX)would allow delayed introduction of CI and reduced CIdosage when initiated and, therefore, result in lessnephrotoxicity and neurotoxicity in our patient popu-lation, particularly in the immediate postoperativeperiod. We also hypothesized that concomitant reduc-tion in perioperative steroid use would be toleratedwithout increasing rates of allograft rejection. As ourpatient population becomes older and sicker and man-ifests more renal dysfunction, attempts to reduce CIand steroid induced toxicities appear eminently reason-able. Watson et al. reported use of sirolimus in conjunc-tion with CI in 15 liver transplant patients and foundacceptable rejection rates and toxicity profiles.7 Simi-larly, Trotter et al. demonstrated lower acute rejectionrates and good tolerance of sirolimus in 39 liver trans-plant recipients.8

In early 2000, sirolimus was added to our immuno-suppressive regimens, initially for patients at high riskof CI toxicity: elderly patients, high Child-Turcotte-Pugh (CTP) status patients (2A and very ill 2Bpatients), patients in fulminant hepatic failure, andthose with pretransplant acute or chronic renal insuffi-ciency. Its use was expanded over the succeeding 18months to include routine patients. We provide here aretrospective analysis of our sirolimus use in the first 55patients who received this agent in a consecutive cohortof 116 liver allograft recipients.

Abbreviations: CI, calcineurin inhibitor; MMF, mycophenolatemofetil; CTP, Child-Turcotte-Pugh; LTX, liver transplantation;CMV, cytomegalovirus; BMI, body mass index; UNOS, United Net-work for Organ Sharing; MELD, Model for End-Stage Liver Disease;LOS, length of stay; IL-2, interleukin-2; CIT, cold ischemia time;WIT, warm ischemia time; q.o.d., every other day.

From the Division of Transplant Surgery, Department of Surgery,New Jersey Medical School–University Hospital, Newark, NJ 07103.

Address reprint requests to Adrian Fisher, M.D., University HospitalRoom E 350, 150 Bergen Street, PO Box 1709, Newark, NJ 07103-1709. Telephone: 973-972-7218; FAX: 973-972-6227; E-mail:fisherad@umdnj.edu.

Copyright © 2004 by the American Association for the Study ofLiver Diseases

Published online in Wiley InterScience (www.interscience.wiley.com).DOI 10.1002/lt.20072

193Liver Transplantation, Vol 10, No 2 (February), 2004: pp 193–198

Methods

A retrospective review was performed of a consecutive cohortof 119 cadaveric LTXs in 116 patients at our center betweenJanuary 1, 2000, and July 31, 2001. This group encompassedall 55 patients who received sirolimus within 60 days afterLTX. The 61 patients who did not receive sirolimus duringthis period served as the comparison group. Sirolimus wasinitiated in the majority of patients within 24 hours afterLTX.

Before the introduction of sirolimus use in our program,liver transplant patients received 1 of 2 immunosuppressiveregimens:

1. Tacrolimus and steroids: 500 mg methylprednisoloneintraoperatively, followed by daily taper from 200 mg to20 mg prednisone over 5 days. Tacrolimus was initiated 12hours after LTX at 0.03–0.05 mg/kg orally every 12hours, with dose adjustment to reach target levels of 8–15ng/mL.

2. Tacrolimus, basiliximab, and steroids: basiliximab 20 mgintravenously intraoperatively and on postoperative day 4;methylprednisolone 250 mg infused intraoperatively;daily taper of methylprednisolone was given as previouslymentioned or on a one-half dose schedule. Tacrolimus wasbegun 24–48 hours after LTX and then started at 1 to 2mg orally every 12 hours, with dose escalation to targettacrolimus levels of 5–10 ng/mL.

In either regimen, postoperative steroids were reducedfurther in patients judged to be particularly sick or debilitated.CTP Status 2A patients received an intraoperative methyl-prednisolone dose of 100–250 mg intravenously, and post-operative steroids were omitted for 72 hours.

