© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Transplant Infectious Disease, ISSN 1398-2273
Case report
Invasive Saccharomyces cerevisiae in a liver transplant patient: case report and review of infection in transplant recipients K.Y. Popiel, P. Wong, M.J. Lee, M. Langelier, D.C. Sheppard, D.C. Vinh. Invasive Saccharomyces cerevisiae in a liver transplant patient: case report and review of infection in transplant recipients. Transpl Infect Dis 2015: 17: 435–441. All rights reserved Abstract: Saccharomyces cerevisiae, an ascosporogenous yeast commonly used in the production of food, is an emerging infection in immunocompromised patients. We report the case of a 60-year-old man whose orthotopic liver transplant was complicated by S. cerevisiae fungemia and peritoneal abscess, successfully treated with caspofungin and drainage. We also review the literature of invasive saccharomycoses in recipients of hematologic and solid organ transplants.
K.Y. Popiel1, P. Wong2, M.J. Lee3, M. Langelier4, D.C. Sheppard3, D.C. Vinh4 1
Division of Infectious Diseases, McGill University Health Centre, Montreal, Quebec, Canada, 2Division of Gastroenterology and Hepatology, McGill University, Montreal, Quebec, Canada, 3Departments of Medicine, Microbiology and Immunology, McGill University, Montreal, Quebec, Canada, 4Division of Infectious Diseases (Infectious Disease Susceptibility Program), McGill University Health Centre, Montreal, Quebec, Canada Key words: Saccharomyces cerevisiae; yeast; fungemia; transplant; BMT; SOT Correspondence to: Dr Donald C. Vinh, McGill University Health Centre – Montreal General Hospital, 1650 Cedar Ave, Rm A5-156, Montreal, QC, H3G 1A4 Canada Tel: +514-934-1934 x42811 Fax: +514-934-8423 E-mail: [email protected]
Received 5 October 2014, revised 28 January 2015, accepted for publication 1 March 2015 DOI: 10.1111/tid.12384 Transpl Infect Dis 2015: 17: 435–441
Infections caused by non-Candida yeasts in solid organ transplant recipients are emerging. This report describes the first case of an orthotopic liver transplant (OLT) recipient with Saccharomyces cerevisiae peritoneal abscess and fungemia who was successfully treated with caspofungin.
Case report A 60-year-old man was admitted for biliary exploration. He had undergone OLT in another province 9 years prior for hepatitis C-related cirrhosis. Subsequently, he developed repeated episodes of cholangitis because of recurrent biliary obstruction, despite the insertion of
several biliary stents. On admission to our hospital, his maintenance immunosuppression included tacrolimus 1 mg twice a day, mycophenolate mofetil 500 mg twice a day, and prednisone 5 mg daily. On surgical exploration of the biliary system, he was found to have significant adhesions precluding accurate isolation and access of anatomical structures. The patient underwent a hepatojejunostomy and enteroenterostomy. Because of the abnormal amount of scar tissue, an injury to the hepatic artery occurred; surgical repair was attempted. However, over the ensuing days, ongoing hepatic ischemia was evident biochemically and radiologically, and efforts for endovascular repair were not successful. The patient therefore underwent another OLT, performed 3 days after biliary
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exploration. Perioperatively, he received antimicrobial prophylaxis with ampicillin, ceftriaxone, and nystatin; no systemic antifungal was administered. Immunosuppression consisted of anti-thymocyte globulin, methylprednisolone, tacrolimus, and mycophenolate mofetil. Intra-operatively, he received 12 units of packed red blood cells and 4 units of platelets. The night before OLT, the patient noted subjective fever and mild chills, for which blood cultures were obtained. On day 3 after OLT, a yeast was isolated from those blood cultures; the patient was started on fluconazole. Repeat blood cultures confirmed the presence of the same yeast, which ultimately was proved to be S. cerevisiae. Postoperatively, he also developed catheter-related bacteremia with Enterobacter aerogenes; culture of catheter tips did not demonstrate yeast. One week after fluconazole was started, fever recurred. Imaging revealed a fluid collection with some fat stranding near the porta hepatis. Cultures of peritoneal fluid from the surgical drain left in place yielded S. cerevisiae. The isolate was sent for antifungal susceptibility testing at the provincial reference laboratory. Meanwhile, antifungal treatment was changed to caspofungin. With caspofungin and ongoing drainage, the patient defervesced with clearance of fungemia. Given that the fungal infection broke through on fluconazole, caspofungin was continued pending antifungal susceptibility testing results; the patient completed 4 weeks with no evidence of further dissemination and eventual radiologic resolution of the abscess. On review of his diet, the patient denied consuming any probiotic capsules, wine, beer, kefir, or significant amount of bread or yogurt. In culture, the isolated yeast demonstrated creamcolored, smooth, moist colonies (Fig. 1). Identification was performed using API 20C Aux Clinical Yeast System (bioM erieux, Marcy L’Etoile, France), producing code 2040073 (99% identification) and the presence of ascospores on sodium acetate plate. Identification was confirmed by the provincial reference laboratory, and antifungal susceptibility testing by broth microdilution method revealed the following: amphotericin B 1 mg/L; 5-fluorocytosine ≤0.06 mg/L; fluconazole: 0.5 mg/L; itraconazole: 0.25 mg/L; voriconazole: 0.03 mg/L; caspofungin: 0.5 mg/L; micafungin: 0.25 mg/L; and anidulafungin: 0.25 mg/L.
