Search strategy

Databases and search terms: PubMed, Scopus, and Web of Science were searched using key terms (and their synonyms/MeSH equivalents) related to the review topic. Boolean operators (AND/OR) combined concepts as appropriate.

Timeframe and language: Searches were limited to 2015–2024, but important earlier publications were captured via references. Only English-language articles were considered.

Additional sources: Reference lists of relevant articles and recent reviews were hand-searched to identify any studies not captured in the database search.

Inclusion and exclusion criteria

Inclusion criteria: Peer-reviewed original studies, reviews, and meta-analyses that focused on the topic of interest (e.g., interventions or outcomes) were included. Studies had to report on at least one outcome relevant to our research question.

Exclusion criteria: Studies were excluded if they were non-English or outside the scope of our topic. For example, case reports, animal studies, or articles without sufficient data were not included.

Incidence and clinical course

FE is rare. Only 892 cases of Candida endocarditis (CE) out of 272,798 endocarditis admissions (0.33%) were found in a recent U.S. analysis [12], and about 23% of the 703 patients with CE in a multicenter U.S. cohort from 2015 to 2019 underwent heart surgery. The inpatient mortality rate was 16.2% [11]. However, worldwide reviews of all FE cases, including those with native and prosthetic valves, have found a higher mortality rate, between 40 and 60 percent [3, 5]. Meena et al. [5] (2022) found a 1-year mortality rate of ≈ 42%. While other studies noted that mortality is > 50–70%, especially without surgery [1, 3]. The disparity implies that although mortality is still too high, results are somewhat improved by more recent management.

Geography and setting

FE can occur on native or prosthetic valves. In reported FE cases, roughly one-third are prosthetic valve endocarditis (PVE) [4, 5]. Meena et al. [5] (2022), among the 250 cases, found 35% PVE and 16% involving intravenous drug use (IVDU). The majority of cases in high-income countries involve prosthetic valves or cardiac devices. In endemic regions (central U.S.), dimorphic fungi (Histoplasma, Coccidioides, Blastomyces) cause a minority of FE, often in specific geographic or travel contexts [13]. A recent Mayo Clinic series showed that endemic fungal IE is becoming more widely recognized in the U.S. Coccidioides accounts for about 18% of cases, and Histoplasma capsulatum for almost half [13]. These endemic fungal cases were often diagnosed late or postmortem, reflecting diagnostic challenges.

Host risk factors

Any condition predisposing to fungemia or abnormal heart valves is a significant risk factor for FE. Prosthetic heart valves, cardiac device implants (pacemakers, defibrillators), previous valve surgery, and congenital heart disease (particularly after repair) are known risk factors [14]. Immunosuppression, whether due to hematologic malignancy, transplant-related drugs, HIV or AIDS, or chronic corticosteroids, is another strong risk factor, particularly for FE [15]. In an extensive review, 64% of native-valve Aspergillus endocarditis cases had severe immunosuppression (cancer, transplant) [15]. Long-term use of invasive vascular lines or devices is critical: The risk of candidemia and subsequent endocarditis is higher in patients receiving total parenteral nutrition or with chronic central venous catheters [16, 17]. Another significant risk factor is IVDU. While IVDU is usually linked with a higher risk of staphylococcal infection, heroin and other drug use can also introduce mold and Candida [5, 18]. Additional factors related to healthcare include extended hospital stays, hemodialysis (central catheter and turbulent flow on calcified valves), and intensive broad-spectrum antibiotics (which disturb normal flora) [9, 19].

Several comorbidities elevate risk. Chronic kidney disease and hemodialysis are essential: one study found hemodialysis conferred ≈ a 2-fold higher mortality risk in CE patients (suggesting also increased occurrence) [11]. Another significant risk is acute or chronic liver disease; according to Huggins et al. [11], acute/subacute liver failure had the strongest mortality association (OR ≈ 9) in CE, suggesting that endocarditis could exacerbate critical illness. Multiple studies have reported this counterintuitive finding: patients who inject drugs (often opioids) sometimes have lower short-term mortality in endocarditis. For example, a large U.S. study of CE learned that a documented history of opioid abuse was independently associated with a significantly reduced risk of inpatient death (OR ≈ 0.4) [11]. Similarly, cohorts of general IE report comparable or even slightly better short-term survival in IVDU vs. non-IVDU patients [20]. In one Finnish registry, 1-year mortality was essentially identical (4.0% vs. 4.1%) in IE patients with vs. without a history of injecting drug use [20]. These findings suggest a “protective” association of IVDU against mortality, though the effect is almost certainly due to patient factors rather than any beneficial effect of drug use.

