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Infectious complications after OKT3 induction in liver transplantation
Infectious Complications After OKT3 Induction in Liver Transplantation James F. Whiting, Stephen J. Rossi, and Douglas W. Hanto The present study examines the incidence, risk factors, bacteriology, and mortality of infectious episodes and the role of antimicrobial prophylactic regimens after OKT3 induction in liver transplantation. Infections occurring in the first 6 months were evaluated according to the Centers for Disease Control criteria in 102 transplant recipients. Patients were administered OKT3 for 5 to 10 days, beginning intraoperatively, azathioprine, low-dose prednisone, and delayed introduction of cyclosporine. There were 140 major and 30 minor infections for an incidence of 1.7 infections per patient. Twenty-seven patients (26%) had no infectious episodes during the 6 months of followup. Bacterial and fungal infections peaked during the first month posttransplantation, whereas viral infections peaked during the second month. Infection-related mortality was 10%. One-year survival rate of patients who suffered a major infection
was less than those who were infection free, but the difference was not statistically significant (79% vs. 89%; P 5 .61). There was a significantly higher incidence of enterococcal infections under cefotetan prophylaxis than under ampicillinsulbactam (.375 vs. 11 infections per patient; P 5 .0017). There were 14 episodes of cytomegalovirus disease (14%) but no cytomegalovirusrelated mortality or graft loss, and all cases responded to ganciclovir treatment. Bivariate and multivariate analyses identified only retransplantation as a risk factor for infection. In conclusion, OKT3 induction after liver transplantation is associated with a manageable incidence of bacterial, viral, or fungal infections. This is caused by, at least in part, improved anti-infective prophylaxis. Copyright r 1997 by the American Association for the Study of Liver Diseases
I
Materials and Methods
t has been a central tenet in transplantation that any therapy that decreases the likelihood of acute rejection is likely to be accompanied by a corresponding increase in the likelihood of infection. A prime example of this paradigm has been the use of the monoclonal antibody OKT3 to treat steroid-resistant rejection. Although extraordinarily effective in reversing established rejections, the use of OKT3 in these circumstances has been accompanied by an increase in the prevalence of infections, especially those of viral etiology.1 In contrast, small, randomized comparative studies of OKT3 as induction immunotherapy vs. cyclosporine therapy have not documented an increase in infections with the use of OKT3 in this setting but have shown immunologic advantages such as a 20%-40% decrease in the incidence of acute rejection.2-5 A detailed examination of infections in liver transplant recipients receiving OKT3 induction has not been published. Therefore, we reviewed an unselected cohort of 102 patients undergoing primary orthotopic liver transplantation to determine the incidence of bacterial, fungal, and viral infections after OKT3 induction, including type, frequency, and risk factors of infections as well as the impact of antimicrobial prophylaxis on the infections.
OKT3 was used as primary induction immunotherapy in 102 patients receiving first transplants at the University of Cincinnati Medical Center between August 1991 and October 1995 and surviving for longer than 48 hours. Infections occurring in the first 6 months posttransplantation were evaluated.
Immunosuppression OKT3 (5 mg intravenously) was administered intraoperatively and continued for a minimum of 7 days postoperatively. The average dose of OKT3 administered was 49.8 6 17 mg for a median of 8 days. Cyclosporine (Sandimmune [Sandoz; now Novartis, East Hanover, NJ] intravenously or Neoral [Sandoz; now Novartis] by mouth) was initiated between POD 4 and 10, and OKT3 was discontinued when therapeutic levels of cyclosporine had been achieved for 2 consecutive days (whole blood TDX of .300 ng/mL). OKT3 dosage was adjusted
From the Transplantation Division, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH. Address reprint requests to James F. Whiting, MD, Transplantation Division, Department of Surgery, University of Cincinnati College of Medicine, 231 Bethesda Ave, PO Box 670558, Cincinnati, OH 45267-0558. Copyright r 1997 by the American Association for the Study of Liver Diseases 1074-3022/97/0306-0002$3.00/0
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to maintain peripheral blood CD3 levels of ,25 cells/ mm3 with monitoring three times per week. OKT3 premedication consisted of 1 g of methylprednisolone before each of the first two doses and 650 mg acetaminophen by mouth, 50 mg indomethacin by mouth, and 50 mg diphenhydramine intravenously for the first 3 days. Methylprednisolone intravenously or prednisone by mouth was instituted at a dose of 1 mg/kg and quickly tapered to 0.20 mg · kg21 · day21 by the end of the 6-month study period. Azathioprine was administered preoperatively and continued daily at a dose of 1.0 mg/kg, adjusted for white blood cell count. Rejection episodes were confirmed histologically and treated with either 500 mg of methylprednisolone intravenously followed by an oral prednisone recycle starting at 2.0 mg · kg21 · day21 or, as in the majority of cases, by an oral prednisone recycle only. OKT3 was used for steroidresistant rejection.
Antimicrobial Prophylaxis Perioperative antibacterials consisted of 2 g cefotetan intravenously every 12 hours or 3 g ampicillin-sulbactam intravenously every 6 hours for 5 days. Patients not allergic to sulfa drugs were treated with Bactrim DS (Roche Pharmaceuticals, Nutley, NJ) twice daily for 2 weeks and then once daily indefinitely for Pneumocystis and Nocardia prophylaxis. Aerosolized pentamidine was substituted for patients allergic to or unable to tolerate Bactrim. Two million international units of nystatin four times a day was given until oral medications could be administered and then clotrimazole troche five times a day was administered after transplantation until treatment of patient no. 32 when a randomized trial of 400 mg fluconazole daily vs. clotrimazole was instituted. After completion of this study, all recipients were treated with fluconazole. Antifungal prophylaxis was continued for 3 months posttransplantation. All patients were treated with 2 weeks of intravenous ganciclovir (5 mg/kg twice a day) as an antiviral prophylaxis, after which they were switched to 800 mg oral acyclovir four times a day for 3 months. Selective bowel decontamination was not used.
Definitions of Infections Infections were recorded in the University of Cincinnati transplant database at the time of occurrence using criteria established by the Centers for Disease Control.6 Invasive fungal infections were diagnosed by either a positive blood culture or evidence of tissue invasion on biopsy or autopsy. Infections were characterized as major or minor. Major infections included bacteremia, invasive fungal infections, intra-abdominal abscesses, wound infections, peritonitis, pneumonia, cholangitis, and all symptomatic cytomegolovirus (CMV) infections. Minor infections included mucocutaneous herpes simplex virus (HSV) infections, herpes zoster virus infections, cystitis,
and asymptomatic CMV viremia. Surveillance cultures were not performed. Clinical diseases caused by CMV were confirmed either by shell-vial culture or histopathology of involved organs. CMV syndrome was defined by fever of .38°C with no other source and positive CMV shell-vial culture.
