Gonzalez-Pinto, I

Jain, A

Kusne, S

Manez, R

Martin, M

Silverman, D

Starzl, TE

Venkataramanan, R

Warty, V

English

Name not available

Fluconazole therapy in transplant recipients under FK506 therapy

D-Scholarship@Pitt

t ~-------------------0041·13371941571()'1521$03.00/0 TRANSPLANTATION Copyright © 1994 by Williams & WIlkins Vol. 57, 1521-1535, No. 10, May 1994 Printed in U.S.A. Transplan tation BRIEF COMMUNICATIONS FLUCONAZOLE THERAPY IN TRANSPLANT RECIPIENTS RECEIVING FK5061 Fungal infections remain an important cause of morbidity and mortality following solid organ and bone marrow trans-plantation (1-3). Use of amphotericin B, the antifungal agent of choice at present, is frequently associated with a high incidence of side effects. In organ transplant patients par-ticularly, the nephrotoxicity of amphotericin may be ampli-fied when combined with immunosuppressive agents such cyclosporine or FK506. F1uconazole, a new antifungal agent with low toxicity and excellent oral bioavailability has been shown to be effective in both the treatment and prophylaxis of fungal infections in immunocompromised patients (4, 5). However, fluconazole is known to inhibit the cytochrome P-450 enzyme system in humans and animals. Coadministration of fluconazole with cyclosporine, a drug that is primarily metabolized in the liver, results in increased cyclosporine blood concentrations in transplant patients (6). Since FK506 is also known to be primarily eliminated by hepatic metabolism, coadministra-tion of fluconazole to patients on FK506 therapy is expected to increase FK506 concentrations in patients (7). In rats, fluconazole is known to increase FK506 blood concentrations (8). In this communication we report our observations on the interaction between FK506 and fluconazole in transplant patients. Twenty organ transplant patients under FK506 immuno-suppression were evaluated while receiving a course of flu-conazole therapy. The patient population included 11 pa-tients who received livers (OLTX); 6 patients who received kidneys (KTX1. 2 patients who received hearts (HTXl and one bone marrow patient. The immunosuppressive regimen in-cluded FK506 and low-dose steroids (20 mg/day). FK506 was given initially as a continuous i.v. infusion at 0.1 mglkg/day, with conversion to the oral dose of 0.15 mglkg every 12 hr with the return of normal bowel function. Subsequent dose adjustments were guided by the quality of the graft. the presence of any evidence of rejection. signs of toxicity, and trough FK506 plasma concentrations (normal range 0.5 to 2 ng/mll. Sixteen of the patients studied had documented fungal infection (7 urinary tract infections. 4 esophagitis. 2 pyelone-phritis. 2 tracheobronchitis. and 1 cholangitis 1. Candida al-bicans was the most common pathogen isolated (14 patients). whereas Candida tropicalis and Cryptococcus neo(ormans were isolated in one patient each. Four additional patients were considered high-risk patients and were treated with prophviactlc fluconazole. The median time from transplanta-tIOn t[) the illltiatlOn of f1uconazole therapy was 60 days I range 2-1680 days). In patients with documented fungal - This work was supported by research grants from the Veterans .-\dminIstration and bv Project Grant 29961 from the National Insti-tutes of Health. Bethesda. MD. infection, fluconazole was given for a median of 14 days (range 7-100 days). Fourteen of the 16 patients were success-fully treated and became culture-negative. Two failures were noted in two kidney transplant patients who required trans-plant nephrectomy for persistent fungal invasion of the graft. Four patients received prophylactic fluconazole for a median of 12 days (range 6-a0 days), and all remained fungal culture negative. F1uconazole was used at a dose of 200 mg/day in 8 patients and 100 mg/day in 12 patients. FK506 plasma con-centrations were measured by an ELISA (9). The intraday coefficient of variation for this assay ranged from 4.2 to 5.5% and the interday coefficient of variation ranged from 14.4 to 