• Age and health status: IVDU patients are typically decades younger than other IE patients (median ≈ 35 vs. ≈ 62 years in one study). They also have far fewer chronic comorbid conditions (much lower Charlson comorbidity scores). Being younger and generally healthier makes them more resilient to a severe infection [20].

• Valve involvement: IVDU-related IE is predominantly right-sided (e.g., tricuspid valve) in one cohort, ≈ 70% of PWID cases vs. < 10%. Right-sided endocarditis generally causes fewer lethal complications than left-sided disease [20].

• Clinical management factors: People who inject drugs often have more acute, obvious infections (e.g., Staphylococcus aureus) that prompt aggressive care. They may also receive valve surgery more often or earlier, which improves survival in IE. In contrast, sicker non‑IVDU patients often have multiple comorbidities that limit treatment options.

In short, the “paradox” arises because IVDU patients with endocarditis tend to be younger and have fewer other illnesses. These favorable baseline features (plus the tendency toward right-sided disease) offset the risks of drug use. Thus, the observed lower mortality in IVDU is likely a confounding effect of patient demographics and disease patterns, not a true protective effect of opioids themselves. Even so, clinicians should remember that IVDU remains a major risk factor for acquiring fungal or bacterial endocarditis; the lower mortality is only relative to other very ill patients, and long-term outcomes (especially if addiction is untreated) remain poor [20]. Finally, emerging reports suggest that even extracardiac risk factors (malignancies of the gastrointestinal tract or genitourinary tract, prolonged steroid therapy) are increasingly seen in FE patients [9].

In conclusion, patients with complicated cardiac histories, prosthetic devices, and substantial healthcare exposures are more likely to develop FE in contemporary practice. The risk is further increased by immunosuppression and the use of broad-spectrum antibiotics. Although fungal IE is rare, a greater portion of the cardiology community is at risk. Patients with persistent candidemia or unexplained IE risk factors should have ongoing FE monitoring [9, 11]. Key host, procedural, and comorbidity-related risk factors for FE are detailed in Table 1.

Candida species

Candida is the most common pathogen causing FE. Recent data show that Candida spp. causes roughly half of all FE cases [1, 5]. In one systematic review of FE, Candida accounted for 49.6% of cases; of these, C. albicans was the major species, followed by C. glabrata (around 20%), C. parapsilosis (15–20%), and Candida tropicalis (5–10%) [5]. C. lusitaniae, C. krusei, C. dubliniensis, and C. guilliermondii have been reported less commonly. Recent large-cohort studies demonstrate that Candida spp. are still the most common cause, ≈ 50–60% of all FE, but non-C. albicans is increasing. C. parapsilosis is currently implicated in 15–41% of cases of CE, C. tropicalis in 10–13% and C. glabrata in 4–9%, dramatically changing the species distribution in the last decade. Aspergillus spp. are the second most frequent etiological agents (≈ 25% of fungal IE), mostly in culture-negative IE (CNIE) and the immunocompromised patient [1, 21].

The species distribution can vary by geography and patient population. For example, C. parapsilosis is often linked to catheter-related biofilm infection and may be overrepresented in intensive care or neonatal populations, while C. Glabrata is more common in older or diabetic hosts [6]. Recent case series note an emergent role for intrinsically drug-resistant species like C. auris (see below).

Clinically, CE tends to form large, friable vegetations, often leading to systemic emboli and metastatic infection. Patients with CE usually have a preceding or simultaneous candidemia, as Candida readily grows in blood culture (unlike many moulds). One review noted that CE was associated with persistent fungemia and relapsing infection [22, 23]. Despite being culture-positive, CE has a poor prognosis; even with antifungal therapy, mortality frequently exceeds 30–40%. Contemporary management emphasizes early combined surgical and medical treatment [24]. Current guidelines (IDSA, 2016) recommend valve surgery plus amphotericin B or echinocandin therapy for CE [25].

