Abstract
Objective
Candiduria is very common in critically ill patients. It is often benign; however, it can develop into a serious systemic infection and treatment is suggested in symptomatic critically ill patients. The optimal duration of therapy is unclear. Long-term therapy (14 days) is recommended by the current guidelines, but previous data suggest that shorter-duration therapy may be effective. Minimizing the use of antifungal agents is desirable to avoid fungal resistance and adverse events. The purpose of this study was to determine the efficacy of short-term treatment of candiduria.
Methods
This was an observational study in medical, surgical, and trauma intensive care unit (ICU) and ICU step-down patients. A pathway utilizing a 3-day course of fluconazole for candiduria was implemented. The candiduria recurrence rate was compared in patients treated before (control groups with short-term, ie, ≤3 days, or long–term, ie, ≥7 days, therapy) and after the implementation of the pathway (study group: ≤3 days).
Results
Thirty-seven study patients were compared to 59 control patients. There were statistically no differences in the recurrence rate for candiduria among study patients, control patients with long-term therapy, and control patients with short-term therapy (32% vs 55% vs 38%, respectively; P > 0.05).
Conclusion
Three days of fluconazole treatment for candiduria appeared to be as effective as long-term therapy in this population.
Keywords
Introduction
Candiduria continues to be a major complication of hospitalization. Urinary tract infections (UTIs) are the second most common hospital-acquired infection, and Candida sp. are the second most common nosocomial UTI pathogens. 1 The severity of candiduria varies. Some patients are asymptomatic and conditions resolve spontaneously, but in up to 36% of patients, candiduria may progress to a life-threatening systemic infection.2–4 According to the current guidelines of the Infectious Diseases Society of America (IDSA), treatment of candiduria is reasonable in symptomatic critically ill patients when candiduria may be related to disseminated candidiasis. 5 The guidelines recommend fluconazole 200 mg (or 3 mg/kg/day) for 14 days as first-line therapy. 5 However, there are relatively few data on the optimal duration of treatment for candiduria.
Retrospective data from the study center suggested that the candiduria recurrence rates after short-term (≤3 days) and long-term (≥7 days) therapy were equivalent. 6 As such, a clinical pathway for candiduria management that featured short-term treatment with fluconazole for 3 days was developed. The purpose of this study was to compare the efficacy of short-term fluconazole therapy after the implementation of the pathway with the efficacy of short- and long-term therapy used before the implementation of the pathway.
Materials and Methods
Study Design
This study was conducted at the Regional Medical Center in Memphis, TN, USA. The study was approved by the University of Tennessee Institutional Review Board and waiver of informed consent was granted. This study complied with the principles of the Declaration of Helsinki. All patients in the medical/surgical and trauma intensive care units (ICUs) and ICU step-down wards with an episode of candiduria were considered for the study. Patients were identified using a hospital database and comprised those admitted between 2002 and 2006. The study had a prepathway phase, wherein data from consecutively treated patients with candiduria in the study units were collected in a retrospective, observational manner (control group). These patients met the inclusion and exclusion criteria for the study group (described below). There was no candiduria clinical pathway in place in the prepathway phase of the study. In this phase, urine cultures were generally ordered as part of a fever/sepsis evaluation in patients with signs and symptoms of infection. Candiduria was considered clinically relevant at ≥10,000 or ≥100,000 colony-forming units (cfu)/mL depending on the admission service. Control group patients may have received either short-term (≤3 days) or long-term (≥7 days) therapy depending on physician preference. An important observation was that long-term antifungal therapy (≥7 days) was found to be a risk factor for subsequent fungal colonization or infection. 6 Based on these results, a clinical pathway for candiduria was implemented (Fig. 1). The vital component was limiting the duration of therapy for candiduria to 3 days. After the implementation of the pathway, all patients treated with the pathway were evaluated prospectively (study group).
Candiduria clinical pathway.
