Antifungals for Candida Infective Endocarditis – Where is the Data?

Candida and staphylococcus are two fairly common isolates of bloodstream infections, as well as part of our own microbiome. These two organisms also instill the fear of God into me, given how sticky they can be. I’ve talked a lot about staphylococcus and endocarditis in general, so candida endocarditis gets the spotlight for this post. I’ll focus on antifungal therapy, since its a bit more interesting.

Let’s look at the guidelines as a launching point. The IDSA guidelines mention that optimum therapy for both native and prosthetic valve endocarditis is that of valve replacement and a long-course of antifungal therapy (1). They advocate the use of lipid formulations of amphotericin B and echinocandins, with higher doses of echinocandins being “thought necessary” to treat endocarditis. The source of this recommendation is a 48 patient case series, of which those with endocarditis and osteomyelitis could get 100mg of caspofungin daily up to 150mg (usual dose is 50mg, 2). While the overall success rate was 81%, it should be noted that there were a total of 7 patients in the higher dose group, of which only 3 had endocarditis, and treatment success for endocarditis was 33%. Looking at the guidelines from the AHA gives you an insight into the lack of data with regards to medical management (3): “Historically, 2 treatment doctrines have prevailed in fungal IE despite the lack of prospective trials conducted to define the most appropriate therapy: Fungal IE is a “stand-alone indication” for surgical management of an infected valve; and amphotericin B, a fungicidal agent, is the initial drug of choice for fungal IE. Because of the alarming mortality rate associated with fungal IE and the availability of newer antifungal drugs, in particular fungicidal drugs like the echinocandins, a re-evaluation of these principles seems to be in order.” In other words, not terribly helpful since no one really knows what they’re doing. Part of the issue with therapy deals with the risk of relapse, and biofilm formation. As some people are aware, the production of biofilms makes penetration of antibiotics incredibly difficult, which is why endocarditis tends to be treated for such a long time; good luck trying to sneak a high amount of antibiotic into an area that is difficult to reach.

This phenomenon seems to have some clinical implications. An interesting paper describes a patient with fungal endocarditis with C. parapsilosis who underwent valve replacement (4). The infected valve was incubated with two different concentrations of amphotericin B. Candida sampled from the excised vegetation continued to grow up to a week later: 

One study evaluated the impact of biofilms on antifungal susceptibility in a bioprosthetic biofilm model (5). Compared to the planktonically grown candida, the MIC in the biofilm Candida for the azole medications was significantly higher:

Notably, the echinocandins and the liposomal versions of amphotericin B retained significant activity against candida.

The best example comes from an animal study that compared the efficacy of amphotericin B, fluconazole, or fluconazole + flucytosine for candida endocarditis, pyelonephritis, and endophthalmitis (6). A relatively high percentage of amphotericin B was able to penetrate vegetation compared to fluconazole:

When looking at colony counts within vegetations, amphotericin B deoxycholate tended to decrease colony counts faster than fluconazole and flucytosine, and it was more effective throughout the days of treatment. Further, when combining fluconazole and amphotericin B, it seemed to have an antagonistic effect as the combination performed worse than amphotericin B alone:

The best clinical data comes from a retrospective cohort of 294 patients with candida bloodstream infection, where isolates were compared based on their ability to form biofilms (7). Multivariate analysis found that infection by biofilm-producing candida species as an independent risk factor for mortality:

Indeed, the raw mortality rate was much higher in the biofilm producing strains, 70%, compared to 45.7% in the rest of the strains.

Surgery:

Given the biofilm issue and high mortality, it is no wonder why fungal endocarditis is thought of as being an absolute indication for valve replacement.  A historical analysis of 270 patients with fungal endocarditis found a crude mortality of 72% (8). When looking at those patients with Candida endocarditis, antifungal and surgical intervention was associated with improved odds of mortality:

A meta-analysis of 105 patients (9) found that monotherapy was associated with the lowest odds of success, although this was mostly seen in the fluconazole group. Surgical intervention plus antifungal therapy yielded a success rate of 67%, which increased to 76% if amphotericin was combined with flucytosine:

Using 22 observational case-series, meta-regression analysis found that adjunctive therapy trended towards mortality benefit, while antifungal monotherapy trended towards increased mortality though these values did not reach statistical significance:

An interesting review of 140 cases found no difference in mortality between any administered antifungal regimens, however a binomial logistic regression found  that cardiac surgery and effective anti-biofilm agents were associated with reduced mortality (10):

Medical Therapy

There is a benefit from surgery, however it should come to no surprise that mnay of the risk factors for candidemia and endocarditis (i.e. central line placement, TPN, antibiotic therapy) tend to occur in patients who are not ideal surgical candidates. If you look through the literature, you will no doubt find case reports highlighting how some authors managed to cure one patient with fluconazole or some combination of agents. For instance, a combination of fluconazole and caspofungin was successful in curing a case of PVE with C. glabrata without surgery after a 9 day course of amphotericin B (11). In another case, a combination of liposomal amphotericin B and caspofungin for three weeks was used for cure in native valve C. glabrata endocarditis (12). Moreover, caspofungin by itself has been used to cure mitral PVE with C. glabrata without suppressive therapy (13). Candida parapsilosis mural endocarditis has been cured with a combination of caspofungin and voriconazole for a total of 60 days with subsequent suppressive voriconazole (14). A summary of several papers is highlighted below (11-22):