17% at concentrations measured in this study. Figure 1 shows the median plasma trough concentration of FK506 on days -1, 0, 1, 2, 3, 4, 5, and 7 after fluconazole therapy as a function of the fluconazole dose administered. On day 1, the median plasma trough concentration ofFK506 increased 1.4· fold in patients receiving 100 mg/day of fluconazole and 3.1-fold in patients receiving 200 mg/day. Thereafter the FK506 plasma concentration decreased as the FK506 dose was re-duced to prevent higher FK506 concentrations. Figure 2 shows the median dose of FK506 and the plasma concentra-tion ofFK506 on days -1, 0,1,2,3,4,5, and 7 of fluconazole therapy. A median FK506 dose reduction of 56% (range 0% to 88%) was required in order to maintain the FK506 concen-trations below 2 ng/ml. There was no change in the route of FK506 administration during the period studied. The initial Rr---------------~----------~~------~ ~ Fluconazole 100mgld - Fluconazole 200 mgl 1\ I \ j.' I ----.. 1 I i l~------------------------------------~ -2 -1 o 2 3 4 5 6 7 8 Days Post-Fluconazole Treatment FIGURE 1. :'vledian plasma trough concentration of FK506 in pa-tients receiving 100 mg (continuous line) and 200 mg (interrupted line) of fluconazole, 1521 1522 TRANSPLANTATION Vol. 57, No. 10 2.5 r------------~-..... FK5OII----L-ev-el---:F:-K508,---.."Do-.. ----,II. 1 0 \ 2 '\ I \ 8 I \ I " .------- ~ \ I , \ I ' .. \ I 6 §. , ,I \ I Q) • (I) 0 C 4 (I) 0 ~ 0.5 2 li-~--~--i-~--~----~--~--~~l -2 -1 0 2 3 4 5 6 7 8 Days Post-Fluconazole Treatment FIGURE 2. Median dose (mg/day) (continuous line) and plasma trough concentration (ng/ml) (interrupted line) ofFK506 during flu-conazole therapy. increase in FK506 plasma concentration during fluconazole therapy was associated with acute renal dysfunction in 3 patients (hemodialysis required in one) and acute changes in the mental status in 2 patients. The pharmacokinetics of FK506 was evaluated in one pa-tient on two occasions, once while on fluconazole therapy (100 mg oral dose, 1 hr prior to FK506 dosing of 3 mg) and again eight days after stopping fluconazole therapy. Figure 3 shows FK506 the plasma concentration vs. time profile over a dos-ing interval in this patient with and without fluconazole therapy. Discontinuation of fluconazole therapy resulted in a significant decrease in the area under the plasma concentration-versus-time curve ofFK506 (from 13 ng/mllhr to 5.4 ng/mllhrl. The half-life maximum plasma concentra-tion and the trough plasma concentration of FK506 also de· creased during this period. FK506 level (ng/ml) PIr-------------------~------=----------K I - Fluconazole ... FK506 ~ S.lOlin. FK500 2.5 ~ J f~ " " 1.5 r- \ \ , 1 1-'" -0.. ~ 0.5 f ,- - - - - -- -0 -1 0 2 3 4 5 6 7 8 9 10 11 12 13 Hours Post·FK506 dose FIGCRE J. FK506 pharmacokinetlc protile or one patient with (con-tinUOUS line, and Wlthout (Interrupted line, tluconazole therapy. FK506 is a new immunosuppressive drug with a proven beneficial effect over currently available agents (10-12). Its elimination through hepatic metabolism by cytochrome P-450 enzyme makes it susceptible to possible interactions with other drugs as that are known to induce or inhibit these enzymes, such as phenobarbital, phenytoin, rifampin, clo-trimazole, ketoconazole, itraconazole, fluconazole, cimeti-dine, and erythromycin (7). In rats, FK506 blood concentra-tions are reported to increase in the presence of fluconazole, erythromycin, ketoconazole, and diltiazam (8). Erythromycin and methylprednisolone have been reported to increase FK506 plasma concentrations (7). Clotrimazole treatment also increases FK506 plasma concentrations in liver trans-plant patients (13). The data reported here show an increase in trough and maximal plasma concentration ofFK506, along with an increase in the half-life of FK506 in the presence of fluconazole. This suggests that fluconazole inhibits FK506 metabolism. It is not possible to predict whether fluconazole decreases FK506 metabolism in the gut and therefore in-creases the extent of absorption or whether