The primary outcome for this study was the recurrence rate of candiduria during hospitalization in the study group compared to the long-term and short-term control groups. Recurrence was defined as a second episode of candiduria (defined below) after the end of therapy for the first episode. Follow-up urine cultures were not routinely performed; rather, they were performed at the discretion of the medical team as clinically indicated. It was hypothesized that candiduria recurrence in the study group would be similar in both control groups; suggesting that short-term therapy of candiduria may be adequate in this patient population. Patients in the study group were enrolled if they were 18 years or older and diagnosed with candiduria defined as ≥10,000 cfu/mL of Candida species in urine. Patients were excluded if they had malignancy, candiduria ≤48 hours from admission, hypersensitivity to fluconazole, septic shock, white blood cell count <4,000/mm3, use of immunosuppressive medications, previous antifungal treatment, presence of documented candidiasis, if they were not treated according to the clinical pathway, or if they had Candida krusei identified on urine culture. The first episode of candiduria in each patient was considered the study episode. Per the clinical pathway, the first episode of candiduria in the study group was treated with fluconazole 200 mg daily either orally or intravenously (IV) for a total of 3 days. Because the treatment course was short, all patients received the same fluconazole dose regardless of their renal function. Patients were monitored daily for resolution of signs and symptoms, and were followed for primary and secondary outcomes until hospital discharge.
Statistical Analysis
Continuous data are expressed as mean ± standard deviation (SD) and were analyzed using StatView software (SAS Institute Inc, Cary, NC, USA). Statistical significance was determined by chi-square test, Fisher's exact test, or Student's t-test for parametric data where appropriate. Nonparametric data were compared using Mann–Whitney U-test. Statistical significance was defined as P < 0.05.
Results
Seventy-four patients in the study group were evaluated for enrollment; 37 met the inclusion criteria (16 medical/surgical and 21 trauma) (Fig. 2). In the control group, there were 37 patients who received short-duration fluconazole therapy (20 medical/surgical and 17 trauma) and 22 patients with a long duration of fluconazole therapy (19 medical/surgical and 3 trauma). The baseline characteristics are presented in Table 1. The only statistically significant difference between the study and control groups was a higher rate of diabetes in the control group.
Flow of study participants.
Demographics of the patients.
Compared to study group, P = 0.013
compared to study group, P = 0.0016. All other comparisons not statistically significant.
Regarding the primary outcome, there was no statistical difference in the recurrence rate of candiduria among the study group, the long-term control group, and the short-term control group (32% vs 55% vs 38%, respectively; P > 0.05). Secondary outcomes were also similar among the three groups (Table 2). Candida species isolated in the study group were C. albicans (43%), C. glabrata (32%), C. tropicalis (16%), and C. parapsilosis (8%). Identification of Candida species was not a laboratory standard during the enrollment period for the control group; therefore, 82% of patients in the control group had an unspeciated isolate.
Clinical outcomes.
Discussion
In this study, a clinical pathway featuring 3 days of fluconazole therapy resulted in a similar candiduria recurrence rate as was seen with longer-term therapy. In addition, the rates of subsequent candidemia were similar. As such, these results question the need to use long-duration therapy to treat symptomatic candiduria in this population. 5 Advantages of short-term fluconazole therapy include limiting the shift toward fluconazole-resistant Candida species, minimizing cytochrome P450 interactions, and cost savings. Other studies also suggest that short-term therapy of candiduria is acceptable.7–13
Leu et al 7 randomized 180 hospitalized patients to one of six different regimens. Five days of fluconazole, single-dose IV amphotericin B, and amphotericin B bladder irrigation (ABBI) (200 mg/L) for 3 days were all equally effective at day 7 (range: 68%–77%) and were significantly better than no treatment (P < 0.05). 7 Jacobs et al 8 randomized 109 elderly hospitalized patients with candiduria to either ABBI (50 mg/L) or fluconazole for 5 days. Both treatments were equally effective after 1 month (84% vs 80%, respectively; P > 0.05). 8 Similarly, Fan-Havard et al 9 randomized 53 patients with candiduria to ABBI 50 mg/L for 1 day, ABBI for 7 days, or fluconazole 200 mg/day for 7 days. The eradication rates were similar among the groups (77%, 75%, and 79%, respectively; P > 0.05). 9 In addition, two nonrandomized observational studies showed that short-term treatment with ABBI for 3–5 days was 80%–100% effective (total n = 126). 12
Two other trials studied longer durations of fluconazole.10,11 Sobel et al 10 randomized 316 patients to fluconazole 200 mg/day for 14 days or catheter replacement alone. Fluconazole resulted in superior eradication at 14 days (50% vs 29%, respectively; P < 0.001), but not at 1 month (61% vs 56%, respectively; P > 0.05). Similarly, Potasman et al 11 randomized 60 patients to receive fluconazole for 14 days or catheter replacement alone. Again, fluconazole resulted in a more rapid clearance of candiduria, but the eradiation rates were similar between the groups after 8 weeks (87% vs 93%, respectively; P > 0.05). 11
Overall, there does not appear to be a clear advantage in efficacy rates for long-term (14 days) therapy over short-term therapy (≤7 days). The candiduria recurrence rate of 32% in the current study seems acceptable in comparison to the recurrence/failure rate in other studies. Importantly, few patients in the previous studies were critically ill, whereas all of the patients in the current study were in an ICU or an ICU step-down unit.
