Once Candida gains access into the bloodstream, secondary infection may occur in a number of organs and tissues, such as the eyes, kidneys, skin, joints and bones, CNS and endocardium, including heart valve prosthesis or other intra-cardiac devices. Moreover, persistent fungaemia resulting from intravascular Candida infection may further facilitate metastatic seeding of the above organs. In neutropenic haemato-oncology patients with chronic haematogeneous candidiasis attributable to intestinal tract damage by cytotoxic chemotherapy, liver and spleen localizations are common. These are described in detail elsewhere.[1]

This paper reviews the epidemiology and treatment of Candida infection in endocarditis and other clinical entities.

1. Candida Endocarditis

Candida endocarditis has long been considered to be a rare and often fatal infectious disease with a presentation similar to that of subacute bacterial endocarditis. Until recently, most data were from case reports or very small series.[2] Initially, most patients were intravenous drug addicts or cardiosurgery patients with prosthetic heart valves.[2–5] During the 1980s, however, several cases of catheter-related, right-sided Candida endocarditis were observed in immunocompromised/oncology patients and major abdominal surgery patients requiring indwelling central venous catheterization for parenteral nutrition and/or cytotoxic chemotherapy.[6,7] The number of reported cases has increased during the last decade, probably as a consequence of increased use of prosthetic intravascular devices, advances in the surgical techniques (including reconstructive heart surgery), and increases in the number of immunocompromised patients. In addition, a growing number of individuals are at high risk for nosocomial candidaemia; for example, those admitted to the intensive care unit (ICU) or those with other forms of health care-associated (HCA) invasive fungal infections.[2,8]

A recent prospective 1-year survey of Candida bloodstream infections (BSIs) in seven university hospitals in western France assessed the epidemiology and clinical features of Candida endocarditis.[9] Of 190 cases of Candida BSI, 7 (3.7%) were complicated by endocarditis (4 on native valves, 2 on artificial [biological] valves and 1 involving a pacemaker). Indeed, the ICE-PCS (International Collaboration on Endocarditis — Prospective Cohort Study) recently indicated that Candida endocarditis accounted for 33 (1.2%) of 2749 cases of definite infectious endocarditis. Patients with Candida endocarditis were more likely to have prosthetic valves or short-term indwelling catheters, and to have an HCA Candida infection.[10] It should be noted that during recent decades, the number of patients undergoing open heart surgery and carrying prosthetic implants has increased. A high proportion of the patients who undergo such operations are critically ill, require prolonged ICU monitoring, and therefore have several of the risk factors for developing nosocomial candidaemia.[11] Most of these patients undergo post-operative splanchnic hypoperfusion, leading to intestinal intramucosal acidosis and increased intestinal mucosal permeability.[12] These patients are also at risk of developing ventilator-associated pneumonia (VAP) requiring antibacterial therapy with associated endotoxaemia, which may damage the intestinal mucosal barrier, thereby favouring Candida translocation.[13] Implantation of a contaminated allograft can also occur. All the aforementioned factors might predispose to the spread of Candida species into the systemic circulation and development of candidaemia. Thus, the scenario of a patient with a prosthetic heart valve or other intravascular prosthetic device who develops candidaemia is becoming more common.

The risk of developing prosthetic valve endocarditis (PVE) in candidaemic patients with prosthetic heart valves was addressed in a retrospective study by Nasser et al.[8] Overall, Candida PVE was documented in 11 of 44 (25%) patients: 7 patients were diagnosed at the same time as candidaemia (group 1), while the remaining 4 (group 2) were diagnosed several weeks after an episode of early postoperative candidaemia. It is noteworthy that in both groups, PVE was diagnosed late after valve replacement (after a mean of 270 days in group 1, and after a mean of 246 days in group 2),[8] suggesting that the episodes had a similar pathogenic mechanism. Thus, Candida PVE may be a two-step process: the first step is represented by a post-operative transitory candidaemia occurring during the ICU stay, which leads to colonization of prosthetic valve and subsequent biofilm formation. After the initial colonization, the fungus, slowly growing on the prosthesis surface, becomes less susceptible to antifungal agents. This speculation lends support for pre-emptive antifungal therapy with agents that display anti-biofilm activity in patients with prosthetic heart valves who are at risk of candidaemia.

The current Infectious Diseases Society of America (IDSA) guidelines on the treatment of candidiasis recommend intravenous lipid formulation of amphotericin B with or without 5-fluorocytosine, in addition to valve surgery as first-line treatment for Candida endocarditis (table I).[14] Recent in vitro studies have shown reduced activity of amphotericin B against Candida biofilm,[15] and poor penetration into vegetations and blood clots in experimental models of infectious endocarditis,[16] whereas echinocandins, and in particular anidulafungin, display potent in vitro activity against sessile Candida cells within biofilms,[17,18] and caspofungin has been successfully used in anedoctal cases of Candida endocarditis.[9,10] Thus, the echinocandins may have a favourable impact on the management of this infection.

Table I
figure Tab1

Infectious Diseases Society of America guidelines for management of endocarditic and localized infections. Adapted from Pappas et al. with permission[14]

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2. Ocular Candidiasis

Contrary to endocarditis, the incidence of ocular candidiasis has been decreasing among inpatients with candidaemia, with recent incidence estimates of less than 2%.[19] It has been suggested that this trend is related to earlier identification and treatment of candidaemia.[20] The clinical presentation may be very indolent, with progression from corioretinitis to vitritis or frank endophthalmitis, especially in patients who are not able to articulate ocular symptoms,[20] and Candida endophthalmitis may occur as a late relapsing of candidiasis. Thus, retinal examination is mandatory in all patients with candidaemia and should be repeated after 2 weeks in patients that show no signs of ocular disease at the first fundoscopy. The therapeutic approach includes prolonged treatment with fluconazole or voriconazole (table I). The role of systemic echinocandins might be limited since they achieve undetectable vitreous concentrations. Vitrectomy with local instillation of amphotericin B, azoles or echinocandins may play a role in the treatment of chronic complications such as epiretinal membrane formation.[19,20]

3. CNS and Osteoarticular Infections

Diffuse encephalitis in the setting of candidaemia is very misleading since alterations of the mental status are generally attributed to the candidaemia-associated sepsis syndrome. In addition, neuroimaging studies and cerebrospinal fluid cultures do not usually contribute to diagnosis. These complications worsen an already ominous prognosis.[21,22] Osteomyelitis caused by Candida is considered infrequent and, when it does occur, it can usually be traced back to the spinal column. However, in our recent experience of nosocomial non-postneurosurgery spondylodiscitis, we observed 3 (27%) of 11 cases caused by Candida species.[23] Optimal management may require surgical debridement and, after initial intravenous antifungal therapy, prolonged administration of oral azoles.

4. Conclusions

The role of Candida in endocarditis is fairly well established. With the increasing incidence of Candida endocarditis, and the increasing numbers of patients at risk, there is a need for agents with potent efficacy against Candida biofilms. Echinocandins represent a potential therapeutic option in this setting. Antifungal agents may also be of use in the treatment of complications in patients with ocular candidiasis, osteoarticular or CNS infections.