Malassezia furfur

Authors: Gerard R. Barber, RPh, MPH, Kent Sepkowitz, M.D.

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History

Mycology

As a skin disease Pityriasis versicolor was described as early as 1846 (10). Malassez observed a diversity and variation of certain yeasts present on the skin for which the genus is named; M. furfur was the first species identified within the genus (4, 23). The genus Malassezia is comprised of lipophilic yeasts that reproduce by unipolar bud fission. M. furfur is a biphasic, lipophilic yeast forming hyphae as well as round or oval structures. Isolated from the skin with far less frequency than the yeast form, the mycelial form was thought to be the organism s only pathogenic form. The organism requires an exogenous source of lipids for growth due to the genus inability to synthesize long-chain (C12 to C24) fatty acids (46, 52). As a skin saphrophyte the yeast phases forming the globose/subglobose or oval cells were identified as P. orbiculare and P. ovale, respectively. These have since been unified to the species M. furfur, as it is now recognized that in vitro culture of the mycelial phase converts to the yeast phase ex vivo.

Epidemiology and Pathogenesis

Malassezia furfur is a common skin commensal. The skin of the human chest, back, and scalp are rich in fatty acids providing M. furfur the required source of exogenous lipids. A study of 11 healthy and 59 hospitalized neonates demonstrated skin colonization by M. furfur within the first 1 to 3 months of life. While the prevalence and densities at all skin sites tested were low in the first 10 days of life, with age sites such as the ear become progressively colonized reaching a prevalence of 100% by age >40 days. In addition, by this time, 80% of cultures yield moderate to heavy growth of the organism (20). M. furfur has also been isolated from the chest region in 92 of 100 subjects with clinically healthy skin (39).

An early, small study of M. furfur recovered from infants with catheter-related sepsis showed that the growth of the organism was supported when it was inoculated into 10% and 20% fat emulsions used for hyperalimentation (33). However, it appears fungemia is facilitated by skin colonization of the organism in a nutrient-rich environment (most typically, compromised patients receiving fat emulsion) and the portal of entry provided by central venous access devices. This has been demonstrated by at least one case of M. furfur fungemia occurring in a patient with a with a subcutaneous port requiring repeated needle punctures of the device as part of the therapeutic regimen. The patient was not receiving fat emulsion or other parenteral nutrition (5). Other risk factors usually associated with systemic infection are low-birth rate in neonates, antibacterial antibiotic use and interestingly, elevated triglyceride levels, even in those not receiving intravenous lipids (5, 36, 51, 53).

Clinical Manifestations

Malassezia furfur (formerly Pityrosporum orbiculare, P. ovale, P. furfur) is best known as the causative agent of the superficial skin infection tinea versicolor (39). M. furfur also may cause systemic fungal infection, usually in neonatal and adult patients with an indwelling central venous access device who are receiving parenteral lipid emulsion (3, 5, 9, 21, 32, 35, 36, 38, 44, 51). Less frequently, the organism has been found to cause systemic infection in the absence of lipid administration among immunocompromised infant and adult hosts (5, 28, 53).

Fungemia

The clinical signs of M. furfur fungemia are non-specific and can include fever, chills, leukocytosis, and thrombocytopenia. In neonates, apnea and bradycardia are also commonly reported. These signs of fungemia can be dif cult to distinguish from other diseases given the possibility of concomitant central venous access device infection, underlying disease states and subsequent directed therapies. There are few reports of M. furfur fungemia in which the organism was isolated from a peripheral line (42, 53). The absence of peripheral blood isolates of M. furfur may be due to rapid clearance by the reticuloendothelial system, or a filtering of the organism by the lungs (9).

Other Systemic Infection

Non-cutaneous infections include M. furfur peritonitis (13, 50), sinusitis (30), pulmonary vasculitis (35), intracardiac septic thrombus (41), meningoencephalitis (44), and a cluster of bronchopneumonia among 3 neonates (38).

Cutaneous

There is a spectrum of cutaneous M. furfur infections that can present as the superficial skin infection, tinea versicolor, to more complex dermatoses such as folliculitis and nonfollicular pustulosis (7,34). Thin white scales over hypo-or hyperpigmented skin lesions most often on the patient s trunk are indicative of tinea versicolor, the most frequent cutaneous manifestation of Malassezia infection.

The organism has been implicated as the most common source of dandruff, while other reports studying seborrheic dermatitis among immunocompromised hosts demonstrate a varied degree of association of the organism and other Malassezia spp. to infection. Case reports and case series of bone marrow transplant recipients describe Malassezia folliculitis that can mimic cutaneous Candida infection. Also presenting along the trunk and upper arms, the lesions progress from inflamed hair follicles to small erythematous and pruritic pustules (7, 27). An association between M. furfur and seborrheic dermatitis in patients with acquired immunodeficiency syndrome (AIDS) was reported in a small study examining the presence of the yeast in skin cultures and clinical disease (15). However, a larger study of 180 HIV-positive homosexual men could only weakly correlate the presentation of seborrheic dermatitis to M. furfur colonization (40).

