Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
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Abstract |
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Methods. During an 8-year study period from January 1992 to December 1999, 37 candidaemic episodes that developed among 653 ARFd patients were assigned to ARFd candidaemic group, and 170 candidaemic episodes developing in patients without ARFd or chronic uraemia as the non-ARFd candidaemic group, and 28 matched ARFd patients without candidaemia were assigned to the ARFd control group. Among these groups, clinical characteristics in ARFd candidaemia patients, predisposing factors, and outcomes were compared. Four management strategies including central catheter removal, anti-fungal therapy, both, or neither were applied. The prognostic factors for attributable death were evaluated by univariate analysis followed by the multivariate logistic regression analysis.
Results. The proportion of ARFd patients with candidaemia was significantly higher than in patients who had no ARFd or chronic uraemia (5.7% vs 0.15%, P<0.001). Compared with the non-ARFd candidaemic group, systemic lupus erythematosus (SLE), administration of corticosteroid, and central venous catheter-associated candidaemia were more common in the ARFd candidaemic group (P<0.05). In matched case-control study, multiple antibiotic usage was shown to be a predisposing factor for developing candidaemia in patients with ARFd, and corticosteroid therapy has a marginal significance (P=0.059). The occurrence of candidaemia increased the mortality rate of ARFd (71% vs 39.2% in ARFd control group, P<0.05). By multivariate logistic analysis, the variables associated with attributable death in ARFd candidaemic group were identified to be an APACHE II score of 18, and anti-fungal therapy for >48 h. Central venous catheters were removed in 32 (86.5%) of the 37 ARFd candidaemic patients, among whom the 18 patients who had received anti-fungal therapy for >48 h had a lower attributable death rate than those patients who had not (27.8% vs 64.3%, P<0.05). Of the remaining five patients who did not have their catheter removed, three patients subsequently died and two patients improved only after catheter removal.
Conclusions. The higher prevalence of candidaemia in ARFd patients is due to their underlying illnesses and multiplicity of predisposing factors, rather than ARF and dialysis therapy per se. Predisposing factors include SLE, indwelling central venous catheter, multiple antibiotic usage, and corticosteroid therapy. Prompt anti-fungal therapy and catheter removal should be mandatory for ARFd patients with candidaemia.
Keywords: acute renal failure; anti-fungal therapy; candidaemia; corticosteroids; dialysis
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Introduction |
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Humoral and cell-mediated immunity are depressed in patients with acute renal failure (ARF). Although bacterial sepsis is a common complication of ARF, and indeed the most common cause of death, fungal septicaemia is rarely discussed and reported. Candidaemia may become prevalent in patients with ARF if they survive longer due to advances in intensive care and dialysis therapy. In some studies [3,4], prior haemodialysis therapy has been shown to be an independent predisposing factor of candidaemia. Although the clinical features and outcomes of candidaemia in oncological, surgical, and neutropenic patients have been well described [1,5,6], data concerning candidaemia developing in ARF patients is scarce, especially in patients on dialysis therapy. The aims of this retrospective study were to elucidate: (i) whether the patients with ARF necessitating dialysis therapy (ARFd) are at high risk of developing candidaemia; (ii) what the predisposing factors for developing candidaemia in ARFd patients are; (iii) what the prognostic factors and therapeutic outcome of ARFd patients with candidaemia are; and (iv) how these patients can be best managed.
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Subjects and methods |
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An episode of candidaemia was defined as having at least one positive blood culture for at least one candidal species during hospitalization. Those patients with two or more candidal species in a single set or different sets of blood culture within a 72-h period were considered to have polymicrobial candidaemia [6]. Concomitant bacteraemia was defined as the isolation of a bacterial organism from a blood culture obtained within 48 h before or after the isolation of Candida from blood culture [6]. Candidaemia was considered to be nosocomial if blood cultures were positive >72 h after hospitalization and no evidence of candidal infection was found at the time of admission. Central venous catheter-associated candidaemia was diagnosed when (i) no apparent source of candidaemia other than central venous catheter could be found or (ii) the same organism was isolated from pus collected at the insertion site or from the catheter tip [8].
