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Review
Fungal endocarditis: current challenges夽 Pierre Tattevin a,b,c,∗ , Matthieu Revest a,c , Agnès Lefort d , Christian Michelet a , Olivier Lortholary e a
Infectious Diseases and ICU, Pontchaillou University Hospital, Rennes, France INSERM U835, Faculté de Médecine, Université Rennes 1, IFR140, Rennes, France Association pour l’Etude et la Prévention de l’Endocardite Infectieuse (AEPEI), Bichat-Claude Bernard Hôpital, Paris, France d Internal Medicine Department, Beaujon Hospital, Clichy, France e Infectious Diseases Unit, Necker Hospital, Paris, France b c
a r t i c l e
i n f o
Article history: Received 24 July 2014 Accepted 24 July 2014 Keywords: Endocarditis Candida sp. Aspergillus sp. Echinocandins -1,3-d-Glucans
a b s t r a c t Whilst it used to affect mostly intravenous drug users and patients who underwent valvular surgery with suboptimal infection control procedures, fungal endocarditis is now mostly observed in patients with severe immunodeficiency (onco-haematology), in association with chronic central venous access and broad-spectrum antibiotic use. The incidence of fungal endocarditis has probably decreased in most developed countries with access to harm-reduction policies (i.e. needle exchange programmes) and with improved infection control procedures during cardiac surgery. Use of specific blood culture bottles for diagnosis of fungal endocarditis has decreased due to optimisation of media and automated culture systems. Meanwhile, the advent of rapid techniques, including fungal antigen detection (galactomannan, mannan/anti-mannan antibodies and -1,3-d-glucans) and PCR (e.g. universal fungal PCR targeting 18S rRNA genes), shall improve sensitivity and reduce diagnostics delays, although limited data are available on their use for the diagnosis of fungal endocarditis. New antifungal agents available since the early 2000s may represent dramatic improvement for fungal endocarditis: (i) a new class, the echinocandins, has the potential to improve the management of Candida endocarditis owing to its fungicidal effect on yeasts as well as tolerability of increased dosages; and (ii) improved survival in patients with invasive aspergillosis with voriconazole compared with amphotericin B, and this may apply to Aspergillus sp. endocarditis as well, although its prognosis remains dismal. These achievements may allow selected patients to be cured with prolonged medical treatment alone when surgery is considered too risky. © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
1. Introduction Fungal endocarditis is a rare disease with a dismal prognosis related to the population affected (e.g. immunocompromised patients), suboptimal diagnostic tools responsible for long diagnostic delays in most cases, and poorly defined activity of most antifungal agents in endocarditis. The characteristics of patients affected by fungal endocarditis have dramatically changed over the last decades, with an overall decrease in the number of cases managed each year in most institutions. Hence, the number of
夽 This paper was presented at the XIIth International Symposium on Modern Concepts in Endocarditis and Cardiovascular Infections (ISCVID), 19–21 May 2013, Dubrovnik, Croatia. ∗ Corresponding author. Present address: Service des Maladies Infectieuses et de Réanimation Médicale, CHU Pontchaillou, 2 rue Henri Le Guilloux, 35033 Rennes Cedex, France. Tel.: +33 2 9928 9564. E-mail address: [email protected] (P. Tattevin).
physicians who maintained expertise in this field has probably declined. We aimed to provide an update on the current challenges in the management of fungal endocarditis based on a literature review and on our own experience. 2. Epidemiology 2.1. Changing profile of fungal endocarditis The characteristics of patients affected by infective endocarditis have dramatically changed since the 1990s, as illustrated by prospective cohort and population-based studies [1–7]. Characteristics of the 270 cases reported during 1965–1995 are as follows: male:female ratio, 2.2; mean age, 44.3 ± 14.3 years; and main risk factors being previous valve surgery/prosthetic valve endocarditis (54%), prolonged use of antibiotics (48%), rheumatic heart disease (24%), surgery other than cardiac (23%), vascular lines (18%), immunosuppressive treatment (17%), non-iatrogenic
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immunodeficiency (17%) and intravenous drug use (IVDU) (13%). A subsequent review of 152 cases reported between 1995 and 2000 found that prosthetic valves (45%), central venous catheters (30%) and broad-spectrum antibiotic use (20%) were the main risk factors, whilst intravenous drug users were much less affected (4%). Two major observations emerged from these large literature reviews: (i) over time, dramatic changes have occurred in the major risk factors for fungal endocarditis; once a disease affecting mostly patients with recent valvular surgery, rheumatic heart disease or IVDU, fungal endocarditis is currently more common in immunocompromised patients, with long-term vascular lines, and who underwent complex non-cardiac surgery; and (ii) the prognosis gradually improved, with a mortality rate that decreased from 86% during 1966–1971 to 56% during 1995–2000 [1,3–5]. Although these figures, mostly based on case reports, are subject to publication bias, an improved outcome over the years would be expected owing to significant success achieved in the field of diagnosis as well as new antifungal agents. For example, diagnosis of fungal endocarditis was obtained before surgery in 43% of cases reported before 1988 compared with 72% of cases reported during 1988–1995 (P = 0.0001), which may be related to the advent of echocardiography (since 1975) as well as progress in automated blood culture systems, with a sensitivity estimated at 54% during 1965–1995 [1] and 81% during 1995–2000 [5]. Likewise, development of lipid formulations of amphotericin B (AmB), new azoles with extended spectrum, and echinocandins, over the last 20 years significantly enhanced the therapeutic armamentarium against fungal endocarditis. 2.2. Characteristics of fungal endocarditis in the 21st century In most contemporary studies, fungal endocarditis represents 80%. For Candida endocarditis: sensitivity, 100% [19] Validated for the diagnosis of invasive aspergillosis in neutropenic patients. Not evaluated for the diagnosis of Aspergillus endocarditis
to be a pan-fungal diagnostic method, as BDG is present in most pathogenic fungal species. Its performance for the diagnosis of candidaemia has been evaluated in a meta-analysis [18]: with a cut-off value of 80 pg/mL, sensitivity would be >65%, specificity >80% and the negative predictive value >85%. In a prospective study of 18 patients with definite cases of Candida endocarditis, Lefort et al. found that the sensitivity of BDG and mannan/anti-mannan antibody detection in serum were 100% and 83%, respectively, for the diagnosis of Candida endocarditis [19]. For the diagnosis of Aspergillus endocarditis, potential diagnostic tests include the detection of BDG and the detection of galactomannan antigen in serum. Galactomannan is a major constituent of the Aspergillus cell wall and has been validated for the diagnosis of invasive aspergillosis in neutropenic patients. Caveats include cross-reactivity with other fungal infections (histoplasmosis, blastomycosis, cryptococcosis and penicilliosis) and with concomitant antibiotics (piperacillin/tazobactam, amoxicillin/clavulanic acid), and a suboptimal sensitivity for A. fumigatus [12]. Recent data suggest that galactomannan may be of interest for the diagnosis of Aspergillus endocarditis [13]. However, owing to the very low incidence of Aspergillus endocarditis since galactomannan antigen and BDG assays have been available, the diagnostic performance of these tests for the diagnosis of Aspergillus endocarditis remains poorly documented.