Rejection Rejection was documented histologically in all cases using Snover’s criteria for rejection.7 Protocol biopsies were performed weekly for the first month until June 1995. After this date, biopsies were performed as clinically indicated by elevated liver function tests.
Statistical Analysis Bivariate analysis of risk factors was accomplished using chi-squared or Fisher’s exact test for discontinuous data and the Mann Whitney U test or Student’s t-test for continuous data. Multivariate analysis was accomplished using multiple logistic regression. Survival analysis was performed using the Kaplan-Meier product-limit survival distribution, and populations were compared using Peto-Wilcoxon and log rank sections. Infection as a possible risk factor for survival was also analyzed using proportional hazard regression. Incidences of enterococcal infections were compared using the Mann Whitney U test. All statistical calculations were performed using the NCSS 6.0 statistical software package (Number Cruncher Statistical Systems, Kaysville, UT).
Results Population Characteristics There were 102 patients who received 122 allografts for a diagnosis other than malignancy and who were treated with OKT3 induction immunotherapy. Twenty patients underwent retransplantation. There were 64 men and 38 women remaining for the analysis, and the average age at the time of transplant was 47 6 11 years. A list of the indications for transplantation is shown in Table 1. Incidence and Bacteriology of Infections There were 170 total infections noted for an average of 1.7 infections per patient. There were 140 major infections and 30 minor infections. Overall, 62 patients (60%) had at least one major infection, whereas 27 patients (26%) had no infections at all during the 6-month follow-up. The most common time for a bacterial or fungal infection was the first month posttransplantation, whereas viral infections peaked during the second month (Fig. 1). There were 130 bacterial infections (76.5%; 18
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Infections After OKT3 Induction in OLTX
Table 1. Indications for Transplantation
Table 2. Bacteriology of Infections
Indication
No.
Organism
EtOH (solely) Hepatitis C cirrhosis (solely) Hepatitis C/ETOH Cryptogenic cirrhosis Sclerosing cholangitis Fulminant hepatic failure Autoimmune Hepatitis B cirrhosis a1 antitrypsin deficiency Primary biliary cirrhosis Non-ETOH steatonecrosis Hemachromatosis Budd-Chiari Drug-induced cirrhosis Total
23 12 10 11 8 6 6 6 6 5 5 2 1 1 102
Bacterial Enterococcus species Staphylococcus epidermidis Staphylococcus aureus Pseudomonas aeruginosa Enterobacter species Clostridia difficile Klebsiella species Citrobacter species E. coli Miscellaneous (no more than two episodes) Fungal Candida albicans Candida glabrata Cryptococcus neoformans Aspergillus fumigatus Viral CMV EBV HSV VZV
Abbreviation: ETOH, ethanol.
minor), 28 viral infections (16.9%; six minor), and 25 fungal infections (14.17%; six minor). The most common organisms were gram positive, with Enterococcus and Staphylococcus species predominating (Table 2). Of gram-negative organisms, Pseudomonas, Enterobacter, and Escherichia coli were the most common. Candida albicans was the most common fungal organism observed and was responsible for 14 infections. Candida glabrata was almost as
Figure 1. Timing of viral, fungal, and bacterial infections posttransplantation.
No. 27 23 17 13 10 9 5 3 9 14 14 8 2 1 22 3 2 1
Abbreviation: VZV, varicella zoster virus.
common and was observed in eight infections, including three intra-abdominal infections and two fungemias. One invasive Aspergillus infection was observed and two cases of Cryptococcus meningitis.
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There were no infectious episodes attributable to Pneumocystis carinii or other protozoa. There was a significantly higher incidence of Enterococcal infections under cefotetan prophylaxis than under ampicillin-sulbactam (37.5% vs. 11%; P 5 .0017). Of the eight C. glabrata infections, five occurred in patients treated with fluconazole prophylaxis, whereas three occurred in patients treated with clotrimazole as fungal prophylaxis. Infectious Diagnoses
CMV and Other Viral Infections
Table 3 shows the diagnoses and numbers of the various infections. Thirty-five infections initially presented with a positive blood culture in addition to clinical signs and symptoms of infection. Of these, 20 were proven to be catheter related, and of the remaining 15, there were only four instances for which a source was not eventually determined. Intra-abdominal locations were the most common source of infection. Thirty-three patients (32%) experienced an intra-abdominal or biliary infection. Eleven of 28 intra-abdominal infections occurred in patients having undergone either reoperation or retransplantation. These infections were predominantly from gram-positive organisms with Enterococcus species being the most common. No statistically significant individual risk factor for intra-abdominal infection could be discerned among age; packed red blood cells transfused; cold isch-
Table 3. Diagnoses Location Major infections Bacteremia (overall) Catheter related No source found Intra-abdominal (excluding biliary) Pneumonia Hepatitis (CMV) Clostridia difficile colitis Wound Biliary CMV syndrome EBV syndrome Miscellaneous Minor infections Urinary tract Dermatologic Miscellaneous
emic time; total OKT3 dose; sex; United Network for Organ Sharing (UNOS) status; type of biliary reconstruction; or the occurrence of dialysis, rejection, reoperation, or retransplantation. There were 12 instances of cholangitis and/or biliary sepsis. Two of these cases occurred in patients with biliary-enteric anastomoses (P 5 NS). Pneumonias were also common with 21 occurrences, and the most common bacterial pathogens were Pseudomonas species.