Emerging threat: C. auris

C. auris, a multidrug-resistant yeast that has been reported on every continent, is a new concern [9]. Despite being a rare cause of IE, C. auris is significant because it is inherently resistant to many azoles and can result in treatment failure if left undiagnosed. Hospitalized patients may develop endocarditis as a result of C. auris because it has been shown to colonize indwelling lines and induce persistent fungemia. If blood cultures reveal an uncommon yeast or a patient with a known C. auris colony exhibits symptoms of IE, clinicians should consider C. auris. (C. auris endocarditis prevalence is currently not quantified by any large series, but its emergence necessitates vigilance [26, 27]).

Aspergillus species

Aspergillus is the second most common cause of FE, especially in prosthetic valves and immunocompromised hosts [1, 15]. Aspergillus accounts for roughly 20–30% of FE cases in major case compilations [5]. Although Aspergillus fumigatus is the most common species, there are other species as well, such as A. flavus, A. terreus, A. niger, etc. Notably, Aspergillus rarely grows in blood culture, so Aspergillus endocarditis frequently occurs in patients without overt fungemia. It usually presents as bacterial IE or as culture-negative endocarditis. A recent case series identified 74 reported cases of native-valve A. fumigatus endocarditis; immunosuppression was present in 64% of cases [15]. Aspergillus also commonly affects cardiac grafts and prosthetic valves. The high mortality rate (> 80% in older reports) reflects the difficulty of diagnosis. Since blood cultures are nearly always negative, diagnosis frequently depends on tissue PCR or galactomannan (GM) antigen [15]. Large vegetations may be seen on echocardiogram, but FE may also invade the myocardium, leading to abscess formation. Optimal therapy requires voriconazole or liposomal amphotericin B (LAmB), usually combined with valve surgery [1, 15].

Rare and emerging fungi

In addition to Candida and Aspergillus, a range of rare fungi have been reported in cases of endocarditis, particularly in severely immunocompromised or geographically exposed hosts. Other dimorphic fungi, like Histoplasma capsulatum, Coccidioides spp., and Blastomyces dermatitidis, rarely cause IE in endemic areas but almost exclusively occur there (or in travelers) and most often in immunocompetent hosts with underlying valvular abnormalities [13]. These fungi usually require special culture or antigen tests (urine Histoplasma antigen), and are notable for frequent delays in diagnosis.

Other moulds (Zygomycetes) and yeasts have been reported in case reports. Fusarium species can cause PVE, especially in neutropenic or oncology patients, but these cases are exceedingly rare and usually fatal [15]. Mucormycetes (e.g., Rhizopus, Mucor) have been reported as causes of focal aggressive angioinvasive IE in selected diabetic or transplant patients. Rare yeasts such as Trichosporon asahii, Cryptococcus neoformans, and Malassezia have all been reported to cause IE, typically in the context of severe immunodeficiency or indwelling devices. Scedosporium/Pseudallescheria and dematiaceous molds (e.g., Exophiala and Lichtheimia) are also anecdotal etiologies. Novel diagnostic methods add increasingly exotic organisms (e.g., Sarocladium kiliense, formerly Gliomastix). When encountering culture-negative endocarditis, clinicians must consider broad fungal possibilities based on patient history (e.g., travel, exposures, and immune status) [13, 15].

Biofilms and host interaction

Prosthetic device-associated biofilm is the cornerstone of FE pathogenesis. Both species of Candida and Aspergillus produce biofilm that adheres to mucosal surfaces and are refractory to immune clearance and antifungal penetration. C. parapsilosis, in particular, has a reputation for being device-related [9]. The pathogenesis typically includes a transient fungemia, which seeds the valve or device; e.g., candidemia from a central line that secondarily infects a valve. A nidus is afforded by endocardial injury due to prior IE or surgery. Importantly, fungal vegetations tend to be large and friable (“fungal balls”), predisposing to embolic strokes, septic emboli, or mycotic aneurysms [5, 23]. Host factors like neutrophil defects (neutropenia, steroids) and cell-mediated immunity deficits are especially relevant in mould infections [6, 15]. The spectrum of fungal pathogens implicated in endocarditis, along with their clinical features and biofilm associations, is presented in Table 2.

