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Case Report |
1 Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan, ROC
2 Departments of Internal Medicine and Laboratory Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan, ROC
Correspondence
Po-Ren Hsueh
hsporen{at}ntu.edu.tw
Received May 4, 2008
Accepted August 14, 2008
Candiduria is an increasingly common condition, and the lack of effective antifungal treatment in many cases has raised great concern. We report a case of persistent Candida parapsilosis funguria associated with urinary tract instrumentation. Molecular typing suggested that during a 7 year period the C. parapsilosis isolates were all the same strain. Prolonged antifungal therapy and regular catheter replacement failed to eradicate the funguria, but improved urinary symptoms and pyuria. The antifungal susceptibility pattern did not significantly change during the clinical course despite repeated exposure to fluconazole.
Abbreviations: RAPD, random amplified polymorphic DNA.
Introduction
Candiduria is an increasingly common condition, especially in hospitalized patients (Lundstrom & Sobel, 2001; Shay & Miller, 2004; Toya et al., 2007). It is often difficult for clinicians to distinguish between colonization and infection in these patients (Lundstrom & Sobel, 2001). The lack of effective antifungal treatment in many cases has also raised great concern (Sobel et al., 2000).
Case report
A 51-year-old man developed stricture of the bilateral ureteral valve due to urinary tuberculosis in December 2000. He received anti-tuberculosis therapy for 1 year after diagnosis. However, tuberculosis-related obstructive uropathy with hydroureter and hydronephrosis were noted. In January 2001, bilateral double-J stents were inserted for the treatment of the ureteral stricture and were replaced regularly every 3 months. Routine replacement of double-J stents every 3 months is a standard procedure at the National Taiwan University Hospital. The result of baseline urinalysis performed after insertion of the double-J stents revealed mild pyuria, and a serum creatinine level of approximately 2 mg dl–1. In February 2001, Candida parapsilosis funguria was detected for the first time. However, the patient did not receive antifungal therapy until November 2001 due to progressive dysuria and pyuria. The pyuria improved with the administration of daily oral fluconazole (200 mg), but funguria with high colony counts (>10 000 c.f.u. ml–1) persisted despite fluconazole treatment and concurrent replacement of catheters. An increase in the fluconazole dose to 300 mg per day did not eradicate the funguria. Fluconazole was discontinued several months later, and the C. parapsilosis funguria persisted. Renal sonography showed mild bilateral hydronephrosis but no fungal ball or other marked abnormalities. Subsequently, the patient received several courses of fluconazole treatment due to the presence of symptomatic C. parapsilosis funguria. In 2006, the patient was treated with caspofungin for 14 days and oral voriconazole for 7 days for the eradication of the C. parapsilosis funguria; however, this treatment strategy also failed. Thereafter, the patient received further courses of oral fluconazole treatment several times as the urinary symptoms and pyuria progressed. For 7 years, i.e. until November 2007, this patient underwent double-J stent replacement 24 times and experienced more than 10 episodes of C. parapsilosis funguria with high colony counts (>10 000 c.f.u. ml–1). Culture of the removed double-J stents was found to be positive for C. parapsilosis on several occasions. In November 2007, the urine culture still yielded C. parapsilosis with colony counts >10 000 c.f.u. ml–1. However, despite the persistent C. parapsilosis funguria, the patient did not acquire ascending infection or disseminated disease during this period. The patient was followed-up regularly at our outpatient clinic and had few urinary tract symptoms. At the time of this study, the patient continued to undergo double-J stent replacement every 3 months.
The four isolates of C. parapsilosis that were recovered from the urine specimens of this patient in 2001 and 2007 were preserved in the microbiology laboratory of the National Taiwan University Hospital. Antifungal susceptibility testing was performed using the reference broth microdilution method according to the guidelines of Clinical and Laboratory Standards Institute (CLSI, 2002). Two reference strains, C. parapsilosis ATCC 22019 and Candida krusei ATCC 6258, were used as quality control strains. MICs were determined after incubation for 48 h. The susceptibility testing results of the four C. parapsilosis isolates are shown in Table 1
. All the isolates were susceptible to fluconazole (MICs 1–4 µg ml–1) and amphotericin B (MICs 1 µg ml–1). MICs of the four isolates were within twofold dilution variation for other agents tested. Random amplified polymorphic DNA (RAPD) patterns of the isolates were determined by arbitrarily primed PCR. The four oligonucleotide primers used, 3 (5'AGTCAGCCAC 3'), H12 (5'ACGCGCATGT 3'), H15 (5'AATGGCGCAG 3') and M13 (5'GAGGGTGGCGGTTCT 3'), were purchased from Operon Technologies. Identical RAPD patterns indicated that all the isolates belonged to the same strain (Fig. 1).