Laboratory Diagnosis

Malassezia spp. are nonfermentive and urease positive. The yeast form assimilates dextrose but not other sugars. M. furfur, with its absolute requirement for long-chain fatty acids grows slowly, if at all, on routine microbiologic media and requires supplementation with a source of fatty acids, such as sterile olive oil, lanolin or Tween 80 (26). Growth on Sabouraud dextrose agar (SDA) without supplementation typically indicates the less fastidious, M. pachydermatis. Anaerobic growth is poor as are yields when grown at 25 °C. When cultures are plated and incubated at 34-37°C on a medium of SDA or Columbia sheep blood agar supplemented with olive oil, M. furfur grows within 2 to 4 days (26, 52). Macroscopically, colonies have a smooth, glistening, creamy appearance. Microscopically, compacted clusters of bottle-or bowling-pin shaped budding yeasts ranging from 2-4.5 µm with a collarette at one pole can be observed. The constriction between the mother and bud cell is not as demonstrable as in Candida spp. In culture, curved hyphae and pseudohyphae are typically absent, although they may be seen in clinical specimens.

In cases of systemic infection, central line blood cultures are the most common clinical source of the organism. When central venous access devices are removed, segments of the device rolled in agar using the Maki method have confirmed the association of the organism with the device (22). In one case M. furfur was cultured from a surgically-excised intracardiac septic thrombus (41). In other cases, a careful review of blood smears (14) and enhancement using buffy coat Gram’s stain (21) has yielded early identification of the organism later confirmed by culture.

As in many other cases of superficial skin infection, the laboratory diagnosis of tinea versicolor is accomplished with microscopy. Skin scrapings of affected areas can be examined using KOH or KOH-Calcofluor wet mounts (25). Stains for fungi such as periodic acid-Schiff (PAS), Grocott, and Gomori-silver methenamine have also been used for scrapings and punch biopsies (2). Simple methods using Scotch tape pressed to the skin and other contact methods to recover the organism have also been described (11, 40).

SUSCEPTIBILITY IN VITRO AND IN VIVO

Systemic Isolates

Reports of the susceptibility of M. furfur to antifungal antibiotics have appeared but are not plentiful. However, because susceptibility results are not standardized, no definitive conclusions can be drawn. Further complicating measurements of clinical response, non-antibiotic approaches including removing the central venous access device or halting intravenous fat administration have frequently resulted in resolution of the infection.

Clinicians therefore should exercise caution interpreting in vitro susceptibility data and rather make judgment based on clinical observation. Standardization of antifungal susceptibility testing by the National Committee for Clinical Laboratory Standards (NCCLS) may result in more frequent testing of this organism to an expanding armamentarium of antifungal agents, ideally with further correlation to clinical outcome. To date, however, the RPMI-1640 medium specified by the NCCLS lacks the requisite lipids to support growth of M. furfur yeast cells (49).

In vitro susceptibility data was given in one report of 15 systemic M. furfur isolates obtained from blood or catheter tip and 10 skin isolates (Table 1) (24). Another, older paper in which the MICs of a lone blood isolate obtained from a catheter reported MICs of 2.5 µg/mL and >100 µg/mL for amphotericin B and 5-flucytosine, respectively (8).

Thus it appears that, similar to many other yeasts, M. furfur is susceptible in vitro to both the polyene and azoles classes of antifungals. Presently, there is no information on the activity of the new echinocandin class of antifungals.

Cutaneous

More information is available regarding the activity of topical medications against M. furfur. Still, a lack of a standard methodology prohibits a thorough analysis of the results. The azoles and tri-azole compounds including ketoconazole, itraconazole, fluconazole, and voriconazole appear to exhibit repeatedly good activity against M. furfur at clinically achievable concentrations. Properties inherent of a particular agent may confer an advantage for one agent over the other and will be discussed below. In vitro, M. furfur seems to have more tolerance to the allyamine, terbinafine, exhibiting a wider variation in MIC 80 results (16, 29, 48).

ANTIMICROBIAL THERAPY

To date, amphotericin B remains the most widely utilized antifungal agent in treating M. furfur fungemia and other deep-seated M. furfur infection. In general, clinical outcome has been favorable in treating this opportunistic infection; however, there are no controlled trials of amphotericin B nor any other antifungal agent in the treatment of Malassezia furfur fungemia. More often than not, the presumed source or nidus for infection -an indwelling central venous access device is removed, complicating interpretation of the effectiveness of the antifungal. In addition, in concert with device removal, intravenous fat emulsion therapy is discontinued or suspended. Indeed, a number of cases of M. furfur fungemia have resolved without antifungal therapy when one or both of these last two variables are discontinued and the patient is carefully monitored (9, 27, 51).