No autopsy was performed in our study. The clinical criteria used for definite candidal dissemination include: (i) culture of organism from tissue (e.g. kidney or lung); (ii) endophthalmitis; (iii) evidence of skin wound invasion; and (iv) culture from closed space fluid (e.g. cerebrospinal or peritoneal fluid). The first two criteria are universally accepted. Based on the studies by Spebar and Pruitt [7] and Solomkin et al. [8], we considered criteria (iii) and (iv) to be adequate for a diagnosis of dissemination. The clinical criteria for likely candidal dissemination include: (i) two positive blood cultures at least 24 h apart (without central venous catheter); (ii) two positive blood cultures with the second being obtained >24 h after the removal of colonized central venous catheter; and (iii) at least three colonized sites (e.g. urine, sputum, and wound) [3].
ARF was defined as a doubling or more of serum creatinine (Cr) levels, when serum Cr 2.5 mg/dl, or an increase of serum Cr of 2 mg/dl or more, when serum Cr >2.5 mg/dl. Indications for dialysis therapy include uraemic symptoms, hyperkalaemia, acidosis, fluid overload, and serum blood urea nitrogen level >100 mg/dl, or serum Cr level >8 mg/dl. The items recorded from medical records included age, sex, initial section of admission, underlying illness, predisposing factors, clinical manifestations and laboratory findings on the date of candidaemia, anti-fungal therapy, outcomes, and all microbiological data. Blood cultures were performed using the BACTEC system (Becton Dickinson Diagnostic Instrument Systems, Paramus, NJ, USA). All Candida isolated from blood cultures were identified according to previously reported methods, including carbohydrate utilization profiles, morphology on cornmeal agar, or other biochemical profiles [9].
The differences in clinical characteristics of candidaemic episodes between patients with ARFd and without ARFd
To elucidate the impact of severe ARF and dialysis therapy on the development of candidaemia and to assess clinical course of candidaemia in ARFd patients, we compared the aetiology, predisposing factors, and outcomes between candidaemic patients with ARFd and those without ARFd. Thirty-seven candidaemic ARFd patients who had received dialysis therapy before the episode of candidaemia and had no evidence of candidal infection at the initiation of dialysis therapy were assigned to ARFd candidaemic group, and 170 candidaemic patients who did not have ARFd or chronic uraemia before the onset of candidaemia were assigned to the non-ARFd candidaemic group. The predisposing factors to assess include: (i) surgery within 2 weeks prior to the episode of candidaemia; (ii) multiple antibiotic usage (more than four antibiotics) administered within 7 days before the episode of candidaemia; (iii) corticosteroid administration at least at an equivalent dose of 20 mg of prednisolone daily for at least 2 weeks or 30 mg for at least 1 week within 2 weeks prior to the episode of candidaemia; (iv) neutropenia (defined as absolute neutrophil count <500/mm3) at the onset of candidaemia; (v) hyperalimentation performed at the onset of candidaemia; (vi) the presence of central venous catheter at the onset of candidaemia; and (vii) the presence of a urinary catheter, nasogastric tube, or endotracheal tube at the onset of candidaemia [3].
Predisposing factors for developing candidaemia in ARFd patient
To determine the predisposing factors for developing candidaemia in ARFd patients, and to assess the effect of candidaemia on the outcome of ARFd, 37 ARFd patients with candidaemia were assigned to the ARFd candidaemic group. A control group of ARFd patients without candidaemia was matched to each case. The seven predisposing factors outlined above were assessed, and outcomes were also evaluated. Controls were individually matched to cases on a 1:1 ratio. Matching criteria included: the type and the number of underlying diseases (systemic lupus erythromatosus (SLE), surgical conditions, severe skin defects, cancers, and other conditions), age difference <10 years, and difference in APACHE II score 3. As all the ARFd candidaemic patients had only one primary underlying illness (Table 2
), all the matched controls were required to have only one type of primary underlying illness (i.e. the number of primary underlying illness was 1 in all ARFd candidaemic patients and controls). A concurrent control matched by the stay date of onset of candidaemia within the same month in the hospital was obtained for each case from the eligible pool of ARFd patients. If more than one candidate met the matching criteria, the candidate with the smallest age difference was selected as the control. If no such match was found, a matched control was searched for from an adjacent month. If a matched control was still not found from the 6 adjacent months, the studied patient was excluded. Accordingly, nine cases were excluded from the analyses.
