Is It Time to Abandon the Use of Amphotericin B Bladder Irrigation?
Abstract
In this article, we review the issues surrounding funguria and its management. With this background, the value of bladder irrigation with amphotericin B for the management of funguria is directly examined. Amphotericin B bladder irrigation is used frequently in clinical practice. Although its use is not standardized, there are multiple studies that attempt to show the impact on funguria management. These bladder irrigations have been used either for treatment of funguria or (less commonly) as a diagnostic test in attempts to identify upper urinary tract disease. Despite their widespread therapeutic use and relative safety, it is not clear from our experience and a review of the literature that amphotericin B bladder irrigations have any diagnostic or therapeutic value. The patient may be best served by removal of the urinary catheter, if possible, rather than by instillation of bladder irrigation with amphotericin B.
Funguria is commonly found in institutionalized patients. Although the incidence or prevalence may vary significantly with the definition of funguria and the population studied, one study reported funguria in 24.8% of nursing home residents with an indwelling urethral catheter [1]. The vast majority of funguria is caused by Candida species, and Candida albicans accounts for ∼50% of the isolates in most series [2–6]. Funguria most often occurs in patients with comorbidities (such as diabetes mellitus, urinary tract abnormalities, and malignancy). Additional risk factors for the development of funguria include instrumentation of the urinary tract, recent use of antibiotics, and advanced age [2, 4, 7].
Among the many controversies surrounding the diagnosis and management of funguria is the identification of patients who require therapy, because funguria often represents colonization rather than disease [3, 4, 8, 9]. However, once patients are considered for treatment, the ability to localize the infection site may help identify treatment options, such as a need for systemic antifungal therapy [9]. Among the primary strategies used to localize lower urinary tract fungal infections and possibly to treat them has been the use of bladder irrigation with amphotericin B.
Introduced in the late 1950s, the intravenous formulation of amphotericin B deoxycholate became the treatment of choice for serious fungal infections because of its broad spectrum of antifungal activity and the lack of alternate treatment options [10]. Numerous dose-limiting adverse reactions (including nephrotoxicity, electrolyte wasting, fever, chills, hypotension, nausea, and anemia) following parenteral administration have limited its usefulness [10]. Therefore, alternate methods to intravenous administration of amphotericin B have been studied in attempts to optimize antifungal drug delivery to the site of the infection while aiming to reduce side effects [11]. Arguably, none of the other methods of delivering amphotericin B directly to the site of infection has been as extensively reported in the literature, yet as poorly studied and controversial, as the use of amphotericin B bladder irrigation [11].
Who Should Receive Treatment for Funguria?
The clinical significance of funguria may depend largely on patient age, the presence of symptoms, and comorbidities [3, 4, 8, 12]. Therefore, optimal management strategies are based on risk assessment. Urinary catheters should be removed whenever possible. In asymptomatic patients with an indwelling urethral catheter, funguria often represents colonization of the catheter (as evidenced by the resolution of funguria with the removal of the urinary catheter in approximately one-third of such cases) [2, 5, 13]. Furthermore, drug treatment does not appear to impact morbidity and mortality in such patients [5, 14, 15]. Therefore, additional urine cultures and specific treatments (except for removal of the urinary catheter, when present) are not recommended for asymptomatic patients in the absence of specific risk factors [12]. In symptomatic patients, funguria may represent true infections of the lower urinary tract [12]. However, many patients with funguria have preceding or concomitant bacterial urinary tract infections, which makes the assessment of symptoms attributable to the fungus problematic. Despite these uncertainties, patients with signs and symptoms of cystitis and with only yeasts found in culture should probably be considered as candidates for treatment.
Certain patient populations thought to be at increased risk of disseminated disease as a consequence of funguria should also be considered for treatment [12]. Patients with funguria who undergo urologic procedures may be at increased risk for fungal dissemination during instrumentation [16, 17]. In a series of 249 patients with candidemia, 26 cases were thought to be secondary to infection via the urinary tract (primarily in those patients with urologic obstruction or manipulation) [16]. Although renal allograft recipients with funguria have been considered to be at increased risk for fungal dissemination [12], a recent survey of such patients suggests that risk factors for dissemination in this population are similar to those for other patient populations [18]. Neutropenic patients with funguria have also been considered to be at increased risk of disseminated fungal infection [19]. It is presumed that eradication of urinary colonization would lower this risk of dissemination, especially for those patients at highest risk, for whom neutropenia will be severe and/or prolonged. Finally, low birth weight infants with evidence of fungal colonization of the bladder are also considered to be at increased risk for disseminated infection [20] and should be considered as candidates for treatment [12].
