Fungal Peri onitis Complicating Continuous Ambulatory Peritoneal Dialysis: Successful Treatment with Fluconazole, a New Orally Active Antifungal Agent JERROLDLEVINE,M.D., DAVIDB.BERNARD,M.D., ALAN M. SUGAR, M.D. Boston, Massachusetts
ungal infections account for between 1 percent [l] and 15 percent  of episodes of peritonitis in patients with end-stage renal disease (ESRD) managed by continuous ambulatory peritoneal dialysis (CAPD). Despite this relatively high frequency and the impression that fungal peritonitis is becoming more common , no clear consensus exists as to the best strategy for treating the condition. Controversy centers on several issues: the choice and total dose of the antifungal agent, the route of administration, the value of continuous peritoneal lavage, and the role of removal of the indwelling Tenckhoff catheter. Although some authors have reported cures solely by removal of the catheter [3,4], most recommend the use of an antifungal agent, whether or not the catheter is left in place [3-71. A variety of antifungal agents have been used to treat fungal peritonitis, including amphotericin, 5fluorocytosine, ketoconazole, miconazole, and econazole [l-8]. For each drug, successes and failures have been reported, and none is without serious drawbacks. Neither amphotericin nor ketoconazole diffuses well into the peritoneal fluid from the blood [2,8]. Intraperitoneal administration of amphotericin is frequently painful and may increase the risk of peritoneal fibrosis and adhesions . 5-Fluorocytosine, which does reach the peritoneal fluid in high concentrations when given orally , is limited in its usefulness by a narrow range of activity, the development of resistance, and serious toxicity . The imidazole agents, miconazole [lo] and econazole , are hampered by poor absorption after oral administration and significant first-pass metabolism. We report herein the successful use of a new oral antifungal agent, fluconazole [ll], in two CAPD patients with Candida peritonitis. Fluconazole, a watersoluble triazole derivative, possesses several pharmacokinetic properties that make it an ideal agent for this condition, including nearly complete absorption after oral administration and excellent penetration into the peritoneal dialysate.
CASE REPORTS Patient 1 A 60-year-old white woman with reflux nephropathy, chronic pyelonephritis, hypertension, and adultonset diabetes mellitus began intermittent peritoneal dialysis in June 1987. During one of her weekly dialysis From the Evans Memorial Department of Clinical Research, The University Hospital, Boston University School of Medicine, Boston, Massachusetts. Pfizer Central Research provided the fluconazole. Requests for reprints
sessions, she received vancomycin and gentamicin empirically because of an episode of hypotension and hypothermia. Concomitant upper endoscopy performed after an episode of hematemesis revealed inflammation, compatible with Candida esophagitis. Cultures were not obtained. In July 1987, she began CAPD with four daily exchanges of 2 liters of Deflex Solution (Delmed Inc., Freehold, New Jersey). Soon thereafter, she developed bacterial peritonitis, which was successfully treated with appropriate antibiotics. A second episode of bacterial peritonitis in September 1987 was also successfully treated with antibiotics. Neither episode of peritonitis required admission to the hospital. Three weeks after administration of the last dose of antibiotics, she developed cloudy peritoneal effluent, nausea, and mild abdominal pain. Physical examination was notable for a temperature of 38.1”C and diffuse abdominal tenderness, with slight guarding and decreased bowel sounds. The peripheral white blood cell count was 8,000/mm3. The peritoneal fluid contained red blood cell and white blood cell counts of nine and 3,020/mm3, respectively, with 92 percent neutrophils and 8 percent lymphocytes. Gram stain demonstrated budding yeast forms and pseudohyphae, later identified as Candida parapsilosis. Treatment with oral fluconazole was started on the second hospital day. An oral loading dose of 200 mg was followed by a single daily dose of 100 mg, administered at 11 P.M. just before the instillation of dialysate for the overnight dwell. Apart from a single empiric intravenous dose of vancomycin, fluconazole was the only antimicrobial agent given. The Tenckhoff catheter was removed on the 12th hospital day because of persistent symptoms and a continued positive Gram stain of the peritoneal effluent. Culture of the catheter tip also revealed C. parapsilosis. After the peritoneal catheter was removed, her symptoms resolved rapidly, and she was discharged from the hospital on the 18th hospital day. Interim hemodialysis was provided through a temporary subclavian access. After six weeks of therapy with fluconazole, a new peritoneal catheter was placed. All subsequent cultures of her peritoneal fluid have shown no growth, and she has successfully resumed CAPD. Patient 2 A 42-year-old black man with ESRD secondary to severe hypertension began CAPD in September 1987 after chronic rejection of a cadaveric renal transplant. He had positive test results for hepatitis B surface antigen without clinical evidence of liver disease. CAPD was done with four daily exchanges of 2 liters of Deflex Solution. In February 1988, an episode of bacJune
CAPD / LEVINE
9 12 15 Time in hours
terial peritonitis was successfully treated with appropriate antibiotics. In March 1988, intravenous antibiotics were given for 10 days. because of pneumonia. Three weeks after discharge, he developed cloudy peritoneal effluent, nausea, &norexia, and abdominal pain. His temperature was 37.O”C and he had diffuse abdominal tenderness with guarding. The peripheral white blood cell count was 11,200/mm3. The peritoneal fluid contained red blood cell and white blood cell counts of 50 and 2,900/mm3, respectively, with 82 percent neutrophils and 18 percent mononuclear cells. Gram stain demonstrated budding yeast forms and pseudohyphae, later identified as Candida albicans. Fluconazole was begun on the first hospital day and was administered in a fashion identical to that for the first patient. Because of persistent symptoms, the Tenckhoff catheter was removed on the fourth hospital day. Within 48 hours of removal of the catheter, the patient’s symptoms resolved. He was discharged on the 10th hospital day. Interim hemodialysis was provided through an existing arteriovenous fistula. After six weeks of therapy with fluconazole, a new indwelling Tenckhoff catheter was placed. All subsequent cultures of his peritoneal fluid have shown no growth, and he has successfully resumed CAPD.
