Probiotics such as Lactobacillus GG, Bifidobacterium spp., and Saccharomyces boulardii have been shown to be useful in treating a variety of diarrheal disorders, including rotavirus infection, antibiotic-associated diarrhea, Clostridium difficile–associated diarrhea, and traveler's diarrhea. 1–4 The use of these agents has traditionally been regarded as safe, and reports of complications are rare. 5–7 We report two cases of S. cerevisiae fungemia related to the use of S. boulardii as treatment of antibiotic-associated diarrhea.
A 42-year-old woman with end-stage renal disease secondary to diabetes mellitus type I underwent kidney–pancreas transplantation in 1997. She subsequently received standard immunosuppressive therapy with cyclosporine (Neoral; Novartis Pharmaceuticals, East Hanover, NJ, 150 mg/d orally), mycophenolate mofetil (Cellcept; Roche Laboratories, Nutley, NJ, 1 g/d orally), and prednisone (5 mg/d orally). In September 2000, she was admitted with a soft tissue infection of her right foot and was treated with parenteral ciprofloxacin and metronidazole. After 4 days of antibiotics, she developed significant diarrhea (400 cc/24 hours) and metronidazole was switched to an oral route after a positive toxin A assay for C. difficile. After 10 days without clinical response, S. boulardii (Perenteryl; Merck, Ñuñoa-Santiago, Chile) 250 mg four times daily orally for 7 days was added to the treatment, with good clinical response. On day 20 of hospitalization, she developed a fever. S. cerevisiae grew out from two simultaneous blood cultures after 5 days of incubation. Fluconazole was then given at dosage of 400 mg/d intravenously for 8 days and was followed by 13 days of oral treatment, with excellent clinical response. She was discharged on day 51 with follow-up in our outpatient infectious disease clinic.
A 41-year-old man with a history of 3 weeks of progressive tetraparesis and confusion was admitted with a diagnosis of meningoencephalomyelitis secondary to Treponema pallidum and Mycobacterium tuberculosis (Venereal Disease Research Laboratory–positive 1:4, cerebrospinal fluid–positive for M. tuberculosis by polymerase chain reaction [PCR]). The patient was newly diagnosed with HIV, with a CD4 count of 14 cells/mm3. Simultaneously, treatment was begun for syphilis (penicillin G intravenously), M. tuberculosis (isoniazid, rifampin and ethambutol for 6 months), and HIV (zidovudine, lamivudine, and efavirenz).
The patient then developed diarrhea (500 cc/24 hours) with a negative C. difficile toxin A assay. After 15 days of persistent diarrhea, he received treatment with S. boulardii (Perenteryl) 250 mg three times daily for 20 days, with a significant clinical response. Fifteen days after probiotic treatment was discontinued, the patient developed a fever. S. cerevisiae grew out from two simultaneous blood cultures. Empiric treatment with amphotericin B had been started and was continued for a total dose of 1,100 mg. He is currently seen in the outpatient infectious disease clinic. After 6 months of antiretroviral treatment, his HIV viral load was undetectable and his CD4 count was 255 cells/mm3.
To further characterize the described clinical cases, we performed cultures of capsules containing 250 mg of lyophilized S. boulardii (Perenteryl, 250-mg equivalent to 5 × 1,085 × 1010 live cells). S. cerevisiae was isolated after 5 days of incubation. In pulsed-field gel electrophoresis assays, samples isolated from patients and strains obtained from a Perenteryl capsule showed identical electrophoretic patterns using Not I restriction enzyme, which were different from the banding pattern resulting from the digestion of a control strain (Fig. 1).
S. boulardii has been used in the treatment of antibiotic-associated diarrhea and in the therapy of recurrent C. difficile diarrhea. 2,4–6 This probiotic is administered orally in the form of capsules containing lyophilized S. boulardii and is considered a safe medication.
Recently, several reports of S. cerevisiae fungemia associated with the use of S. boulardii have been published. 8–16 A debate exists concerning the genotyping identity of S. cerevisiae and S. boulardii. Two published case reports and the two cases presented here showed identity between the strains isolated from blood cultures and the strains isolated from probiotic capsules using pulsed-field gel electrophoresis. 8,15 Although Mc Farland 17 has proposed that S. cerevisiae and S. boulardii are different microorganisms with taxonomic, metabolic, and molecular differences, McCullough et al. 18 showed that isolates of S. boulardii were not separable from authentic isolates of S. cerevisiae using restriction fragment-length polymorphisms (RFLPs) of the PCR-amplified intergenic transcribed spacer regions. Moreover, RFLP analysis of cellular DNA with EcoRI showed that all analyzed strains of S. boulardii had identical patterns and were similar to other authentic S. cerevisiae isolates tested. Thus, it can be stated that S. boulardii strains are asporogenous strains of the species S. cerevisiae and therefore are not representatives of a distinct and separate species. 18 This is also supported by a recent study using microsatellite typing as a new tool for identification of S. cerevisiae strains. 19 These observations also explain the isolation of S. cerevisiae after culture of capsules containing 250 mg of lyophilized S. boulardii.
S. cerevisiae fungemia was first reported in 1970 in a patient with a prosthetic mitral valve. 20 Since then, many other fungemia cases caused by this yeast have been reported. 8–16,21–29 Although S. cerevisiae is considered a safe and nonpathogenic biotherapeutic agent, several reports show that this fungus may indeed cause severe infections with a wide clinical spectrum, including unexplained fever, fungemia, endocarditis, pneumonia, liver abscess, peritonitis, and septic shock. Review of published cases indicates that populations at risk are mainly elderly or immunocompromised patients with very low risk for immunocompetent subjects. Only nine cases related to the oral administration of S. boulardii have been reported. 8–16 These cases are summarized in Table 1. As expected, most of the patients reported were immunosuppressed because of HIV infection, use of corticosteroids or immunosuppressive agents, neutropenia, bone marrow transplantation, and neonate state. 8–16 However, there are two reports of fungemia in critically ill patients with no previous severe immunosuppression. 11,12 The two patients reported here had severe immunosuppressive underlying disease, such as HIV infection in IIIC stage and kidney–pancreas transplantation.
Most cases of S. cerevisiae fungemia related to oral administration of S. boulardii have been treated with conventional therapy, such as amphotericin B or fluconazole. There have been no reported deaths caused by this condition. We treated one patient with amphotericin B and the other with fluconazole, both with successful outcomes.
S. boulardii and other probiotics are increasingly being used in routine clinical practice to treat diarrheal disorders. Complications seen in the two patients described here, along with previous reports (Table 1), indicate that caution is warranted in treating certain populations (e.g., HIV-infected and transplant patients, neonates, patients with malnutrition, and any other disease associated with a immunosuppressed state).
The authors thank Meredith Turetz, M.D., for her critical review of the manuscript.
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