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Candiduria has become an increasingly common problem in hospitalized patients (Lundstrom & Sobel, 2001; Shay & Miller, 2004; Toya et al., 2007). The risk factors for candiduria include urinary tract instrumentation, diabetes mellitus, malignancy, recent antibiotic therapy and old age (Hamory & Wenzel, 1978; Kauffman et al., 2000). Differentiating between Candida infection and colonization is difficult in cases where candiduria alone is detected (Lundstrom & Sobel, 2001). In most patients, the isolation of Candida species from urine samples is indicative of benign colonization. The principles regarding when to treat, whom to treat and how long to treat are still controversial (Lundstrom & Sobel, 2001). In the present case, mild pyuria was noted upon baseline urinalysis, which was considered to be related to the placement of double-J catheters. Both the severity of pyuria and the colony count of Candida in urine were used to guide treatment. However, candiduria could not be resolved successfully despite a prolonged course of fluconazole and the regular replacement of indwelling catheters. Molecular typing suggested that the same strain of C. parapsilosis was isolated from the urine of the patient before and after the administration of antifungal treatment and throughout the 7 year clinical course. Voriconazole and caspofungin administration also failed to eradicate candiduria despite the high in vitro potency of these antifungal drugs.
Although not proved by microscopic methods, the formation of a biofilm was considered as the cause of the persistent candiduria in this patient. It is well known that indwelling medical devices can support Candida colonization and biofilm formation, and that the biofilm cells are relatively resistant to antifungal treatment (Kojic & Darouiche, 2004). The process of fungal biofilm development, which involves adherence to device surfaces, morphogenic conversions, extracellular matrix production and induction of drug-resistance, has been described in detail (Blankenship & Mitchell, 2006; Ramage et al., 2005). Due to the unique characteristics of the Candida biofilm, in vitro susceptibility to antifungal agents cannot guarantee efficacy of the use of these agents in the clinical treatment of candiduria, as illustrated in the present case.
Other studies have also demonstrated the minimal benefits of antifungal therapy for eradicating Candida funguria (Kauffman et al., 2000; Sobel et al., 2000). These findings do not mean that antifungal therapy is unnecessary for patients with candiduria; however, the treatment should not be expected to eradicate the organism. The Infectious Diseases Society of America has suggested that the treatment goal should be to eliminate the associated signs and symptoms, and reduce the risk of ascending or disseminated infection (Pappas et al., 2004). Furthermore, catheter change alone rarely results in the clearance of candiduria, but the discontinuation of catheter use may help eradicate this infection (Kauffman et al., 2000).
Despite repeated exposure to fluconazole, the C. parapsilosis isolates in the present study remained susceptible to fluconazole (Table 1
). The antifungal susceptibility pattern of each isolate was unremarkable except for a mild increase in the MIC of fluconazole after treatment. Similar observations have been reported in a another study (Clancy et al., 2000).
In conclusion, we report a case of persistent and difficult-to-treat C. parapsilosis funguria associated with urinary tract instrumentation. During a 7 year period, the patient had 10 episodes of funguria caused by the same strain of C. parapsilosis. Prolonged antifungal therapy and regular catheter replacement failed to eradicate the funguria but improved urinary symptoms and pyuria. The antifungal susceptibility pattern did not significantly change during the clinical course despite repeated exposure to fluconazole.
References
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Hamory, B. H. & Wenzel, R. P. (1978). Hospital-associated candiduria: predisposing factors and review of the literature. J Urol 120, 444–448.[Medline]
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Pappas, P. G., Rex, J. H., Sobel, J. D., Filler, S. G., Dismukes, W. E., Walsh, T. J. & Edwards, J. E. (2004). Guidelines for treatment of candidiasis. Clin Infect Dis 38, 161–189.[CrossRef][Medline]
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Shay, A. C. & Miller, L. G. (2004). An estimate of the incidence of candiduria among hospitalized patients in the United States. Infect Control Hosp Epidemiol 25, 894–895.[Medline]
Sobel, J. D., Kauffman, C. A., McKinsey, D., Zervos, M., Vazquez, J. A., Karchmer, A. W., Lee, J., Thomas, C., Panzer, H. & other authors (2000). Candiduria: a randomized, double-blind study of treatment with fluconazole and placebo. Clin Infect Dis 30, 19–24.[CrossRef][Medline]
Toya, S. P., Schraufnagel, D. E. & Tzelepis, G. E. (2007). Candiduria in intensive care units: association with heavy colonization and candidaemia. J Hosp Infect 66, 201–206.[CrossRef][Medline]
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