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Prognostic factors, outcome, and management in ARFd patients with candidaemia
The following prognostic factors were studied: age of >60 years, medical vs surgical service, respiratory failure, shock, APACHE II score 18, administration of anti-fungal therapy for >48 h, dissemination (definite+likely), concomitant bacteraemia or not, non-Candia albicans fungaemia, corticosteroid therapy, malignancy, and neutropenia [10]. The threshold (60 years for the age, 18 for APACHE II score, and 48 h after anti-fungal therapy) in prognostic factors was chosen after reviewing the literature and considering the characteristics of our patients [11,12]. The above 12 prognostic variables were analysed by univariate analysis, and four variables, which were significant in univariate analysis, were subsequently assessed by multivariate analysis. Four management strategies were used, including: central catheter removal within 3 days of the first positive candidal blood culture, anti-fungal therapy involving amphotericin B or fluconazole, both, or neither. Cure was defined as survival of the episode of candidaemia, without sign and symptom of candidaemia, and with negative blood culture for Candida species. Death due to candidaemia was defined as death clinically attributable to candidaemia (i.e. attributable death). In the same admission, attributable death and death due to other conditions (e.g. underlying disease, etc.) were defined as crude death (i.e. overall mortality).
Statistical analysis
Chi-square test and Fisher's exact test were used to assess statistical differences in proportions, and Student's t-test for continuous variables. The McNemar and the Sign tests were used for paired data in the case-control study. In addition, multivariate analysis was performed to assess the independent prognostic factors for attributable mortality.
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Results |
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Clinical features and microbiological data in ARFd patients with candidaemia
The study population consisted of 37 candidaemic ARFd patients (16 males and 21 females). The ages of the patients ranged from 17 to 86 years (median 59 years). Twenty-eight patients were admitted to the medical department, eight to the surgical department (including six with surgical condition and two to the burn centre), and one to the gynecological department. The causes of ARFd were acute tubular necrosis in eight patients (including hypotension and/or hypovolaemia in five and drug-related in three), lupus nephritis in five, obstructive uropathy in three, and multifactorial in 21 (Table 1). Ten of 37 patients had underlying SLE, and the causes of ARFd were lupus nephritis in five, and multifactorial in five. Four of 37 ARFd candidaemic patients were younger than 40 years, all of whom had underlying lupus nephritis as the cause of ARFd.
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Overall, we found 20 (54%) candidaemic ARFd patients who met the criteria of (definite+likely) dissemination. Fifteen (40.5%) patients met the criteria of definite dissemination, proven by skin biopsy in five patients, pleural fluid culture in four, peritoneal fluid culture in three, and cerebrospinal fluid culture in three. Five (13.5%) patients met the criteria of likely dissemination, which was diagnosed in three patients with positive second culture obtained >24 h after removal of the colonized indwelling catheter, and two patients with positive culture from the three colonization sites of urine, sputum, and endotracheal tube.
The differences in clinical characteristics for candidaemic episodes between patients with ARFd and without ARFd
The primary underlying illnesses, predisposing factors, and outcomes were compared between ARFd candidaemic group and non-ARFd candidemic group (Table 2). Underlying illness of SLE was more common in the ARFd candidaemic group, while other types of underlying illness showed no significant difference. All patients had more than one predisposing factors for candidaemia. In both candidaemic groups, an average of four of predisposing factor were present (Table 2
), and the most common predisposing factors were multiple antibiotic usage (97.3% in ARFd group, and 87.1% in non-ARFd group, P>0.05) and central venous catheterization (94.6% in the ARFd group, and 82.9% in the non-ARFd group, P>0.05). The administration of corticosteroid was more frequently noted in the ARFd group than in the non-ARFd group (37.8% vs 10.6%, P<0.01). The percentage of catheter-associated candidaemia in the ARFd group was higher than in the non-ARFd group (56.8% vs 25.9%, P<0.01). However, no significant difference in candidal dissemination (likely+definite), attributable death, and crude death were observed between the two candidaemic groups.