Despite several studies that have failed to demonstrate the value of funguria as a predictor of systemic fungal infections in most patients [2, 19, 21–23], funguria may be the sole or earliest manifestation of invasive candidiasis in select patient populations and may require treatment [19, 21, 24, 25]. These patients may include oncology patients [19, 21] or, possibly, critically ill surgery patients with signs and symptoms of ongoing sepsis [24, 25]. Funguria may be particularly significant for immunocompromised oncology patients with Candida tropicalis infection, since one study reported isolation of this pathogen in surveillance cultures for all 14 patients who subsequently had disseminated disease [21]. In another study, 8 of 11 patients with ⩾1 surveillance urine cultures positive for C. tropicalis had evidence of invasive disease [19]. Most of these patients had signs of systemic infection at the time urine was obtained for culture [19]. Furthermore, funguria in neonates is often a manifestation of upper urinary tract disease [26, 27], and the incidence of renal candidiasis in infants with funguria reached 42% in one study [26].
Use and Methods for Amphotericin B Bladder Irrigation
The first report of the use of amphotericin B bladder irrigations was published in 1960 [28]. As summarized elsewhere [11], subsequent case reports, uncontrolled trials, retrospective case series, and prospective controlled clinical trials have attempted to define the potential role of amphotericin B bladder irrigations in the treatment of funguria (see table 1). Efficacy rates for elimination of funguria in these reports vary widely, from 43% to 100% [11]. Despite the lack of adequate objective evidence to define the optimal dose, duration, and method of administration for amphotericin B bladder irrigations, the treatment continues to be used. In a survey published in 1999, amphotericin B bladder irrigation was used to treat one-third of patients with funguria, and an additional 15% of patients received bladder irrigation combined with fluconazole therapy [32]. In other reports, amphotericin B bladder irrigations were used as antifungal therapy (alone or in combination with intravenous amphotericin B therapy) in ∼13% of treated patients with candiduria [2].
View this table:
Table 1
Randomized, controlled trials of amphotericin B (AmB) bladder irrigation for the treatment of funguria.
The optimal dose and/or concentration of amphotericin B in bladder irrigation for elimination of funguria has been a source of much debate and few definitive studies. Concentrations in most reports range from 5 to 50 mg/L [11]. Two randomized trials have compared different concentrations of amphotericin B in bladder irrigation used for the treatment of funguria [30, 33]. The first of these trials compared concentrations of 5 mg/L, 100 mg/L, and 200 mg/L, each administered 3 times daily for 3 days [30]. Although, on day 1, efficacy rates for elimination of funguria (∼80%–85% for all treatment groups) were significantly better for amphotericin B bladder irrigations than for placebo (P ⩽.01), by day 10, clearance rates for the 3 concentrations fell to 42.9%, 68.4%, and 68.2%, respectively [30]. Another randomized study comparing concentrations of 10 mg/L and 50 mg/L administered by continuous irrigation for 72 h to 26 evaluable patients reported efficacy rates of 67% and 100%, respectively [33].
The optimal method of delivery (i.e., continuous or intermittent) for amphotericin B bladder irrigation has also not been established. Descriptions of drug administration range from intermittent instillation (up to 3 times daily with medication dwell times of 2–3 h) to continuous irrigation (usually via 3-way Foley catheter) [11]. A randomized, prospective study compared the efficacy on day 1 of treatment delivered as a continuous irrigation of 50 mg/L for 48 h with that of intermittent instillation of 10 mg/100 mL 3 times daily [34]. Eight of 10 patients in the continuous infusion group had clearance of fungus from the urine at 72 h, compared with 3 of 10 patients in the intermittent treatment group (P = .035). By day 7, relapse was seen in 2 patients in the continuous treatment group and 1 patient in the intermittent treatment group.
The duration of therapy associated with the best outcome is also unknown for amphotericin B bladder irrigations. A single dose has shown limited success for patients without apparent upper tract disease [13] and may not be significantly different from drug delivery for 7 days [29]. Two-day regimens have also been evaluated, with efficacy rates of ∼75% reported in one study [1]. Additional therapy may not benefit all patients unresponsive to 2-day regimens [1]. Adverse effects associated with amphotericin B bladder irrigation have not been frequent but may include hematuria, cramping, bladder discomfort, dysuria, and burning during irrigation [29, 31, 34, 35].
Diagnostic Utility of Amphotericin B Bladder Irrigation
Although differentiation of colonization from infection in an asymptomatic patient with candiduria usually requires only the removal of the catheter, it may be an imprecise method to differentiate upper and lower urinary tract candidal infection by clinical studies. Prior studies attempting to examine the utility of fungal casts determined that such methods were insensitive [36], and quantitative yeast cultures have never been validated as predictors of disease. The use of amphotericin B bladder irrigation as a diagnostic intervention to differentiate upper tract from lower tract infections was evaluated in 47 catheterized patients with 62 episodes of persistent candiduria [13]. In these patients, amphotericin B bladder irrigation (30 mg instilled via 3-way catheter and allowed to dwell for 2 h) was administered as a single dose. None of the 44 episodes associated with clearance of candiduria after therapy had subsequent evidence of invasive infection, whereas 8 of 18 episodes of persistent candiduria after therapy had evidence (either clinical or at autopsy) of invasive infection. Although the authors stated that the sensitivity and specificity of the test were 100% (95% CI, 63%–100%) and 81% (95% CI, 47%–100%), respectively, limitations of this study must be considered. Among these are that episodes (rather than individual patients) were analyzed and that 12 patients were included 2–3 times in the analysis. Most important is the positive predictive value of only 44%. Therefore, unresolved candiduria after single-dose amphotericin B bladder irrigation remains a diagnostic dilemma.