Cultural negativity and delayed growth

Culture-negative endocarditis is common in fungal infections. One study mentions that Candida accounted for only ≈ 25–30% of FE, while most cases are due to molds or fastidious yeasts [28]. Blood cultures of CE often require multiple samples and can still be negative in up to 50% of cases. Non-Candida fungi (e.g., Aspergillus, Fusarium, Histoplasma, Coccidioides) virtually never grow in routine blood culture and can only be detected by tissue culture or serology [28, 29]. Automated systems consistently miss dimorphic fungi like Histoplasma capsulatum and Coccidioides immitis, which require specialized media or antigen tests [21, 28]. Delayed growth can occur: some Candida species exhibit prolonged lag phases. Clinicians should communicate with microbiology labs to hold cultures for extended periods (up to 4–6 weeks) when FE is suspected [21]. In practice, the combination of negative cultures and high clinical suspicion often triggers empiric therapy or alternative diagnostics.

Advanced biomarkers and imaging

Serologic and molecular markers: Fungal cell-wall assays can greatly aid diagnosis. For example, serum 1,3-β-D-glucan (BDG), a pan-fungal marker, has moderate accuracy—pooled sensitivity ≈ 78% and specificity ≈ 81% for invasive fungal infections [30]. The GM assay (for Aspergillus) has a sensitivity of ≈ 71% and a specificity of ≈ 89% [31]. These tests are often strongly positive in reported FE cases. Pan-fungal PCR (broad-range fungal DNA PCR) on blood or excised valve tissue can markedly improve detection in culture-negative cases (one review notes that PCR-based methods “expedite the diagnosis” when blood cultures fail) [23]. Metagenomic next-generation sequencing (mNGS) of blood or tissue is an emerging tool—in one surgical endocarditis series, valve mNGS had ≈ 82% sensitivity and 100% specificity vs. the adjudicated diagnosis [32]. Combining markers can boost yield (e.g., using both BDG and GM together may improve sensitivity for Aspergillus infections) [23]. Note: False negatives can occur, for example, neutrophil clearance may lower BDG levels, and cutoffs for endocarditis are not firmly established.

Imaging modalities: Echocardiography and advanced imaging are crucial. Transesophageal echocardiography (TEE) is far more sensitive than transthoracic echocardiography (TTE) in IE. In studies of S. aureus bacteremia, for example, TEE detected endocarditis in ≈ 93–100% of cases, vs. only ≈ 40–80% for TTE [33]. Both tests have very high specificity (often > 95%) when findings are positive [33]. Thus, a negative TTE does not rule out endocarditis; a TEE is recommended if suspicion remains. Cardiac computed tomography (CT) (especially modern ECG-gated 4D CT angiography) can identify vegetations or abscesses not seen on echo. For instance, one study found 4D-CT had ≈ 96% sensitivity and 97% specificity for prosthetic-valve vegetations [34]. ¹⁸F-FDG PET/CT is also a valuable adjunct: meta-analysis shows PET/CT sensitivity ≈ 77% and specificity ≈ 78% for endocarditis overall [35], higher sensitivity, ≈ 81%, in prosthetic-valve cases. FDG PET/CT has been incorporated into diagnostic criteria [e.g., as a significant criterion in European Society of Cardiology (ESC) guidelines] and improves the detection of occult infection [36]. AI-enhanced image analysis is an active research area: machine learning algorithms applied to TEE and FDG-PET improve sensitivity and standardize interpretation [36]. In practice, a multimodal approach is used, e.g., serial TEE plus PET/CT (and CT angiography) to maximize detection of the infection.

When to suspect FE?