No. 35 20 4 28 21 13 9 7 12 8 4 14 20 2 8
There were eight episodes of CMV syndrome without evidence of invasive disease. There were 14 episodes of CMV disease, and in 13 cases, the presentation was mild hepatitis. There were no episodes of colitis and only one mild pneumonitis. No mortality was related to CMV. All patients responded to a 10- to 14-day course of ganciclovir. Other viral infections consisted of benign skinrelated HSV or varicella and three Epstein-Barr virus (EBV)-related syndromes. Mortality There were 15 deaths in the study period, of which 10 were infectious related. Five patients died of multiple-organ system failure after manifesting multiple episodes of sepsis. Three patients died of respiratory insufficiency with overwhelming pneumonias, two of the pneumonias being secondary to an antibiotic-resistant Pseudomonas species. Lastly, 2 patients died from ruptures of mycotic pseudoaneurysms of the hepatic artery. Five of the patient deaths occurred after retransplantation during the original hospitalization. One of the remaining 5 patients had undergone reoperation. Of the 10 infectious-related deaths, 2 patients underwent transplantation originally as UNOS status 1, 5 as UNOS status 2, and 3 as UNOS status 3. Only 3 of the patients who died of infectious-related causes had at any point been well and at home after their transplantation. The 1 year survival rate of patients who suffered a major infection in the first 6 months was less than those who were infection free, but the difference was not statistically significant (79% vs. 89%; P 5 .61). Rejection There were 65 episodes of rejection in 44 patients (43%). The average time to onset of first rejection was 50 6 42 days (range, 8-146 days; median, 32 days). Twelve patients experienced more than one
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Infections After OKT3 Induction in OLTX
rejection, and 6 patients had three episodes. Steroids were used as the first therapy in all cases. OKT3 was reused in 6 cases (5 of the 6 patients’ third rejection and 1 of the patient’s second rejection). One patient required conversion to FK506. Two of the patients with multiple rejections were noncompliant. There were no instances of chronic rejection and there was no graft loss caused by uncontrolled rejection. Risk Factors Risk factors for infection examined included age, etiology of liver disease, UNOS status, ABO compatibility, intraoperative packed red blood cells received, cold ischemic time, type of biliary reconstruction, abdominal reoperation, rejection, total OKT3 dose, retransplantation, bilirubin 1-week posttransplantation, and creatinine 1 week posttransplantation (Table 4). Bivariate analysis identified only retransplantation as a statistically significant risk for infection. Stepwise multivariate regression confirmed retransplantation as the only significant risk factor in our series. Retransplantation There were 20 patients who required retransplantation. The causes of first graft failure were as follows: preservation injury and/or bile duct necrosis, 6; hepatic artery or portal vein thrombosis, 5; recurrent disease, 4, primary nonfunction, 4; and trauma, 1. Forty-four infections (35 major) occurred in these patients for an average of 2.2 infections per patient. There were 24 major bacterial infections, four invasive fungal infections, and seven episodes of CMV hepatitis.
Discussion Our analysis supports previous work by others documenting the serious and aggressive nature of infections after liver transplantation. Although early series reporting on infections after orthotopic liver transplantation have reported infection-related mortality to be as high as 40%, our 6-month infectious mortality rate of 9% is similar to more recent series. Our analysis also supports previous small, randomized comparative studies between OKT3 and cyclosporine-immunosuppressive regimens that have noted that the incidence of infectious complications after OKT3 induction is not different than that observed with cyclosporine-based regimens.3,5 Single-center series such as ours are difficult to
Table 4. Risk Factors Major Infection
No Infection
Age (mean yr) 47.9 6 10 43.7 6 13 Intraoperative packed cells (mean units) 14.7 6 12 9.4 6 6 Cold ischemic time (mean min) 716.9 6 244 713.7 6 254 Total OKT3 dose (mean mg) 50.4 6 17.8 48.4 6 15.5 Sex Men 43 21 Women 26 12 UNOS status 1 6 5 2 25 9 3 39 18 ABO compatibility Identical 60 25 Compatible 8 6 Incompatible 2 1 Biliary reconstruction Duct to duct 59 28 Roux-en-Y 11 4 Dialysis Yes 9 1 No 61 32 Rejection None 39 19 1 20 12 .1 11 1 Reoperation Yes 26 9 No 43 24 Retransplantation Yes 18 2 No 52 30
P Value .07
.08
.95
.77
. .98 NS*
NS*
. .76 . .16 NS*
. .34 . .03
*No difference between any groups or combinations of groups.
compare secondary to differences in patient selection, anti-infective prophylactic regimens, and especially in definitions of infections because many series do not focus on the myriad of minor infections, such as cystitis, bacterial colitis, or minor
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skin infections, that we have included. Nevertheless, our overall incidence of infection of 1.7 infections per patient is strikingly similar to the 1.66 incidence observed in the European multicenter trial of cyclosporine- and tacrolimus-based induction,8 and our incidences of CMV disease, deep fungal infection, and intra-abdominal bacterial infections are quite close to those documented by Hadley et al who used a tacrolimus-based regimen.9 The spectrum of fungal infections observed is also similar to others’ experience. Only 11 invasive fungal infections in 102 patients were noted. We initially began our study (November 1995) period using a protocol of clotrimazole as fungal prophylaxis, but we then undertook a randomized, prospective trial of clotrimazole vs. fluconazole prophylaxis (manuscript in preparation) that convinced us of the efficacy of the latter protocol. Lumbreras et al have also shown that oral fluconazole is effective in reducing Candida colonization and infection after liver transplantation.10 One potential drawback of fluconazole prophylaxis would be the emergence of infections secondary to resistant fungi, especially C. glabrata.11 This has not been problematic in our patients. There were eight infections caused by C. glabrata, including five in patients treated with fluconazole, and all responded to amphotericin therapy without significant morbidity. We have not found viral infection to be a particularly difficult problem after OKT3 induction. The optimal prophylaxis against CMV infection after solid organ transplantation has been controversial, and several different combinations of ganciclovir, both intravenous and oral; oral acyclovir; and human anti-CMV immunoglobulin have been described with varying effectiveness.12-16 We used a short course of intravenous ganciclovir followed by high-dose oral acyclovir for 3 months without regard to serological status. Our incidence of invasive CMV disease was only 14%. Thirteen of 14 cases were manifested as mild hepatitis, and there was no mortality related to CMV and no graft failures attributed to CMV. In several cases, the hepatitis was diagnosed on a protocol biopsy and had been clinically unsuspected. Furthermore, there were no cases of colitis and only one case of pneumonitis. A 2-week course of intravenous ganciclovir (10 mg · kg21 · day21) again followed by 3 months of oral acyclovir was sufficient therapy in all cases of CMV infection.
