A literature review of C. tropicalis non-prosthetic arthritis is included. The isolate .... (1800 mg/d). AMB ... approximately 65 cases were described in the literature.
Brief Report G. Weers-Pothoff, J. E H a v e r m a n s , J. K a m p h u i s , H. A . M. Sinnige, J. E G. M. M e i s
Candida tropicalis Arthritis in a Patient with Acute Myeloid Leukemia Successfully Treated with Fluconazole: Case Report and Review of the Literature Summary: The case of a 77-year-old woman with acute myeloid leukemia who developed Candida tropicalis septic arthritis of the knee after remission-inducing chemotherapy is reported. A literature review of C. tropicalis non-prosthetic arthritis is included. The isolate was susceptible to fluconazole (MIC 0.25 mgh). She was treated with fluconazole (400 mg orally) and frequent relieving synovial aspirations. After 1 month of antifungal therapy the synovial fluid became culture negative. Fluconazole concentration in the synovial fluid and serum were 20 mg/! and 19.4 mg/l, respectively. The patient was treated for a total of 7 months and made a full recovery. This is the first report of the successful use of fluconazole in the treatment of septic arthritis due to C. tropicalis.
Introduction Systemic candidosis is a f r e q u e n t complication o f intensive i m m u n o s u p p r e s s i v e therapy, total parenteral nutrition, multiple a b d o m i n a l surgery and long-term use of b r o a d spectrum antimicrobial c h e m o t h e r a p y . T h e vast majority of cases of candidosis are caused by Candida albicans. In several published studies Candida tropicalis has b e e n recognized as an increasingly i m p o r t a n t p a t h o g e n , especially in g r a n u l o c y t o p e n i c patients [1]. A m p h o t e r i c i n B remains the mainstay of t h e r a p y for serious infection in n e u t r o p e nic patients, but fluconazole appears to be an attractive, less toxic, alternative [2]. H e r e we r e p o r t successful t r e a t m e n t with fluconazole of septic arthritis due to C. tropicalis in a patient after remission-inducing c h e m o t h e r a p y for leukemia.
Case Report A 77-year old woman was diagnosed with acute myeloid leukemia (FAB classification M2). Eleven years earlier a total hip arthroplasty was done because of osteoarthritis. At the time of diagnosis the leukocyte count was 57.4 × 109/1with 89% blast cells. The erythrocyte sedimentation rate (ESR) was 32 mm in the first hour. Chemotherapy (cytarabine 100 mg/m 2 i.v. for 7 days and mitoxantrone 10 mg/m 2 i.v. for 3 days) was administered via a Hiekmann catheter. During chemotherapy the patient received selective bowel decontamination with ofloxacin (200 mg every 12 h), amphotericin B oral suspension (5 ml every 12 h) and miconazole oral gel ( l g every 6 h). Surveillance cultures on admission showed C. albicans colonization in throat and faeces. She became granulocytopenic with less than 0.5 x 109 granulocytes/1 for a total of 21 days, The teukopenic period was complicated by pneumonia of unknown etiology (treated with cefuroxime 750 mg every 8 h and tobramycin 4 mg/kg once daily) and herpes labialis (treated with acyclovir 800 mg every 8 h orally). Six weeks after start of the first cycle of chemotherapy asternum biopsy showed a partial remission with 8 % blasts and she was admitted to the hospital for another course of chemotherapy. Ten days before admission her right knee became swollen and pain-
ful without fever. At admission these symptoms had waned. Physical examination showed a slightly swollen right knee join t with minimal tenderness. There were no complaints or abnormalities in the other joints. After the second course of chemotherapy she was granulocytopenic with less than 0.5 × 109 granulocytes/1 for a total of 18 days. A suspected pneumonia was again treated with cefuroxime and tobramycin. At the end of the neutropenic period she became febrile with temperatures up to 38.5°C and the knee became more painful and swollen. The ESR rose to 118 mm and C-reactive protein (CRP) was 92 mg/1. A roentgenogram of the right knee showed arthrosis, hydrops and subchondral elucidation. A gallium scan demonstrated high activity in the right knee and the prosthetic right hip joint. Radiographically the hip was unchanged and she had no hip-related complaints. Several blood cultures, throat-swabs, nose-swabs and stool cultures were taken but only one throat swab was positive for both C. albicans and C. tropicalis at the start of chemotherapy. Arthrocentesis of the knee revealed turbid synovial fluid with, in the Gram-stained smear, several leukocytes and sporadic erythrocytes. Cultures became positive for C. tropicalis susceptible to fluconazole (MIC 0.25 rag/l) and amphotericin B (MIC 0.5 mg/1). Speciation of the germ-tube negative yeast isolate was performed with the Auxacolor (Sanofi Diagnostics Pasteur, Marnes-la-Coquette, France) system and read after 48 h of incubation (profile number 7147005). Susceptibility testing was performed with a microtiter broth dilution method [3] using RPMI-1640 with MOPS buffer according to the proposed NCCLS standard [4]. No change in MIC could be measured during therapy. Since amphotericin B was considered to be too toxic, the patient was treated orally with fluconazole 400 mg once daily and frequent relieving synovial aspirations. The Hickmann catheter was removed. After 17 days of treatment,fluconazole concentrations Received: 19 August 1996/Revision accepted: 3 November 1996 G. Weers-Pothoff, M. D., Dept. of Medical Microbiology, J. F. Haverrnans, M. D., Dept. of Rheumatology, 9".Kamphuis, M. D., H. A. M. Sinnige, M. D., Dept. of Internal Medicine, Bosch Medicentrum, Den Bosch; J. 17. G. M. Meis, M. D., Dept. of Medical Microbiology, MMB 440 University Hospital Nijmegen, P. O. Box 9101, NL-6500 HB Nijmegen, The Netherlands.