Discussion The genus Saccharomyces comprises ascomycetous yeasts that are commonly employed in the food industry. S. cerevisiae is the most recognized because
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Fig. 1. Saccharomyces cerevisiae growing on Sabouraud’s dextrose agar (with black background), demonstrating creamy-white colored, glabrous colonies.
of its use in the production of bread and of beer or wine, hence the common term “baker’s” or “brewer’s” yeast, respectively. In the clinical microbiology laboratory, S. cerevisiae may also be isolated from human samples, as colonization of the respiratory, gastrointestinal (GI), or genitourinary tracts have been reported (1). Colonization appears to be increased in the setting of chronic underlying disease, although it currently remains unclear if the yeast establishes itself as a commensal member of mucosal flora, or whether it is present only transiently following exposure (e.g., ingestion). Saccharomyces boulardii, an isolate often used in probiotic preparations to alleviate various GI diseases, is currently classified as a cluster of strains assigned to the S. cerevisiae species (2, 3). Other species/complexes within this genus (e.g., Saccharomyces bayanus, Saccharomyces pastorianus) are important industrial organisms whose taxons are being refined (4), but for whom no published reports of human infection were identified. Invasive disease caused by S. cerevisiae is thought to occur via 2 main routes: translocation from the GI lumen, or breaches in the skin barrier, primarily within the context of vascular access devices. Evidence for GI-derived saccharomycosis derives primarily from clinical reports of infection following consumption of the yeast, in significant doses (e.g., 107–1010 yeast cells/day), from foods or probiotics used for treatment/prophylaxis of diarrheal disease, in both immunocompetent as well as immunosuppressed patients. Invasive S. cerevisiae disease also has been reported after abdominal surgery, in the absence of known
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intentional consumption (5, 6), likely reflecting its occasional role as colonizer. Elegant experiments by Perez-Torrado et al. have clarified this pathogenic mechanism further (7). They demonstrate, in an in vitro epithelial barrier model, that S. cerevisiae possesses a low ability for epithelial adherence, as well as poor capacity to induce epithelial cytotoxicity or to disrupt intestinal barrier integrity. Thus, it appears that S. cerevisiae has inherently low pathogenicity, requiring gross (e.g., surgical transection; diverticular disease) (8) or microscopic (e.g., enteritis) dysfunction of the intestinal barrier, coinciding with large enteral fungal burden, to cause systemic infection. In this patient, disruption of intestinal barrier integrity followed by induction immunosuppression likely account for development of this infection. Similarly, epithelial disruption accounts for vascular catheter-associated S. cerevisiae fungemia. The latter has occurred as sporadic cases (9, 10), as well as local outbreaks with molecular evidence for nosocomial transmission (11, 12), highlighting the need for proper infection control handling of probiotics in such patients. Invasive saccharomycosis specifically occurring in recipients of hematologic or solid organ transplants is summarized in Table 1 (13–19). Although some cases lack sufficient clinical details, the reported onset of fungal disease following bone marrow transplant ranged from day +43 to day +180; 1 case reported fungemia 8 months after transplantation, but in the context of palliative chemotherapy. On the other hand, only 2 other cases in solid organ transplant were identified: 1 occurring 3 years after simultaneous kidney-pancreas transplantation in a patient receiving probiotics for Clostridium difficile-associated diarrhea (13), and 1 with fungal peritonitis complicating liver transplantation (14), similar to our patient. As most of the reports do not comment on consumption of products that harbor S. cerevisiae, it is unclear what role this feature of the medical history plays in assessing risk for fungal disease. The fact that our patient denied any such consumption illustrates that it is not a prerequisite for considering S. cerevisiae in the differential diagnosis of yeasts isolated from transplant recipients. Laboratory identification of S. cerevisiae is relatively straightforward. Colonies grow rapidly on Sabouraud’s dextrose agar, producing white-cream, smooth, moist colonies, as in this case (Fig. 1). Growth is inhibited on cycloheximide-containing medium. The yeast cells are round to oval, measuring 4–8 by 5–10 lm, slightly larger than Candida glabrata, to which it is closely related phylogenetically (20). S. cerevisiae produces blastoconidia, but no anneloconidia, arthroconidia, or