Clinicians should maintain a high index of suspicion for FE in any patient with culture-negative endocarditis or persistent endocarditis symptoms and relevant risk factors. Important risk factors include: prior valve surgery or prosthetic valve, indwelling central venous catheters or grafts, prolonged broad-spectrum antibiotics or total parenteral nutrition, intravenous drug use, and immunosuppression (e.g., transplant, steroids, hematologic malignancy) [23]. Native valves in patients on immunosuppressants or with congenital heart disease are also at risk. FE often presents subacutely with fever and new or changing murmurs, and tends to produce large, friable vegetations (often causing emboli) even when blood cultures are repeatedly negative. Blood cultures are positive in < 50% of FE cases [23].

Key clinical scenarios that should prompt additional fungal testing include:

• Culture-negative endocarditis with risk factors. Any patient meeting Duke criteria for endocarditis (e.g., fever + murmur + embolic phenomena) who has negative blood cultures and one or more fungal risk factors should trigger work-up for FE.

• Persistent infection despite antibiotics. If a presumed bacterial endocarditis fails to improve, especially with bulky vegetations or systemic emboli, consider fungal etiology.

• Recurrent candidemia or fungal sepsis in a patient with a new murmur or valve lesion.

In these settings, additional tests are warranted. For example, serum BDG and GM assays should be obtained (a high BDG or positive GM suggests invasive candidiasis or aspergillosis, respectively) [30, 31]. Fungal PCR on blood and especially on excised valve tissue (if surgery is done) can detect pathogen DNA even when cultures are sterile [23]. Metagenomic NGS of blood or tissue can also be considered (one case series showed that valve mNGS gave definitive results in cases with negative cultures [32]). Repeat imaging is important, for example, if the initial TTE was negative, a TEE or PET/CT should be done to look for vegetations or abscesses. In summary, any culture-negative endocarditis with suggestive clinical features or risk factors should prompt fungal-specific tests (BDG/GM serology, fungal PCR/mNGS) and advanced imaging to avoid missing FE [23, 30].

Biofilm-associated false negatives

Fungal biofilms on valves and devices further hinder diagnosis. Mature biofilms may harbor organisms that intermittently seed the bloodstream, leading to transient or absent positive cultures [37]. Patients with prosthetic material (pacemakers, valves) often have negative blood cultures despite heavy fungal colonization [38]. Molecular tests (PCR, mNGS) on valve tissue are particularly valuable for biofilm-associated infections, as cultures from tissue can still be falsely negative [39]. For example, a 2023 study demonstrated that 16S/18S rRNA PCR/sequencing of valve tissue identified pathogens in 75% of blood culture-negative endocarditis cases, compared to 55% for blood cultures alone [40]. Clinicians should prioritize histopathological examination and molecular testing of surgically resected tissue, as biofilm-embedded fungi often evade conventional cultures [41, 42]. A case of C. parapsilosis PVE highlighted this necessity: blood cultures were negative, but valve tissue analysis confirmed the diagnosis, enabling targeted therapy [41].

In summary, sterile blood cultures do not exclude FE in biofilm-associated cases. A multimodal approach that combines surgery, molecular assays, and histopathology is crucial for accurate diagnosis.

The framework still has the modified Duke/ISCVID criteria, but no fungal-specific diagnostic score exists. In practice, a methodical approach is used, in which standard serologies (Coxiella and Bartonella) are obtained first, followed by several extended blood cultures [28, 43]. Clinicians frequently use PCR and fungal biomarkers (BDG, GM) in all culture-negative cases. Early imaging (TEE, TTE) is performed, and if suspicion is still high, PET/CT is added [43–45]. A surgical consultation for valve excision may be crucial if the results are still nondiagnostic [23, 45, 46]. The 2023 ESC Guidelines and external validation studies endorse combining microbiologic, imaging, and surgical criteria to improve diagnostic sensitivity, especially for fungal IE [45, 47]. Overall, high clinical suspicion and a low threshold for combining microbiological, serological, and imaging modalities are key to diagnosing FE.

First-line antifungal therapy

Echinocandins, triazoles, and amphotericin B all have different functions in treating FE. Because of its effectiveness and wide range of applications, LAmB is frequently suggested as an initial treatment. The usual dosage for LAmB is 3–5 mg/kg IV daily (deoxycholate amphotericin B 0.7–1 mg/kg), with flucytosine (25 mg/kg Q6h) added for synergy if tolerated. Echinocandins, such as caspofungin, micafungin, and anidulafungin, have activity against Candida spp. and are a desirable substitute, particularly in patients who are at high risk for amphotericin toxicity [49]. However, one study found better survival with liposomal amphotericin vs echinocandins alone (6‑month survival) [50].

