Journal of Medicaland VeterinaryMycology (1992),30, 309-315

CASE REPORT

Cryptococcal peritonitis in a CAPD patient B. M O R R I S 1, Y.-F. C H A N 1, J. R E D D Y 2 AND A. W O O D G Y E R 3

(Accepted 25 March 1992)

A 50-year-olddiabetic woman with end-stage renal disease, who had been on continuous ambulatory peritoneal dialysis for 8 months, developed peritonitis caused by Cryptococcusneoformans var. neoformans.The patient was completelyasymptomaticand infection was confirmedby detection of budding yeast cells in Gram-stained smears of turbid peritoneal fluid. The infection was cleared after intravenous fluconazolewith delayed removal of the catheter. Fluconazolemay be a suitable alternative drug in treating cryptococcalperitonitis.

Peritonitis is a major and potentially serious complication of continuous ambulatory peritoneal dialysis (CAPD) and accounts for 16% of the failures in treatment by this method [8]. Over 70% of these infections are caused by Gram-positive bacteria [27]. Fungal infections account for between i to 15% of episodes of peritonitis complicating C A P D [5, 12, 22]. Candida species account for the majority (approximately 75%) of such infections [5, 6]. Less commonly, filamentous fungi including Exophiala jeanselmei, Bipolaris spicifera, Fusarium species [12], Mucor species [1, 21] and the dimorphic fungus Coccidioides immitis [2] have been documented in the literature as the cause of peritonitis in C A P D patients. Cryptococcal peritonitis complicating C A P D is rare, and only four cases have been reported in the literature [10, 11, 18, 28, 29]. We report another case in a chronic diabetic woman and discuss the management of the infection.

CASE H I S T O R Y In 1985, a 45-year-old Maori woman was admitted to Gisborne Hospital for investigation of a large right parotid mass. This was resected and histology revealed a well-differentiated liposarcoma. During her stay in hospital investigations revealed that the patient had diabetes. In February 1985 she was put on a diabetic diet and started on glibenclamide, 5 mg day- 1. There was a history of poor patient compliance in taking the medication. Correspondence address: Mr Brian Morris, Pathology Laboratory, Gisborne Hospital, Gisborne, New Zealand. 309

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~Pathology Laboratory and 2Department of Medicine, Gisborne Hospital, Gisborne, and 3Mycology Reference Laboratory, New Zealand Communicable Disease Centre, Porirua, New Zealand

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Treatment

The Gram-stain of the deposit of the peritoneal fluid indicated a yeast aetiology and treatment with oral ketoconazole 200 mg twice a day was initiated and continued over

FIG. 1. Gram-stain of peritoneal fluid showing budding yeast cell (× 1000).

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In July 1989, the patient was re-admitted because of a 3 week history of a flu-like illness and anuria. She was found to be in acute renal failure with gross haematuria, proteinuria, and markedly impaired renal function. Peritoneal dialysis was started. A renal biopsy was unsuccessful but glomerular basement membrane antibody was significantly raised to 13 units (normally 0-3 units). Anti-glomerular basement membrane disease was diagnosed and she was transferred to Auckland Hospital for haemodialysis. A Tenckhoff catheter was later inserted for CAPD, and she was discharged 6 weeks later with dialysis four times daily using 1500 ml bags of 2.5% dialysate. In April 1990, the patient was re-admitted to improve control of her diabetic state. Physical examination showed the patient to be grossly oedematous but otherwise well. She was afebrile and did not complain of abdominal pain. Laboratory investigations on admission were as follows: haemoglobin 126 g 1 1, white cell count 7.9 × 10 61 1, serum sodium 133 mmol 1-~, potassium 4.1 mmol 1-1, urea 15.9 mmol 1 1 creatinine 0-73 mmol 1-1, and sugar 31.7 mmol 1-I. Forty three hours after admission it was noticed that the peritoneal fluid had become cloudy although the patient remained asymptomatic. Microscopic examination of the fluid showed that the white cell count exceeded 670 x 10 61 I. Examination of a Gram-stain of the centrifuged sediment of the peritoneal fluid showed large Gram-positive budding yeast cells (Fig. 1). These were seen in consecutive samples taken from the bags over the next 3 days. The yeast isolated on Sabouraud glucose agar (Gibco Laboratory, Wisconsin, USA) produced large, mucoid, creamy colonies after incubation at 30°C for 4 days. The yeast was identified as Cryptococcus neoformans using an API 20C yeast identification kit. This was subsequently confirmed by the Mycology Reference Laboratory at the New Zealand Communicable Disease Centre. The isolate failed to grow on canavanine-glycine bromothymol blue agar [14] and was thus further identified as C. neoformans var. neoformans.