Overview of Alternate Treatment Options
Numerous potential treatment options exist for patients with funguria. Among the azoles, fluconazole has been the most extensively studied. This is primarily because of its favorable pharmacokinetic and safety profiles. Administration of fluconazole, 200 mg/day orally for 7–14 days, is currently recommended as a treatment option [12]. Published experience with other agents such as itraconazole and voriconazole is limited, since these agents undergo a high degree of hepatic metabolism and achieve limited concentrations in the urinary tract [37]. Likewise, published experience with the echinocandin caspofungin in the treatment of urinary tract infections is limited. Although caspofungin may be adequate to treat renal parenchymal candidiasis, it is anticipated to have limited clinical utility in the management of candiduria because of poor penetration of the active drug into the urinary tract collecting system [37]. Parenteral amphotericin B deoxycholate in dosages of 0.3–1.0 mg/kg/day for 1–7 days has been proposed for treatment of funguria but requires parenteral administration and has increased adverse effects, compared with fluconazole [38]. Flucytosine, at a dosage of 25 mg/kg (rounded to the nearest 250 mg) orally 4 times daily, may also be useful in the management of candiduria [12, 39]. Its use is limited primarily by the potential for adverse effects (including hematologic toxicity) [40]. Concern about the development of treatment-emergent resistance reported for flucytosine may be less relevant to the treatment of funguria, because of the high concentrations of drug in urine and the relatively short duration of therapy.
Among the considerations for use of alternate therapies instead of amphotericin B bladder irrigation are the procedures, costs, and discomforts associated with drug administration and monitoring. Unlike fluconazole and flucytosine (which are administered orally), administration of amphotericin B by bladder irrigation requires drug preparation, skilled nursing, and urinary catheterization, with its associated costs and complications.
Conclusion
Optimal management of funguria begins with identification of those patients whose condition requires treatment. Asymptomatic patients without risk factors probably do not benefit from any treatment. Except among patients receiving surgical manipulation of the urinary tract (possibly with a urologic structural abnormality), neutropenic patients, and neonates, there are no convincing data that funguria limited to the bladder is a risk factor for upper urinary tract disease or dissemination. Catheter removal can result in resolution of funguria in a substantial number of patients. In certain high-risk groups (such as neutropenic patients and neonates), funguria may actually reflect invasive disseminated candidiasis. Therefore, funguria in these patients requires prompt administration of systemic antifungal therapy, and its management should not be limited to local antifungal therapy.
Despite the low acquisition cost and minimal side effects of amphotericin B bladder irrigation, its utility is highly questionable. As a diagnostic strategy to detect upper urinary tract infection, it is rarely employed and, in fact, is not a particularly robust method for localization of infection. Its use for the treatment of funguria is significantly limited, primarily because of the required maintenance of a urinary catheter; lack of adequately controlled and powered studies to define the optimal dose, duration, and method of administration; restriction of its use to uncomplicated lower urinary tract infections; and availability of more convenient treatment options (such as oral fluconazole therapy).
In our opinion, the use of amphotericin B bladder irrigation is a strategy rarely needed in our present clinical armamentarium. We suspect that the clinical benefit of simply removing the urinary catheter outweighs any possible positive outcome from the use of amphotericin B bladder irrigation.
Acknowledgments
Potential conflicts of interest. J.R.P. has received research, consulting, and/or speaking support from Pfizer, Merck & Co, Fujisawa, Enzon, Schering-Plough, Pliva, and Vicuron. R.H.D. has received research, consulting, and/or speaking support from Enzon and Schering-Plough. R.R.A.: no conflicts.
- Received November 16, 2004.
- Accepted January 7, 2005.
- © 2005 by the Infectious Diseases Society of America
References
This Article
- AbstractFree
- » Full Text (HTML)Free
- Full Text (PDF)Free
Classifications
-
- Clinical Practice
Services
Citing Articles
Google Scholar
PubMed
Related Content
Share
- Email this article
-
CiteULike
Connotea
Delicious
Facebook
Google+
Mendeley
Twitter
Published on behalf of
IDSA Members: For your free access to this journal, log in via the IDSA members area.
The Journal
Impact Factor: 8.186
5-Yr impact factor: 7.898
For The Media
For Authors
- Services for authors
- Self-archiving Policy
- IDSA Conflict of Interest policy
- Instructions for Authors
- ICMJE Form
- Submit Now!
Open access options for authors visit Oxford Open
This journal enables compliance with the NIH Public Access Policy
Corporate Services
Alerting Services
Related IDSA Publications