3.2. Blood cultures
4. Treatment
Blood cultures remain the main evidence for diagnosis of Candida endocarditis. Most cases are diagnosed in the setting of prolonged candidaemia, which is a standalone indication for transoesophageal echocardiography and fundoscopic examination. Diagnostic procedures for Candida diseases have been reviewed by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in 2012 [14] and by the Infectious Diseases Society of America (IDSA) in 2013 [15]. Briefly, these guidelines recommend to inoculate 60 mL of blood obtained by venipuncture and divided into six 10-mL aliquots among three aerobic and three anaerobic bottles to be incubated for ≥5 days. Although the sensitivity of automated blood culture systems is lower for fungal than for bacterial bloodstream infections, there is no evidence that use of specific blood culture bottles for fungal detection increases the diagnostic yield. Hence, guidelines for blood culture sampling in patients suspected of infective endocarditis applies for fungal as for bacterial endocarditis [16]. The sensitivity of blood culture for the diagnosis of C. albicans endocarditis has been estimated at 50–75% [14], and somewhat lower for non-albicans Candida endocarditis. Unfortunately, the yield of blood cultures is almost zero in Aspergillus endocarditis, estimated at 4% (2/53) in a recent review [12]. Most cases of Aspergillus endocarditis are diagnosed by tissue culture (e.g. valves in patients who underwent valve replacement), galactomannan antigen assay or post-mortem examination.
4.1. Antifungal agents
3.3. Innovative diagnostic tests (Table 3) Given the shortcomings of blood cultures for the diagnosis of fungal endocarditis, innovative biological diagnostic tests are being developed and were recently reviewed [14]. The combined detection of mannan and anti-mannan antibodies in serum has been developed for the diagnosis of Candida bloodstream infections [17], and may also apply to Candida endocarditis. Its diagnostic performance for the diagnosis of candidaemia has been estimated at ca. 80% for sensitivity and 85% for specificity, which translates into an estimated accuracy of 50–70%. The most promising test for the diagnosis of fungal endocarditis may be -1,3-d-glucan (BDG) detection in serum, considered
3
Most cases of fungal endocarditis reported in the literature have been treated with amphotericin B deoxycholate (AmBD): 93% of patients reported during 1965–1995 (of whom 22% also received flucytosine) [7], and 78% of those reported during 1995–2000 (of whom 28% also received flucytosine or azoles) [5]. AmB is a polyene, fungicidal for most yeast and moulds potentially involved in fungal endocarditis, but tolerability of conventional AmB (i.e. AmBD) is poor, especially when a prolonged duration of treatment is mandatory for cure, as is the case for fungal endocarditis. Hence, owing to its improved tolerability and the ability to administer higher doses, lipid formulations of AmB are favoured over the deoxycholate preparation in all guidelines recently published, based on experimental studies and expert opinion rather than on clinical studies [16,20–22]. In addition, lipid formulations of AmB may also exert enhanced fungicidal activity on biofilms, which may be of interest in patients with prosthetic valve fungal endocarditis, especially when surgery is not feasible. Of note, Candida lusitaniae is naturally resistant to polyenes. For the treatment of Candida endocarditis, the echinocandins are promising alternatives to polyenes (i.e. AmB and derivatives) for the following reasons: (i) they are rapidly fungicidal against most Candida spp., including azole-resistant Candida spp.; (ii) they remain active against Candida biofilms [23]; and (iii) their tolerability is much better than that of polyenes, allowing prolonged treatment, at high doses, when necessary. Most recent reports illustrate the trend towards increased use of echinocandins (e.g. 77% of patients with Candida endocarditis in the recent French observational prospective study [19]), either instead of, or in association with, lipid formulations of AmB. Azoles are only fungistatic in yeasts; hence, they cannot be considered as primary treatment of Candida endocarditis. However, these compounds retain some potential indications for the treatment of fungal endocarditis in at least three situations: (i) as a primary choice for the medical treatment of Aspergillus endocarditis, on the grounds that voriconazole is fungicidal against Aspergillus spp. and has proven its superiority over AmB in invasive
Please cite this article in press as: Tattevin P, et al. Fungal endocarditis: current challenges. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.07.003