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DISCUSSION The principal cause of human cryptococcosis is the yeast C. neoformans var. neoformarts which has a worldwide distribution. The major environmental reservoir of this variant is bird excreta, especially that of pigeons, and the infectious propagules are believed to be desiccated yeast cells. Infection is believed to follow inhalation of the airborne infectious particles. C. neoformans var. gattii is geographically restricted to tropical and subtropical regions including southern California, parts of Australia and Europe [24]. An ecological niche of this variant was unknown until recently when Ellis & Pfeiffer showed that the yeast could be isolated from flowering river red gum trees (Eucalyptus camaldulensis); it was postulated that the principal infectious propagules of this variant were basidiospores [7]. Peritonitis is an unusual manifestation of cryptococcosis and five cases in nonCAPD patients have been described. Each of these patients had ascites caused either by severe underlying hepatic disease or by lupus nephritis and four died as a result of the infection [20]. C. neoformans has been reported as causing peritonitis in a patient on chronic intermittent peritoneal dialysis (CIPD) but no details of this case were given [13]. There have only been four previous reported cases of C. neoformans causing peritonitis in CAPD patients (Table 1) [10, 11, 18, 28, 29]. One of these patients [10] became hypotensive and confused with high fever and C. neoformans was isolated from the peritoneal fluid and blood. This was the first documented case in which there had been systemic spread from the initial focus of infection in the peritoneal fluid. The other three patients reported in the literature had infections which were confined to the peritoneal fluid. One of these [28, 29] appears to have been eliminated by the simple expedient of the patient carrying out peritoneal lavage on first noticing the cloudiness of the fluid. By the time the yeast had been cultured the fluid had cleared again and subsequent cultures were negative. The patients in the other two reported cases were treated with antifungals (see Table 1) and both had their catheters removed. Our patient was never symptomatically unwell and remained afebrile throughout her illness. The only sign of the infection was the persistent cloudy peritoneal fluid. After 1 week of antifungal treatment the fluid was still cloudy and the catheter was subsequently removed.

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the course of the next 2 days. A supply of fluconazole became available and treatment with ketoconazole was discontinued. The fluconazole was administered intravenously at a dose of 100 mg four times a day for 5 days. At the end of this course of treatment the peritoneal fluid was still cloudy and the catheter was subsequently removed the following day. The catheter was not cultured. The patient was again transferred to Auckland Hospital for intermittent haemodialysis. On four occasions during the patient's stay at Auckland Hospital the latex test for cryptococcal capsular antigen was performed on serum with negative results each time. She experienced a stormy course including an episode of enterobacter septicaemia and abdominal wall infection but appeared to be cleared of the cryptococcal infection. She was finally discharged 5 months later with a new Tenckhoff catheter. In November 1990 she was readmitted after a stroke and developed right hemiparesis. Her right lower leg became gangrenous but amputation was declined. Before her death 2 months later there were two brief episodes of bacterial peritonitis which were cleared by antibiotics. No further cryptococcal infection was detected.

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TABLE 1. Cases of cryptococcal peritonitis in CAPD patients

Reference [11 ] (1985)

Underlying illness(es)

Isolation sites of C. neoformans

Y2

Success

Peritoneal lavage

N

Success

Peritoneal fluid

Amp B (i.p., i.v.)

Y 1

Success

ESRD No cause given Probable pulmonary tuberculosis

Peritoneal fluid

A m p B (i.v.) Flucy (OR)

Y ?

Success

ESRD Antiglomerular basement membrane disease Diabetes mellitus

Peritoneal fuid

Keto Flucon

Y7

Success

ESRD Insulin-dependent diabetes mellitus Antibiotic treatment of chest infection

Peritoneal fluid

[28, 29] (1985, 88)

ESRD No cause given

Peritoneal fluid

[18] (1986)

ESRD Medullary cystic disease

[10] (1989)

Mi Ke

Blood

ESRD - end-stage renal disease. Mi - miconazole; Ke = ketoconazole; A m p B = amphotericin B; Flucy = flucytosine; Flucon = fluconazole; i.p. = intraperitoneal; i.v. = intravenous; OR = oral. ESRD = end-stage renal disease.