Only retransplantation could be identified as a statistically significant independent predictor of infection in our series both by bivariate and multivariate analysis. We believe that this reflects both the changing nature of liver transplantation in 1997 as well as center-specific factors. Better organ preservation as well as improved anesthetic and surgical techniques have brought operating times down, decreased the likelihood of postoperative technical complications, decreased transfusion requirements, and increased the likelihood of immediate graft function. As a result, the number of patients with any one of the above characteristics has decreased to a point where few single-center studies can realistically be sufficiently powered to detect these as risk factors. There are several possible explanations why the increased immunosuppression afforded by OKT3 induction has not resulted in an excess of infections. First, the minimal nephrotoxicity observed when cyclosporine or tacrolimus is delayed in introduction may be an ameliorating factor because the increased predilection to infection of patients with renal insufficiency is well recognized.17-19 Second, our rejection rate is low, sparing many patients the extra immunosuppression needed to treat a rejection, and the onset of rejection when it does occur is typically delayed until the second postoperative month. By this time the patient is out of the inpatient setting, and an oral recycle of steroids is adequate therapy in .85% of patients. This effectively ‘‘decouples’’ the treatment of rejection from the high-risk first postoperative month. This ability to reliably exclude rejection from the differential of early posttransplant graft dysfunction without a need for biopsy is a major reason that we have continued quadruple immunosuppression even as the introduction of other immunosuppressive agents, such as FK506, has lowered the incidence of acute rejection.8,20 Last, we believe that aggressive prophylaxis of bacterial, fungal, and viral infections is important. Although controlled randomized trials of antibacterial prophylaxis in this population of patients is lacking, extrapolation of data from general surgery patients would certainly indicate that some type of antibiotic prophylaxis is justified.21 We have recently decreased the length of time antibiotics are continued from 5 days to 48 hours in the face of a lack of data supporting any benefit from the longer time period. Certainly the role of viral prophylaxis has been well documented,13,15,16 and we believe that aggressive
Infections After OKT3 Induction in OLTX
fungal prophylaxis is warranted in these high-risk patients as well. Recent work has suggested that infectious complications of liver transplantation can be decreased through the use of selective bowel decontamination.22 Although we did not use this in the current cohort of patients, the strategy may be especially effective in patients treated with OKT3 because recent evidence has documented bacterial translocation and bacteremia as a result of the T-cell activation resulting from OKT3 administration.23 Other strategies such as surveillance culturing or the prophylactic administration of granulocyte colony–stimulating factor may also help ameliorate morbidity from infections.24 In summary, OKT3 induction immunosuppression after liver transplantation is associated with a manageable incidence of bacterial, viral, and fungal infections. Aggressive antimicrobial prophylaxis is important in this setting.
7.
8.
9.
10.
11. 12.
Acknowledgment The authors would like to acknowledge the dedicated patient care of transplant coordinators Mary Etta Bass, Beth Mannix, and Samira Jones; the special abilities of nurse specialist Sharon Goretsky; the data coordination of Sheryl Drexilius and Brenda Adams-Buchanan; and the secretarial skills of Jan Doench and especially Kathy Storer.
13.
14.
References 1. Singh N, Dummer JS, Kusne S, Breinig MK, Armstrong JA, Makowka L, et al. Infections with cytomegalovirus and other herpes viruses in 121 liver transplant recipients: Transmission by donated organ and the effect of OKT3 antibodies. J Infect Dis 1988;158:124-131. 2. Cosimi AB, Jenkins RL, Rohrer RJ, Delmonico FL, Hoffman M, Monaco AP. A randomized clinical trial of prophylactic OKT3 monoclonal antibody in liver allograft recipients. Arch Surg 1990;125:781-785. 3. Hockerstedt K, Ericzon B, Bismuth H, Chapuis Y, Farges O, Faure JL, et al. OKT3 prophylaxis in liver transplant patients: A European and Australian multicenter, prospective controlled trial. Transplant Proc 1993;25:556557. 4. Elkashab M, Reizig M, Greig PD, Cameron R, Phillips MJ, Chung S, et al. Incidence and patterns of rejection using different induction therapies in liver transplant recipients. Transplant Proc 1994;26:2669-2671. 5. McDiarmid SV, Millis MJ, Terasaki PI, Ament ME, Busuttil RW. OKT3 prophylaxis in liver transplantation. Dig Dis Sci 1991;36:1418-1426. 6. Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes
15.
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20.
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JM. CDC definitions for nosocomial infections, 1988. Am J Infect Control 1988;16:128-140. Snover DC, Sibley RK, Freese DK, Sharp HL, Bloomer JR, Najarian JS, et al. Orthotopic liver transplantation: A pathological study of 63 serial liver biopsies from 17 patients with special reference to diagnostic features and natural history of rejection. Hepatology 1984;4:12121222. European FK506 Multicentre Liver Study Group. Randomised trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rejection. Lancet 1994;344:423-428. Hadley S, Samore MH, Lewis WD, Jenkins RL, Karchmer AW, Hammer SM. Major infectious complications after orthotopic liver transplantation and comparison of outcomes in patients receiving cyclosporine or FK506 as primary immunosuppression. Transplantation 1995; 59:851-859. Lumbreras C, Cuervas-Mons V, Jara P, del Palacio A, Turrion S, Barrios C, et al. Randomized trial of fluconazole versus nystatin for the prophylaxis of Candida infection following liver transplantation. J Infect Dis 1996;174:583-588. Lam HH, Althaus BL. Antifungal prophylaxis in bone marrow transplant. Ann Pharmacol 1995;29:921-924. Singh N, Yu VL, Mieles L, Wagener MM, Miner RC, Miner BA, et al. High-dose acyclovir compared with short-course preemptive ganciclovir therapy to prevent cytomegalovirus disease in liver transplant recipients. Ann Int Med 1994;120:375-381. Winston DJ, Wirin D, Shaked A, Busuttil RW. Randomized comparison of ganciclovir and high-dose acyclovir for long-term cytomegalovirus prophylaxis in livertransplant recipients. Lancet 1995;346:69-74. Dunn DL, Gillingham KJ, Kramer MA, Schmidt WJ, Erice A, Balfour HHJ, et al. A prospective randomized study of acyclovir versus ganciclovir plus human immune globulin prophylaxis of cytomegalovirus infection after solid organ transplantation. Transplantation 1994; 57:876-884. Balfour HHJ, Chace BA, Stapleton JT, Simmons RL, Fryd DS. A randomized, placebo-controlled trial of oral acyclovir for the prevention of cytomegalovirus disease in recipients of renal allografts. N Engl J Med 1989;320: 1381-1387. Patel R, Snydman DR, Rubin RH, Ho M, Pescovitz M, Martin M, et al. Cytomegalovirus prophylaxis in solid organ transplant recipients. Transplantation 1996;61: 1279-1289. Singh N, Gayowski T, Wagener MM, Yu VL. Infectious complications in liver transplant recipients on tacrolimus. Transplantation 1994;58:774-778. Colonna JO II, Winston DJ, Brill JE, Goldstein LI, Hoff MP, Hiatt JR, et al. Infectious complications in liver transplantation. Arch Surg 1988;123:360-364. Mora NP, Gonwa TA, Goldstein RM, Husberg BS, Klintmalm GB. Risk of postoperative infection after liver transplantation: A univariate and stepwise logistic regression analysis of risk factors in 150 consecutive patients. Clin Transplant 1992;46:443-449. The U.S. Multicenter FK506 Liver Study Group. A comparison of tracrolimus (FK 506) and cyclosporine for
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immunosuppression in liver transplantation. N Engl J Med 1994;331:1110-1115. 21. Meijer WS, Schmitz PI, Jeekel J. Meta-analysis of randomized, controlled clinical trials of antibiotic prophylaxis in biliary tract surgery. Br J Surg 1990;77:283-290. 22. Arnow PM. Prevention of bacterial infection in the transplant recipient. The role of selective bowel decontamination. Infect Dis Clin North Am 1995;9:849-862.