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aspergillosis in a landmark randomised controlled trial [24]; (ii) in combination with an echinocandin (preferably) or a polyene in difficult-to-treat fungal endocarditis; and (iii) as a long-term suppressive treatment to prevent late relapses of Candida endocarditis. Indeed, relapses have been reported in as many as 30–40% of patients who survive after the acute phase of fungal endocarditis and these relapses may occur as late as 9 years after patients have been considered as ‘cured’ [25]. Hence, most experts would recommend lifelong treatment with fluconazole in any situations when Candida endocarditis could not be adequately managed: this includes patients who were not treated with valvular replacement, patients who had positive valve cultures when valvular replacement was performed, patients with prolonged candidaemia, or patients with intracardiac devices that were not extracted. Flucytosine demonstrates broad antifungal activity against most Candida spp., with the exception of Candida krusei. It is sometimes used at a dosage of 100 mg/kg/day in combination with a lipid formulation of AmB or an echinocandin during initial treatment of difficult-to-treat Candida endocarditis cases. Owing to bone marrow toxicity, therapeutic drug monitoring is recommended in prolonged treatment, as well as dose adjustment in patients with renal dysfunction [21]. 4.2. Cardiac surgery Fungal endocarditis has long been considered as a ‘standalone’ indication for surgical valvular replacement for the following reasons: (i) prognosis in patients who received only medical treatment has consistently been very poor, with mortality rates estimated at 96% for Aspergillus endocarditis [12] and 50–70% for Candida endocarditis [5,19]; (ii) most antifungal agents have limited activity within biofilm, vegetations and prosthetic devices; (iii) late relapses are common in patients who did not undergo valve replacement; and (iv) large vegetations commonly encountered in fungal endocarditis may lead to severe embolic events, even under optimised antifungal treatment. However, with the advent of new antifungal agents, including the echinocandins, and better use of older antifungal agents, a significant proportion of patients with native valve Candida endocarditis may be controlled without cardiac surgery [26]. A recent meta-analysis of medical versus surgical therapy for Candida endocarditis found a non-significant impact of surgical valve replacement, with an odds ratio of 0.56 (95% confidence interval 0.16–1.99) for death [27]. Another meta-analysis of 64 cases of Candida endocarditis who did not undergo surgical valvular replacement found that failure was more common in patients who received only fluconazole compared with patients who received fluconazole combined with another antifungal agent (42% vs. 16%; P = 0.02) [28]. 4.3. Current guidelines for the treatment of fungal endocarditis (Table 4) Although polyenes are proposed as the potential first choice for most cases of fungal endocarditis, a switch towards preferred use of echinocandins for Candida endocarditis has been observed in recent cohorts [8,19] as well as in updated guidelines [16,20–22]. Accordingly, the recommended first-line treatment of Candida endocarditis includes high doses of echinocandins as an alternative to lipid formulations of AmB for primary treatment of Candida endocarditis in the USA (caspofungin 50–150 mg/day, anidulafungin 100–200 mg/day or micafungin 100–150 mg/day [21]), caspofungin ± flucytosine as an alternative to lipid formulations of AmB ± flucytosine in Europe [20], and micafungin (200 mg/day), caspofungin (70 mg loading dose, then 50–100 mg/day) or
Table 4 Treatment of fungal endocarditis according to recent guidelines (2009–2012). Antifungal agents
Surgery
European guidelines on infective endocarditis, 2009 [16] a
• Amphotericin B or derivatives with or without azoles • or caspofungin • Prolonged or lifelong fluconazole suppressive treatment
• Valve replacement for all patients
US guidelines on Candida infections, 2009 [21] b
• Liposomal amphotericin B or other lipid formulations with or without flucytosine • or an echinocandin at high doses (caspofungin 50–150 mg/day, micafungin 100–150 mg/day or anidulafungin 100–200 mg/day) • Prolonged fluconazole suppressive treatment (400–800 mg/day)
• Valve replacement strongly recommended • Lifelong fluconazole suppressive treatment in patients with prosthetic valve Candida endocarditis who were not operated
European guidelines on Candida infections, 2012 [20] b
• Liposomal amphotericin B with or without flucytosine • or caspofungin 70 mg/day or 50 mg/day with or without flucytosine • Prolonged, fluconazole suppressive treatment (400–800 mg/day)
• Surgical valve replacement within a week if native valve • Surgical valve replacement within days if prosthetic valve
British guidelines on infective endocarditis, 2012 [22] a
• First-line: an echinocandin at high doses (caspofungin 70 mg loading dose, then 50–100 mg/day, micafungin 200 mg/day or anidulafungin, licensed doses) • Second-line: liposomal amphotericin B or other lipid formulations with or without flucytosine • Prolonged, fluconazole suppressive treatment (400–800 mg/day)
• Valve replacement highly desirable if technically feasible for Candida endocarditis • Valve replacement mandatory for survival in Aspergillus endocarditis
a b
Guidelines apply both for Candida and Aspergillus endocarditis. Guidelines apply only for Candida endocarditis.
