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Healthcare-associated fungal infections: beyond Candida and Aspergillus.

Healthcare-associated invasive fungal infections are an important cause of morbidity and mortality in the United States. (1,2) Candida and Aspergillus cause most healthcare-associated fungal infections, and are associated with crude mortality rates of 40 to 61% (for invasive candidiasis (3,4)) and 40 to 88% (for invasive aspergillosis (5)). Increasingly immunocompromised patient populations, more frequent use of medical devices, and excessive use of antimicrobial agents has now led to the emergence of an increasing array of less common fungal pathogens. (6)

Neofytos et al report a case of infection with one these rare pathogens, Rhodotorula mucilaginosa. (7) Species of Rhodotorula most often isolated from humans include Rhodotorula mucilaginosa, R glutinis, and R minuta. Yeast members of the family Cryptococcaceae, Rhodotorula spp. have been increasingly reported to cause human disease. (8) Immunocompromised patients, especially those with central venous catheters and other indwelling devices, are at highest risk for infection. While Rhodotorula appear to be less virulent than the more common yeast pathogens such as Candida and Cryptococcus neoformans, Rhodotorula infections have been described to cause sepsis syndrome and other significant complications. (8-10) In addition, Rhodotorula are almost uniformly resistant in vitro to two of the most commonly used systemic antifungal agents, fluconazole and caspofungin. (11)

The case reported by Neofytos et al illustrates several challenges associated with the emergence of previously rare fungal pathogens. The first challenge relates to accurate diagnosis. Many clinical laboratories have only recently begun to provide species-level identification of Candida and Aspergillus isolates. The accurate identification of the stunning array of rare and emerging fungi pose an even greater challenge to the microbiologist. Every hospital providing care for immunocompromised patients should either have the ability to identify fungal organisms to the genus (and sometimes, species) level or should have a close relationship with a referral clinical mycology laboratory that can do so. For Rhodotorula, fortunately, the identification is made easier by virtue of the carotenoid pigments they produce, leading to the characteristic color of Rhodotorula colonies (salmon pink to coral red), and by their urease positivity. (12)

A second challenge posed by emerging fungi relates to the determination of their pathogenic roles. As the spectrum of fungal pathogens expands in an ever more immunocompromised patient population, fungi that were traditionally felt to be of low or no pathogenic potential are increasingly isolated in clinical cultures. (6) We should now recognize that almost any fungus can cause disease in a sufficiently immunocompromised host, making it unwise to dismiss the isolation of an unusual fungus as a contaminant. In the patient described by Neofytos et al, the organism appears to have been relatively avirulent, producing little by way of signs or symptoms of infection. Nonetheless, the repeated isolation of the organism from a normally sterile site (bloodstream) clearly established it as a pathogen, and case reports of Rhodotorula spp. causing clinical disease such as ocular infection, peritonitis, and meningitis provide reason enough to institute therapy.

A third challenge posed by emerging fungal pathogens is uncertainty regarding therapeutic options. Unlike Candida and Aspergillus, for which treatment guidelines are available and can be based upon randomized clinical trials data, little or no data exists to guide the therapy of less common fungi. In these circumstances, one must rely upon the combination of case reports, expert opinion, and any existing in vitro susceptibility data from surveillance programs. As reviewed by Neofytos et al, the available data for Rhodotorula infections suggests that the combination of device removal and amphotericin B is the most conservative therapeutic approach, with the possible addition of flucytosine (5FC) to amphotericin B for severe or refractory disease. While it is true that some Rhodotorula spp., including the isolate causing infection in this case, may have low minimum inhibitory concentrations (MICs) to voriconazole or posaconazole, other Rhodotorula may demonstrate high MICs, (11) and insufficient data are available to document efficacy or to suggest whether in vivo emergence of cross resistance is likely to occur among these inherently fluconazole-resistant organisms. Had this patient not been lost to follow-up, it would have been interesting to examine the in vitro susceptibility of any recrudescent Rhodotorula isolated after prolonged exposure to voriconazole.

Finally, this case should remind us of the importance of device removal when fungal infections involve devices. Had the patient allowed it, removal of the infected catheter would have greatly increased the likelihood of clearing the infection. In the absence of follow-up, it is not possible to determine whether failure to clear the organism was due to inadequate antifungal therapy, or to an inability to remove the infected device, or both.

In summary, Rhodotorula spp. are one among several opportunistic yeast-like fungi emerging as causes of infection in immunocompromised hosts (others include Saccharomyces cerevisiae, Trichosporon spp., and Geotrichum capitatum [Blastoschizomyces capitatus]). Given that Rhodotorula spp. are resistant to the two agents most commonly used to treat invasive candidiasis (fluconazole and caspofungin), it is important to recognize these infections so that appropriate therapy can be instituted. The increasing diversity of fungal pathogens will continue to pose considerable diagnostic and therapeutic challenges.

References

1. McNeil MM, Nash SL, Hajjeh RA, et al. Trends in mortality due to invasive mycotic diseases in the United States, 1980-1997. Clin Infect Dis 2001;33:641-647.

2. Pfaller MA, Diekema DJ. The epidemiology of invasive candidiasis: A persistent public health problem. Clin Microbiol Rev 2006. In press.

3. Edmond MB, Wallace SE, McClish DK, et al. Nosocomial bloodstream infections in United States hospitals: a three-year analysis. Clin Infect Dis 1999;29:239-244.

4. Gudlaugsson O, Gillespie S, Lee K, et al. Attributable mortality of nosocomial candidemia, revisited. Clin Infect Dis 2003;37:1172-1177.

5. Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis 2001;32:358-366.

6. Pfaller MA, Diekema DJ. Rare and emerging opportunistic fungal pathogens: concern for resistance beyond Candida albicans and Aspergillus fumigatus. J Clin Microbiol 2004;42:4419-4431.

7. Neofytos D, Horn D, DeSimone JA. Rhodotorula mucilaginosa catheter-related fungemia in a patient with sickle cell disease: Case presentation and literature review. South Med J 2007;100:198-200.

8. Hazen KC. New and emerging yeast pathogens. Clin Microbiol Rev 1995;8:462-78.

9. Krcmery Krupova I, Denning DW. Invasive yeast infections other than Candida spp. in acute leukaemia. J Hosp Infect 1999;41:181-194.

10. Kiehn TE, Gorey E, Brown AE, et al. Sepsis due to Rhodotorula related to use of indwelling central venous catheters. Clin Infect Dis 1992;14:841-846.

11. Diekema DJ, Petroelje B, Messer SA, et al. Activities of available and investigational antifungal agents against rhodotorula species. J Clin Microbiol 2005;43:476-478.

12. Hazen KC, Howell SA. Candida, Cryptococcus, and other yeasts of medical importance. In Murray PR, Baron EJ, Jorgensen JH, Pfaller MA, Yolken RH (ed). Manual of Clinical Microbiology, 8th ed. Washington, DC, ASM Press.
I You gain strength, courage, and confidence by every experience in
which you really stop to look fear in the face ... You must do the thing
you cannot do.
--Eleanor Roosevelt


Daniel J. Diekema, MD, FACP

From the Departments of Internal Medicine and Pathology, University of Iowa Carver College of Medicine, Iowa City, IA.

Reprint requests to Daniel J. Diekema, MD, FACP, Clinical Associate Professor, Departments of Internal Medicine and Pathology, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242. Email: daniel-diekema@uiowa.edu

Accepted October 17, 2006.
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Author:Diekema, Daniel J.
Publication:Southern Medical Journal
Article Type:Editorial
Geographic Code:1USA
Date:Feb 1, 2007
Words:1227
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