chlamydoconidia. It does not produce hyphae (i.e., the test for germ tube – the parallel-sided, non-pinched-off hyphal bud – is negative). S. cerevisiae does not typically produce pseudohyphae under routine conditions of the diagnostic microbiology laboratory, although they can grow in pseudohyphal form under conditions of nitrogen starvation, which triggers mitotic growth (21). No capsule or urease activity is apparent microscopically. In culture, Saccharomyces species produce b-D-glucan (22) and at least theoretically can be a cause for positivity of this surrogate marker of invasive fungal disease; 1 such case has been reported (23), although no clinical studies have evaluated the diagnostic performance of this marker in this infection. The serum b-D-glucan test was not performed in our patient, because the test is not available in our center. S. cerevisiae is able to ferment various carbohydrates (e.g., glucose, maltose, sucrose) and assimilate raffinose, but is unable to utilize nitrate. A characteristic feature of S. cerevisiae is the capacity to sporulate, forming ascospores, when cultured on nutrient-depleted agar (e.g., acetate agar). In this assay, the absence of nitrogen, along with the presence of a nonfermentable carbon source (i.e., acetate), induces the formation of ascospores, in which 1–4 spores are contained within an ascus; the ascospore can be visualized by differential staining (e.g., Gram stain; Kinyoun stain). Antifungal susceptibility testing of S. cerevisiae can be performed by broth micro- and macro-dilution methods, which provide minimal inhibitory concentration (MIC) relative to different antifungal agents, as well as by disk diffusion, which assesses susceptibility by diameter zone size inhibition around an antifungalimpregnated disk. Studies using broth microdilution, summarized in an analysis by Enache-Angoulvant and Hennequin (24), reveal relatively low in vitro susceptibility to amphotericin B (MIC50: 0.25–1 lg/mL; median MIC50: 0.75 lg/mL), with wider in vitro susceptibility results to fluconazole (MIC50: 0.5–64 lg/mL; median MIC50: 2 lg/mL) and to itraconazole (MIC50: 0.063– 64 lg/mL; median MIC50: 0.5 lg/mL). Studies on a large number (i.e., >10) of non-superficial clinical S. cerevisiae isolates reveal greater in vitro susceptibility to voriconazole (MIC50: ≤0.008 to 8; median MIC50: 0.125 lg/mL) (25) and to posaconazole (MIC50: 0.015 to >4 lg/mL; median MIC50: 0.325 lg/mL) (26). As no standardized interpretive criteria to determine susceptibility have been established for Saccharomyces species, breakpoints adopted for Candida species have previously guided interpretation. However, earlier Clinical and Laboratory Standards Institute clinical breakpoints for fluconazole and voriconazole were directed to all Candida species (i.e., for fluconazole: susceptible:
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437
438
Age in years Gender
Transplant Infectious Disease 2015: 17: 435–441 Allo-BMT (MUD) for CML
1 case, NS
24F
29F (possible)
27M
4 (17)
5 (18)
7 (13)
42F
Solid organ transplant
51F
Allo-BMT (MUD) for CML
48F
3 (16)
6 (19)
Allo-BMT (MUD) for CML
36M
2 (15)
Kidney-Pancreas
Allo-BMT for relapsed AML, followed by AML relapse 8 months later and started on clofarabine
BMT
Allo-BMT (MRD) for CML
Allo-BMT for acute leukemia
30F
Allo-BMT for CML
Type of transplant
1 (15)
Hematological transplant
Patient no. (reference)
Blood
Blood
Sputum, throat and rectal swabs
Pre-mortem: throat swab, BAL
Pre-mortem: sputum, feces, vulval swab. Post-mortem: lymph node
Blood and on autopsy
Blood (peripheral and Hickman catheter)
Lung
Blood
Sites of isolation
Characteristics of transplant patients with invasive Saccharomyces cerevisiae infection
Liposomal amphotericin and 5-flucytosine
Day +62
3 years
Fluconazole 400 mg daily 9 21 days
Amphotericin B and voriconazole
Liposomal amphotericin
Day +79
8 months
NS Liposomal amphotericin
NS
Fluconazole 150 mg po daily 9 54 days
Day +180
Day +43
NS
NS
Treatment
NS
NS
Onset of infection relative to transplant
Survived
Palliative support for relapsing AML
Survived
Death
Death
Death
Survival
Survival
Survival
Outcome
Fungemia developed following administration of Saccharomyces boulardii for Clostridium difficile infection (on day 7 of S. boulardii treatment)
Histopathology of skin lesions revealed fungal emboli
On prophylactic fluconazole (50 mg once daily)
On prophylactic fluconazole (50 mg once daily). Autopsy revealed no histopathological or microbiological evidence of any infection
On prophylactic fluconazole (50 mg once daily). Autopsy revealed PTLD, as well as lymphadenitis with Saccharomyces
BMT was non-T-depleted. Conditioning: Cyclophosphomide 120 mg/kg + fractionated total body irradiation. GVHD prophylaxis: CsA and MTX
Comment
Popiel et al: Saccharomycosis in transplant patients
Table 1
F, female; Allo-BMT, allogeneic bone marrow transplant; CML, chronic myeloid leukemia; NS, not specified; M, male; MRD, matched-related donor; po, by mouth; GVHD, graft-versus-host disease; CsA, cyclosporine; MTX, methotrexate; MUD, matched-unrelated donor; PTLD, post-transplant lymphoproliferative disorder; BAL, bronchoalveolar lavage; MMF, mycophenolate mofetil; AML, acute myeloid leukemia; OKT3, muromonab-CD3; ATG, anti-thymocyte globulin.