it affects only the hepatic metabolism of FK506. Additional studies are re-quired to understand the extent to which this interaction takes place in the small bowel and/or the liver. The increases in the plasma concentration of FK506 were higher at a 200 mg/day fluconazole dose than at a 100 mg/day dose. This dose-related effect, also reported with CsA (6), may have important implications when fluconazole is used in the treat-ment of severe fungal infections. Recently, a new fluconazole dosing regimen (200-400 mg/day) has been suggested for the treatment of invasive candidiasis (14). FK506 concentrations should be carefully monitored when using these dosing regi-mens. Despite the similarities between fluconazole's interac-tion with CsA and FK506, some differences were observed. In renal transplant recipients, fluconazole slowly increased cy-closporine trough concentrations over a two-week period. reaching a maximum of twice the baseline level (6). In our patients the highest concentration of FK506 was seen within three days after the introduction of fluconazole therapy. In summary, fluconazole therapy in patients under FK506 immunosuppression appears to be beneficial for both prophy-laxis and treatment offungal infections. Fluconazole doses of up to 200 mg/day can be safely and effectively administered to transplant patients on FK506 therapy provided that the FK506 dose is reduced by half. Use of higher doses offlucon-azole would require careful monitoring of trough FK506 plasma concentrations and corresponding reduction in FK506 doses to avoid nephrotoxicity. RAFAEL MANEZ· MAUREEN l\WTIN" VENKATARAMANAN RAMAN.! DREW SILVERMAN" AsHOK JAIN>! VIJA y WARTY' IGNACIO dlkwAibw-mfkql~ SHIMON KUSNE'; THOMAS E. STARZL2.5 University or Pittsburgh Medical Center Pittsburgh, Pennsyiuanza 15213 'The Pittsburgh Transplant Institute and the Departments of Surgery and Medicine. -~ i ~ i ----~-- -~K-~---K~-May 1994 BRIEF COMMUNICATIONS 1523 3 School of Pharmacy. 4 Department of Pathology. S Address correspondence to Thomas E. Starzl, M.D., Ph.D., De-partment of Surgery, 3601 Fifth Ave., 4 Falk Clinic, University of Pittsburgh, Pittsburgh, PA 15213. REFERENCES 1. Kusne S, Dummer JS, Singh N, et al. Fungal infections after liver transplantation. Transplant Proc 1988; 20: 650. 2. Wajszczuk CP, Dummer JS, Ho M, et al. Fungal infections in liver transplant recipients. Transplantation 1985; 40: 347. 3. Castaldo P, Stratta RJ, Wood RP, et al. Clinical spectrum of fungal infections after orthotopic liver transplantation. Arch Surg 1991; 126: 149. 4. Flannery MT, Simmons DB, Saba H, Altus P, Wallach PM, Adelman HM. Fluconazole in the treatment of hepatosplenic candidiasis. Arch Intern Med 1992; 152: 406. 5. Goodman JL, Winston DJ, Greenfield RA. et al. A controlled trial of fluconazole to prevent fungal infections in patients under-going bone marrow transplantation. N Engl J Med 1992; 326: 845. 6. Canafax DM, Graves NM, Hilligoss DM, Carleton BC, Gardner MJ, Matas AJ. Interaction between cyclosporine and flucon-azole in renal allograft recipients. Transplantation 1991; 51: 1014. 7. Venkataramanan R, Jain A, Warty VS, et al. Pharmacokinetics of FK506 in transplant patients. Transplant Proc 1991; 23: 2736. 8. Rui X, Flowers J, Warty VS, Venkataramanan R. Drug interac-tions with FK 506. Pharm Res 1992; 9: S314. 9. Warty VS, Venkataramanan R, Zendehrouh P, et al. Practical aspects ofFK506 analysis. Transplant Proc 1991; 23: 2730. 10. Fung J, Abu-Elmagd K, Jain A, et al. A randomized trial of primary liver transplantation under immunosuppression with FK506 vs cyciosporine. Transplant Proc 1991; 23: 2977. 11. Armitage JM, Kormos RL, Fung J, Starzl TE. The clinical trial of FK506 and rescue immunosuppression in adult cardiac trans-plantation. Transplant Proc 1991; 23: 3054. 12. Shapiro R, Jordan M, Scantlebury V, et al. FK506 in clinical kidney transplantation. Transplant Proc 1991; 23: 3065. 13. Mieles L, Venkataramanan R, Yokoyama I, Warty V J, Starzl TE. Interaction between FK506 and clotrimazole in a liver trans-plant recipient. Transplantation 1991; 52: 1086. 