Predisposing factors for candidaemia, and the outcome in ARFd patient populations
To assess the predisposing factors and outcomes of candidaemia in ARFd patients, a case-control study was performed. The 28 ARFd candidaemic patients were matched to 28 ARFd controls without candidaemia (Table 3). After matching, all 28 ARFd candidaemic patients and 26 of 28 matched controls (P>0.05, OR=5, CI=0.24; 104.1) had evidence or clinical suspicion of bacterial infection and had received antibiotics. Prior multiple antibiotic usage was identified as a significant predisposing factor for candidaemia in ARFd patients (P<0.01), and corticosteroid therapy was a nearly significant predisposing factor (P=0.059). The total number of predisposing factors for each patient was significantly higher in ARFd candidaemic patients than in ARFd patient without candidaemia (4.3±1.0 vs 3.0±1.2, P<0.05). Overall mortality (i.e. crude death) was significantly higher in the ARFd candidaemic group than in the ARFd patients without candidemia (71% vs 39.2%, P<0.05).
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Prognostic factors for candidaemia in patients with ARFd
To assess the prognostic factors for candidaemia in ARFd patients, we performed univariate and multivariate analysis using attributable death as the outcome variable. In the univariate analysis, older age (>60 years), respiratory failure, an APACH II score 18, and receiving anti-fungal therapy for >48 h were correlated with attributable death. Fungal dissemination (likely+definite), concomitant bacteraemia or not, non-C. albicans fungaemia, corticosteroid therapy, malignancy, and neutropenia had no influence on the death rate (Table 4
). The four variables, which were significant in the univariate analysis, were further assessed in the multivariate logistic regression analysis. In multivariate analysis, only a high APACHE II score (
18) and anti-fungal therapy for >48 h were independent prognostic factors (Table 5
).
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Management of candidaemia in patients with ARFd
Four management strategies were used, including: central catheter removal, anti-fungal therapy (with amphotericin B or fluconazole), both, or neither. The catheters were removed in 32 (86.5%) patients. Anti-fungal therapy (amphotericin B in 13 and fluconazole in 16) was administered in 29 (78.4%) of the 37 patients. The mean cumulative dose of amphotericin B in the treated patients was 850 mg (range 203200 mg), and the mean cumulative dose of fluconazole was 2000 mg (range 10012000 mg). On an average, the treatment was initiated at 3.1 days (range 112 days) after the first positive blood specimen was drawn.
Among the 29 patients treated with an anti-fungal agent, 18 patients underwent catheter removal and received anti-fungal therapy for >48 h, six patients underwent catheter removal and received anti-fungal therapy for <48 h, four patients did not undergo catheter removal and received anti-fungal therapy for >48 h, and one patient did not undergo catheter removal and received anti-fungal therapy for <48 h. As shown in Table 6, when the catheter was removed, the attributable death rate was significantly lower in patients receiving anti-fungal therapy for >48 h than that in patients not receiving anti-fungal therapy or receiving anti-fungal therapy for <48 h (27.8% vs 64.3%, P<0.05). But, the crude death rate showed no significant difference between these two groups. Among the six patients who had undergone catheter removal and had received anti-fungal therapy for <48 h, five died, possibly due to delayed administration of anti-fungal drugs (5, 7, 8, 11, and 12 days after first positive culture, respectively). Four patients received anti-fungal therapy for >48 h while their central catheter remained in situ, including one with Port-A catheter and three with temporary dialysis catheter. The reasons of no catheter removal included a tendency to bleed, long-term catheter used, and difficulty in reinsertion of dialysis catheter. Two of these patients died of candidaemia despite a total dose of amphotericin B of 1200 and 800 mg, respectively. The remaining two patients, who survived, initially received fluconazole 2000 and 2400 mg, respectively. When fluconazole therapy was discontinued, the candidaemia recurred in these two patients, and the central venous catheter was eventually removed. These two patients required an additional course of fluconazole of 2000 and 4000 mg, respectively. One patient subsequently died of intracranial haemorrhage, although the candidaemia was cured. In addition, only one patient received anti-fungal therapy for <48 h, during which his central venous catheter was not removed. He died when anti-fungal therapy started on the fourth day after positive culture for Candida (Table 6
).
