Candidal Endocarditis – Looking for Sasquash

Infective endocarditis is a rare enough disease in and of itself that many folks won’t see much of in their lifetimes, though the rise in IV drug abuse means this may not be the case in the future. Staphylococcus aureus and streptococci, as well as enterococci, tend to be the most common organisms associated with endocarditis. Rarer still is fungal endocarditis. With the older and more immunosuppressed population full of central lines and prosthetic valves, it would not surprise me if we see a rise in native and prosthetic valve endocarditis with fungi. I will focus my discussion on Candida endocarditis, as this is likely the most common fungi that tends to be seen, and will pay special attention to the (lack of) data with regards to treatment.

Yay Candida!

As most people are aware, the most common type of Candida is C. albicans. Despite this, the microbiology of infections is changing. C. parapsilosis occurs through central venous lines and TPN solutions, while C. tropicalis has been associated with malignancy and neutropenia (1). Obvious risk factors that are obvious include IV drug abuse, cardiac devices such as ICD/PPM, prosthetic valves, central catheters, immunosuppression (either HIV or transplant), end stage renal disease, and prior valve surgery (1, 2, 3):

Left sided endocarditis, usually aortic valve, tends to be more common (1-3).  One study found that the aortic valve was involved in in 53% of the cases (2), while it accounted for 44% of cases in another series (3):

Duration of symptoms prior to diagnosis was roughly around one month, usually 34 +/- 31 days (3) and less than a month in another series (4).

Guidelines and In Vitro Data

IDSA and ACC guidelines for candida endocarditis suggest the use of either amphotericin B or echinocandins along with surgical intervention (4, 5). IDSA guidelines suggest treatment with liposomal amphotericin with or without flucytosine or high dose echinocandin, however there is no good data for this approach (4). Further, suppression with any azole, as long as the yeast is susceptible, is a common approach for those who do not undergo valve replacement. ACC guidelines echo this sentiment (5), though which therapy to use is less clear. Some insights come from animal studies. An animal model of several invasive candida infections, including endocarditis, evaluated amphotericin B monotherapy, fluconazole monotherapy, flucytosine monotherapy, combination fluconazole/amphotericin B and fluconazole/flucytosine (6). All rats in the control and flucytosine monotherapy died, compared to only 7% of rats in the other groups. When looking at fungal counts in cardiac vegetations, amphotericin B was more effective than fluconazole or flucytosine monotherapy or in combination:

Moreover, amphotericin B alone was more effective than fluconazole/amphotericin B combination, suggesting antagonistic effect. How this translates to clinical data is unclear. 

Early administration seems to be key. In another animal study (7), treatment 72hrs after inoculation failed to reduce fungal load in vegetations when compared to controls, while treatment within 24hrs of  inoculation lead to reduced cardiac fungal loads for those treated with amphotericin B when compared to controls, fluconazole, or flucytosine. Notably, 48hrs after the last dose, there was no fluconazole detected in the vegetations of 5 out of 6 animals compared to amphotericin B, which was detected in all vegetations. 

So it seems that amphotericin B is more potent in animal studies compared to fluconazole when it comes to antifungal activity, at least as measured in fungal density. The choice between amphotericin B and echinocandins tends to be based on tolerability and side effect profile, though both seem to have similar effects when it comes to biofilm penetration. A study evaluated MICs to different antifungals for C. albicans and C. parapsilosis in the setting of either experimental bio-film or normal growth (8). While the MIC to all azoles increased for BioFilm, including amphotericin B. Lipid vehicles all had favorable MICs even for the biofilm Candida, which was a similar result seen for both Micafungin and Caspofungin:

Guidelines recommend the use of higher-dose echinocandins for candida endocarditis. While data for this is limited to case studies (9), there is a concern for paradoxical resistance when higher doses are used. An Eagle-like effect has been described for some echinocandins (note: I have written about the Eagle-effect in the past. While the original term refers to higher concentration of penicillin having lower efficacy, nowadays, I hear it being used in terms of lower efficacy in high-inoculum infections. Here, I’ll use the “original” definition of the Eagle-effect) when higher doses of these antifungals are used. A few reviews are available for this topic (10, 11). The mechanism behind this is unclear, however by inhibiting beta-1,3-glucan synthesis, chitin content increases, leading to increased overall fungal growth. While some of the cited studies suggest this effect exists in-vitro for caspofungin, this does not hold true for anidulafungin or micafungin, though certain species of Candida do show this effect with micafungin. High doses of echinocandins in invasive candidiasis do not show differences in clinical outcomes, so this effect may not be clinically relevant. 