ATG, methylprednisolone, tacrolimus, MMF Survival Fluconazole (400 mg daily) with isolation of yeast, changed to caspofungin when yeast identified Blood (Day 0); Peritoneal fluid (Day +7) Blood and peritoneal abscess fluid 60M Present case
Liver (ischemic injury to first liver transplant for hepatitis C)
OKT3, CsA, Prednisone, Azathioprine. Nysatatin prophylaxis NS NS Day +67 NS 8 (14)
Liver (indication NS)
Peritoneal fluid
Treatment Patient no. (reference)
Table 1 Continued
Age in years Gender
Type of transplant
Sites of isolation
Onset of infection relative to transplant
Outcome
Comment
Popiel et al: Saccharomycosis in transplant patients
≤8 lg/mL; susceptible dose-dependent: 16–32 lg/mL; resistant: ≥64 lg/mL; and for voriconazole: susceptible: ≤1 lg/mL; susceptible dose-dependent: 2 lg/mL; resistant: ≥4 lg/mL) (27). Since 2012, species-specific clinical breakpoints for fluconazole and voriconazole have been developed that are considerably different (28). Their relevance to interpretation of S. cerevisiae susceptibility remains to be determined. This limitation also applies to extrapolation of susceptibility interpretation in previously published results using the disk diffusion method (29). Despite the absence of interpretive criteria, it appears that S. cerevisiae may demonstrate a wide MIC range to fluconazole. In what was deemed to be a nosocomial outbreak in a hematology unit, Salonen et al. (30) reported fluconazole MICs ranging from 1 to 128 lg/ mL; as these rates were considerably high, the authors speculate that antifungal selective pressure from extensive use of fluconazole in their patients may have accounted for this resistance pattern, possibly along with clonal dissemination via the hands of healthcare workers. However, Olver et al. (31) did not observe a similar effect among a cluster of S. cerevisiae clinical isolates from their hematology unit, despite affected patients receiving fluconazole prophylaxis; their fluconazole MICs ranged from 2 to 4 lg/mL. As these 2 reports were from different countries, it is likely that that regional epidemiologic variability exists in susceptibility patterns for S. cerevisiae; this is supported by the ARTEMIS DISK study (29), in which disk diffusion method and interpretive criteria for Candida species demonstrated rates of resistance to fluconazole ranging from 0% (in Africa/Middle East) to 24.1% (in Latin America). Given the potential for relative in vitro resistance to fluconazole and to amphotericin B, the identification of S. cerevisiae in our patient prompted an empiric change to caspofungin pending final susceptibility results. As 30–60% of the fungal cell wall of Saccharomyces species is composed of glucan in the form of b-1,3-glucan with b-1,6 linkages (32), the echinocandins, which function to inhibit b-1,3-D-glucan synthase, are a reasonable antifungal agent for this yeast. Only 1 other case in which an echinocandin has been used to successfully treat Saccharomyces fungemia has been reported (33); that patient was admitted with pneumonia and septic shock and developed fungemia following initiation of probiotics for diarrhea. No report of echinocandin use for saccharomycosis in transplant recipients was identified. However, given that the echinocandins, unlike the azoles, demonstrate few interactions with drugs such as transplant-related immunosuppressants (34), this antifungal selection may be an appropriate option for empiric therapy for
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Saccharomyces species in transplant recipients, pending susceptibility results. Additional measures, such as catheter removal in the case of line-related bloodstream infection or drainage of abscess (as in this case), are also necessary to eradicate infection.
Conclusion S. cerevisiae may cause invasive disease in transplant recipients, even in the absence of obvious ingestion. Infection occurs most commonly via breach of the GI barrier or by vascular catheters. Antifungal susceptibility testing by broth microdilution provides MIC results that may guide therapy. Limited evidence suggests echinocandins may be a therapeutic alternative, although further confirmatory evidence is required.
Acknowledgements: Author contributions: K.P.: Data acquisition, drafting article, and approval of article. P.W.: Data acquisition/ interpretation, critical revision of article, and approval of article. M.L.: Patient management and data acquisition. M.J.L.: Data acquisition and figure production. D.C.S.: Data analysis/interpretation, critical revision of article, and approval of article. D.C.V.: Concept/design; data analysis/interpretation, drafting article, critical revision of article, and approval of article.
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8. Jensen DP, Smith DL. Fever of unknown origin secondary to brewer’s yeast ingestion. Arch Intern Med 1976; 136 (3): 332–333. 9. Nielsen H, Stenderup J, Bruun B. Fungemia with Saccharomycetaceae. Report of four cases and review of the literature. Scand J Infect Dis 1990; 22 (5): 581–584. 10. Krcmery V, Krupova I, Denning DW. Invasive yeast infections other than Candida spp. in acute leukaemia. J Hosp Infect 1999; 41 (3): 181–194. 11. Zerva L, Hollis RJ, Pfaller MA. In vitro susceptibility testing and DNA typing of Saccharomyces cerevisiae clinical isolates. J Clin Microbiol 1996; 34 (12): 3031–3034. 12. Cassone M, Serra P, Mondello F, et al. Outbreak of Saccharomyces cerevisiae subtype boulardii fungemia in patients neighboring those treated with a probiotic preparation of the organism. J Clin Microbiol 2003; 41 (11): 5340–5343. 13. Riquelme AJ, Calvo MA, Guzman AM, et al. Saccharomyces cerevisiae fungemia after Saccharomyces boulardii treatment in immunocompromised patients. J Clin Gastroenterol 2003; 36 (1): 41–43. 14. Alexander J, Limaye AP, Ko CW, Bronner MP, Kowdley KV. Association of hepatic iron overload with invasive fungal infection in liver transplant recipients. Liver Transpl 2006; 12 (12): 1799–1804. 