Sirolimus was used initially for patients at high risk of CItoxicity: elderly patients, high CTP status patients (2A andvery ill 2B patients), patients in fulminant hepatic failure, andthose with pretransplant acute or chronic renal insufficiency.Its use was expanded over the succeeding 18 months toinclude routine patients at the transplant surgeon’s prefer-ence. Nearly all sirolimus group patients received sirolimuswithin 24 hours after LTX; all received it within 72 hours.Sirolimus was added initially at a loading dose of 8–12 mgdaily, followed by maintenance doses of 4–8 mg to achievetarget levels of 10–15 ng/mL, based on available literature.Because of the difficulty in obtaining timely sirolimus levels inour early experience, the loading and maintenance dosageswere reduced to 4–8 mg daily, and periodic levels wereobtained to ensure that levels less than 15 ng/mL were main-tained. After an increase in infections and in the severity ofinfected and poorly healing surgical wounds were identified,initial and maintenance doses were further reduced to 1–4 mgdaily, and no attempt was made to achieve “therapeutic”levels.

When sirolimus was added to the immunosuppressive reg-imens, an intraoperative methylprednisolone dose of 100–250 mg was infused. Methylprednisolone was then taperedfrom 100 mg to 5–20 mg over the first 5 postoperative days.

Frequently, the standard steroid taper was truncated or elim-inated. Maintenance prednisone at 5–20 mg daily was thenused, based on perceived degree of patient debilitation. Pred-nisone dose at patient discharge ranged from 5 mg to 20 mgdaily. Prednisone taper to discontinuation occurred over 3–9months. Tacrolimus was begun 24–48 hours after LTX whenbasiliximab was not used or 72 hours after LTX when basil-iximab was used. No attempt was made to achieve tacrolimuslevels greater than 5 ng/mL. MMF was used only when CI usewas not feasible because of renal insufficiency or CI toxicity orwhen rejection could not be treated with escalation of CIdose. Therapeutic monitoring of tacrolimus was performedby measuring whole-blood, 12-hour trough levels using anenzyme immunoassay. For each patient, a mean tacrolimuslevel for the entire study period of 60 days was determined bycalculating a mean of 9 individual weekly values (a median ofdaily values in each week for in-patients and a single value forout patients). Sirolimus levels in whole blood were measuredby high-performance liquid chromatography at an outsidelaboratory much less frequently than tacrolimus. A mean of allavailable levels during the study period was calculated for eachpatient receiving sirolimus.

Standard antibacterial, antifungal, and antiviral protocolswere used. Patients received 3 g ampicillin/sulbactam intrave-nously preoperatively and for 48 hours postoperatively.Patients allergic to Penicillin or cephalosporin received levo-floxacin for 48 hours, usually in conjunction with a preoper-ative dose of vancomycin. Fluconazole 100 mg intravenous/oral was administered postoperatively until hospitaldischarge. Thereafter, nystatin oral suspension (500,000 unitsq.i.d.) was administered for 3 months. Ganciclovir 5 mg/kg/day was administered intravenously to all patients duringintensive care unit stay. Cytomegalovirus (CMV) seronega-tive patients who received livers from seropositive donorsreceived intravenous ganciclovir for 30 postoperative days,then oral therapy for an additional 60 days. All other patientsreceived acyclovir 200 mg t.i.d. for 3 months. All patientsreceived 80 mg of sulfamethoxazole /trimethoprim everyother day indefinitely.

All bacterial, viral, and fungal infectious episodes occur-ring within 60 days of LTX were evaluated. No protocolcultures were performed. All cultures were performed on clin-ical suspicion of infection. Appropriate therapeutic agentswere administered for all positive cultures in consultationwith infectious disease specialists. Blood infection was definedas 2 positive cultures or positive catheter tip plus 1 positiveblood culture. Urinary infection was defined by a culturepositive for more than 105 bacteria. Pulmonary sepsis wasdefined by the presence of 2 of the following 3 findings: (1)positive sputum culture, (2) gram stain with a dominantorganism and many polymorphonuclear leukocytes, or (3)radiologic infiltrate.