Age	Gender	Comorbidities	Candida spp	Type	Therapy	Surgery	Citation
72	male	Diabetes, CKD	C. glabrata	Prosthetic valve	fluconazole 400mg +amphotericin B -> fluconazole + Caspofungin	No	Lye et al 2005
84	female	relapsing UTI	C. glabrata	Native valve	LAm-B + caspofungin for 3 weeks -> caspofungin x 8 weeks -> caspofungin thrice weekly	No	Jimenez-Esposito et al 2004
64	female	Atrial fibrillation, mitral valve replacement	C. glabrata	Prosthetic valve	Fluconazole for 6 days -> caspofungin for 6 weeks	No	Rajendram et al 2004
59	female	EtOH cirrhosis, pancreatitis	C. parapsilosis	Mural	fluconazole for 17 days, caspofungin for 72hrs, then voriconazole + caspofungin for 60 days and 9 months of suppressive voriconazole	No	Lopez-Ciudad et al 2006
68	Male	AAA, ICM, sleep apnea, aortic valve replacement	C. albicans	Prosthetic valve	LAm-B for 47 days after surgery, fluconazole suppressive therapy	No	Aaron et al 2003
58	male	aortic dissection	C. parapsilosis	Prosthetic valve	Amphotericin B for 27 days, fluconazole suppression	No	Czwerwiec et al 1992
47	female	HIV, IVDU	C. albicans	Native valve	IV fluconazole for 4 weeks, 8 months oral fluconazole	No	Westling et al, 2004
47	female	major depressive disorder	C. albicans	native valve	Fluconazole IV for 14 days -> 6 weeks	No	Wells et al, 1995
62	female	Rheumatic heart disease	C. parapsilosis	Prosthetic valve	Amphotericin B followed by fluconazole for 8 months	No	Lejko-Zupanc and Kozelj, 1996
65	female	HCV-cirrhosis, autoimmune hemolytic anemia	C. glabrata	Prosthetic valve	Anidulafungin for 2 weeks prior to surgery, and 4 weeks after	Yes	De Rosa et al, 2012
48	male	CAD, mitral valve replacement	C. parapsilosis	Prosthetic valve	Amphotericin B + flucytosine for 5 weeks; amphotericin B + flucytosine during relapse, followed by fluconazole/ketoconazole	No	Zahid et al, 1994
21	male	Diffuse polyposis, colectomy	C. albicans	Native valve, folliculitis	Fluconazole for 28 days, intravitreal amphotericin B	No	Venditti et al, 1992

The point is there is no great data source for antifungal therapy. And most of it comes from retrospective data, with the commonly used antifungals being echinocandins and amphotericin B. 

One retrospective cohort of candida endocarditis compared the impact of either an amphotericin B based or echinocandin-based antifungal therapy in 70 patients (23). Around 46% of patients underwent surgical intervention, with overall in-hospital and one-year mortality being 36% and 59%, respectively. When comparing amphotericin B therapy and echinocandin therapy, mortality at 3 different time points was not statistically different (45% in-hospital mortality for amphotericin B vs 29% for echinocandin, 64% for amphotericin B at one year vs 69% at one year for echinocandins) despite the higher rate of surgical intervention in the amphotericin B group (55% vs 35%). A meta-analysis of 62 patients with candidal endocarditis found that 58% of patients who received only fluconazole survived compared to 84% in those who had an additional antifungal along with fluconazole (24). Moreover, the type of amphotericin B had an impact on mortality. Those who received amphotericin B had a 35% failure rate, compared to liposomal amphotericin which had a 22%. When the authors looked at 23 historical controls, they found that fluconazole-containing regimens plus valvular surgery had a survival rate of 91%. This suggests that fluconazole alone is likely not enough and combination therapy is the name of the game. It could also be that those who received azoles had a less toxic therapy compared to older amphotericin B formulations and had some degree of susceptibility to azoles. 

A retrospective cohort of 46 cases of prosthetic valve candida endocarditis found 67% had combined antifungal therapy (usually liposomal amphotericin B and flucytosine), and 41% underwent surgical intervention (25). Relapse rates were 25% in the combined surgery-medical cohort who got maintenance compared to 50% in those who got only surgical therapy without maintenance therapy, 50% in those who got treated medically but got no maintenance therapy, and 15% in those who got medical therapy and maintenance therapy. One interesting bit was that, by multivariate analysis, there was a higher odds of 6-month survival if liposomal amphotericin B was used when compared to echinocandin therapy (aOR 13.52, 95% CI 1.03-838). A review of 140 cases of endocarditis found no difference in mortality between any administered antifungal regimens (10):

Moreover, chronic suppressive therapy was associated with reduced risk of death for both prosthetic and native valve candida endocarditis (RR 0.30, 95% CI 0.17-0.55). A monte-carlo simulation found that antifungal regimens that contained fluconazole showed improved survival in those who did not undergo surgery:

How long to treat remains a difficult question to answer, and it seems that long-term suppression with something oral such as fluconazole is a reasonable option, given the high relapse rates. For the most part, I’ve seen at least 6 weeks based on UpToDate and guidelines, but it may depend on whether source control is achieved or not. For now, either liposomal amphotericin B with or without flucytosine or high dose echinocandins followed by suppressive azole therapy. Unfortunately, the question of the efficacy of combined antifungal therapy remains to be answered. One review notes that for candida spp, amphotericin B and flucytosine have synergy in vivo and improved survival. This is in contrast to echinocandins and amphotericin B, which had an indifferent pattern in vivo but has had some improved tissue burden in combination (26):

A study evaluating different C. parapsilosis strains found that all combinations in the echinocandin resistant strains had some degree of antagonism, with the exception of the amphotericin B and fluconazole group (27). Moreover, flucytosine + amphotericin B OR voriconazole and fluconazole and voriconazole did not demonstrate antagonism:

One letter also notes micafungin has some degree of synergy with amphotericin B (28):

How this applies clinically remains to be seen, however given the lack of good data for dual-therapy in staph aureus endocarditis, I am not terribly optimistic. 

References:

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