23. Kane T, Alexander JW, Johannigman JA. The detection of microbial DNA in the blood: A sensitive method for diagnosing bacteremia and/or bacterial translocation in surgical patients. Ann Surg (in press). 24. Foster PF, Mital D, Sankary HN, McChesney LP, Marcon J, Koukoulis G, et al. The use of granulocyte colony stimulating factor (GCSF) after liver transplantation. Transplantation 1995;59:1557-1563.
was less than those who were infection free, but the difference was not statistically significant (79% vs. 89%; P 5 .61). There was a significantly higher incidence of enterococcal infections under cefotetan prophylaxis than under ampicillinsulbactam (.375 vs. 11 infections per patient; P 5 .0017). There were 14 episodes of cytomegalovirus disease (14%) but no cytomegalovirusrelated mortality or graft loss, and all cases responded to ganciclovir treatment. Bivariate and multivariate analyses identified only retransplantation as a risk factor for infection. In conclusion, OKT3 induction after liver transplantation is associated with a manageable incidence of bacterial, viral, or fungal infections. This is caused by, at least in part, improved anti-infective prophylaxis. Copyright r 1997 by the American Association for the Study of Liver Diseases
I
Materials and Methods
t has been a central tenet in transplantation that any therapy that decreases the likelihood of acute rejection is likely to be accompanied by a corresponding increase in the likelihood of infection. A prime example of this paradigm has been the use of the monoclonal antibody OKT3 to treat steroid-resistant rejection. Although extraordinarily effective in reversing established rejections, the use of OKT3 in these circumstances has been accompanied by an increase in the prevalence of infections, especially those of viral etiology.1 In contrast, small, randomized comparative studies of OKT3 as induction immunotherapy vs. cyclosporine therapy have not documented an increase in infections with the use of OKT3 in this setting but have shown immunologic advantages such as a 20%-40% decrease in the incidence of acute rejection.2-5 A detailed examination of infections in liver transplant recipients receiving OKT3 induction has not been published. Therefore, we reviewed an unselected cohort of 102 patients undergoing primary orthotopic liver transplantation to determine the incidence of bacterial, fungal, and viral infections after OKT3 induction, including type, frequency, and risk factors of infections as well as the impact of antimicrobial prophylaxis on the infections.
OKT3 was used as primary induction immunotherapy in 102 patients receiving first transplants at the University of Cincinnati Medical Center between August 1991 and October 1995 and surviving for longer than 48 hours. Infections occurring in the first 6 months posttransplantation were evaluated.
Immunosuppression OKT3 (5 mg intravenously) was administered intraoperatively and continued for a minimum of 7 days postoperatively. The average dose of OKT3 administered was 49.8 6 17 mg for a median of 8 days. Cyclosporine (Sandimmune [Sandoz; now Novartis, East Hanover, NJ] intravenously or Neoral [Sandoz; now Novartis] by mouth) was initiated between POD 4 and 10, and OKT3 was discontinued when therapeutic levels of cyclosporine had been achieved for 2 consecutive days (whole blood TDX of .300 ng/mL). OKT3 dosage was adjusted
From the Transplantation Division, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH. Address reprint requests to James F. Whiting, MD, Transplantation Division, Department of Surgery, University of Cincinnati College of Medicine, 231 Bethesda Ave, PO Box 670558, Cincinnati, OH 45267-0558. Copyright r 1997 by the American Association for the Study of Liver Diseases 1074-3022/97/0306-0002$3.00/0
Liver Transplantation and Surgery, Vol 3, No 6 (November), 1997: pp 563-570
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to maintain peripheral blood CD3 levels of ,25 cells/ mm3 with monitoring three times per week. OKT3 premedication consisted of 1 g of methylprednisolone before each of the first two doses and 650 mg acetaminophen by mouth, 50 mg indomethacin by mouth, and 50 mg diphenhydramine intravenously for the first 3 days. Methylprednisolone intravenously or prednisone by mouth was instituted at a dose of 1 mg/kg and quickly tapered to 0.20 mg · kg21 · day21 by the end of the 6-month study period. Azathioprine was administered preoperatively and continued daily at a dose of 1.0 mg/kg, adjusted for white blood cell count. Rejection episodes were confirmed histologically and treated with either 500 mg of methylprednisolone intravenously followed by an oral prednisone recycle starting at 2.0 mg · kg21 · day21 or, as in the majority of cases, by an oral prednisone recycle only. OKT3 was used for steroidresistant rejection.
Antimicrobial Prophylaxis Perioperative antibacterials consisted of 2 g cefotetan intravenously every 12 hours or 3 g ampicillin-sulbactam intravenously every 6 hours for 5 days. Patients not allergic to sulfa drugs were treated with Bactrim DS (Roche Pharmaceuticals, Nutley, NJ) twice daily for 2 weeks and then once daily indefinitely for Pneumocystis and Nocardia prophylaxis. Aerosolized pentamidine was substituted for patients allergic to or unable to tolerate Bactrim. Two million international units of nystatin four times a day was given until oral medications could be administered and then clotrimazole troche five times a day was administered after transplantation until treatment of patient no. 32 when a randomized trial of 400 mg fluconazole daily vs. clotrimazole was instituted. After completion of this study, all recipients were treated with fluconazole. Antifungal prophylaxis was continued for 3 months posttransplantation. All patients were treated with 2 weeks of intravenous ganciclovir (5 mg/kg twice a day) as an antiviral prophylaxis, after which they were switched to 800 mg oral acyclovir four times a day for 3 months. Selective bowel decontamination was not used.
Definitions of Infections Infections were recorded in the University of Cincinnati transplant database at the time of occurrence using criteria established by the Centers for Disease Control.6 Invasive fungal infections were diagnosed by either a positive blood culture or evidence of tissue invasion on biopsy or autopsy. Infections were characterized as major or minor. Major infections included bacteremia, invasive fungal infections, intra-abdominal abscesses, wound infections, peritonitis, pneumonia, cholangitis, and all symptomatic cytomegolovirus (CMV) infections. Minor infections included mucocutaneous herpes simplex virus (HSV) infections, herpes zoster virus infections, cystitis,
and asymptomatic CMV viremia. Surveillance cultures were not performed. Clinical diseases caused by CMV were confirmed either by shell-vial culture or histopathology of involved organs. CMV syndrome was defined by fever of .38°C with no other source and positive CMV shell-vial culture.
Rejection Rejection was documented histologically in all cases using Snover’s criteria for rejection.7 Protocol biopsies were performed weekly for the first month until June 1995. After this date, biopsies were performed as clinically indicated by elevated liver function tests.