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G. Weers-Pothoff et al.: Candida tropical& Arthritis Treated with Fluconazole Table 1 : Clinical features of r e p o r t e d c a s e s of
112], 1976
77/M
Candida tropicalis n o n - p r o s t h e t i c arthritis.
Leukopenia; central venous catheter; IV antibiotics Cytotoxic regimens; prednisone, trauma
[13], 1978
12/M
[14], 1982
59/M
Chemotherapy; corticosteroids; antibiotics; neutropenia
[14], 1982
67/M
[15], 1984
66/F
Chemotherapy; corticosteroids; antibiotics; neutropenia Antibiotics/chemotherapy
[16], 1993
1 month/M
Multiple antibiotics; hyperalimentation
PR, 1997
77/F
Granutocytopenia; intensive chemotherapy, intravascular catheter
Bladder carcinoma; sepsis
Right shoulder
AMB. 9 weeks
Arthritis cured
(i,001mg) 5-FC 6 g/d, Acute lymphocytic Knee 21 days leukemia, multiple AMB relapses (40 mg) Acute myelogenous Right knee AMB (245 mg) leukemia miconazole IV 1 week (1800 rag/day) Chronic myelocytic Left knee Ketoconazole 800 rag/day leukemia orally 4 weeks AMB Lymphocytic lymKnee (158 mg), phoma miconazole IV, 3 weeks (1800 mg/d) AMB Prematurity Knee (320 mg), 5 FC, orally 100 mg/kg/day, 71 days Ftuconazole (400 mg) Acute myeloid leuke- Knee orally, mia 7 months
Arthritis resolved clinically; at autopsy disseminated candidiasis Arthritis cured
Arthritis cured
Arthritis cured
Arthritis cured
Arthritis cured
AMB = amphotericin B; 5 FC = 5-flucytosine.
in synovial fluid and in blood were 20 mg/l and 19.4 mg/1, respectively, as measured by high-performance liquid chromatography with ultraviolet detection [5]. The patient improved slowly and after 1 month of antifungal therapy the synovial fluid became culture negative for C. tropicalis. Treatment with fluconazole (400 mg daily) was continued for a total of 7 months. During this period she suffered from weakness, slight nausea and vomiting. Another arthrocentesis of the knee at the end of the treatment demonstrated negative cultures and CRP dropped to 7 mg/1. Although a second gallium scan, 7 months after start of fluconazole therapy, still showed some activity in the right knee, it was decided to discontinue therapy. Since then, the clinical situation has improved further. CRP dropped to 1 mg/1 and ESR was 35 mm in the first hour. Blood counts show only a thrombocytopenia (92 × 109/1), hemoglobin and leukocyte counts are normal. Discussion Septic arthritis caused by Candida species is rare in patients who are not intravenous drug users. Until 1995 only approximately 65 cases were described in the literature [6-11] of which six were caused by C. tropicalis not associated with a prosthesis (Table 1 ) [12-16]. Animal studies have shown that C. tropicalis was more invasive than C. al42 / 110
bicans in mice with granulocytopenia [17, 18]. A post-mortern study of disseminated C. tropicalis infection demonstrated that gastrointestinal invasion was only found in granulocytopenic patients [19]. Conditions predisposing to C. tropicalis in humans are granulocytopenia, intensive chemotherapy, long-term use of broad-spectrum antibiotics, immunosuppressive drugs, trauma of the skin, intravascular catheters, multiple abdominal surgery and hyperalimentation [6, 11]. Our patient had several of these predisposing conditions that made her susceptible to an infection with C. tropicalis. Dissemination to the knee is possible by direct inoculation (surgery or intra-articular inoculation) or by hematogenous dissemination [6, 11]. In our case the arthritis developed gradually several weeks after a granulocytopenic period without any invasive manipulation. Therefore hematogenous spread to the synovium of the knee was the most likely cause of the isolated joint infection. Transient C. tropicalis ftmgemia in immunocompromised patients was responsible for late infectious complications such as osteomyelitis [20].
Infection 25 (1997)No. 2 © MMV Medizin Verlag GmbH Mtinchen, M0nchen 1997
G. W e e r s - P o t h o f f et al.: Candida tropicalis A r t h r i t i s T r e a t e d with F l u c o n a z o l e
Until recently, amphotericin B was the only effective treatment for systemic and deep-seated infections with Candida but new azole compounds such as bis-triazole ftuconazole are less toxic alternatives [21]. A large study comparing amphotericin B and fluconazote in patients with candidemia without neutropenia or major immunodeficiency showed no significant difference in effectiveness but demonstrated tess toxicity in the fluconazole group [2]. Successful treatment of septic arthritis with fluconazole has been reported in case reports of C. albicans septic arthritis in a patient with leukemia [22], C. albicans osteomyelitis [23], and Candida prosthetic arthritis [24, 251. Fluconazole was chosen instead of amphotericin B because of the patient's clinical condition, the reported in vi-
tro susceptibility of the isolate and the fact that it could be administered orally. Fluconazole was present in sufficient articular concentrations equal to the serum level and 40 times above the MIC. Cultures of synovial fluid became negative after i month of treatment. She was treated for a total of 7 months with minor side-effects and the clinical symptoms of the knee resolved during treatment. Two years after discontinuation of therapy with fluconazole the patient is still doing well without any signs of infection of the knee. Fluconazole might be a promising alternative for treatment of arthritis due to C. tropicalis in immunocompromised patients for whom amphotericin B is too toxic.
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