Azoles like fluconazole, voriconazole, posaconazole, and isavuconazole are generally used for consolidation and chronic suppression once the patient is stable. Following initial treatment with echinocandins or amphotericin B, fluconazole, 400–800 mg/day, is frequently used for step-down therapy. However, because azoles are known to cause QT interval prolongation and hepatotoxicity, their use necessitates close monitoring of liver function [51, 52]. Being a potent CYP3A4 inhibitor, fluconazole raises the risk of drug interactions. Blocking CYP2C9 and CYP3A4, for example, raises serum levels of warfarin and direct oral anticoagulants, requiring careful monitoring of bleeding risk [52, 53]. Furthermore, while studies indicate the absolute risk is still low (≈ 4.7% when combined with ciprofloxacin), co-administration of other QT-prolonging agents (such as amiodarone) may increase cardiac risks [54].

Alternatives to Aspergillus molds include voriconazole and posaconazole; however, therapeutic drug monitoring (TDM) is necessary for optimal effectiveness and to prevent toxicity [55]. Compared to voriconazole, isavuconazole is a more recent triazole with benefits like a lower risk of QT-prolongation and fewer CYP450 interactions, making it safer for patients with cardiac comorbidities [55, 56]. All azoles mandate liver function tests and ECG monitoring as needed.

However, certain rare fungi causing endocarditis require pathogen-specific, aggressive regimens. Trichosporon endocarditis is intrinsically resistant to echinocandins [57], and often refractory to amphotericin alone; published cases therefore report using LAmB induction followed by voriconazole [58]. Likewise, Lomentospora prolificans endocarditis is virtually untreatable with monotherapy, so salvage therapy is usually voriconazole plus terbinafine [59]. Similar combination approaches are described for other uncommon agents: a Fusarium solani PVE was cleared with LAmB plus voriconazole [60], and Malassezia furfur endocarditis has been successfully managed with LAmB and voriconazole [61]. Even C. parapsilosis PVE has been treated with combination regimens (e.g., amphotericin B with flucytosine) in case series [62]. In each scenario, early combination therapy (typically with surgery) is followed by prolonged azole suppressive therapy, as per standard practice. Notably, these tailored regimens have led to survival in infections otherwise usually lethal with standard therapy. Taken together, these cases underscore that FE often demands therapy customized to the pathogen with synergistic drug combinations, rather than standard monotherapy.

Routine laboratory monitoring is essential. Amphotericin B carries well-known nephrotoxicity; serum creatinine, electrolytes (Mg, K), and hydration must be closely tracked [48]. In summary, treatment regimens typically involve an initial induction phase (LAmB ± flucytosine) followed by step-down to an azole for prolonged (≥ 6–12 months) suppressive therapy.

Surgical intervention

Early surgical consultation is mandatory in FE. Valve replacement or device removal for infected hardware is considered source control and significantly improves outcomes [48, 63]. In cases of heart failure, abscess formation, large vegetations (> 10 mm or rapid growth), or persistent fungemia despite the best antifungal treatment, surgery is recommended. Many experts suggest surgery as soon as the patient can handle it, ideally during the same admission, because fungal vegetations frequently result in structural damage (valve perforation, regurgitation). Crucially, compared to antifungal therapy alone, combined therapy (antifungal plus surgery) has been linked to noticeably lower mortality. For example, a systematic review found that patients managed medically without surgery had much worse survival [5, 63].