15. Morrison VA, Haake RJ, Weisdorf DJ. The spectrum of nonCandida fungal infections following bone marrow transplantation. Medicine (Baltimore) 1993; 72 (2): 78–89. 16. Cairoli R, Marenco P, Perego R, de Cataldo F. Saccharomyces cerevisiae fungemia with granulomas in the bone marrow in a patient undergoing BMT. Bone Marrow Transplant 1995; 15 (5): 785–786. 17. Sparrelid E, Hagglund H, Remberger M, et al. Bacteraemia during the aplastic phase after allogeneic bone marrow transplantation is associated with early death from invasive fungal infection. Bone Marrow Transplant 1998; 22 (8): 795–800. 18. Olver WJ, James SA, Lennard A, et al. Nosocomial transmission of Saccharomyces cerevisiae in bone marrow transplant patients. J Hosp Infect 2002; 52 (4): 268–272. 19. Williams JS, Mufti GJ, Powell S, Salisbury JR, Higgins EM. Saccharomyces cerevisiae emboli in an immunocompromised patient with relapsed acute myeloid leukaemia. Clin Exp Dermatol 2007; 32 (4): 395–397. 20. Roetzer A, Gabaldon T, Schuller C. From Saccharomyces cerevisiae to Candida glabrata in a few easy steps: important adaptations for an opportunistic pathogen. FEMS Microbiol Lett 2011; 314 (1): 1–9. 21. Neiman AM. Ascospore formation in the yeast Saccharomyces cerevisiae. Microbiol Mol Biol Rev 2005; 69 (4): 565–584. 22. Odabasi Z, Paetznick VL, Rodriguez JR, et al. Differences in betaglucan levels in culture supernatants of a variety of fungi. Med Mycol 2006; 44 (3): 267–272. 23. Yoshida M, Obayashi T, Iwama A, et al. Detection of plasma (1 –> 3)-beta-D-glucan in patients with Fusarium, Trichosporon, Saccharomyces and Acremonium fungaemias. J Med Vet Mycol 1997; 35 (5): 371–374. 24. Enache-Angoulvant A, Hennequin C. Invasive Saccharomyces infection: a comprehensive review. Clin Infect Dis 2005; 41 (11): 1559–1568. 25. Morace G, Polonelli L; GISIA Group. Voriconazole activity against clinical yeast isolates: a multicentre Italian study. Int J Antimicrob Agents 2005; 26 (3): 247–253. 26. Barchiesi F, Arzeni D, Fothergill AW, et al. In vitro activities of the new antifungal triazole SCH 56592 against common and
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emerging yeast pathogens. Antimicrob Agents Chemother 2000; 44 (1): 226–229. 27. Clinical and Laboratory Standards Institute. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts. (3rd edn.) Approved standard M27-A3 edn. Wayne, PA: Clinical and Laboratory Standards Institute, 2008. 28. Clinical and Laboratory Standards Institute. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; 4th informational supplement. CLSI document M27-S4. edn. Wayne, PA: Clinical and Laboratory Standards Institute, 2012. 29. Pfaller MA, Diekema DJ, Gibbs DL, et al. Results from the ARTEMIS DISK Global Antifungal Surveillance Study, 1997 to 2007: 10.5-year analysis of susceptibilities of noncandidal yeast species to fluconazole and voriconazole determined by CLSI standardized disk diffusion testing. J Clin Microbiol 2009; 47 (1): 117–123.
30. Salonen JH, Richardson MD, Gallacher K, et al. Fungal colonization of haematological patients receiving cytotoxic chemotherapy: emergence of azole-resistant Saccharomyces cerevisiae. J Hosp Infect 2000; 45 (4): 293–301. 31. Olver WJ, Galloway A, Boswell TC, Russell NH. Sensitivity of S. cerevisiae in haematology patients. J Hosp Infect 2001; 47 (1): 75. 32. Deresinski SC, Stevens DA. Caspofungin. Clin Infect Dis 2003; 36 (11): 1445–1457. 33. Lolis N, Veldekis D, Moraitou H, et al. Saccharomyces boulardii fungaemia in an intensive care unit patient treated with caspofungin. Crit Care 2008; 12 (2): 414. 34. Girmenia C, Iori AP. Safety and interactions of new antifungals in stem cell transplant recipients. Expert Opin Drug Saf 2012; 11 (5): 803–818.
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Case report
Invasive Saccharomyces cerevisiae in a liver transplant patient: case report and review of infection in transplant recipients K.Y. Popiel, P. Wong, M.J. Lee, M. Langelier, D.C. Sheppard, D.C. Vinh. Invasive Saccharomyces cerevisiae in a liver transplant patient: case report and review of infection in transplant recipients. Transpl Infect Dis 2015: 17: 435–441. All rights reserved Abstract: Saccharomyces cerevisiae, an ascosporogenous yeast commonly used in the production of food, is an emerging infection in immunocompromised patients. We report the case of a 60-year-old man whose orthotopic liver transplant was complicated by S. cerevisiae fungemia and peritoneal abscess, successfully treated with caspofungin and drainage. We also review the literature of invasive saccharomycoses in recipients of hematologic and solid organ transplants.
K.Y. Popiel1, P. Wong2, M.J. Lee3, M. Langelier4, D.C. Sheppard3, D.C. Vinh4 1
Division of Infectious Diseases, McGill University Health Centre, Montreal, Quebec, Canada, 2Division of Gastroenterology and Hepatology, McGill University, Montreal, Quebec, Canada, 3Departments of Medicine, Microbiology and Immunology, McGill University, Montreal, Quebec, Canada, 4Division of Infectious Diseases (Infectious Disease Susceptibility Program), McGill University Health Centre, Montreal, Quebec, Canada Key words: Saccharomyces cerevisiae; yeast; fungemia; transplant; BMT; SOT Correspondence to: Dr Donald C. Vinh, McGill University Health Centre – Montreal General Hospital, 1650 Cedar Ave, Rm A5-156, Montreal, QC, H3G 1A4 Canada Tel: +514-934-1934 x42811 Fax: +514-934-8423 E-mail: [email protected]
Received 5 October 2014, revised 28 January 2015, accepted for publication 1 March 2015 DOI: 10.1111/tid.12384 Transpl Infect Dis 2015: 17: 435–441
Infections caused by non-Candida yeasts in solid organ transplant recipients are emerging. This report describes the first case of an orthotopic liver transplant (OLT) recipient with Saccharomyces cerevisiae peritoneal abscess and fungemia who was successfully treated with caspofungin.