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Discussion |
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To characterize candidaemia in the ARFd population, we compared the clinical features, possible predisposing factors, and outcomes of candidaemia in the ARFd patients with the other two groups (the non-ARFd candidemic group and the ARFd control group). In the case-control study, we demonstrated that multiple antibiotic usage and corticosteroid therapy were the most important predisposing factors for candidaemia in ARFd patients (Table 3). In addition, compared with the non-ARFd candidaemic patients, ARFd candidaemic patients were significantly more likely to have underlying SLE, corticosteroid therapy, and catheter-associated candidaemia (Table 2
). These data suggest the underlying mechanisms of developing candidaemia in ARFd patients. The best-known sources of candidaemia are the gut and intravascular catheter [3]. It is possible that ARFd patients are more prone to manipulate and contaminate their central venous catheter than non-ARFd groups. Usage of multiple antibiotics in ARFd patients may be associated with the colonization and the translocation of Candida from the gastrointestinal tract to the blood or body fluid, and may cause candidaemia directly or through catheter contamination. Also, underlying SLE and corticosteroid therapy can depress humoral and cellular immunity, which are the critical defence mechanisms for preventing deep tissue invasion by Candida. These data have clinical implications in prevention and diagnosis of candidaemia. Also, we emphasize that candidaemia should be suspected in infected ARFd patients, especially those with underlying SLE, corticosteroid therapy, multiple antibiotic usage, and indwelling central venous catheters.
The percentage of patients with attributable death and crude death in our ARFd candidaemic group was not significantly different from those in the non-ARFd candidaemic group (Table 2), and was comparable with those reported in other patient populations [3,14]. These data suggest that the clinical severity of candidaemia in ARFd patients is similar to those in other patient groups. In addition, the mortality rate was significantly higher in the ARFd candidaemic patients than in ARFd patients without candidaemia when matched for underlying illness, age, and APACH II scores (Table 3
). It implies that candidaemia has a major impact on the outcome of ARFd and should be managed carefully. We also assessed possible prognostic factors by using univariate and multivariate analysis and studying the attributable death. Although crude death was used for analysis in many previous studies [3,5], this may include many deaths not associated with candidaemia, thus confounding the results of the analysis. In a multivariate logistic analysis (Table 5
), an APACHE II score of
18 and receiving anti-fungal therapy for >48 h were both demonstrated to be independent prognostic factors. These findings suggest that the severity of acute illness affects the outcome of candidaemia, although, early and aggressive anti-fungal therapy may improve survival independently. Surprisingly, candidal dissemination (definite+likely) was not correlated with attributable death, a finding that may be due to the failure of the clinical criteria to predict the true fungal dissemination. It might also be possible that candidal dissemination is indeed not an independent risk factor for attributable death under aggressive anti-fungal therapy, as physicians are more likely to administer anti-fungal therapy to candidaemic patients meeting the clinical criteria of dissemination. Nguyen et al. [10] have reported better survival rates in C. albicans fungaemia, but this finding was not confirmed in our study of ARFd patients (Table 4
).