Superficial and deep wound complications were definedby any of the following 4 findings: (1) superficial abscess orfocal fluid collection with positive culture or gram stain, (2)gross tissue necrosis, (3) positive peritoneal fluid culture or

194 Fisher et al.

gram stain, or (4) fascial dehiscence in the presence of apositive culture or gram stain. CMV disease was defined bythe presence of CMV immunoglobulin M antibodies in bloodsamples or the presence of viral inclusion bodies on liverbiopsy specimens. CMV-DNA levels were measured in allsuch patients to confirm the diagnosis. Immunohistochemicalstaining was performed on suspicious biopsy specimens.Although all sepsis events were tallied, patients with multipleinfectious events were credited with only 1 infectious episodefor purposes of statistical comparison.

Recipient variables examined included age, gender, bodymass index (BMI), pretransplant creatinine, graft warm andcold ischemia times, United Network for Organ Sharing(UNOS) status, and disease etiology. Model for End-StageLiver Disease (MELD) scores were calculated for each patientto provide an additional method of comparison of recipientdisease severity. Hepatocellular carcinoma incidence wascompared between groups to assess comparability of MELDscores. Primary end points included infection, patient andgraft survival, and acute rejection. Length of hospital stay andincidence of hepatic artery thrombosis constituted secondaryend points. Rejection was, in most cases, diagnosed by liverbiopsy. Presumptive acute rejection was defined as a 2-fold or3-fold increase in liver function enzymes without otherdefined etiology, which responded to methylprednisolonebolus therapy and subsequent steroid taper in conjunctionwith increase in CI dosage or addition of a third agent. Iso-lated steroid bolus doses were recorded for comparisonbetween groups but were not counted as rejection episodes.

The 26 patients who received sirolimus in the last 6months of the study period were, in general, treated with 1–4mg sirolimus daily. Sirolimus levels and infection incidence inthis group were compared with those indices in the first 29patients who received sirolimus in our program.

Statistical Analysis

Results were evaluated by Chi-square analysis for categoricalvariables. Student t test or analysis of variance were used forcontinuous variables. Logistic regression analysis was used toassess independence of multiple variables such as recipientage, MELD score, wound dehiscence with use of basiliximab,and incidence of infection. Six-month, 1-year and 2-year sur-vival data were plotted using actuarial analysis. Trend log-rank test was used to test significance for differences in sur-vival between the two groups.

Results

One hundred sixteen patients received 119 liver allo-grafts over a 19-month period. Fifty-five patients whoreceived sirolimus underwent 57 liver transplants.Sixty-one patients who received 62 allografts were nottreated with sirolimus. Demographic variables (Table1) were similar between the two groups. Mean MELDscores did not differ between groups (21.6 vs. 21.9).There was no significant difference for occurrence ofhepatocellular carcinoma between the groups (7/61 inthe no sirolimus arm and 2/55 in the sirolimus arm;P�0.11). Pretransplant creatinine levels were slightlyhigher in patients who received sirolimus but did notreach significance (P�0.08). As shown in Fig. 1, asignificant difference (P�0.001) in infection rate wasfound between patients who received sirolimus (26/55,47%) and those who did not receive sirolimus (11/61,18%). Analysis of UNOS status and infection (Table 2)revealed that more CTP status 2A patients receivedsirolimus (7 vs. 1) and that 57% of the sirolimus groupexperienced infection (4/7). Illness severity was coun-terbalanced in the sirolimus group patients, however,

Figure 1. infection and rejection outcomes in 116 liverrecipients who did and did not receive sirolimus (infectionepisodes limited to one per patient).