Although our patient's diabetes was poorly controlled there is no evidence that this is a risk factor in the development of fungal peritonitis in CAPD patients. A number of studies have shown that the risk of peritonitis, either caused by bacteria or fungi, is not significantly different between diabetic or non-diabetic patients receiving CAPD [1, 13, 27]. One of the previously reported cases of cryptococcal peritonitis complicating CAPD was an insulin-dependent diabetic [11]. It has been estimated that a patient on CAPD using four exchanges daily will break the sealed system approximately 1500 times a year [19] and that contamination occurs during changing of the bag/transfer set. It is essential that CAPD "patients be taught a scrupulous, standardized, aseptic technique for bag change" [22]; the present patient did not have a particularly good technique in this regard. In a report by a Working Party of the British Society for Antimicrobial Chemotherapy it was stated that clinical peritonitis usually becomes apparent 24-48 h following contamination [22]. However the majority of aetiologic agents considered in that report were bacterial and in view of the slower growth rates of the fungi, it is probable that the incubation time would be somewhat longer. In the experience of one group of workers fungal peritonitis had a very slow onset, the only sign being intermittent cloudiness of the peritoneal fluid, sometimes over a period of several weeks, eventually becoming continuously turbid without any other clinical signs or symptoms such as fever, abdominal pain, or digestive disturbances [3]. In common with many public buildings in New Zealand, there are appreciable numbers of pigeons in permanent residence at Gisborne Hospital and it is remotely possible that our patient's infection was nosocomial in origin; the time between admittance and the appearance of the first turbid dialystate of only 43 h, how-

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Present case

Therapy

Removal of catheter (Y/N) days after diagnosis Outcome

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ever, does make this unlikely. Our patient, in common with three of the other CAPD patients who developed cryptococcal peritonitis, showed no evidence of a pulmonary infection and the most likely portal of entry would have been via the catheter. The need for a careful regular check of the dialysate from CAPD patients cannot be over-emphasized as it is by far the most reliable indicator of infection. In one study it was reported that in terms of symptoms, only 80% of patients had abdominal pain and only 23% developed fever [27]. Confirmation of infection depends on the demonstration of neutrophilis in the fluid (>100 × 106 1-1) [22] and the detection of microorganisms by Gram-stain and culture. In the present case we found that Gram-stains of centrifuged deposits were very useful as yeast cells were first detected by this method. The reported rate of detection of organisms using this method ranges from 9 to 50% [22, 23, 26]. However in view of its simplicity and possible immediate diagnosis, as seen in our patient, a Gram-stain of the deposit of the peritoneal fluid should be considered to be an important adjunct to culture. Fungal peritonitis in patients receiving peritoneal dialysis has a high morbidity and mortality and in a recent study more than 50% of the patients either died or had to be transferred to haemodialysis [5]. There are essentially two approaches to the management of CAPD patients who develop fungal peritonitis. Some authorities advocate early removal of the catheter following rapid fluid exchanges, to eliminate gross turbidity and the risk of adhesions, with concurrent parenteral administration of antifungal [12, 22]. In those patients where the peritoneal effluent is viscid at the time of removal, peritoneal lavage with antifungal drugs via a temporary peritoneal dialysis catheter has been found to be successful in eliminating the infection and offers the possibility of re-establishing CAPD in these patients [5]. Alternatively, other authors suggest aggressive chemotherapy with the catheter in situ, with peritoneal lavage in those cases where the fluid is viscid. Removal of the catheter is then reserved for those cases which show persistently abnormal clinical signs, positive culture results or where the catheter has become obstructed [5, 6, 16]. In the management of the present case, the second of these options was chosen. The reasons for this were that firstly there are no haemodialysis facilities available at Gisborne Hospital so that in the event that the early removal of the catheter was not successful the patient would have to be transferred to another hospital. Secondly, because of a history of poor patient compliance it was considered that she might refuse to have a second catheter. There is little consensus in the literature as to the choice of antifungal(s), the means of administration or the duration of therapy in the treatment of fungal peritonitis in CAPD patients. Amphotericin given via the intraperitoneal route can cause considerable discomfort and may be responsible for producing peritoneal fibrosis and thus is contraindicated [6, 15, 22]. Flucytosine readily passes from the blood into the peritoneal fluid and can reach potentially toxic levels so that the dose must be adjusted accordingly. Additionally the development of resistance to flucytosine is well documented when used as the sole chemotherapeutic agent [6, 12] and it should therefore be used in combination with other antifungals. Flucytosine, in combination with amphotericin B, or with either ketoconazole or miconazole has been used successfully in the treatment of this type of infection [5, 10, 12, 15]. It has been demonstrated that ketoconazole reaches very low concentrations in the peritoneal fluid and these would be unlikely to be effective against the fungi involved in peritonitis [4, 17, 26]. A recent report showed fluconazole to be effective in the treatment of Candida peritonitis in two CAPD patients. The levels of fluconazole detected in the peritoneal fluid represented a

