Candida spp

Candida spp. is the most common cause of FE and is responsible for 33-44% of all cases [339]. Approximately 50% of FE cases are caused by C. albicans [339]. Candida endocarditis occurs in the setting of particular risk factors, including structural cardiac valvular abnormalities, use of broad-spectrum antibiotics, central lines, par-enteral nutrition, and surgery [339,406]. A previous review had reported intravenous drug abuse as a major risk factor for FE [407]. The epidemiology of risk factors, however, has since changed, and in a more recent review, only 4% of patients were reported as drug abusers [406].

With the increasing use of the above risk factors as a reflection of medical progress, it is probable that the incidence of candidal FE will increase.

The management of candidal FE remains poorly defined. An inherent difficulty in establishing treatment guidelines is the low incidence of this disease, thus precluding any appropriately powered, randomized, controlled clinical trials.

Prior to the advent of newer antifungal therapies, AmB was the only agent available. As such, the dogma in management of FE was to remove the infected tissue, replace the valve, and provide six to eight weeks of AmB therapy [408]. The importance of surgical intervention in the management of Candida endocarditis is exemplified by the differences in mortality rate without (~90% [395]) and with (~45% [407]) surgery. Surgical intervention should be performed as soon as possible, with removal of the valve and surrounding infected tissue. Current guidelines in North America recommend combined medical and surgical therapy, with medical therapy defined as AmB with or without flucytosine at maximal tolerated doses for a total duration of therapy of > 6 weeks after surgery [376]. This recommendation is based on a non-statistically significant trend toward better outcome among patients who underwent surgery. It is also supported by a report that 160 days of AmB therapy did not sterilize a cardiac valve [409], emphasizing the need for surgical removal. This initial step of combined medical/surgical therapy, termed the "induction phase," is the first of a two-phase management plan. The purpose is to provide rapid control of infection. After a clinical response to the initial "induction phase," "prophylactic therapy" should be instituted. Typically, oral azoles have been used for this purpose.

The development of the azoles may now provide an alternative to AmB in the treatment of this condition. It has been shown that flucona-zole is as effective as AmB for the treatment of candidemia (without endocarditis) [410]. Furthermore, in non-neutropenic, non-endocarditis patients, fluconazole in combination with AmB (0.7 mg/kg per day given only for the first five or six days) trended toward improved success and more rapid clearance of candidemia (excluding C. krusei) from the bloodstream, although it was not statistically significant [411]. It has also been used during the "prophylactic" stage (see below). Animal models, however, have suggested that fluconazole may be an effec tive agent for primary therapy of Candida endocarditis, as it demonstrates superior ability to penetrate cardiac vegetations than AmB [378]. The clinical data regarding the use of flucona-zole for treatment of Candida NVE, however, is limited to a few successfully managed cases in the English literature [412-414]. Future studies are required.

Candida endocarditis has a propensity for relapse after valve replacement, and therefore requires careful follow-up for > 1 year. This recommendation is based on small series of patients, in which typical follow-ups have ranged 6-12 months. However, relapse has been described in patients several years after treatment was discontinued [368,415]. Thus, it has been suggested that "cure" be defined as the absence of infection for > 2 years after withdrawal of antifungal treatment [412]. Therefore, "prophylactic therapy" is used after a clinical response to the "induction phase" to minimize the risk of relapse and to attempt a cure. The duration of this phase is poorly defined, but given the potential disastrous complication of recurrence, lifelong suppressive therapy has been suggested [416]. In patients that are not deemed appropriate surgical candidates for valve replacement, or that refuse surgery, prophylactic therapy is used with the goal being lifelong suppression [376,406].

An alternative antimycotic is the echinocan-din, caspofungin. The advantage of this agent is that it is fungicidal in vitro and in vivo against most isolates of Candida spp., including C. krusei and C. glabrata [376]. These two yeasts may demonstrate intrinsic (C. krusei) or acquired (C. glabrata) resistance to fluconazole, and they may also be less susceptible to AmB [376]. Furthermore, it has a benign toxicity profile and requires no modification of dose in patients with renal insufficiency. Case reports have described its successful use in the treatment of Candida endocarditis, both native [400,417] and prosthetic [401] valves. However, it may not be the agent of choice if cerebral septic emboli complicate the endocarditis, as it penetrates poorly across the CNS and may permit the development of candidal brain abscesses [405]. Further studies on its efficacy are required.

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