14. Milatovic D, Voss A. Efficacy of fluconazole in the treatment of systemic fungal infections. Eur J Clin Microbiol Infect Dis 1992; 11: 395. Received 10 August 1993. Accepted 23 November 1993. POSTTRANSPLANT BLADDER RECOVERY -A PROSPECTIVE RANDOMIZED TRIAL OF TWO TECHNIQUES OF URETERIC ANASTOMOSIS There is good evidence that vesical function deteriorates significantly while patients with end-stage renal failure are on dialysis (1-3) but the extent of its recovery posttrans-plantation is not clear. Prat et a1. (4) reported on bladder evacuating capacity after renal transplantation and found it to be impaired, especially in the presence of a urinary tract infection. The impairment could not be related to age, the volume of urine passed prior to transplantation. or the length of the postoperative period. They attributed the dis-turbed bladder evacuating ability to the degree of bladder wall injury sustained on ureteral implantation, with subse-quent predisposition to recurrent urinary tract infection. This study investigates the extent of recovery of the bladder function posttransplantation and whether the less-traumatic technique of extravesical ureteroneocystostomy allows greater improvement than the intravesical tunneled ureteric implantation. This prospective randomized study allocated 48 patients to either intravesical <Int) or extra vesical (Ext)* ureteroneocys-tostomy lUNC) following an initial preoperative urodynamic study and clinical examination (5). Patients with a previous history of a surgical operation on the urinary bladder and those With a vesical capacity of less than 150 ml were ex-cluded. Randomization was carried out by using a statistical package lEpistat. Round Rock, TX) to produce a numerical sequence for allocation of patients to either arm of the study. usmg sealed blank envelopes opened following revasculariza-tion of the kidney. Immediately pnor to surgery all patients completed two • AbbreVlations: Ext. extravesical: Int. intravesical: UNe. ure-teroneocystostomy. detailed urological questionnaires at the time of the initial study (one surveying the pre-renal failure stage and the other the pretransplant period) that provided information on vesical function (such as frequency of micturition, nocturia, quality of flow, and hesitancy). The internal ureteroneocystostomy (int. UNC) involved re-flecting the peritoneum off the posterolateral aspect of the bladder, after which a 4-5-cm midline cystotomy was made. A 1-2-cm submucosal tunnel was then created, and, after marking the superior aspect of the ureter with a suture, it was pulled through into the tunnel. The ureter was anasto-mosed to the vesical mucosa, using interrupted 3/0 plain catgut in such a way as to produce a nipple at the junction. The cystotomy was closed in two layers using 210 catgut and Surgilon (braided nylon). The external ureteroneocystostomy (ext. UNC) comprised the creation of a small1-cm cystotomy and direct anastomo-sis of the ureter to the edge of the bladder mucosa using interrupted 3/0 plain catgut sutures. A short (1-cm) extravesi-cal tunnel was then created by suturing the perivesical tissue over the distal ureter and the anastomosis. At 3 months posttransplant the patients completed a fur-ther questionnaire and also underwent a repeat urodynamic study of the bladder. Follow-up data on graft function has been obtained for up to 2 years. Only patients with full data are included in the final evalu-ation. The Mann-Whitney U test was used for statistical analysis of the data. A total of 39 completed studies (19 ext. UNC; 20 into UNC) are available for full analysis because the randomized proce-dure was not carried out in one patient, one recipient with-drew immediately after the pretransplant study and random-

http://d-scholarship.pitt.edu/5032/1/31735062124981.pdf

Fluconazole therapy in transplant recipients under FK506 therapy

Abstract

Similar works

Full text

Available Versions

Name not available

Name not available

D-Scholarship@Pitt