Treatment of candidemia in adult patients without neutropenia - an inconvenient truth

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.


Introduction
Fungal infections, in particular candidemia, are a growing problem in immunocompetent patients [1]. 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 [1]. 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 effi cacy; 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]. Th e primary recommendation for treatment of candidemia in non-neutropenic patients was administration of fl uconazole or an echinocandin. Th e alternative approach was administration of lipid formulation (LF)-AmB, AmB-deoxycholate (AmB-d) or voriconazole. Th e recommendation for echinocandins was extended to patients with moderately severe to severe illness or with recent azole exposure.

A critical review of the evidence
Th e 2009 IDSA guidelines [1] represent a marked change in the recommended therapeutic approach, and is not supported by the effi cacy of the diff erent 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]. Th e use of AmB-d and LF-AmB are supported by very solid data from well designed clinical trials and that have consequently been twice graded A-I [1]. Moreover, echinocandins are not suitable for the treatment of endophtalmitis, meningitis and endocarditis [5] whilst AmB remains the drug of choice.
Th erefore, 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 [1] 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 [6] suggests that anidulafungin might be superior to fl uconazole as primary therapy for candidemia in non-neutropenic patients (75.6% success with anidul afungin compared to 60.2% with fl uconazole). However, in a noninferiority trial, only noninferiority can be demonstrated and any benefi t of the new treatment should be interpreted with great caution [7] and only be based on other advantages, such as safety, convenience and cost [8]. 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 fl uconazole. In addition, more patients in the anidulafungin group had their central venous catheter removed than in the fl uconazole arm (96% versus 89%). Consequently, as Sobel and Revankar wrote in an editorial [9], anidulafungin was, at best, noninferior in comparison to fl uconazole.

The myths on nephrotoxicity
Th e change of the positioning of AmB preparations in the 2009 guidelines [1,2] seems to be supported by the nephrotoxicity fi ndings of two studies, one showing that

Abstract
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 fl uconazole or an echinocandin. Amphotericin-B formulations were considered an alternative. However, careful assessment of published data showed similar effi cacy between these drugs.
AmB-d could result in ARF in up to 50% of patients [10] and the other that AmB-d-induced nephrotoxicity is asso ciated with a 6.6-fold increased risk of death [11] ( Table 2).
Th e fi rst study is a review about AmB nephrotoxicity [10]; in this review, the author cited another study published in 1999 [12] where those fi ndings were presented. However, patients included in this retro spective analysis were markedly immunosupressed, received concomitantly nephrotoxic agents, and received long courses of AmB (20.4 days) for sus pected or proven aspergillosis, not invasive candidiasis. Accordingly, these fi ndings cannot be extrapolated to non-neutropenic patients with candidemia.
Th e second study [11] 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 vio lation of the assumptions necessary to compare groups with the statistical methods used. Roughly, 30% of these admissions were complicated with ARF. Th e 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). Th e 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 diffi cult 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 eff ect on prognosis, it would be expected that this fi nding would have a negative eff ect 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-threaten ing 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 [13]. Th at is probably because AmB-d remains the antifungal with the most rapid time-kill rate and the largest post-antifungal eff ect [14] and with effi cacy that increases with its concen tra tion [15]. LF-AmB could present a better safety profi le, but its cost constitutes a major limitation to its routine use. In addition, there are no solid data to support any benefi t from LF-AmB in comparison to AmB-d if administered with correct pre-medication.

Conclusion
Careful assessment of published data on the treatment of candidemia in non-neutropenic patients showed similar effi cacy between AmB preparations, fl uconazole and echino chandins. Th e choice of fi rst line therapy should be based on individual risk factors, patterns of Candida susceptibility, clinical experience, as well as local availability of the diff erent drugs and their costs.