METHODS AND RESULTS Serum and dialysate fluid were frozen and shipped on dry ice to The Fungus Testing Laboratory, University of Texas Health Science Center, San Antonio, Texas, for measurement of fluconazole levels. Figure 1 shows simultaneous serum and dialysate concentrations of fluconazole measured on a single day (several days after the start of therapy) for the first patient; the standard lOO-mg dose had been given at 11 P.M. the night before. Serum levels ranged from 8 to 9 pg/ml, with corresponding dialysate levels ranging from 5 to 9 pg/ml. These concentrations represent a peritoneal penetration of greater than 60 percent. Figure 2 shows simultaneous serum and dialysate concentrations of fluconazole measured repeatedly over the-first four days of therapy for the second patient. A 200-mg loading dose was administered at 11 P.M. on the first evening; all subsequent doses of 100 826
Figure 1. Simultaneous fluconazole concentrations in serum and peritoneal dialysatefluidfor Patient 1 following 100 mg offluconazolegiven at 11 P.M. the previous evening. Abscissa represents the time in hours after the administration of fluconazole. Arrow Indicates the time of administration of the drug.
mg were given at the same time each day. Serum levels ranged from 3.2 to 5.9 pg/ml, with corresponding dialysate levels ranging from 2.3 to 7.3 fig/ml. These concentrations represent a peritoneal penetration of greater than 60 percent. At the end of the course of therapy in Patient 2, the serum concentration of fluconazole in random samples was approximately 8 PgI ml.
COMMENTS Our two cases illustrate several important aspects in the diagnosis and management of fungal peritonitis in patients receiving CAPD. Fungal peritonitis frequently occurs following a course of antimicrobial therapy given for bacterial peritonitis or other infections [2,3,5]. Although Candida esophagitis may have been the source of the first patient’s peritonitis, an extraperitoneal site of fungal infection is rarely identified [31* Major controversy continues with regard to the role of early removal of the indwelling catheter. Some believe that early removal of the catheter is essential to successful eradication of fungal peritonitis and may even be the only therapy needed [1,2,4,12-141. Others have shown, however, that despite negative peritoneal fluid culture results, fungi may be cultured from the removed catheters [2,3], suggesting that antifungal therapy is essential if cure is to be achieved in most cases. Indeed, we believe the major reason for recommending the avoidance of antifungal therapy is the fact that currently available antifungal drugs are extremely toxic or have unfavorable pharmacokinetic properties, a problem not shared by fluconazole. Routine early catheter removal seems to increase the risk of peritoneal adhesions and diminishes the chances of successful resumption of CAPD [5-71. In one large review, only 13 percent of patients whose catheters were removed were able to resume peritoneal dialysis . Two approaches have been offered to avoid this complication. The first is vigorous peritoneal lavage [lo]; the second is a trial of antifungal agents alone, with catheter removal being reserved for cases characterized by persistently abnormal clinical signs or positive culture results [5-71. In some reports, cures have
Figure 2. Simultaneous fluconazole concentrations in serum and peritoneal dialysate fluid for Padent 2 over the first four days of therapy. Abscissa represents the time in hours after the loading dose of fluconazole. Arrows show the time of administration and the dosage of fluconazole. A loading dose of 200 mg was given on the first evening, followed by a maintenance dose of 100 mg on all subsequent evenings.