Case report A 60-year-old man was admitted for biliary exploration. He had undergone OLT in another province 9 years prior for hepatitis C-related cirrhosis. Subsequently, he developed repeated episodes of cholangitis because of recurrent biliary obstruction, despite the insertion of
several biliary stents. On admission to our hospital, his maintenance immunosuppression included tacrolimus 1 mg twice a day, mycophenolate mofetil 500 mg twice a day, and prednisone 5 mg daily. On surgical exploration of the biliary system, he was found to have significant adhesions precluding accurate isolation and access of anatomical structures. The patient underwent a hepatojejunostomy and enteroenterostomy. Because of the abnormal amount of scar tissue, an injury to the hepatic artery occurred; surgical repair was attempted. However, over the ensuing days, ongoing hepatic ischemia was evident biochemically and radiologically, and efforts for endovascular repair were not successful. The patient therefore underwent another OLT, performed 3 days after biliary
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exploration. Perioperatively, he received antimicrobial prophylaxis with ampicillin, ceftriaxone, and nystatin; no systemic antifungal was administered. Immunosuppression consisted of anti-thymocyte globulin, methylprednisolone, tacrolimus, and mycophenolate mofetil. Intra-operatively, he received 12 units of packed red blood cells and 4 units of platelets. The night before OLT, the patient noted subjective fever and mild chills, for which blood cultures were obtained. On day 3 after OLT, a yeast was isolated from those blood cultures; the patient was started on fluconazole. Repeat blood cultures confirmed the presence of the same yeast, which ultimately was proved to be S. cerevisiae. Postoperatively, he also developed catheter-related bacteremia with Enterobacter aerogenes; culture of catheter tips did not demonstrate yeast. One week after fluconazole was started, fever recurred. Imaging revealed a fluid collection with some fat stranding near the porta hepatis. Cultures of peritoneal fluid from the surgical drain left in place yielded S. cerevisiae. The isolate was sent for antifungal susceptibility testing at the provincial reference laboratory. Meanwhile, antifungal treatment was changed to caspofungin. With caspofungin and ongoing drainage, the patient defervesced with clearance of fungemia. Given that the fungal infection broke through on fluconazole, caspofungin was continued pending antifungal susceptibility testing results; the patient completed 4 weeks with no evidence of further dissemination and eventual radiologic resolution of the abscess. On review of his diet, the patient denied consuming any probiotic capsules, wine, beer, kefir, or significant amount of bread or yogurt. In culture, the isolated yeast demonstrated creamcolored, smooth, moist colonies (Fig. 1). Identification was performed using API 20C Aux Clinical Yeast System (bioM erieux, Marcy L’Etoile, France), producing code 2040073 (99% identification) and the presence of ascospores on sodium acetate plate. Identification was confirmed by the provincial reference laboratory, and antifungal susceptibility testing by broth microdilution method revealed the following: amphotericin B 1 mg/L; 5-fluorocytosine ≤0.06 mg/L; fluconazole: 0.5 mg/L; itraconazole: 0.25 mg/L; voriconazole: 0.03 mg/L; caspofungin: 0.5 mg/L; micafungin: 0.25 mg/L; and anidulafungin: 0.25 mg/L.
Discussion The genus Saccharomyces comprises ascomycetous yeasts that are commonly employed in the food industry. S. cerevisiae is the most recognized because
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Fig. 1. Saccharomyces cerevisiae growing on Sabouraud’s dextrose agar (with black background), demonstrating creamy-white colored, glabrous colonies.
of its use in the production of bread and of beer or wine, hence the common term “baker’s” or “brewer’s” yeast, respectively. In the clinical microbiology laboratory, S. cerevisiae may also be isolated from human samples, as colonization of the respiratory, gastrointestinal (GI), or genitourinary tracts have been reported (1). Colonization appears to be increased in the setting of chronic underlying disease, although it currently remains unclear if the yeast establishes itself as a commensal member of mucosal flora, or whether it is present only transiently following exposure (e.g., ingestion). Saccharomyces boulardii, an isolate often used in probiotic preparations to alleviate various GI diseases, is currently classified as a cluster of strains assigned to the S. cerevisiae species (2, 3). Other species/complexes within this genus (e.g., Saccharomyces bayanus, Saccharomyces pastorianus) are important industrial organisms whose taxons are being refined (4), but for whom no published reports of human infection were identified. Invasive disease caused by S. cerevisiae is thought to occur via 2 main routes: translocation from the GI lumen, or breaches in the skin barrier, primarily within the context of vascular access devices. Evidence for GI-derived saccharomycosis derives primarily from clinical reports of infection following consumption of the yeast, in significant doses (e.g., 107–1010 yeast cells/day), from foods or probiotics used for treatment/prophylaxis of diarrheal disease, in both immunocompetent as well as immunosuppressed patients. Invasive S. cerevisiae disease also has been reported after abdominal surgery, in the absence of known
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intentional consumption (5, 6), likely reflecting its occasional role as colonizer. Elegant experiments by Perez-Torrado et al. have clarified this pathogenic mechanism further (7). They demonstrate, in an in vitro epithelial barrier model, that S. cerevisiae possesses a low ability for epithelial adherence, as well as poor capacity to induce epithelial cytotoxicity or to disrupt intestinal barrier integrity. Thus, it appears that S. cerevisiae has inherently low pathogenicity, requiring gross (e.g., surgical transection; diverticular disease) (8) or microscopic (e.g., enteritis) dysfunction of the intestinal barrier, coinciding with large enteral fungal burden, to cause systemic infection. In this patient, disruption of intestinal barrier integrity followed by induction immunosuppression likely account for development of this infection. Similarly, epithelial disruption accounts for vascular catheter-associated S. cerevisiae fungemia. The latter has occurred as sporadic cases (9, 10), as well as local outbreaks with molecular evidence for nosocomial transmission (11, 12), highlighting the need for proper infection control handling of probiotics in such patients. Invasive saccharomycosis specifically occurring in recipients of hematologic