Statistical Analysis Bivariate analysis of risk factors was accomplished using chi-squared or Fisher’s exact test for discontinuous data and the Mann Whitney U test or Student’s t-test for continuous data. Multivariate analysis was accomplished using multiple logistic regression. Survival analysis was performed using the Kaplan-Meier product-limit survival distribution, and populations were compared using Peto-Wilcoxon and log rank sections. Infection as a possible risk factor for survival was also analyzed using proportional hazard regression. Incidences of enterococcal infections were compared using the Mann Whitney U test. All statistical calculations were performed using the NCSS 6.0 statistical software package (Number Cruncher Statistical Systems, Kaysville, UT).
Results Population Characteristics There were 102 patients who received 122 allografts for a diagnosis other than malignancy and who were treated with OKT3 induction immunotherapy. Twenty patients underwent retransplantation. There were 64 men and 38 women remaining for the analysis, and the average age at the time of transplant was 47 6 11 years. A list of the indications for transplantation is shown in Table 1. Incidence and Bacteriology of Infections There were 170 total infections noted for an average of 1.7 infections per patient. There were 140 major infections and 30 minor infections. Overall, 62 patients (60%) had at least one major infection, whereas 27 patients (26%) had no infections at all during the 6-month follow-up. The most common time for a bacterial or fungal infection was the first month posttransplantation, whereas viral infections peaked during the second month (Fig. 1). There were 130 bacterial infections (76.5%; 18
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Infections After OKT3 Induction in OLTX
Table 1. Indications for Transplantation
Table 2. Bacteriology of Infections
Indication
No.
Organism
EtOH (solely) Hepatitis C cirrhosis (solely) Hepatitis C/ETOH Cryptogenic cirrhosis Sclerosing cholangitis Fulminant hepatic failure Autoimmune Hepatitis B cirrhosis a1 antitrypsin deficiency Primary biliary cirrhosis Non-ETOH steatonecrosis Hemachromatosis Budd-Chiari Drug-induced cirrhosis Total
23 12 10 11 8 6 6 6 6 5 5 2 1 1 102
Bacterial Enterococcus species Staphylococcus epidermidis Staphylococcus aureus Pseudomonas aeruginosa Enterobacter species Clostridia difficile Klebsiella species Citrobacter species E. coli Miscellaneous (no more than two episodes) Fungal Candida albicans Candida glabrata Cryptococcus neoformans Aspergillus fumigatus Viral CMV EBV HSV VZV
Abbreviation: ETOH, ethanol.
minor), 28 viral infections (16.9%; six minor), and 25 fungal infections (14.17%; six minor). The most common organisms were gram positive, with Enterococcus and Staphylococcus species predominating (Table 2). Of gram-negative organisms, Pseudomonas, Enterobacter, and Escherichia coli were the most common. Candida albicans was the most common fungal organism observed and was responsible for 14 infections. Candida glabrata was almost as
Figure 1. Timing of viral, fungal, and bacterial infections posttransplantation.
No. 27 23 17 13 10 9 5 3 9 14 14 8 2 1 22 3 2 1
Abbreviation: VZV, varicella zoster virus.
common and was observed in eight infections, including three intra-abdominal infections and two fungemias. One invasive Aspergillus infection was observed and two cases of Cryptococcus meningitis.
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There were no infectious episodes attributable to Pneumocystis carinii or other protozoa. There was a significantly higher incidence of Enterococcal infections under cefotetan prophylaxis than under ampicillin-sulbactam (37.5% vs. 11%; P 5 .0017). Of the eight C. glabrata infections, five occurred in patients treated with fluconazole prophylaxis, whereas three occurred in patients treated with clotrimazole as fungal prophylaxis. Infectious Diagnoses
CMV and Other Viral Infections
Table 3 shows the diagnoses and numbers of the various infections. Thirty-five infections initially presented with a positive blood culture in addition to clinical signs and symptoms of infection. Of these, 20 were proven to be catheter related, and of the remaining 15, there were only four instances for which a source was not eventually determined. Intra-abdominal locations were the most common source of infection. Thirty-three patients (32%) experienced an intra-abdominal or biliary infection. Eleven of 28 intra-abdominal infections occurred in patients having undergone either reoperation or retransplantation. These infections were predominantly from gram-positive organisms with Enterococcus species being the most common. No statistically significant individual risk factor for intra-abdominal infection could be discerned among age; packed red blood cells transfused; cold isch-
Table 3. Diagnoses Location Major infections Bacteremia (overall) Catheter related No source found Intra-abdominal (excluding biliary) Pneumonia Hepatitis (CMV) Clostridia difficile colitis Wound Biliary CMV syndrome EBV syndrome Miscellaneous Minor infections Urinary tract Dermatologic Miscellaneous
emic time; total OKT3 dose; sex; United Network for Organ Sharing (UNOS) status; type of biliary reconstruction; or the occurrence of dialysis, rejection, reoperation, or retransplantation. There were 12 instances of cholangitis and/or biliary sepsis. Two of these cases occurred in patients with biliary-enteric anastomoses (P 5 NS). Pneumonias were also common with 21 occurrences, and the most common bacterial pathogens were Pseudomonas species.
No. 35 20 4 28 21 13 9 7 12 8 4 14 20 2 8
There were eight episodes of CMV syndrome without evidence of invasive disease. There were 14 episodes of CMV disease, and in 13 cases, the presentation was mild hepatitis. There were no episodes of colitis and only one mild pneumonitis. No mortality was related to CMV. All patients responded to a 10- to 14-day course of ganciclovir. Other viral infections consisted of benign skinrelated HSV or varicella and three Epstein-Barr virus (EBV)-related syndromes. Mortality There were 15 deaths in the study period, of which 10 were infectious related. Five patients died of multiple-organ system failure after manifesting multiple episodes of sepsis. Three patients died of respiratory insufficiency with overwhelming pneumonias, two of the pneumonias being secondary to an antibiotic-resistant Pseudomonas species. Lastly, 2 patients died from ruptures of mycotic pseudoaneurysms of the hepatic artery. Five of the patient deaths occurred after retransplantation during the original hospitalization. One of the remaining 5 patients had undergone reoperation. Of the 10 infectious-related deaths, 2 patients underwent transplantation originally as UNOS status 1, 5 as UNOS status 2, and 3 as UNOS status 3. Only 3 of the patients who died of infectious-related causes had at any point been well and at home after their transplantation. The 1 year survival rate of patients who suffered a major infection in the first 6 months was less than those who were infection free, but the difference was not statistically significant (79% vs. 89%; P 5 .61). Rejection There were 65 episodes of rejection in 44 patients (43%). The average time to onset of first rejection was 50 6 42 days (range, 8-146 days; median, 32 days). Twelve patients experienced more than one
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Infections After OKT3 Induction in OLTX
rejection, and 6 patients had three episodes. Steroids were used as the first therapy in all cases. OKT3 was reused in 6 cases (5 of the 6 patients’ third rejection and 1 of the patient’s second rejection). One patient required conversion to FK506. Two of the patients with multiple rejections were noncompliant. There were no instances of chronic rejection and there was no graft loss caused by uncontrolled rejection. Risk Factors Risk factors for infection examined included age, etiology of liver disease, UNOS status, ABO compatibility, intraoperative packed red blood cells received, cold ischemic time, type of biliary reconstruction, abdominal reoperation, rejection, total OKT3 dose, retransplantation, bilirubin 1-week posttransplantation, and creatinine 1 week posttransplantation (Table 4). Bivariate analysis identified only retransplantation as a statistically significant risk for infection. Stepwise multivariate regression confirmed retransplantation as the only significant risk factor in our series. Retransplantation There were 20 patients who required retransplantation. The causes of first graft failure were as follows: preservation injury and/or bile duct necrosis, 6; hepatic artery or portal vein thrombosis, 5; recurrent disease, 4, primary nonfunction, 4; and trauma, 1. Forty-four infections (35 major) occurred in these patients for an average of 2.2 infections per patient. There were 24 major bacterial infections, four invasive fungal infections, and seven episodes of CMV hepatitis.