anidulafungin (licensed doses) as primary choices (preferably to AmB or derivatives) in the UK [22]. Regarding surgical indications, although case reports of Candida endocarditis controlled by medical treatment alone have accumulated over recent years, fungal endocarditis is still considered as a standalone indication for valvular surgery by most experts. Interestingly, guidelines differ in the way they express these requirements: 2009 European guidelines for endocarditis stated that ‘treatment of fungal endocarditis necessitates dual therapy with antifungal agent and valve replacement [16]’; 2009 US guidelines for Candida diseases stated that ‘valve replacement is strongly recommended. For those who are unable to undergo surgical replacement of the valve, lifelong therapy with fluconazole, 400–800 mg/day is recommended [21]’; 2012 European guidelines for Candida diseases stated that ‘in patients with native valve Candida endocarditis, surgery within a week is recommended, and in prosthetic valve Candida endocarditis, earlier surgery may even be beneficial [20]’; and lastly, 2012 guidelines for endocarditis in the UK separated Aspergillus endocarditis where ‘surgical valve replacement is mandatory for survival’ and Candida endocarditis where
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‘surgical valve replacement is highly desirable if technically feasible [22]’. 5. Perspectives and challenges Significant progress in the prevention, diagnosis and management of fungal endocarditis has been achieved over the last decades. These include: (i) dramatic reduction in the proportion of infective endocarditis due to fungus in most settings, thanks to improvement in infection control procedures during cardiac surgery as well as harm-reduction policies with access to needle exchange programmes; (ii) development of antifungal agents with rapid fungicidal activity against most Candida spp. (echinocandins) or improved survival in patients with invasive aspergillosis (voriconazole); and (iii) although less dramatic, significant improvement in diagnostic tests (transoesophageal echocardiography, automated blood culture systems). Challenges for the future include: (i) expanded access to policies that have proven effective in the reduction of fungal endocarditis (e.g. needle exchange programmes in the USA and Eastern Europe countries); (ii) development of innovative diagnostic tests based on antigen or specific nucleic acid detection in serum (e.g. universal fungal PCR targeting 18S rRNA genes, galactomannan, mannan/anti-mannan antibodies and BDGs); (iii) identification of clinical or biological criteria to select patients who may be cured without surgical valvular replacement; and (iv) optimised treatment of difficult-to-treat fungal endocarditis (e.g. C. parapsilosis endocarditis with diminished susceptibility to echinocandins). 6. Conclusions In conclusion, fungal endocarditis remains one of the most severe infectious diseases, with mortality rates ranging from 96% in Aspergillus endocarditis patients who could not undergo surgical valvular replacement to 32% in patients with Candida endocarditis treated with medical and surgical treatment. However, significant progress has been achieved over the last decades, illustrated by the dramatic decrease in the proportion of infective endocarditis caused by fungus and the development of new antifungal agents that increase the rate of success in patients who cannot undergo surgical valve replacement. Funding: No funding sources. Competing interests: The authors have received support from Astellas, Astra-Zeneca, Aventis, Bristol-Myers Squibb, Gilead Sciences, Janssen-Cilag, MSD, Novartis and Pfizer for research activities, consultancies, workshops or travel to meetings and accommodation. Ethical approval: Not required. References [1] Ellis M. Fungal endocarditis. J Infect 1997;35:99–103. [2] Moyer DV, Edwards JE. Fungal endocarditis. In: Kaye D, editor. Infective endocarditis. New York, NY: Raven Press; 1992. p. 299–311. [3] Rubinstein E, Lang R. Fungal endocarditis. Eur Heart J 1995;16(Suppl. B):84–9. [4] Varghese GM, Sobel JD. Fungal endocarditis. Curr Infect Dis Rep 2008;10: 275–9. [5] Pierrotti LC, Baddour LM. Fungal endocarditis, 1995–2000. Chest 2002;122:302–10.
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[6] Rubinstein E, Noriega ER, Simberkoff MS, Holzman R, Rahal Jr JJ. Fungal endocarditis: analysis of 24 cases and review of the literature. Medicine (Baltimore) 1975;54:331–4. [7] Ellis ME, Al-Abdely H, Sandridge A, Greer W, Ventura W. Fungal endocarditis: evidence in the world literature, 1965–1995. Clin Infect Dis 2001;32:50–62. [8] Baddley JW, Benjamin Jr DK, Patel M, Miró J, Athan E, Barsic B, et al. Candida infective endocarditis. Eur J Clin Microbiol Infect Dis 2008;27:519–29. [9] Falcone M, Barzaghi N, Carosi G, Grossi P, Minoli L, Ravasio V, et al. Candida infective endocarditis: report of 15 cases from a prospective multicenter study. Medicine (Baltimore) 2009;88:160–8. [10] Bor DH, Woolhandler S, Nardin R, Brusch J, Himmelstein DU. Infective endocarditis in the U.S., 1998–2009: a nationwide study. PLOS ONE 2013;8:e60033. [11] Selton-Suty C, Celard M, Le Moing V, Doco-Lecompte T, Chirouze C, Iung B, et al. Preeminence of Staphylococcus aureus in infective endocarditis: a 1-year population-based survey. Clin Infect Dis 2012;54:1230–9. [12] Kalokhe AS, Rouphael N, El Chami MF, Workowski KA, Ganesh G, Jacob JT. Aspergillus endocarditis: a review of the literature. Int J Infect Dis 2010;14:e1040–7. [13] Riviere S, Lortholary O, Michon J, Bougnoux ME, Mainardi JL, Sendid B, et al. Aspergillus endocarditis in the era of new antifungals: major role for antigen detection. J Infect 2013;67:85–8. [14] Cuenca-Estrella M, Verweij PE, Arendrup MC, Arikan-Akdagli S, Bille J, Donnelly JP, et al. ESCMID guideline for the diagnosis and management of Candida diseases 2012: diagnostic procedures. Clin Microbiol Infect 2012;18(Suppl. 