Treatment Strategies

To be honest, there is no clear algorithm when it comes to therapy. Antifungals + surgery seems to be the general way to go, but it should be noted that data is not great here and surgery may not be an option for a certain percentage of patients. For instance, a case of C. glabrata infective endocarditis was treated with a combination of liposomal amphotericin B + caspofungin for a total of 8 weeks (only 3 weeks of dual therapy) followed by suppressive caspofungin three times per week for 12 weeks without recurrence (12). Another case described mural C. parapsilosis endocarditis treated with a combination of voriconazole and caspofungin (13). I mention this to highlight that it is possible to manage this without surgery, however as you will see, mortality remains incredibly high.

One early review evaluated 270 patients from 1965-1995 (14). 60% of patients here received a combination of surgical and medical management, with amphotericin B being given in 162 cases. Patients with combined management had higher survival rates compared to medical management alone, although it is unclear if those who only underwent medical management were poor surgical candidates or if there was another variable here: 

The authors note that most of the patients who underwent surgery had at least one indication. 39 patients had amphotericin B and flucytosine combination therapy, though at the time of this paper, triazoles were not widely available. A similar finding was reported in a meta-analysis (15) of 879 cases, with those who underwent adjunctive surgery having lower proportion of death (pOR 0.56, 95% CI .16-1.99), while patients treated with antifungal monotherapy had higher mortality (pOR 1.49, 95% CI 0.39-5.81). In a smaller cohort of 30 patients, of which 13 had surgical intervention, mortality was higher in those who did not undergo surgery (70% vs 62%) but this was not statistically significant. Multivariate analysis found that IV drug abuse was associated with lower mortality while age >60 was associated with higher mortality:

These findings are in contrast with a 2015 study evaluating two large prospective cohorts of 70 patients (17). Thirty-two (46%) of patients were surgically managed, however this was not associated with improved outcome (RR 1.06, 95% CI 0.73-1.54). Notably, surgical management tended to occur more frequently in younger patients or those with intracardiac abscesses. 45% of patients in these cohorts received dual-antifungal therapy, but this was not associated with improved outcomes either, nor was the use of either echinocandin or amhotericin B. A review of 18 cases of prosthetic valve endocarditis found that 2/4 patients who underwent surgery died; of those managed with antifungals, only 4 had combination antifungals (usually amphotericin backbone) with some receiving up to 6 months of fluconazole suppressive therapy (18). 

Combination medical and surgical therapy was not associated with improved mortality in a case series of 46 patients with prosthetic valve candida endocarditis (19):

In univariate analysis, L-amB-based therapy alone or in combination with 5FC was associated with survival:

And compared to echinocandin-based therapy alone, those who got L-AmB therapy had a higher 6-month survival rate (aOR 13.52, 95% CI 1.03-838.10), though the wide confidence intervals should tell you how robust this result is. Overall, it seems that either echinocandin or liposomal amphotericin B are reasonable upfront options for therapy, with fluconazole having a high rate of failure. A meta-analysis of 64 cases of endocarditis found that fluconazole was administered as sole therapy in 21 patients (31%) while it was given in combination in 44 (69%) other patients, most of which got amphotericin B (usually conventional, 20). 58% of those treated with fluconazole alone achieved treatment success (cure or improved) compared to 84% of those who had combination therapy (p=0.02). Further, liposomal amphotericin B was associated with lower failure rate (22%) compared to conventional amphotericin (35%) though the numbers here were fairly small to draw any meaningful conclusions.

Overall duration of therapy is unclear, with regimens ranging from 6-8 weeks, though this can depend on culture positivity and surgical management. Guidelines do recommend at least 6 weeks from surgery or perhaps longer, with possible step-down to a PO azole if this options is available. 