Discussion Our analysis supports previous work by others documenting the serious and aggressive nature of infections after liver transplantation. Although early series reporting on infections after orthotopic liver transplantation have reported infection-related mortality to be as high as 40%, our 6-month infectious mortality rate of 9% is similar to more recent series. Our analysis also supports previous small, randomized comparative studies between OKT3 and cyclosporine-immunosuppressive regimens that have noted that the incidence of infectious complications after OKT3 induction is not different than that observed with cyclosporine-based regimens.3,5 Single-center series such as ours are difficult to
Table 4. Risk Factors Major Infection
No Infection
Age (mean yr) 47.9 6 10 43.7 6 13 Intraoperative packed cells (mean units) 14.7 6 12 9.4 6 6 Cold ischemic time (mean min) 716.9 6 244 713.7 6 254 Total OKT3 dose (mean mg) 50.4 6 17.8 48.4 6 15.5 Sex Men 43 21 Women 26 12 UNOS status 1 6 5 2 25 9 3 39 18 ABO compatibility Identical 60 25 Compatible 8 6 Incompatible 2 1 Biliary reconstruction Duct to duct 59 28 Roux-en-Y 11 4 Dialysis Yes 9 1 No 61 32 Rejection None 39 19 1 20 12 .1 11 1 Reoperation Yes 26 9 No 43 24 Retransplantation Yes 18 2 No 52 30
P Value .07
.08
.95
.77
. .98 NS*
NS*
. .76 . .16 NS*
. .34 . .03
*No difference between any groups or combinations of groups.
compare secondary to differences in patient selection, anti-infective prophylactic regimens, and especially in definitions of infections because many series do not focus on the myriad of minor infections, such as cystitis, bacterial colitis, or minor
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skin infections, that we have included. Nevertheless, our overall incidence of infection of 1.7 infections per patient is strikingly similar to the 1.66 incidence observed in the European multicenter trial of cyclosporine- and tacrolimus-based induction,8 and our incidences of CMV disease, deep fungal infection, and intra-abdominal bacterial infections are quite close to those documented by Hadley et al who used a tacrolimus-based regimen.9 The spectrum of fungal infections observed is also similar to others’ experience. Only 11 invasive fungal infections in 102 patients were noted. We initially began our study (November 1995) period using a protocol of clotrimazole as fungal prophylaxis, but we then undertook a randomized, prospective trial of clotrimazole vs. fluconazole prophylaxis (manuscript in preparation) that convinced us of the efficacy of the latter protocol. Lumbreras et al have also shown that oral fluconazole is effective in reducing Candida colonization and infection after liver transplantation.10 One potential drawback of fluconazole prophylaxis would be the emergence of infections secondary to resistant fungi, especially C. glabrata.11 This has not been problematic in our patients. There were eight infections caused by C. glabrata, including five in patients treated with fluconazole, and all responded to amphotericin therapy without significant morbidity. We have not found viral infection to be a particularly difficult problem after OKT3 induction. The optimal prophylaxis against CMV infection after solid organ transplantation has been controversial, and several different combinations of ganciclovir, both intravenous and oral; oral acyclovir; and human anti-CMV immunoglobulin have been described with varying effectiveness.12-16 We used a short course of intravenous ganciclovir followed by high-dose oral acyclovir for 3 months without regard to serological status. Our incidence of invasive CMV disease was only 14%. Thirteen of 14 cases were manifested as mild hepatitis, and there was no mortality related to CMV and no graft failures attributed to CMV. In several cases, the hepatitis was diagnosed on a protocol biopsy and had been clinically unsuspected. Furthermore, there were no cases of colitis and only one case of pneumonitis. A 2-week course of intravenous ganciclovir (10 mg · kg21 · day21) again followed by 3 months of oral acyclovir was sufficient therapy in all cases of CMV infection.
Only retransplantation could be identified as a statistically significant independent predictor of infection in our series both by bivariate and multivariate analysis. We believe that this reflects both the changing nature of liver transplantation in 1997 as well as center-specific factors. Better organ preservation as well as improved anesthetic and surgical techniques have brought operating times down, decreased the likelihood of postoperative technical complications, decreased transfusion requirements, and increased the likelihood of immediate graft function. As a result, the number of patients with any one of the above characteristics has decreased to a point where few single-center studies can realistically be sufficiently powered to detect these as risk factors. There are several possible explanations why the increased immunosuppression afforded by OKT3 induction has not resulted in an excess of infections. First, the minimal nephrotoxicity observed when cyclosporine or tacrolimus is delayed in introduction may be an ameliorating factor because the increased predilection to infection of patients with renal insufficiency is well recognized.17-19 Second, our rejection rate is low, sparing many patients the extra immunosuppression needed to treat a rejection, and the onset of rejection when it does occur is typically delayed until the second postoperative month. By this time the patient is out of the inpatient setting, and an oral recycle of steroids is adequate therapy in .85% of patients. This effectively ‘‘decouples’’ the treatment of rejection from the high-risk first postoperative month. This ability to reliably exclude rejection from the differential of early posttransplant graft dysfunction without a need for biopsy is a major reason that we have continued quadruple immunosuppression even as the introduction of other immunosuppressive agents, such as FK506, has lowered the incidence of acute rejection.8,20 Last, we believe that aggressive prophylaxis of bacterial, fungal, and viral infections is important. Although controlled randomized trials of antibacterial prophylaxis in this population of patients is lacking, extrapolation of data from general surgery patients would certainly indicate that some type of antibiotic prophylaxis is justified.21 We have recently decreased the length of time antibiotics are continued from 5 days to 48 hours in the face of a lack of data supporting any benefit from the longer time period. Certainly the role of viral prophylaxis has been well documented,13,15,16 and we believe that aggressive
Infections After OKT3 Induction in OLTX
fungal prophylaxis is warranted in these high-risk patients as well. Recent work has suggested that infectious complications of liver transplantation can be decreased through the use of selective bowel decontamination.22 Although we did not use this in the current cohort of patients, the strategy may be especially effective in patients treated with OKT3 because recent evidence has documented bacterial translocation and bacteremia as a result of the T-cell activation resulting from OKT3 administration.23 Other strategies such as surveillance culturing or the prophylactic administration of granulocyte colony–stimulating factor may also help ameliorate morbidity from infections.24 In summary, OKT3 induction immunosuppression after liver transplantation is associated with a manageable incidence of bacterial, viral, and fungal infections. Aggressive antimicrobial prophylaxis is important in this setting.