Table 1. Demographic Variables in 116 Liver RecipientsWho Did and Did Not Receive Sirolimus

SirolimusGroup

(N � 55)

No SirolimusGroup

(N � 61)

Gender (M/F) 34 / 21 41 / 20Age (yr) 53.1 � 13.4 49.4 � 11.5Body mass index (kg/m2) 27.4 � 5.3 29.8 � 7.3Pretransplant creatinine

(mg/dL) 1.4 � 1.1 1.1 � 0.7MELD score 21.6 � 9.2 21.9 � 8.7CIT (min) 453.9 � 99.1 452.0 � 103.4WIT (min) 43.1 � 9.9 42.4 � 7.5Basiliximab 49 39Hepatocellular carcinoma 2 7

Note: The continuous variables shown in the table representmean � SD.Abbreviations: MELD, Model for End-Stage Liver Disease;CIT, cold ischemia time; WIT, warm ischemia time.

195Sirolimus in Liver Transplantation

by a preponderance of Status 3 patients (15 vs. 3) in thesirolimus arm. Forty percent (6/15) of these patientssuffered sepsis episodes. The BMI did not differ signif-icantly between all patients with and without infectionsor within the sirolimus group between patients withand without infections. Eleven patients in the sirolimusgroup received no CI inhibitor at anytime during thestudy period. The mean tacrolimus trough level in 46patients who received both sirolimus and tacrolimuswas significantly lower (5.7�2.6 vs. 9.8�3.1 ng/mL,P�0.001).

The mean sirolimus level of the entire sirolimusgroup was (9.3�4.8 ng/mL).The mean sirolimus levelsdid not differ significantly between infected sirolimuspatients (9.4�3.8 ng/mL) and noninfected sirolimuspatients (9.2�6.1 ng/mL, P�0.92). Thirteen of the 26patients who received sirolimus (1–4 mg daily) in thelast 6 months of the study period suffered infection(50%). Mean sirolimus level of this group was6.7�3.7ng/mL. In comparison, 12 of the first 29patients to receive sirolimus became infected (41%).Mean sirolimus level in this group was (11.7�4.7ng/mL), which was significantly different at p�0.002

The distribution of infections and wound dehis-cence is shown in Table 3. Blood and wound sepsisconstituted the majority of infections. Superficial anddeep wound infections associated with tissue necrosis ordehiscence accounted for 18/40 (45%) of all sepsisevents. Although the wounds in patients receivingsirolimus took longer to heal than those not receivingsirolimus, the difference was not significant (78�42days vs. 60�41 days, P�0.33). More frequent debride-ment and lavage were required. The trend towardincreased length of hospital stay in this patient groupsupports these observations.

A standard variety of gram-positive and gram-nega-tive organisms was cultured. Viral and fungal infectionswere rare. CMV (hepatitis and viremia) was the onlyviral infection encountered; it occurred in 4 patients inthe control group and 2 patients in the sirolimus grouppatients. Fungal infections were limited to Candidaalbicans species. No primary fungal infections wereidentified. Fungal infections were encountered onlyafter bacterial infection occurred first.

More sirolimus group patients received basiliximab.However, logistic likelihood ratio analysis of independentvariables (recipient age, MELD score, wound dehiscence,and use of basiliximab) demonstrated no correlation withincidence of infection. Further, infection rate in ourpatient population did not increase in comparison to his-torical control when we began using basiliximab in ourimmunosuppressive protocols, well before introduction ofsirolimus into our patient population.

Rejection rates did not differ significantly betweenthe sirolimus (17.5%) and the no sirolimus (22.6%)groups (P�0.55) (Fig. 1). Steroid-resistant rejectionwas very rare and did not differ significantly betweengroups. Posttransplant creatinine values did not differbetween groups at weeks 1, 4, or 8, despite the lowertacrolimus levels in the no sirolimus group. Despite thesignificant increase in infections in the sirolimus group,the graft and patient survival were not significantly dif-ferent between the two groups (P�0.18) (Fig. 2A andB). Hospital length of stay (LOS) showed a trendtoward significance between the study groups (P�0.07).Patients who did not receive sirolimus had a mean LOS of9.6�7.2 days compared with 15.6�25.4 days in patientswho received sirolimus. We detected no significant differ-ence in hepatic artery thrombosis between the sirolimus(1/57) and the no sirolimus (3/62) groups in our cohort.