or solid organ transplants is summarized in Table 1 (13–19). Although some cases lack sufficient clinical details, the reported onset of fungal disease following bone marrow transplant ranged from day +43 to day +180; 1 case reported fungemia 8 months after transplantation, but in the context of palliative chemotherapy. On the other hand, only 2 other cases in solid organ transplant were identified: 1 occurring 3 years after simultaneous kidney-pancreas transplantation in a patient receiving probiotics for Clostridium difficile-associated diarrhea (13), and 1 with fungal peritonitis complicating liver transplantation (14), similar to our patient. As most of the reports do not comment on consumption of products that harbor S. cerevisiae, it is unclear what role this feature of the medical history plays in assessing risk for fungal disease. The fact that our patient denied any such consumption illustrates that it is not a prerequisite for considering S. cerevisiae in the differential diagnosis of yeasts isolated from transplant recipients. Laboratory identification of S. cerevisiae is relatively straightforward. Colonies grow rapidly on Sabouraud’s dextrose agar, producing white-cream, smooth, moist colonies, as in this case (Fig. 1). Growth is inhibited on cycloheximide-containing medium. The yeast cells are round to oval, measuring 4–8 by 5–10 lm, slightly larger than Candida glabrata, to which it is closely related phylogenetically (20). S. cerevisiae produces blastoconidia, but no anneloconidia, arthroconidia, or
chlamydoconidia. It does not produce hyphae (i.e., the test for germ tube – the parallel-sided, non-pinched-off hyphal bud – is negative). S. cerevisiae does not typically produce pseudohyphae under routine conditions of the diagnostic microbiology laboratory, although they can grow in pseudohyphal form under conditions of nitrogen starvation, which triggers mitotic growth (21). No capsule or urease activity is apparent microscopically. In culture, Saccharomyces species produce b-D-glucan (22) and at least theoretically can be a cause for positivity of this surrogate marker of invasive fungal disease; 1 such case has been reported (23), although no clinical studies have evaluated the diagnostic performance of this marker in this infection. The serum b-D-glucan test was not performed in our patient, because the test is not available in our center. S. cerevisiae is able to ferment various carbohydrates (e.g., glucose, maltose, sucrose) and assimilate raffinose, but is unable to utilize nitrate. A characteristic feature of S. cerevisiae is the capacity to sporulate, forming ascospores, when cultured on nutrient-depleted agar (e.g., acetate agar). In this assay, the absence of nitrogen, along with the presence of a nonfermentable carbon source (i.e., acetate), induces the formation of ascospores, in which 1–4 spores are contained within an ascus; the ascospore can be visualized by differential staining (e.g., Gram stain; Kinyoun stain). Antifungal susceptibility testing of S. cerevisiae can be performed by broth micro- and macro-dilution methods, which provide minimal inhibitory concentration (MIC) relative to different antifungal agents, as well as by disk diffusion, which assesses susceptibility by diameter zone size inhibition around an antifungalimpregnated disk. Studies using broth microdilution, summarized in an analysis by Enache-Angoulvant and Hennequin (24), reveal relatively low in vitro susceptibility to amphotericin B (MIC50: 0.25–1 lg/mL; median MIC50: 0.75 lg/mL), with wider in vitro susceptibility results to fluconazole (MIC50: 0.5–64 lg/mL; median MIC50: 2 lg/mL) and to itraconazole (MIC50: 0.063– 64 lg/mL; median MIC50: 0.5 lg/mL). Studies on a large number (i.e., >10) of non-superficial clinical S. cerevisiae isolates reveal greater in vitro susceptibility to voriconazole (MIC50: ≤0.008 to 8; median MIC50: 0.125 lg/mL) (25) and to posaconazole (MIC50: 0.015 to >4 lg/mL; median MIC50: 0.325 lg/mL) (26). As no standardized interpretive criteria to determine susceptibility have been established for Saccharomyces species, breakpoints adopted for Candida species have previously guided interpretation. However, earlier Clinical and Laboratory Standards Institute clinical breakpoints for fluconazole and voriconazole were directed to all Candida species (i.e., for fluconazole: susceptible:
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437
438
Age in years Gender
Transplant Infectious Disease 2015: 17: 435–441 Allo-BMT (MUD) for CML
1 case, NS
24F
29F (possible)
27M
4 (17)
5 (18)
7 (13)
42F
Solid organ transplant
51F
Allo-BMT (MUD) for CML
48F
3 (16)
6 (19)
Allo-BMT (MUD) for CML
36M
2 (15)
Kidney-Pancreas
Allo-BMT for relapsed AML, followed by AML relapse 8 months later and started on clofarabine
BMT
Allo-BMT (MRD) for CML
Allo-BMT for acute leukemia
30F
Allo-BMT for CML
Type of transplant
1 (15)
Hematological transplant
Patient no. (reference)
Blood
Blood
Sputum, throat and rectal swabs
Pre-mortem: throat swab, BAL
Pre-mortem: sputum, feces, vulval swab. Post-mortem: lymph node
Blood and on autopsy
Blood (peripheral and Hickman catheter)
Lung
Blood
Sites of isolation
Characteristics of transplant patients with invasive Saccharomyces cerevisiae infection
Liposomal amphotericin and 5-flucytosine
Day +62
3 years
Fluconazole 400 mg daily 9 21 days
Amphotericin B and voriconazole
Liposomal amphotericin
Day +79
8 months
NS Liposomal amphotericin
NS
Fluconazole 150 mg po daily 9 54 days
Day +180
Day +43
NS
NS
Treatment
NS
NS
Onset of infection relative to transplant
Survived
Palliative support for relapsing AML
Survived
Death
Death
Death
Survival
Survival
Survival
Outcome
Fungemia developed following administration of Saccharomyces boulardii for Clostridium difficile infection (on day 7 of S. boulardii treatment)
Histopathology of skin lesions revealed fungal emboli
On prophylactic fluconazole (50 mg once daily)
On prophylactic fluconazole (50 mg once daily). Autopsy revealed no histopathological or microbiological evidence of any infection
On prophylactic fluconazole (50 mg once daily). Autopsy revealed PTLD, as well as lymphadenitis with Saccharomyces
BMT was non-T-depleted. Conditioning: Cyclophosphomide 120 mg/kg + fractionated total body irradiation. GVHD prophylaxis: CsA and MTX
Comment
Popiel et al: Saccharomycosis in transplant patients
Table 1
F, female; Allo-BMT, allogeneic bone marrow transplant; CML, chronic myeloid leukemia; NS, not specified; M, male; MRD, matched-related donor; po, by mouth; GVHD, graft-versus-host disease; CsA, cyclosporine; MTX, methotrexate; MUD, matched-unrelated donor; PTLD, post-transplant lymphoproliferative disorder; BAL, bronchoalveolar lavage; MMF, mycophenolate mofetil; AML, acute myeloid leukemia; OKT3, muromonab-CD3; ATG, anti-thymocyte globulin.
