Treatment of candidemia in adult patients without neutropenia - an inconvenient truth
Critical Care volume 15, Article number: 114 (2011)
In 2009 the Infectious Diseases Society of America reviewed the guidelines on the treatment of candidemia in non-neutropenic patients. In this document the preferred treatment was either fluconazole or an echinocandin. Amphotericin-B formulations were considered an alternative. However, careful assessment of published data showed similar efficacy between these drugs.
Fungal infections, in particular candidemia, are a growing problem in immunocompetent patients . Despite several guidelines, concern exists on the value of evidence supporting recommendations for the optimal treatment of candidemia in non-neutropenic adult patients [1, 2].
In the midst of this controversy a critical reappraisal of the 2009 Infectious Diseases Society of America (IDSA) guidelines is appropriate . Although many relevant aspects of the guidelines are thoroughly discussed, there are three topics that deserve a closer look: the weight and quality of the evidence; the evidence of efficacy; and the evidence of amphotericin-B (AmB)-induced renal failure.
What is recommended by the 2009 IDSA guidelines?
In 2009, IDSA updated their 2004 guidelines (Table 1) [1, 2]. The primary recommendation for treatment of candidemia in non-neutropenic patients was administration of fluconazole or an echinocandin. The alternative approach was administration of lipid formulation (LF)- AmB, AmB-deoxycholate (AmB-d) or voriconazole. The recommendation for echinocandins was extended to patients with moderately severe to severe illness or with recent azole exposure.
A critical review of the evidence
The 2009 IDSA guidelines  represent a marked change in the recommended therapeutic approach, and is not supported by the efficacy of the different antifungals. In all nine clinical trials, AmB-d and LF-AmB were never inferior to any comparator and two recent meta-analyses showed the same results [3, 4]. The use of AmB-d and LFAmB are supported by very solid data from well designed clinical trials and that have consequently been twice graded A-I . Moreover, echinocandins are not suitable for the treatment of endophtalmitis, meningitis and endocarditis  whilst AmB remains the drug of choice.
Therefore, even though not explicit in the guidelines, the change is probably related to a possible advantage of echinochandins and the perceived renal dysfunction associated with AmB. In fact, the 2009 IDSA guidelines  attribute to AmB-d therapy a high risk of acute renal failure (ARF) and mortality.
The new evidence
A recent study from Reboli and colleagues  suggests that anidulafungin might be superior to fluconazole as primary therapy for candidemia in non-neutropenic patients (75.6% success with anidulafungin compared to 60.2% with fluconazole). However, in a noninferiority trial, only noninferiority can be demonstrated and any benefit of the new treatment should be interpreted with great caution  and only be based on other advantages, such as safety, convenience and cost . Besides, the evaluation of the primary end-point was made at the end of intravenous therapy, after a median of 14 days of anidulafungin against only 11 days of fluconazole. In addition, more patients in the anidulafungin group had their central venous catheter removed than in the fluconazole arm (96% versus 89%). Consequently, as Sobel and Revankar wrote in an editorial , anidulafungin was, at best, noninferior incomparison to fluconazole.
The myths on nephrotoxicity
The change of the positioning of AmB preparations in the 2009 guidelines [1, 2] seems to be supported by the nephrotoxicity findings of two studies, one showing that AmB-d could result in ARF in up to 50% of patients  and the other that AmB-d-induced nephrotoxicity is associated with a 6.6-fold increased risk of death  (Table 2).
The first study is a review about AmB nephrotoxicity ; in this review, the author cited another study published in 1999  where those findings were presented. However, patients included in this retrospective analysis were markedly immunosupressed, received concomitantly nephrotoxic agents, and received long courses of AmB (20.4 days) for suspected or proven aspergillosis, not invasive candidiasis. Accordingly, these findings cannot be extrapolated to non-neutropenic patients with candidemia.
The second study  is also a retrospective analysis published in 2001, using data from 707 admissions of 551 patients treated with AmB-d. However, the inclusion of the same patient several times constitutes a major violation of the assumptions necessary to compare groups with the statistical methods used. Roughly, 30% of these admissions were complicated with ARF. The average highest creatinine in this group was 3.3 ± 1.3 mg/dL, whereas in those without ARF it was 1.6 ± 0.7 mg/dL (P < 0.0001). The mortality rate in the admissions complicated with ARF was 54.2% and in those without ARF it was only 16% (odds ratio for death, 6.6). From these data, it is difficult to envisage that patients with a mean increase in creatinine of 1.7 mg/dL had a 6.6-fold increased risk of death.
Besides, as we have already pointed out, AmB was never inferior to any comparator in six randomised controlled trials with non-neutropenic adult patients with candidemia [3, 4]. If AmB-induced nephrotoxicity was so common and has such a detrimental effect on prognosis, it would be expected that this finding would have a negative effect on mortality.
Should we still use AmB-d?
Even though AmB-d is an old drug, it is still regarded as one of the drugs of choice for treatment of life-threatening mycoses as well as for the empirical therapy of febrile neutropenia. A Cochrane review published in 2000, but left unchanged after reassessments in 2007 and in 2009, provides support for this practice . That is probably because AmB-d remains the antifungal with the most rapid time-kill rate and the largest post-antifungal effect  and with efficacy that increases with its concentration . LF-AmB could present a better safety profile, but its cost constitutes a major limitation to its routine use. In addition, there are no solid data to support any benefit from LF-AmB in comparison to AmB-d if administered with correct pre-medication.
Careful assessment of published data on the treatment of candidemia in non-neutropenic patients showed similar efficacy between AmB preparations, fluconazole and echinochandins. The choice of first line therapy should be based on individual risk factors, patterns of Candida susceptibility, clinical experience, as well as local availability of the different drugs and their costs.
PP is coordinator of the Polyvalent Intensive Care Unit and president of the Antibiotic Commission of São Francisco Xavier Hospital. PP is Professor of Medicine of the Faculty of Medical Sciences from the New University of Lisbon, Portugal. JGP is consultant in Polyvalent Intensive Care Unit whose main field of interest is infection and antibiotic chemotherapy.
acute renal failure
Infectious Diseases Society of America
lipid formulation of amphotericin-B.
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We would like to express our gratitude to Prof. Jorge Salluh for critical reading of this manuscript. This commentary was supported by an unrestricted grant from Gilead.
PP has received honoraria and served as advisor of Astra Zeneca, Ely-Lilly, Gilead, Janssen-Cilag, Merck Sharp and Dohme, Novartis and Pfizer. JGP has received honoraria and served as advisor of Pfizer, Astra-Zeneca, Abbott, Wyeth-Lederle, Janssen-Cilag, Merck Sharp and Dohme, and received an unrestricted research grant from Astra-Zeneca.
PP and JGP contributed to the conception, analysis and interpretation of data of the present commentary and were involved in drafting the manuscript and its revision.
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Póvoa, P., Gonçalves-Pereira, J. Treatment of candidemia in adult patients without neutropenia - an inconvenient truth. Crit Care 15, 114 (2011). https://doi.org/10.1186/cc9414
- Acute Renal Failure
- Invasive Candidiasis