Surgery timing is unique to each patient. Some centers recommend an initial 1–2 weeks of antifungal induction to lower fungal burden and embolic risk before surgery [23, 64]. Others place a higher priority on hemodynamic compromise and urgent surgery. Unless emergency care is needed, patients are frequently operated on after stabilizing on antifungals [64, 65]. Lifetime suppressive therapy may be required in cases where surgery is not practical (for example, due to prohibitive operative risk or refusal); patients in these situations should be advised of the high risk of relapse [66, 67]. Notably, the mainstay of treatment continues to be removing all possible sources of infection, including pacemakers, indwelling catheters, and prosthetic materials [23, 65]. Recurrent emboli and drug interactions are among the complications that patients with retained devices or high surgical risk must deal with. Case studies show how combination treatments, such as amphotericin B + flucytosine, can be used to treat breakthrough infections in situations where source control is not possible [48, 68]. For a stepwise visualization of the diagnostic and treatment pathway in FE, refer to Figure 2.

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Figure 2. Diagnostic and treatment pathway in fungal endocarditis

Novel & adjunctive therapies

Emerging antifungals and adjunctive strategies may improve FE outcomes. Among new agents, rezafungin is a second-generation echinocandin approved in 2023 for candidemia and invasive candidiasis [69, 70]. Its once-weekly dosage and ability to fight Candida, including some resistant species, may make long-term treatment in FE more convenient [69]. Oral triterpenoid glucan synthase inhibitor ibrexafungerp penetrates biofilms and exhibits broad activity against Aspergillus and Candida, including azole-resistant strains. Ibrexafungerp demonstrated efficacy against multidrug-resistant C. auris biofilms in animal models. Ibrexafungerp is safe and effective, according to clinical studies (non-endocarditis), but its function in IE is still being studied [71].

Immunotherapy is still in the experimental stage. Animal models have demonstrated the effectiveness of monoclonal antibodies or vaccines that target fungal cell-surface antigens, such as Candida Als3p. For instance, mice were protected from deadly C. auris endocarditis by the NDV-3A (Als3p) vaccine, which improved antifungal treatment [72].

For FE, isolated case reports have investigated passive immunotherapies like intravenous immune globulin (IVIG) and cytokine adjuncts like interferon-gamma (IFN-γ). In immunocompromised patients, these treatments strengthen the host immune response. Nevertheless, the search results show no concrete clinical proof of their effectiveness in FE. For example, although IFN-γ is known to increase neutrophil and macrophage activity against fungal pathogens such as Candida and Aspergillus, its use in FE is still anecdotal [63, 73]. Likewise, IVIG has been used to neutralize toxins or control inflammation in cases of severe fungal infections; however, there is a dearth of reliable data from FE-specific research [63].

The limited adoption of these treatments results from clinical trial gaps and the variability of FE cases, where immunosuppression and comorbidities make results more difficult to interpret. Although translation to human FE has not been confirmed, preclinical models indicate possible advantages [73].

To break down biofilms and get rid of infections, antimicrobial lock therapy (ALT) involves injecting high-concentration antifungal solutions into infected catheters. Although it has been extensively researched concerning bacterial infections caused by catheters (Staphylococcus), its use in FE is less well-established [74].

Fungal infections, such as Candida, were not included in a 2025 study on ALT for catheter-related bacteremia because of insufficient data, but bacterial cases showed an 88.9% success rate. Because biofilm persistence increases the chance of relapse, guidelines advise against using ALT for Candida unless catheter removal is not feasible [75]. Compared to bacterial cases, fungal biofilms have intrinsic resistance mechanisms (such as efflux pumps and extracellular matrix barriers), which lower ALT efficacy.

Hyperbaric oxygen therapy (HBOT) increases tissue oxygenation, potentially enhancing antifungal activity and immune responses. When conducting the literature search and data extraction for this article, I obtained conflicting evidence.

• Preclinical support: HBOT enhanced survival in murine models of invasive pulmonary aspergillosis and decreased A. fumigatus biofilm proliferation by 50% in vitro [64]. Additionally, it reduces tissue hypoxia, a characteristic of fungal vegetations, which may enhance antibiotic penetration and neutrophil function [73, 76].

• Clinical data: Although no clinical trials specifically for FE, a 2022 review suggested HBOT as a treatment for IE because of its anti-biofilm and immunomodulatory properties [73]. HBOT has limited standalone utility, as evidenced by a 2018 study that found no synergy between HBOT and subtherapeutic antifungals (such as voriconazole) [76].