Some may argue that even a short course of antifungal therapy may be unwarranted. Two randomized trials suggested that catheter removal or replacement alone was equivalent to 14 days of antifungal therapy.10,11 However, two other studies provide a warning that not treating with antifungal agents can result in worse outcomes.2,7 It is likely that the need for antifungal therapy comes down to patient-specific factors and symptoms of active infection. Ultimately, we feel that it is important to treat candiduria in symptomatic critically ill patients because up to 36% of critically ill patients with candiduria go on to develop candidiasis.2–4 This view seems to be corroborated by the IDSA guidelines. 10
This study has three primary strengths. First, this study is unique because it compared short- and long-term fluconazole for treating candiduria. Second, the candiduria recurrence rates in the study group were in the range of those reported in other studies. Third, this study included both trauma and medical ICU patients. Thus, the data should be applicable to a wide variety of patient groups.
This study also has several limitations. First, the sample size was relatively small and thus there is a potential for a Type II statistical error in the primary outcome. Second, this was not a randomized trial, but it rather used a before/after design. Obviously, larger randomized studies are needed to validate or refute these findings. However, the control and study time periods were consecutive and we do not feel that there were significant changes in the standards of care over these time periods that would have affected the efficacy of candiduria therapy. Third, there were more patients with diabetes in the control group than in the study group. It is possible that diabetic patients were more susceptible to recurrence of candiduria, which could bias the results in favor of short-term therapy. It is unclear to us why there was this disparity in patients.
Conclusion
In conclusion, this study compared short- and long-term fluconazole therapy for the treatment of candiduria in ICU and ICU step-down patients using a before/after study design. Three days of fluconazole treatment resulted in similar candiduria recurrence rates as with therapy for ≥7 days. These results suggest that 3 days of fluconazole administration could be used to treat candiduria in this patient population.
Author Contributions
Conceived and designed the experiments: GCW, KA, BAB, MAC, DAK, MC, AXF, TCF. Analyzed the data: GCW, KA, DAK, CLR, JMS. Wrote the first draft of the manuscript: GCW, KA. Contributed to the writing of the manuscript: BAB, MAC, DAK, CLR, MC, JMS, AXF, TCF. Agree with manuscript results and conclusions: GCW, KA, BAB, MAC, DAK, CLR, MC, JMS, AXF, TCF. Jointly developed the structure and arguments for the paper: GCW, KA, BAB, MAC, DAK, CLR, MC, JMS, AXF, TCF. Made critical revisions and approved final version: GCW, KA, BAB, MAC, DAK, CLR, MC, JMS, AXF, TCF. All authors reviewed and approved of the final manuscript.
Footnotes
Acknowledgments
A portion of the data from the control group (early period) was presented as an abstract (Chambers MP, Kuhl DA, Wood GC, Boucher BA, Freire AX. Increased systemic candidiasis with prolonged antifungal treatment in patients with candiduria in the ICU. Chest. 2005;128(suppl):134S–135S) and as a platform presentation at the American Thoracic Society International Conference, 2005.