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peritoneal penetration of more than 60% [16]. Because there is little or no tissue or protein binding of fluconazole, it rapidly reaches high concentrations in the CSF and other sites including the peritoneal fluid [9]. Characteristically there is a rapid response to fluconazole [9] and in one report where it was used in the treatment of cryptococcal meningitis in AIDS patients, there was a clinical improvement in the patients within 3-5 days [25]. Although the present patient was only treated for 5 days with this antifungal, this appears to have been sufficient to have reduced the numbers of viable yeasts thus preventing any recrudescence of the infection over the next 7 months prior to the patient's death from other causes.

The authors wish to thank Mrs D. Parr of the Wallace Laboratory, Auckland Hospital, for providing the results of the cryptococcal serology performed in her laboratory. The authors would also like to acknowledge the assistance given by Pfizer Laboratories Limited in supplying fluconazole on compassionate grounds.

REFERENCES 1. AMAIR, P., KHANNA, R., LEIBEL, B., PIERRATOS, A., VAS, S., MEEMA, E., BLAIR, G., CHISOLM, L., VAS, M., ZINGG, W., DIGENIS,G. • OREOPOULOS,D. 1982. Continuous ambulatory peritoneal dialysis in diabetics with end-stage renal disease. New England Journal of Medicine, 306, 625~530. 2. AMPEL,N. M., WHITE,J. D., VARANASI,U. R., LARWOOD,Z. R., VAN WYCK,D. B. & GALGANI,J. N. 1988. Coccidioidal peritonitis associated with continuous ambulatory peritoneal dialysis. American Journal of Kidney Disease, I I, 512-514. 3. BENEVENT,O., REYRONNET, P., LAGARDE, C. & LEROUX-ROBERT,C. 1985. Fungal peritonitis in patients on continuous ambulatory peritoneal dialysis. Three recoveries in 5 cases without catheter removal.

Nephron, 41,203-206. 4. CHAPMAN, J. R. • WARNOCK, D. W. 1983. Ketoconazole and fungal CAPD peritonitis (Correspondence). Lancet, ii, 510-51 i. 5. CHENG,I. K. P., FANG,G-X., CHAN, T-M., CHAN, P. C. K. & CHAN, M-K. 1989. Fungal peritonitis complicating peritoneal dialysis: report of 27 cases and review of treatment. Quarterly Journal of Medicine

(Oxford), 71,407-416. 6. EISENBERG,E.S., LEVITON,1. & SOEIRO,R. 1986. Fungal peritonitis in patients receiving peritoneal dialysis: experience with 11 patients and review of the literature. Reviews of Infectious Diseases, 8, 309-321. 7. ELLIS, D. H. & PFEIFFER,Z. J. 1990. Ecology, life cycle, and infectious propagule of Cryptococcus neoformans. Lancet, ii, 923-925. 8. GOKAL,R., RAMOS,J. M., FRANCIS,D. M. A., FERNER, R. E., GOODSHIP,Z. H. J., PROUD, G.. BINT, A. J., WARD, M. K. & KERR, M. K. 1982: Peritonitis in continuous ambulatory peritoneal dialysis. Lancet, ii, 1388-1391. 9. HAY, R. J. 1991. Antifungal therapy and the new azole compounds. Journal of Antimicrobial Chemotherapy, 28 (Supplement A), 35-46. 10. KACZMARSKI,E. B., TOOTH, J. A., ANASTASSIADES,E., MANOS, J. & GOKAL, R. 1989. Cryptococcosis complicating continuous ambulatory peritoneal dialysis. Journal of Infection, 18, 289-292. 11. KEOGH,J. A. B., CARR, M. E., MURRAY,F., MCEVO¥, M., GRANT,G. & KEANE,C. T. 1985. Treatment of fungal peritonitis in CAPD patients using peritoneal lavage. Peritoneal Dialysis Bulletin, 5, 67~59. 12. KERR, C. M., PERFECT,J. R., CRAVEN,P. C., JORGENSEN,J. H., DRUTZ, D. J., SHELBURNE,J. D., GALLIS, H. A. & GUTMAN,R. A. 1983. Fungal peritonitis in patients on continuous ambulatory peritoneal dialysis. Annals of Internal Medicine, 99, 334-337. 13. KRAUS,E. S. & SPECTOR,D. A. 1983. Characteristics and sequelae of peritonitis in diabetics and non-diabetics receiving chronic intermittent peritoneal dialysis. Medicine, 62, 52-57. 14. KWON-CHUNG,K. J., POLACHECK,I. & BENNETT,J. E. 1982. Improved diagnostic medium for separation of Cryptococcus neoformans var. neoformans (serotypes A and D) and Cryptoeoccus neoformans vat. gattii (serotypes B and C). Journal of Clinical Microbiology, 15, 535-537.