7):9–18. [15] Baron EJ, Miller JM, Weinstein MP, Richter SS, Gilligan PH, Thomson Jr RB, et al. A guide to utilization of the microbiology laboratory for diagnosis of infectious diseases: 2013 recommendations by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM). Clin Infect Dis 2013;57:e22–121. [16] Habib G, Hoen B, Tornos P, Thuny F, Prendergast B, Vilacosta I, et al. Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009): the Task Force on the Prevention, Diagnosis, and Treatment of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and the International Society of Chemotherapy (ISC) for Infection and Cancer. Eur Heart J 2009;30:2369–413. [17] Mikulska M, Calandra T, Sanguinetti M, Poulain D, Viscoli C. The use of mannan antigen and anti-mannan antibodies in the diagnosis of invasive candidiasis: recommendations from the Third European Conference on Infections in Leukemia. Crit Care 2010;14:R222. [18] Koo S, Bryar JM, Page JH, Baden LR, Marty FM. Diagnostic performance of the (1 → 3)--d-glucan assay for invasive fungal disease. Clin Infect Dis 2009;49:1650–9. [19] Lefort A, Chartier L, Sendid B, Wolff M, Mainardi JL, Podglajen I, et al. Diagnosis, management and outcome of Candida endocarditis. Clin Microbiol Infect 2012;18:E99–109. [20] Cornely OA, Bassetti M, Calandra T, Garbino J, Kullberg BJ, Lortholary O, et al. ESCMID guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients. Clin Microbiol Infect 2012;18(Suppl. 7):19–37. [21] Pappas PG, Kauffman CA, Andes D, Benjamin Jr DK, Calandra TF, Edwards Jr JE, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009;48:503–35. [22] Gould FK, Denning DW, Elliott TS, Foweraker J, Perry JD, Prendergast BD, et al. Guidelines for the diagnosis and antibiotic treatment of endocarditis in adults: a report of the Working Party of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother 2012;67:269–89. [23] Kuhn DM, George T, Chandra J, Mukherjee PK, Ghannoum MA. Antifungal susceptibility of Candida biofilms: unique efficacy of amphotericin B lipid formulations and echinocandins. Antimicrob Agents Chemother 2002;46:1773–80. [24] Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE, Oestmann JW, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347:408–15. [25] Melgar GR, Nasser RM, Gordon SM, Lytle BW, Keys TF, Longworth DL. Fungal prosthetic valve endocarditis in 16 patients. An 11-year experience in a tertiary care hospital. Medicine (Baltimore) 1997;76:94–103. [26] Talarmin JP, Boutoille D, Tattevin P, Abgueguen P, Ansart S, Roblot F, et al. Candida endocarditis: role of new antifungal agents. Mycoses 2009;52:60–6. 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Contents lists available at ScienceDirect
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Review
Fungal endocarditis: current challenges夽 Pierre Tattevin a,b,c,∗ , Matthieu Revest a,c , Agnès Lefort d , Christian Michelet a , Olivier Lortholary e a
Infectious Diseases and ICU, Pontchaillou University Hospital, Rennes, France INSERM U835, Faculté de Médecine, Université Rennes 1, IFR140, Rennes, France Association pour l’Etude et la Prévention de l’Endocardite Infectieuse (AEPEI), Bichat-Claude Bernard Hôpital, Paris, France d Internal Medicine Department, Beaujon Hospital, Clichy, France e Infectious Diseases Unit, Necker Hospital, Paris, France b c
a r t i c l e
i n f o
Article history: Received 24 July 2014 Accepted 24 July 2014 Keywords: Endocarditis Candida sp. Aspergillus sp. Echinocandins -1,3-d-Glucans
a b s t r a c t Whilst it used to affect mostly intravenous drug users and patients who underwent valvular surgery with suboptimal infection control procedures, fungal endocarditis is now mostly observed in patients with severe immunodeficiency (onco-haematology), in association with chronic central venous access and broad-spectrum antibiotic use. The incidence of fungal endocarditis has probably decreased in most developed countries with access to harm-reduction policies (i.e. needle exchange programmes) and with improved infection control procedures during cardiac surgery. Use of specific blood culture bottles for diagnosis of fungal endocarditis has decreased due to optimisation of media and automated culture systems. Meanwhile, the advent of rapid techniques, including fungal antigen detection (galactomannan, mannan/anti-mannan antibodies and -1,3-d-glucans) and PCR (e.g. universal fungal PCR targeting 18S rRNA genes), shall improve sensitivity and reduce diagnostics delays, although limited data are available on their use for the diagnosis of fungal endocarditis. New antifungal agents available since the early 2000s may represent dramatic improvement for fungal endocarditis: (i) a new class, the echinocandins, has the potential to improve the management of Candida endocarditis owing to its fungicidal effect on yeasts as well as tolerability of increased dosages; and (ii) improved survival in patients with invasive aspergillosis with voriconazole compared with amphotericin B, and this may apply to Aspergillus sp. endocarditis as well, although its prognosis remains dismal. These achievements may allow selected patients to be cured with prolonged medical treatment alone when surgery is considered too risky. © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
1. Introduction Fungal endocarditis is a rare disease with a dismal prognosis related to the population affected (e.g. immunocompromised patients), suboptimal diagnostic tools responsible for long diagnostic delays in most cases, and poorly defined activity of most antifungal agents in endocarditis. The characteristics of patients affected by fungal endocarditis have dramatically changed over the last decades, with an overall decrease in the number of cases managed each year in most institutions. Hence, the number of
夽 This paper was presented at the XIIth International Symposium on Modern Concepts in Endocarditis and Cardiovascular Infections (ISCVID), 19–21 May 2013, Dubrovnik, Croatia. ∗ Corresponding author. Present address: Service des Maladies Infectieuses et de Réanimation Médicale, CHU Pontchaillou, 2 rue Henri Le Guilloux, 35033 Rennes Cedex, France. Tel.: +33 2 9928 9564. E-mail address: [email protected] (P. Tattevin).