• Limitations: HBOT’s adoption in FE management is restricted by its temporary fungistatic effect and practical issues (such as access to hyperbaric chambers) [73, 76].

Antifungal resistance & stewardship

FE management is made more difficult by antifungal resistance, especially in emerging species such as multidrug-resistant C. glabrata and C. auris, which often show azole and/or echinocandin resistance as a result of chromosomal aneuploidy, efflux pump upregulation, or mutations in ERG11 [77–79]. Biofilm-related tolerance on prosthetic valves or devices further mimics resistance by shielding fungi from antifungals, as seen in C. glabrata and C. auris biofilms [79–81]. Stewardship strategies, such as de-escalating from amphotericin B to fluconazole in susceptible cases, reduce toxicity and pressure, aligning with IDSA guidelines. Table 3 summarizes the major antifungal regimens, surgical indications, and emerging therapies utilized in the management of FE.

Mortality and morbidity trends

Recent studies reveal a slight increase in survival over several decades, mainly due to combined treatment. Meena et al. [5] found an overall mortality rate of about 40% in 220 cases, which is lower than previous reports and probably reflects more frequent surgeries. Similarly, retrospective data indicate that patients managed surgically have significantly lower mortality than those treated medically [5]. CE tends to have better outcomes than non-Candida: in one cohort, mortality was lower in Candida (15%) vs. others (47%) [21]. Thompson et al. [1] reported in a multinational cohort that CE carries an in-hospital mortality of 36% and a 1-year mortality of 59%. Nevertheless, FE survivors frequently suffer complications such as embolic infarcts, extended hospital stays, and heart failure due to valve destruction.

Evidence from recent series indicates substantially higher mortality when FE is managed with antifungals alone. For example, Arnold et al. [83] reported in-hospital mortality of 34% with medical therapy vs. 38% with adjunctive surgery in a multicenter cohort of CE patients (1‐year mortality ≈ 62% vs. 66%). By contrast, Siciliano et al. [84] found overall in-hospital mortality of 54% among 78 FE cases (85% Candida) and identified exclusive medical management as a strong independent risk factor (OR ≈ 11.1) for death. In that series, ≈ 68% of patients treated without surgery died vs. roughly 46% of those having surgery (≈ 22% absolute risk reduction). Taken together, these data suggest that combining valve surgery with antifungals lowers mortality compared to medical therapy alone, roughly translating to ≈ 30–40% survival with surgery vs. ≈ 10–30% without (i.e., ≈ 20–30% absolute difference) in recent series [5, 83].

Predictors of poor outcome

Aspergillus etiology, absence of surgery, postponed therapy, and host factors all predict unfavorable results. According to Meena et al. [5], immunocompromise (HR 2.8) and Aspergillus infection (HR 3.7) were independent risk factors for death. Patients who have intracardiac devices or prosthetic valves have worse outcomes than those who have native valves [5]. The risk is significantly increased when infected material is not removed surgically; multivariate analysis revealed that antifungals plus surgery decreased mortality by about 80% [5]. Despite treatment, perivalvular abscess, ample vegetation (> 10 mm), and ongoing fungemia are further indicators of a poor prognosis. Mortality is further increased by renal failure brought on by treatment and end-organ damage from septic emboli (such as stroke). According to these findings, the best chance of lowering FE mortality is early diagnosis and vigorous intervention [5, 21].

Quality of life and follow-up

There is a lack of research on the long-term impacts of FE survivors. The information that is currently available indicates that quality of life (QoL) is considerably impacted, even among survivors. Disabilities from embolic strokes, pacemaker dependence, or chronic heart failure due to valve damage may endure. Patients frequently need long-term antifungal treatment (months to lifelong suppression), which calls for regular checkups and observation. Anecdotal evidence suggests that the severity of the illness causes anxiety and post-traumatic stress disorder. If necessary, follow-up care should involve neurologic evaluation and cardiac rehabilitation. Serial imaging and serological monitoring are recommended due to the high relapse rates (recurrence ≈ 10% in one systematic review [5]). Although there aren’t many formal studies on QoL, FE survivors ultimately require multidisciplinary follow-up to manage medication side effects, optimize cardiac function, and screen for reinfection.