7.
8.
9.
10.
11. 12.
Acknowledgment The authors would like to acknowledge the dedicated patient care of transplant coordinators Mary Etta Bass, Beth Mannix, and Samira Jones; the special abilities of nurse specialist Sharon Goretsky; the data coordination of Sheryl Drexilius and Brenda Adams-Buchanan; and the secretarial skills of Jan Doench and especially Kathy Storer.
13.
14.
References 1. Singh N, Dummer JS, Kusne S, Breinig MK, Armstrong JA, Makowka L, et al. Infections with cytomegalovirus and other herpes viruses in 121 liver transplant recipients: Transmission by donated organ and the effect of OKT3 antibodies. J Infect Dis 1988;158:124-131. 2. Cosimi AB, Jenkins RL, Rohrer RJ, Delmonico FL, Hoffman M, Monaco AP. A randomized clinical trial of prophylactic OKT3 monoclonal antibody in liver allograft recipients. Arch Surg 1990;125:781-785. 3. Hockerstedt K, Ericzon B, Bismuth H, Chapuis Y, Farges O, Faure JL, et al. OKT3 prophylaxis in liver transplant patients: A European and Australian multicenter, prospective controlled trial. Transplant Proc 1993;25:556557. 4. Elkashab M, Reizig M, Greig PD, Cameron R, Phillips MJ, Chung S, et al. Incidence and patterns of rejection using different induction therapies in liver transplant recipients. Transplant Proc 1994;26:2669-2671. 5. McDiarmid SV, Millis MJ, Terasaki PI, Ament ME, Busuttil RW. OKT3 prophylaxis in liver transplantation. Dig Dis Sci 1991;36:1418-1426. 6. Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes
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JM. CDC definitions for nosocomial infections, 1988. Am J Infect Control 1988;16:128-140. Snover DC, Sibley RK, Freese DK, Sharp HL, Bloomer JR, Najarian JS, et al. Orthotopic liver transplantation: A pathological study of 63 serial liver biopsies from 17 patients with special reference to diagnostic features and natural history of rejection. Hepatology 1984;4:12121222. European FK506 Multicentre Liver Study Group. Randomised trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rejection. Lancet 1994;344:423-428. Hadley S, Samore MH, Lewis WD, Jenkins RL, Karchmer AW, Hammer SM. Major infectious complications after orthotopic liver transplantation and comparison of outcomes in patients receiving cyclosporine or FK506 as primary immunosuppression. Transplantation 1995; 59:851-859. Lumbreras C, Cuervas-Mons V, Jara P, del Palacio A, Turrion S, Barrios C, et al. Randomized trial of fluconazole versus nystatin for the prophylaxis of Candida infection following liver transplantation. J Infect Dis 1996;174:583-588. Lam HH, Althaus BL. Antifungal prophylaxis in bone marrow transplant. Ann Pharmacol 1995;29:921-924. Singh N, Yu VL, Mieles L, Wagener MM, Miner RC, Miner BA, et al. High-dose acyclovir compared with short-course preemptive ganciclovir therapy to prevent cytomegalovirus disease in liver transplant recipients. Ann Int Med 1994;120:375-381. Winston DJ, Wirin D, Shaked A, Busuttil RW. Randomized comparison of ganciclovir and high-dose acyclovir for long-term cytomegalovirus prophylaxis in livertransplant recipients. Lancet 1995;346:69-74. Dunn DL, Gillingham KJ, Kramer MA, Schmidt WJ, Erice A, Balfour HHJ, et al. A prospective randomized study of acyclovir versus ganciclovir plus human immune globulin prophylaxis of cytomegalovirus infection after solid organ transplantation. Transplantation 1994; 57:876-884. Balfour HHJ, Chace BA, Stapleton JT, Simmons RL, Fryd DS. A randomized, placebo-controlled trial of oral acyclovir for the prevention of cytomegalovirus disease in recipients of renal allografts. N Engl J Med 1989;320: 1381-1387. Patel R, Snydman DR, Rubin RH, Ho M, Pescovitz M, Martin M, et al. Cytomegalovirus prophylaxis in solid organ transplant recipients. Transplantation 1996;61: 1279-1289. Singh N, Gayowski T, Wagener MM, Yu VL. Infectious complications in liver transplant recipients on tacrolimus. Transplantation 1994;58:774-778. Colonna JO II, Winston DJ, Brill JE, Goldstein LI, Hoff MP, Hiatt JR, et al. Infectious complications in liver transplantation. Arch Surg 1988;123:360-364. Mora NP, Gonwa TA, Goldstein RM, Husberg BS, Klintmalm GB. Risk of postoperative infection after liver transplantation: A univariate and stepwise logistic regression analysis of risk factors in 150 consecutive patients. Clin Transplant 1992;46:443-449. The U.S. Multicenter FK506 Liver Study Group. A comparison of tracrolimus (FK 506) and cyclosporine for
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immunosuppression in liver transplantation. N Engl J Med 1994;331:1110-1115. 21. Meijer WS, Schmitz PI, Jeekel J. Meta-analysis of randomized, controlled clinical trials of antibiotic prophylaxis in biliary tract surgery. Br J Surg 1990;77:283-290. 22. Arnow PM. Prevention of bacterial infection in the transplant recipient. The role of selective bowel decontamination. Infect Dis Clin North Am 1995;9:849-862.
23. Kane T, Alexander JW, Johannigman JA. The detection of microbial DNA in the blood: A sensitive method for diagnosing bacteremia and/or bacterial translocation in surgical patients. Ann Surg (in press). 24. Foster PF, Mital D, Sankary HN, McChesney LP, Marcon J, Koukoulis G, et al. The use of granulocyte colony stimulating factor (GCSF) after liver transplantation. Transplantation 1995;59:1557-1563.