been achieved in about 25 percent of such patients without catheter removal [3,5]. In our cases, we had hoped to avoid removing the catheter, but clinical and microbiologic evidence of peritonitis persisted despite clearly adequate peritoneal levels of fluconazole. After catheter removal, clinical symptoms resolved within 48 hours. Moreover, peritoneal adhesions did not seem to develop and CAPD was successfully resumed in both patients after completion of therapy. This favorable outcome was likely the result of our ability both to administer fluconazole for many weeks without significant side effects and to achieve sustained antifungal activity in the peritoneal cavity. This experience leads us to propose treating fungal peritonitis in hemodynamically stable patients undergoing CAPD with oral fluconazole therapy while continuing CAPD. If a clinical or bacteriologic response is not seen within five to seven days, the catheter should be removed and oral fluconazole therapy should be continued for four to six weeks. This approach may decrease the likelihood of peritoneal adhesions. The triazole derivative fluconazole is a new antifungal agent currently undergoing phase III trials in patients with a variety of fungal diseases. Fluconazole’s pharmacokinetic profile makes this agent a most promising drug for the treatment of fungal peritonitis [ll]. Oral bioavailability in human volunteers was greater than 60 percent, whereas plasma levels in mice were proportional to the administered dose over a 40fold range [ll]. A calculated volume of distribution was 0.7 liters/kg, a value similar to that of total body water and consistent with the drug’s water-soluble nature. A minimal degree of protein binding, on the order of 11 percent [ll], probably explains the drug’s high penetration into the peritoneal dialysate by the end of four hours. Dosing is relatively simple, since the major route of clearance is the kidney, with hepatic metabolism accounting for less than 10 percent of the drug’s elimination. To date, the drug seems remarkably free of toxicity and can be used safely for prolonged periods. In summary, this report describes the first use of fluconazole in the treatment of fungal peritonitis. Flu-
CAPD / LEVINE ET AL
conazole offers two major advantages over other antifungal drugs. An extremely favorable pharmacokinetic profile permits once daily oral administration, and, perhaps of even greater significance, both our patients were able successfully to resume CAPD. If these results are confirmed, we believe fluconazole will become the treatment of choice in cases of fungal peritonitis in patients receiving CAPD.
ACKNOWLEDGMENT We thank Drs. Michael Rinaldi and Jack Wellan for performing the fluconazole measurement. We also thank Patricia MacDonald for expert secretarial help.
REFERENCES 1. Report of Working Party of the British Society for Antimicrobial Chemotherapy: Diagnosis and management of peritonitis in continuous ambulatory peritoneal dialysis. Lancet 1987; I: 845-849. 2. Kerr CM, Perfect JR, Craven PC, eta/: Fungal peritonitis in patients on continuous ambulatory peritoneal dialysis. Ann Intern Med 1983; 99: 334-337. 3. Eisenberg ES, Leviton I, Soeiro R: Fungal peritonitis in patients receiving peritoneal dialysis: experience with 11 patients and review of the literature. Rev Infect Dis 1986; 8: 309-321. 4. Fabris A, Biasioli S, Borin D, et al: Fungal peritonitis in peritoneal dialysis: our experience and review of treatments. Perit Dial Bull 1984; 3: 75-77. 5. Rault R: Candida peritonitis complicating chronic peritoneal dialysis: a report of 5 cases and review of the literature. Am J Kidney Dis 1983; 2: 544-547. 6. Benevent D, Peyronnet P, Lagarde C, Leroux-Robert C: Fungal peritonitis in patients on continuous ambulatory peritonitis. Three recoveries in 5 cases without catheter removal. Nephron 1985; 41: 203-206. 7. Struijk DG, Krediet RT. Boeschoten EW, Rietra PJGM, Arisz L: Antifungal treatment of Candida peritonitis in continuous ambulatory peritoneal dialysis patients. Am J Kidney Dis 1987; 9: 66-70. 8. Chaoman JR. Warnock DW: Ketoconazole and fungal - oeritonitis. Lancet 1983; II: 510-5il. 9. Bennett JE: Flucytosine. Ann intern Med 1977; 86: 319-322. 10. Keogh JAB, Carr ME, Murray F, McEvoy M, Grant G. Keane CT: Treatment of fungal peritonitis in CAPD patients using peritoneal lavage. Perit Dial Bull 1985; 4: 67-69. 11. Humphrey MJ, Jevons S, Tarbit MH: Pharmacokinetic evaluation of UK49,858, a metabolically stable triazole antifungal drug, in animals and humans. Antimicrob Agents Chemother 1985; 28: 648-653. 12. Khanna R, Oreopoulos D. Vas S, McCready W, Dombros N: Fungal peritonitis in patients undergoing chronic intermittent or continuous ambulatory peritoneal dialysis. Proc EDTA 1980; 17: 291-296. 13. Cecchin E, de Marchi S, Panarello G: Chemotherapy and/or removal of the peritoneal catheter in the management of fungal peritonitis complicating CAPD. Nephron 1985; 40: 251-252. 14. Travenol Peritonitis Management Advisory Committee: CAPD related peritonitis management and antibiotic therapy recommendations. Perit Dial Bull 1987; 7: 5568.