Both the administration of anti-fungal drugs and the removal of central venous catheters are major concerns in the management of candidaemia. Fichtenbaum et al. [15] showed that treatment with amphotericin B or fluconazole improved the mortality rate; however, Dyess et al. [13] and Meunier-Carpenter et al. [5] did not identify a benefit from anti-fungal therapy. As mentioned above, anti-fungal therapy for >48 h was found to be an independent prognostic factor for outcome. This finding also held when the effects of both anti-fungal therapy and catheter removal were analysed together. In ARFd patients, when central venous catheters were removed, the attributable death rate (27.8%) in patients receiving anti-fungal therapy for >48 h was significantly less than that (64.3%, P<0.05) in patients receiving anti-fungal therapy for <48 h (including patients without anti-fungal therapy) (Table 6). The relationship between treatment and outcome is further complicated as four of eight patients not receiving any anti-fungal therapy in this study even survived the episode of candidaemia (although two of four subsequently died of bacterial pneumonia). However, no predictors of who these untreated survivors might be were identified at the time of onset of candidaemia. Thus, our results indicate that early and aggressive anti-fungal therapy in ARFd patients with candidaemia should be mandatory. Another problem is whether to remove the central venous catheter. A central venous catheter may serve as a persistent source of candidaemia or as the target of haematogenous seeding. Although some cases of candidaemia have been reported to be successfully managed without catheter removal, the removal of central catheter has been suggested in the standard management of candidaemia [16]. In most of our ARFd candidaemic patients, the central catheter was removed and changed. Four patients initially received anti-fungal therapy for >48 h while their central catheter remained in place. Two of these four patients died, and the other two patients improved only after their catheters were removed (Table 6
). The small group in whom central catheters were not removed is a heterogeneous one; however, these observations suggest that central catheter should be removed in all ARFd patients with candidaemia.
There continues to be debate over which anti-fungal agent to use, appropriate dosage, and the optimal duration of treatment of candidaemia, particularly in ARFd patients. Our study could not reach a conclusion on drug choice because of its small sample size, retrospective nature, and disparities between amphotericin B-treated and fluconazole-treated patient groups (underlying illness, APACH II scores, and the delay between onset of candidaemia and the start of anti-fungal therapy). Amphotericin B has historically been the drug of choice for candidaemia; however, a multicentre clinical trial comparing fluconazole with amphotericin B for invasive fungal infections showed comparable efficacy [17]. Because the renal toxicity of amphotericin B is well documented, it is reasonable to try fluconazole first in ARFd candidaemic patients. High-dose therapy with fluconazole 800 mg/day has been suggested in the treatment of candidaemia in non-neutropenic patients [18]; however, the pharmacokinetics of fluconazole changes in patients with renal failure. Valtonen et al. [19] suggested a daily dose of 200 mg fluconazole in patients undergoing continuous venovenous haemodiafiltration, and in patients on continuous venovenous haemofiltration a smaller daily dose of fluconazole may be enough. Dahl et al. [20] also demonstrated that administration of fluconazole 200 mg, intraperitoneally every 24 or 48 h in patients on continuous cycling peritoneal dialysis, is sufficient to maintain effective serum and peritoneal concentration for most Candida spp. Toons et al. [21] showed that the half-life of fluconazole in patients with renal failure (a glomerular filtration rate of <20 ml/min) is approximately three times that in normal volunteers, and haemodialysis removed approximately 38% of fluconazole. The limited number of investigations suggests that the empirical initiation of fluconazole with a daily dose of 200 mg may be appropriate for ARFd candidaemic patients. The clinical status and laboratory data of these patients should receive close observation. If there is no clinical improvement or a minimal inhibitory concentration of fluconazole >8 µg/ml [1], a higher dosage of fluconazole (
400 mg/day) or amphotericin B may be indicated. Due to the lack of reliable activity of fluconazole for Candida glabrata and Candida krusei, amphotericin B is likely to be needed in patients infected with these Candida spp. [1]. The optimal dosage of amphotericin B in ARFd patients is uncertain, and a daily dose of 0.30.5 mg/kg may be sufficient [22]. In general, therapy should be continued for at least 7 days after the resolution of fever [18].
In conclusion, ARFd patients are susceptible to developing candidaemia primarily due to underlying illnesses and multiple predisposing factors, rather than to ARF and dialysis therapy per se. These underlying illnesses and predisposing factors included SLE, indwelling central venous catheter, multiple antibiotic usage, and corticosteroid therapy. The mortality rate is high in ARFd patients with candidaemia, especially in those with APACH II scores of 18 and in those who receive anti-fungal therapy for <48 h. In ARFd patients with candidaemia, central venous catheters should be removed and anti-fungal therapy should be started immediately.
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Notes |
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References |
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