Table 3. Types of Infections in 55 Liver Recipients WhoReceived Both Sirolimus and Tacrolimus and 61 Recipients

Who Did Not Receive Sirolimus

Site of Infection

SirolimusGroup

(N � 55)

NoSirolimus

Group(N � 61)

Blood 13 (24%) 2 (3%)Wound infection/dehiscence 18 (33%) 5 (8%)Pneumonitis 5 (9%) 5 (8%)Urinary tract 2 (4%) 1 (2%)Cytomeglovirus disease 2 (4%) 4 (7%)

Note: Includes infection episodes in patients with multipleinfection sites.

Table 2. Distribution of United Network for OrganSharing (UNOS) Status and the Incidence of Infections in

116 Liver Recipients Who Did and Did Not ReceiveSirolimus

UNOS StatusSirolimus(N � 55)

No Sirolimus(N � 61)

1 2/6 (33) 1/4 (25)2a 4/7 (57) 0/12b 14/27 (52)* 9/53 (17)3 6/15 (40) 0/3Total 26/55 (47) 11/61 (18)

Note: The values shown in the parentheses represent percent-ages of patients developing infections.*P � 0.001.

196 Fisher et al.

Discussion

The major finding in our study is the significantlygreater incidence of infections in liver recipients givensirolimus immediately after transplantation. Althoughthe increased infections did not result in greater graftloss and patient death, increased morbidity of patientsin the sirolimus group was reflected by the increasedLOS trend. In spite of the structural resemblance ofsirolimus with tacrolimus, it does not act on cal-cineurin; instead, sirolimus inhibits interleukin-2 (IL-2)–mediated signal transduction.3,5,6,9 The lack of vaso-motor-induced renal injury demonstrated by CIsuggests a role for sirolimus in solid organ transplanta-tion via reduction or limitation of CI toxicities.1,3 Sev-eral trials of sirolimus use in renal transplantation haveshown a reduction of acute rejection rates. In several,pneumonia and herpes-derived aphthous ulcers weremore common, especially when doses approaching 5mg per day were administered.1,9,10 Kahan reported noincrease in infection rates in a U.S. multicenter, ran-

domized, sirolimus trial in renal transplantation.10 In aEuropean randomized renal transplant trial, however,Groth et al. reported a higher incidence and severity ofinfections in sirolimus group patients.9

Several authors have reported the use of sirolimus inLTX, most in small numbers of patients. In some ofthese studies, infections were common, and wounddehiscence was reported.7,11–13 In a randomized trial ofsirolimus and tacrolimus immunotherapy in liver trans-plant recipients, Wiesner and the Rapamune LiverTransplant Study Group found a higher rate of woundinfection and a reduced 1-year survival rate (with infec-tion at or near the time of death) in patients whoreceived sirolimus.14 Contrary to our experience,Kneteman et al., in a study similar to ours in samplesize, managed 56 liver recipients with daclizumabinduction, sirolimus, and low-dose delayed tacrolimusin a steroid-free protocol and found no increase inwound complications (dehiscence or diminished heal-ing) or in viral or other infections.15 Very recently,Trotter et al.8 and Dunkelberg et al.16, in the largestseries of liver recipients given sirolimus in the immedi-ate post transplant period, reported a decrease in rejec-tion but no increase in infections or wound complica-tions. It is noteworthy that, unlike our practice, steroidswere either avoided or eliminated early by these 2groups. Data suggest that sirolimus inhibits growth fac-tor elaboration in response to tissue injury.1 In light ofthe several mechanisms by which steroids interfere withwound healing and broadly compromise immune sur-veillance, the combination of sirolimus and steroidsmay potentiate both infection and delayed wound heal-ing. This combination may have been important in theincreased wound complications in our patients receiv-ing sirolimus. Thus a steroid-free regimen may facilitatethe use of sirolimus in the immediate post-LTX period.