physicians who maintained expertise in this field has probably declined. We aimed to provide an update on the current challenges in the management of fungal endocarditis based on a literature review and on our own experience. 2. Epidemiology 2.1. Changing profile of fungal endocarditis The characteristics of patients affected by infective endocarditis have dramatically changed since the 1990s, as illustrated by prospective cohort and population-based studies [1–7]. Characteristics of the 270 cases reported during 1965–1995 are as follows: male:female ratio, 2.2; mean age, 44.3 ± 14.3 years; and main risk factors being previous valve surgery/prosthetic valve endocarditis (54%), prolonged use of antibiotics (48%), rheumatic heart disease (24%), surgery other than cardiac (23%), vascular lines (18%), immunosuppressive treatment (17%), non-iatrogenic
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immunodeficiency (17%) and intravenous drug use (IVDU) (13%). A subsequent review of 152 cases reported between 1995 and 2000 found that prosthetic valves (45%), central venous catheters (30%) and broad-spectrum antibiotic use (20%) were the main risk factors, whilst intravenous drug users were much less affected (4%). Two major observations emerged from these large literature reviews: (i) over time, dramatic changes have occurred in the major risk factors for fungal endocarditis; once a disease affecting mostly patients with recent valvular surgery, rheumatic heart disease or IVDU, fungal endocarditis is currently more common in immunocompromised patients, with long-term vascular lines, and who underwent complex non-cardiac surgery; and (ii) the prognosis gradually improved, with a mortality rate that decreased from 86% during 1966–1971 to 56% during 1995–2000 [1,3–5]. Although these figures, mostly based on case reports, are subject to publication bias, an improved outcome over the years would be expected owing to significant success achieved in the field of diagnosis as well as new antifungal agents. For example, diagnosis of fungal endocarditis was obtained before surgery in 43% of cases reported before 1988 compared with 72% of cases reported during 1988–1995 (P = 0.0001), which may be related to the advent of echocardiography (since 1975) as well as progress in automated blood culture systems, with a sensitivity estimated at 54% during 1965–1995 [1] and 81% during 1995–2000 [5]. Likewise, development of lipid formulations of amphotericin B (AmB), new azoles with extended spectrum, and echinocandins, over the last 20 years significantly enhanced the therapeutic armamentarium against fungal endocarditis. 2.2. Characteristics of fungal endocarditis in the 21st century In most contemporary studies, fungal endocarditis represents 80%. For Candida endocarditis: sensitivity, 100% [19] Validated for the diagnosis of invasive aspergillosis in neutropenic patients. Not evaluated for the diagnosis of Aspergillus endocarditis
to be a pan-fungal diagnostic method, as BDG is present in most pathogenic fungal species. Its performance for the diagnosis of candidaemia has been evaluated in a meta-analysis [18]: with a cut-off value of 80 pg/mL, sensitivity would be >65%, specificity >80% and the negative predictive value >85%. In a prospective study of 18 patients with definite cases of Candida endocarditis, Lefort et al. found that the sensitivity of BDG and mannan/anti-mannan antibody detection in serum were 100% and 83%, respectively, for the diagnosis of Candida endocarditis [19]. For the diagnosis of Aspergillus endocarditis, potential diagnostic tests include the detection of BDG and the detection of galactomannan antigen in serum. Galactomannan is a major constituent of the Aspergillus cell wall and has been validated for the diagnosis of invasive aspergillosis in neutropenic patients. Caveats include cross-reactivity with other fungal infections (histoplasmosis, blastomycosis, cryptococcosis and penicilliosis) and with concomitant antibiotics (piperacillin/tazobactam, amoxicillin/clavulanic acid), and a suboptimal sensitivity for A. fumigatus [12]. Recent data suggest that galactomannan may be of interest for the diagnosis of Aspergillus endocarditis [13]. However, owing to the very low incidence of Aspergillus endocarditis since galactomannan antigen and BDG assays have been available, the diagnostic performance of these tests for the diagnosis of Aspergillus endocarditis remains poorly documented.
3.2. Blood cultures
4. Treatment
Blood cultures remain the main evidence for diagnosis of Candida endocarditis. Most cases are diagnosed in the setting of prolonged candidaemia, which is a standalone indication for transoesophageal echocardiography and fundoscopic examination. Diagnostic procedures for Candida diseases have been reviewed by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in 2012 [14] and by the Infectious Diseases Society of America (IDSA) in 2013 [15]. Briefly, these guidelines recommend to inoculate 60 mL of blood obtained by venipuncture and divided into six 10-mL aliquots among three aerobic and three anaerobic bottles to be incubated for ≥5 days. Although the sensitivity of automated blood culture systems is lower for fungal than for bacterial bloodstream infections, there is no evidence that use of specific blood culture bottles for fungal detection increases the diagnostic yield. Hence, guidelines for blood culture sampling in patients suspected of infective endocarditis applies for fungal as for bacterial endocarditis [16]. The sensitivity of blood culture for the diagnosis of C. albicans endocarditis has been estimated at 50–75% [14], and somewhat lower for non-albicans Candida endocarditis. Unfortunately, the yield of blood cultures is almost zero in Aspergillus endocarditis, estimated at 4% (2/53) in a recent review [12]. Most cases of Aspergillus endocarditis are diagnosed by tissue culture (e.g. valves in patients who underwent valve replacement), galactomannan antigen assay or post-mortem examination.