Suppressive therapy

Oral suppressive therapy has been used following IV therapy, usually with fluconazole (18). Another review notes 2 patients with prosthetic valve endocarditis who have not had relapse at 1-2 years while on fluconazole (2). Long-term fluconazole was also associated with improved mortality at 6 months in one prospective cohort (19) and another case of successful suppressive therapy following relapse has also been described (18). Favorable outcomes for suppressive therapy were seen in 56 cases of fungal infections associated with hardware (21).

Monitoring Invasive Candida Infections with BD Glucan

The adjunct use of beta-d glucan for the monitoring of invasive candidiasis is something I have seen been done in practice, however the guidelines do not suggest its use. There are a few small studies that have evaluated BD glucan for therapeutic monitoring. In a study of 148 patients, BD glucan in septic ICU patients <80 was used as a safe cutoff to stop antifungals (22). Another study of invasive candidiasis found that patients who responded had a drop in beta-d glucan after antifungal therapy (figure A), compared to those who did not respond to therapy (figure B):

A larger study of around 200 patients (23) found that treatment success for invasive fungal infections was associated with a decrease in BD glucan, although a significant portion of these continued to have positive values:

Despite this, successful treatment tended to have a negative slope in BG levels with sensitivity, specificity, PPV and NPV of 62%, 61%, 90% and 22%. It should be noted this study excluded neutropenic patients as well as patients with infective endocarditis, but this does suggest that occasionally trending BD glucan can, at minimum, alert you to a possible relapse or lack of response and that adjustments to therapy should be made. In another study of neutropenic patients with candidiasis (24), BD glucan declined in 20 out of 22 patients with therapy, but remained above 80 in 15/20 patients:

How long it takes for BD glucan to drop to negative in infective endocarditis is unclear, however case report (25) notes that it took 197 days of fluconazole therapy for BD glucan to drop. Therapy was stopped 16 months into therapy, and follow up with BD glucan 21 weeks afterwards revealed a negative BD glucan. This suggests this can also be used to monitor someone off therapy, and it can be used to either de-escalate or resume therapy in someone who is on long-term azole suppressive therapy. How often to get it and for how long to monitor is unclear, so this is going to be individualized according to each case. 

TL;DR

• Candidal endocarditis is associated with traditional risk factors for endocarditis, including TPN, central line placement, valve surgeries, and immunosuppression
• Therapy is a combination of antifungals and surgery
• Antifungals: liposomal amphotericin alone or in combination with flucytosine or high dose echinocandin, as these have good efficacy in biofilms in comparison to other antifungals
  • There is concern for antagonistic effect when amphotericin B and fluconazole are used together, so would avoid this combination for the time being, though there is some cases of amphotericin B and mould active triazoles being used
  • There is also a possible role for combination echinocandin and L-AmB, though there is scarce data here
  • Duration: no one knows, can do 6-8 weeks at least 
• Suppressive therapy is the name of the game as long as someone can tolerate it if surgery is not an option
• BD glucan can be used as an adjunct to guide progress and duration of therapy. How often to get it is unclear, but response has been associated with a negative BD glucan slope, while lack of response is associated with increased BD glucan levels. 

References:

1.  Mamtani S, Aljanabi NM, Gupta Rauniyar RP, Acharya A, Malik BH. Candida Endocarditis: A Review of the Pathogenesis, Morphology, Risk Factors, and Management of an Emerging and Serious Condition. Cureus. 2020 Jan 18;12(1):e6695. doi: 10.7759/cureus.6695. PMID: 32104631; PMCID: PMC7026878.
2. Lefort A, Chartier L, Sendid B, Wolff M, Mainardi JL, Podglajen I, Desnos-Ollivier M, Fontanet A, Bretagne S, Lortholary O; French Mycosis Study Group. Diagnosis, management and outcome of Candida endocarditis. Clin Microbiol Infect. 2012 Apr;18(4):E99-E109. doi: 10.1111/j.1469-0691.2012.03764.x. Epub 2012 Feb 13. PMID: 22329526.
3. Ellis ME, Al-Abdely H, Sandridge A, Greer W, Ventura W. Fungal endocarditis: evidence in the world literature, 1965-1995. Clin Infect Dis. 2001 Jan;32(1):50-62. doi: 10.1086/317550. Epub 2000 Dec 12. PMID: 11118386.
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