ATG, methylprednisolone, tacrolimus, MMF Survival Fluconazole (400 mg daily) with isolation of yeast, changed to caspofungin when yeast identified Blood (Day 0); Peritoneal fluid (Day +7) Blood and peritoneal abscess fluid 60M Present case
Liver (ischemic injury to first liver transplant for hepatitis C)
OKT3, CsA, Prednisone, Azathioprine. Nysatatin prophylaxis NS NS Day +67 NS 8 (14)
Liver (indication NS)
Peritoneal fluid
Treatment Patient no. (reference)
Table 1 Continued
Age in years Gender
Type of transplant
Sites of isolation
Onset of infection relative to transplant
Outcome
Comment
Popiel et al: Saccharomycosis in transplant patients
≤8 lg/mL; susceptible dose-dependent: 16–32 lg/mL; resistant: ≥64 lg/mL; and for voriconazole: susceptible: ≤1 lg/mL; susceptible dose-dependent: 2 lg/mL; resistant: ≥4 lg/mL) (27). Since 2012, species-specific clinical breakpoints for fluconazole and voriconazole have been developed that are considerably different (28). Their relevance to interpretation of S. cerevisiae susceptibility remains to be determined. This limitation also applies to extrapolation of susceptibility interpretation in previously published results using the disk diffusion method (29). Despite the absence of interpretive criteria, it appears that S. cerevisiae may demonstrate a wide MIC range to fluconazole. In what was deemed to be a nosocomial outbreak in a hematology unit, Salonen et al. (30) reported fluconazole MICs ranging from 1 to 128 lg/ mL; as these rates were considerably high, the authors speculate that antifungal selective pressure from extensive use of fluconazole in their patients may have accounted for this resistance pattern, possibly along with clonal dissemination via the hands of healthcare workers. However, Olver et al. (31) did not observe a similar effect among a cluster of S. cerevisiae clinical isolates from their hematology unit, despite affected patients receiving fluconazole prophylaxis; their fluconazole MICs ranged from 2 to 4 lg/mL. As these 2 reports were from different countries, it is likely that that regional epidemiologic variability exists in susceptibility patterns for S. cerevisiae; this is supported by the ARTEMIS DISK study (29), in which disk diffusion method and interpretive criteria for Candida species demonstrated rates of resistance to fluconazole ranging from 0% (in Africa/Middle East) to 24.1% (in Latin America). Given the potential for relative in vitro resistance to fluconazole and to amphotericin B, the identification of S. cerevisiae in our patient prompted an empiric change to caspofungin pending final susceptibility results. As 30–60% of the fungal cell wall of Saccharomyces species is composed of glucan in the form of b-1,3-glucan with b-1,6 linkages (32), the echinocandins, which function to inhibit b-1,3-D-glucan synthase, are a reasonable antifungal agent for this yeast. Only 1 other case in which an echinocandin has been used to successfully treat Saccharomyces fungemia has been reported (33); that patient was admitted with pneumonia and septic shock and developed fungemia following initiation of probiotics for diarrhea. No report of echinocandin use for saccharomycosis in transplant recipients was identified. However, given that the echinocandins, unlike the azoles, demonstrate few interactions with drugs such as transplant-related immunosuppressants (34), this antifungal selection may be an appropriate option for empiric therapy for
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Saccharomyces species in transplant recipients, pending susceptibility results. Additional measures, such as catheter removal in the case of line-related bloodstream infection or drainage of abscess (as in this case), are also necessary to eradicate infection.
Conclusion S. cerevisiae may cause invasive disease in transplant recipients, even in the absence of obvious ingestion. Infection occurs most commonly via breach of the GI barrier or by vascular catheters. Antifungal susceptibility testing by broth microdilution provides MIC results that may guide therapy. Limited evidence suggests echinocandins may be a therapeutic alternative, although further confirmatory evidence is required.
Acknowledgements: Author contributions: K.P.: Data acquisition, drafting article, and approval of article. P.W.: Data acquisition/ interpretation, critical revision of article, and approval of article. M.L.: Patient management and data acquisition. M.J.L.: Data acquisition and figure production. D.C.S.: Data analysis/interpretation, critical revision of article, and approval of article. D.C.V.: Concept/design; data analysis/interpretation, drafting article, critical revision of article, and approval of article.
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