4.1. Antifungal agents
3.3. Innovative diagnostic tests (Table 3) Given the shortcomings of blood cultures for the diagnosis of fungal endocarditis, innovative biological diagnostic tests are being developed and were recently reviewed [14]. The combined detection of mannan and anti-mannan antibodies in serum has been developed for the diagnosis of Candida bloodstream infections [17], and may also apply to Candida endocarditis. Its diagnostic performance for the diagnosis of candidaemia has been estimated at ca. 80% for sensitivity and 85% for specificity, which translates into an estimated accuracy of 50–70%. The most promising test for the diagnosis of fungal endocarditis may be -1,3-d-glucan (BDG) detection in serum, considered
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Most cases of fungal endocarditis reported in the literature have been treated with amphotericin B deoxycholate (AmBD): 93% of patients reported during 1965–1995 (of whom 22% also received flucytosine) [7], and 78% of those reported during 1995–2000 (of whom 28% also received flucytosine or azoles) [5]. AmB is a polyene, fungicidal for most yeast and moulds potentially involved in fungal endocarditis, but tolerability of conventional AmB (i.e. AmBD) is poor, especially when a prolonged duration of treatment is mandatory for cure, as is the case for fungal endocarditis. Hence, owing to its improved tolerability and the ability to administer higher doses, lipid formulations of AmB are favoured over the deoxycholate preparation in all guidelines recently published, based on experimental studies and expert opinion rather than on clinical studies [16,20–22]. In addition, lipid formulations of AmB may also exert enhanced fungicidal activity on biofilms, which may be of interest in patients with prosthetic valve fungal endocarditis, especially when surgery is not feasible. Of note, Candida lusitaniae is naturally resistant to polyenes. For the treatment of Candida endocarditis, the echinocandins are promising alternatives to polyenes (i.e. AmB and derivatives) for the following reasons: (i) they are rapidly fungicidal against most Candida spp., including azole-resistant Candida spp.; (ii) they remain active against Candida biofilms [23]; and (iii) their tolerability is much better than that of polyenes, allowing prolonged treatment, at high doses, when necessary. Most recent reports illustrate the trend towards increased use of echinocandins (e.g. 77% of patients with Candida endocarditis in the recent French observational prospective study [19]), either instead of, or in association with, lipid formulations of AmB. Azoles are only fungistatic in yeasts; hence, they cannot be considered as primary treatment of Candida endocarditis. However, these compounds retain some potential indications for the treatment of fungal endocarditis in at least three situations: (i) as a primary choice for the medical treatment of Aspergillus endocarditis, on the grounds that voriconazole is fungicidal against Aspergillus spp. and has proven its superiority over AmB in invasive
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aspergillosis in a landmark randomised controlled trial [24]; (ii) in combination with an echinocandin (preferably) or a polyene in difficult-to-treat fungal endocarditis; and (iii) as a long-term suppressive treatment to prevent late relapses of Candida endocarditis. Indeed, relapses have been reported in as many as 30–40% of patients who survive after the acute phase of fungal endocarditis and these relapses may occur as late as 9 years after patients have been considered as ‘cured’ [25]. Hence, most experts would recommend lifelong treatment with fluconazole in any situations when Candida endocarditis could not be adequately managed: this includes patients who were not treated with valvular replacement, patients who had positive valve cultures when valvular replacement was performed, patients with prolonged candidaemia, or patients with intracardiac devices that were not extracted. Flucytosine demonstrates broad antifungal activity against most Candida spp., with the exception of Candida krusei. It is sometimes used at a dosage of 100 mg/kg/day in combination with a lipid formulation of AmB or an echinocandin during initial treatment of difficult-to-treat Candida endocarditis cases. Owing to bone marrow toxicity, therapeutic drug monitoring is recommended in prolonged treatment, as well as dose adjustment in patients with renal dysfunction [21]. 4.2. Cardiac surgery Fungal endocarditis has long been considered as a ‘standalone’ indication for surgical valvular replacement for the following reasons: (i) prognosis in patients who received only medical treatment has consistently been very poor, with mortality rates estimated at 96% for Aspergillus endocarditis [12] and 50–70% for Candida endocarditis [5,19]; (ii) most antifungal agents have limited activity within biofilm, vegetations and prosthetic devices; (iii) late relapses are common in patients who did not undergo valve replacement; and (iv) large vegetations commonly encountered in fungal endocarditis may lead to severe embolic events, even under optimised antifungal treatment. However, with the advent of new antifungal agents, including the echinocandins, and better use of older antifungal agents, a significant proportion of patients with native valve Candida endocarditis may be controlled without cardiac surgery [26]. A recent meta-analysis of medical versus surgical therapy for Candida endocarditis found a non-significant impact of surgical valve replacement, with an odds ratio of 0.56 (95% confidence interval 0.16–1.99) for death [27]. Another meta-analysis of 64 cases of Candida endocarditis who did not undergo surgical valvular replacement found that failure was more common in patients who received only fluconazole compared with patients who received fluconazole combined with another antifungal agent (42% vs. 16%; P = 0.02) [28]. 4.3. Current guidelines for the treatment of fungal endocarditis (Table 4) Although polyenes are proposed as the potential first choice for most cases of fungal endocarditis, a switch towards preferred use of echinocandins for Candida endocarditis has been observed in recent cohorts [8,19] as well as in updated guidelines [16,20–22]. Accordingly, the recommended first-line treatment of Candida endocarditis includes high doses of echinocandins as an alternative to lipid formulations of AmB for primary treatment of Candida endocarditis in the USA (caspofungin 50–150 mg/day, anidulafungin 100–200 mg/day or micafungin 100–150 mg/day [21]), caspofungin ± flucytosine as an alternative to lipid formulations of AmB ± flucytosine in Europe [20], and micafungin (200 mg/day), caspofungin (70 mg loading dose, then 50–100 mg/day) or