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ACKNOWLEDGEMENTS

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15. LEMPERT,K. D. & JONES,J. M. 1982. Flucytosine-miconazole treatment of Candida peritonitis. Archives of lnternal Medicine, 142, 577-578. 16. LEVINE,J., BERNARD,D. B., IDELSON,B. A., FARNHAM,H., SAUNDERS,C. & SUGAR,A. M. 1989. Fungal peritonitis complicating continuous ambulatory peritoneal dialysis: successful treatment with fluconazole, a new orally active antifungal agent. American Journal of Medicine, 86, 825-827. 17. McGuIRE, N. M., PORT, F. K. & KAUFFMAN,C. A. 1984. Ketoconazole pharmacokinetics in continuous ambulatory peritoneal dialysis. Peritoneal Dialysis Bulletin, 4, 199-201. 18. MORFORD,D. W. & SANDRONI,S. E. 1986. Cryptococcal peritonitis review. In: R. KHANNA,K. NOLPH, B. PROWANT,Z. TWARDOWSKI& D. OREOPOULOUS(Eds) Advances in CAPD, Proceedings of the 6th Annual CAPD Conference, pp. 141-142, Kansas, Missouri. University of Toronto Press, Toronto. 19. PARSONS,F. M., AHMED-JUSHUF,I. H., BROWNJOHN,A. M., COLTMAN,S. J., GIBSON,J., YOUNG,G. A. & YOUNG,J. B. 1983. CAPD peritonitis. Lancet, i, 348-349. 20. POBLETE,R. B. & KIRBY,B. D. 1987. Cryptococcal peritonitis - report of a case and review of the literature. American Journal of Medicine, 82, 665~567. 21. POLO, J. R., LUNO, J., MENARGUEZ,C., GALLEGO, E., ROBLES, R. & HERNANDEZ,P. 1989. Peritoneal mucormycosis in a patient receiving continuous ambulatory peritoneal dialysis. American Journal of Kidney Disease, 13, 237-239. 22. Report of a working party of the British Society for Antimicrobial Chemotherapy. 1987. Diagnosis and management of peritonitis in continuous ambulatory peritoneal dialysis. Lancet, i, 845--849. 23. RUBIN,J., ROGERS, W. A., TAYLOR,H. M., EVERETt, D., PROWANT,B. F., FRUTO, L. V. & NOLPH, K. D. 1980. Peritonitis during continuous ambulatory peritoneal dialysis. Annals of Internal Medicine, 92, 7-13. 24. SMITH,J. M. B. 1989. Opportunistic Mycoses of Man and Other Animals, pp. 53-80. C.A.B. International Mycological Institute, London. 25. SUGAR,m. M., STERN,J. J. & DUPONT,B. 1990. Overview: treatment of cryptococcal meningitis. Reviews of Infectious Diseases, 12 (Supplement 3), $338-348. 26. VALAINIS,G. T. & MORFORD,D. W. Ketoconazole levels in peritoneal fluid (Correspondence). Peritoneal Dialysis Bulletin, 5, 136. 27. VAS, S. I. 1983. Microbiologic aspects of chronic ambulatory peritoneal dialysis. Kidney International 23, 83-91. 28. WANG,F. 1985. Cryptococcus peritonitis (Correspondence). Peritoneal Dialysis Bulletin, 5, 78. 29. WANG,F. 1988. Cryptococcus peritonitis. Singapore Medical Journal 29, 88-89.

Cryptococcal peritonitis in a CAPD patient.

A 50-year-old diabetic woman with end-stage renal disease, who had been on continuous ambulatory peritoneal dialysis for 8 months, developed peritonit...
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