A relative excess of immunosuppression may, in fact,explain our early high sepsis rates. The fact that ourinfection rate did not decline significantly despitereduction of sirolimus dosing to very low levels (con-firmed by assays) is both troubling and perplexing. It isunclear what role the IL-2 receptor antagonist played inincreasing the incidence of infections in our patientsreceiving sirolimus. Note also that use of an IL-2 recep-tor antibody in combination with sirolimus differenti-ates our series from all preceding reports except Knete-man et al.15 Kahan stated that the effects of sirolimusare “complementary to IL-2 receptor monoclonal anti-bodies.”1;p.1181 This combination may therefore resultin more than merely additive immunosuppression.

The lack of statistical difference in acute rejectionrates despite higher infection rates argues, in some mea-

Figure 2. Actuarial graft (A) and patient (B) survivalcurves in the sirolimus (N�55) and no sirolimus (N � 61)groups. There were no significant differences between thetwo groups.

197Sirolimus in Liver Transplantation

sure, against simple excessive immunosuppression ofour patients receiving sirolimus. However, it is alsopossible that any incremental increase of total immuno-suppressive therapy from a relatively low baseline rejec-tion rate of 22% favors increased sepsis without a sta-tistically significant further reduction in allograftrejection rate. Alternatively, our patients may have been“incorrectly,” but not necessarily “over,” immunosup-pressed. That is, our policy of delayed initiation of CItherapy may have allowed higher rejection rates thanwould have occurred if CI were initiated immediatelyafter LTX but at very low dose. The rejection cascademight thus be more fully inhibited at multiple pointsearly in the posttransplant period, while CI toxicity isstill obviated. Earlier initiation of very low dose CI mayallow rapid elimination of postoperative steroids, whichmay in turn reduce sepsis rates.

A role for routine use of low dose sirolimus in theimmediate posttransplant phase potentially exists.Although our study is retrospective, and thus may sufferpossible unidentified confounding issues, the fact thatthe infections increased significantly during a very shortperiod of sirolimus use and declined after its discontin-uation indicates that sirolimus should not be used in themanner described in our study. In patients with notableacute or chronic renal insufficiency, the advantage ofimproved renal function with sirolimus use may out-weigh the risk of sepsis or delayed wound healing. Wecould not substantiate such an effect in our data, how-ever. Other CI-sparing regimens, including MMF andIL-2 receptor antagonists, exist and may have advan-tages over sirolimus with regard to both efficacy andcomplications. It is possible that a steroid-free protocolmay limit, or eliminate, the delay in wound healing aswell as the increased infection rate, as shown in theexperience of Trotter et al. and Kneteman et al. Alter-natively, optimal use of sirolimus in LTX may occurafter wound healing has been completed. It may thenprove an ideal agent to which patients with threatenedrenal function may be converted. Elderly patients andothers suffering neurotoxic side effects also may be goodcandidates for conversion to sirolimus after woundhealing has occurred. Such an approach may allow sub-stantial dose reduction, or even elimination of CI, andbetter overall patient recovery and function in the early(2–6 month) phase after LTX.

Conclusions

Addition of sirolimus to immediate after LTX immuno-suppressive regimens, especially those with steroids,

appears to increase rates of sepsis and to delay woundhealing. If sirolimus is to be used during this period, anelimination or drastic reduction in steroids appears to benecessary. Conversion to sirolimus after wound healingand early postoperative recovery has occurred may be theoptimal therapy for patients with persistently threatenedrenal function and patients manifesting CI toxicity.

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198 Fisher et al.