Table 4 Treatment of fungal endocarditis according to recent guidelines (2009–2012). Antifungal agents
Surgery
European guidelines on infective endocarditis, 2009 [16] a
• Amphotericin B or derivatives with or without azoles • or caspofungin • Prolonged or lifelong fluconazole suppressive treatment
• Valve replacement for all patients
US guidelines on Candida infections, 2009 [21] b
• Liposomal amphotericin B or other lipid formulations with or without flucytosine • or an echinocandin at high doses (caspofungin 50–150 mg/day, micafungin 100–150 mg/day or anidulafungin 100–200 mg/day) • Prolonged fluconazole suppressive treatment (400–800 mg/day)
• Valve replacement strongly recommended • Lifelong fluconazole suppressive treatment in patients with prosthetic valve Candida endocarditis who were not operated
European guidelines on Candida infections, 2012 [20] b
• Liposomal amphotericin B with or without flucytosine • or caspofungin 70 mg/day or 50 mg/day with or without flucytosine • Prolonged, fluconazole suppressive treatment (400–800 mg/day)
• Surgical valve replacement within a week if native valve • Surgical valve replacement within days if prosthetic valve
British guidelines on infective endocarditis, 2012 [22] a
• First-line: an echinocandin at high doses (caspofungin 70 mg loading dose, then 50–100 mg/day, micafungin 200 mg/day or anidulafungin, licensed doses) • Second-line: liposomal amphotericin B or other lipid formulations with or without flucytosine • Prolonged, fluconazole suppressive treatment (400–800 mg/day)
• Valve replacement highly desirable if technically feasible for Candida endocarditis • Valve replacement mandatory for survival in Aspergillus endocarditis
a b
Guidelines apply both for Candida and Aspergillus endocarditis. Guidelines apply only for Candida endocarditis.
anidulafungin (licensed doses) as primary choices (preferably to AmB or derivatives) in the UK [22]. Regarding surgical indications, although case reports of Candida endocarditis controlled by medical treatment alone have accumulated over recent years, fungal endocarditis is still considered as a standalone indication for valvular surgery by most experts. Interestingly, guidelines differ in the way they express these requirements: 2009 European guidelines for endocarditis stated that ‘treatment of fungal endocarditis necessitates dual therapy with antifungal agent and valve replacement [16]’; 2009 US guidelines for Candida diseases stated that ‘valve replacement is strongly recommended. For those who are unable to undergo surgical replacement of the valve, lifelong therapy with fluconazole, 400–800 mg/day is recommended [21]’; 2012 European guidelines for Candida diseases stated that ‘in patients with native valve Candida endocarditis, surgery within a week is recommended, and in prosthetic valve Candida endocarditis, earlier surgery may even be beneficial [20]’; and lastly, 2012 guidelines for endocarditis in the UK separated Aspergillus endocarditis where ‘surgical valve replacement is mandatory for survival’ and Candida endocarditis where
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‘surgical valve replacement is highly desirable if technically feasible [22]’. 5. Perspectives and challenges Significant progress in the prevention, diagnosis and management of fungal endocarditis has been achieved over the last decades. These include: (i) dramatic reduction in the proportion of infective endocarditis due to fungus in most settings, thanks to improvement in infection control procedures during cardiac surgery as well as harm-reduction policies with access to needle exchange programmes; (ii) development of antifungal agents with rapid fungicidal activity against most Candida spp. (echinocandins) or improved survival in patients with invasive aspergillosis (voriconazole); and (iii) although less dramatic, significant improvement in diagnostic tests (transoesophageal echocardiography, automated blood culture systems). Challenges for the future include: (i) expanded access to policies that have proven effective in the reduction of fungal endocarditis (e.g. needle exchange programmes in the USA and Eastern Europe countries); (ii) development of innovative diagnostic tests based on antigen or specific nucleic acid detection in serum (e.g. universal fungal PCR targeting 18S rRNA genes, galactomannan, mannan/anti-mannan antibodies and BDGs); (iii) identification of clinical or biological criteria to select patients who may be cured without surgical valvular replacement; and (iv) optimised treatment of difficult-to-treat fungal endocarditis (e.g. C. parapsilosis endocarditis with diminished susceptibility to echinocandins). 6. Conclusions In conclusion, fungal endocarditis remains one of the most severe infectious diseases, with mortality rates ranging from 96% in Aspergillus endocarditis patients who could not undergo surgical valvular replacement to 32% in patients with Candida endocarditis treated with medical and surgical treatment. However, significant progress has been achieved over the last decades, illustrated by the dramatic decrease in the proportion of infective endocarditis caused by fungus and the development of new antifungal agents that increase the rate of success in patients who cannot undergo surgical valve replacement. Funding: No funding sources. Competing interests: The authors have received support from Astellas, Astra-Zeneca, Aventis, Bristol-Myers Squibb, Gilead Sciences, Janssen-Cilag, MSD, Novartis and Pfizer for research activities, consultancies, workshops or travel to meetings and accommodation. Ethical approval: Not required. References [1] Ellis M. Fungal endocarditis. J Infect 1997;35:99–103. [2] Moyer DV, Edwards JE. Fungal endocarditis. In: Kaye D, editor. Infective endocarditis. New York, NY: Raven Press; 1992. p. 299–311. [3] Rubinstein E, Lang R. Fungal endocarditis. Eur Heart J 1995;16(Suppl. B):84–9. [4] Varghese GM, Sobel JD. Fungal endocarditis. Curr Infect Dis Rep 2008;10: 275–9. [5] Pierrotti LC, Baddour LM. Fungal endocarditis, 1995–2000. Chest 2002;122:302–10.
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