Despite some success using non-antifungal measures, treatment of M. furfur fungemia in the immunocompromised host should routinely include intravenous antifungal therapy until the patient is stabilized and cultures have become negative. The decision regarding removal of the central venous access device depends on the patient s clinical condition, the immediate need for central intravenous access, and the long-term requirements to main intravenous access. Among neonates and cancer patients, the removal of a central venous access device and interruption of other therapies may result in substantial morbidity.

The optimal dose and duration of systemic therapy is uncertain. In a retrospective study describing 7 cases of fungemia among immunocompromised patients at a comprehensive cancer center, 5 cases were deemed "cured", defined as culture-negative with resolution of any clinical signs and symptoms. The range of follow-up was 13 to 48 months. All 7 cases had long-term venous access device placement prior to their first positive culture and only 2 patients (1 cured/1 expired) were receiving concurrent intravenous lipids. All received amphotericin B at 1mg/kg/day. Total doses ranged from 5.6mg/kg (336 total mg) to 29.5mg/kg (1,327 total mg). Among the 5 cured patients, only 1 (receiving a total of 12.8mg/kg of amphotericin B) had the device removed due to persistently positive central venous access device cultures yielding M. furfur as well as gram-negative bacteria. Two of 7 patients expired, presumably from gram-negative sepsis; both had subsequent central venous access device cultures negative for M. furfur. One patient had received lipids prior to the first positive M. furfur culture and had an elevated serum triglyceride level. Four days later, colony counts remained > 1,000 cfu/mL, although central venous access device cultures the fifth day were negative for M. furfur (5).

An earlier study describes two cases of M. furfur fungemia in 2 adult patients, both with underlying gastrointestinal disorders. Both patients had central venous access devices and were receiving intravenous lipids. Both retained their devices, although in the second case the original device could not be removed due to extensive venous thrombosis. The first case continued to receive lipids; amphotericin B was initiated only after the patient again appeared ill two weeks following positive blood cultures and a subsequent set of central venous access device blood cultures grew M. furfur. Amphotericin B was administered for 10 days (dose not disclosed) until the patient expired of cardiac arrest. Autopsy revealed squamous cell carcinoma in the lungs without evidence of pulmonary or coronary artery vasculitis or thromboemboli. The patient had maintained normal serum cholesterol and triglyceride levels throughout hospitalization. In the second patient, amphotericin B therapy was initiated upon persistence of M. furfurfrom central venous access device culture and a temperature of 40.6°C. Intravenous lipid therapy was discontinued. Over 4 weeks the patient received a total of 685mg amphotericin B. The following 8 weeks were marked with episodes of central venous access device-related bacteremias and pulmonary aspiration. In the 2 weeks preceding death, intravenous lipid therapy was again initiated, with M. furfur isolated from the central venous access device 4 days prior to the patient s demise (12).

In a cluster of Malassezia furfur pulmonary infections in 3 neonates, each weighing < 1000g, the organism was cultured postmortem from Broviac catheter blood and lung tissue of 2 neonates. Because of heightened awareness from the first neonate, amphotericin B was initiated in the third neonate prior to microbiological confirmation of the organism, which was later recovered in samples of Broviac catheter blood, urine and stool samples. Antifungal therapy had not been initiated in the 2 earlier cases and the dose and duration of amphotericin B for the third neonate was not specified. This infant survived; the study did employ case-control methodology, but the premise of the study was to elucidate risk factors for the illness and investigate this outbreak (38).

Although there are no firm studies to guide therapy, we recommend treating M. furfur -associated catheter infections like any other catheter-associated fungemia, including catheter removal when possible and discontinuation of intravenous lipid administration if they are being administered. This includes a 7-10 day course of systemic antifungal therapy from the time of catheter removal, first negative blood culture, resolution of clinical symptoms, or all of these. In unstable patients, or patients with evidence of end-organ infection, a substantially longer duration of therapy may be required.

Cutaneous

In common with systemic infection, suppression of cell-mediated immunity may support chronic or refractory cutaneous infection. Clinical observation and further consideration of nonimmunologic factors should influence the selection of topical and/or systemic agents and duration of treatment.

Selenium sulfide 2.5% lotion, ketoconazole 2% cream, and clotrimazole 1% in either cream or lotion formulations are most commonly employed. A series of 5 cases of folliculitis was noted among 5 patients undergoing recent (< 18 days) allogeneic bone marrow transplantation. Common to their presentation was a papular rash; all were diagnosed by skin biopsy and were receiving total parenteral nutrition and broad-spectrum antibacterial antibiotics. All 5 patients were febrile and granulocytopenic (granulocyte count <500cells/mm3). Each of the patients responded slowly to topical clotrimazole therapy (frequency and formulation undefined) with one patient receiving oral ketoconazole after 17 days of topical therapy until a second skin biopsy, 2 days later, showed evidence of graft-versus-host disease without M. furfurorganisms. An impression among all cases was that clinical improvement was either slow or occurred only after granulocyte recovery to > 500cells/mm3. With granulocyte recovery, the investigators noted no relapse of folliculitis following cessation of antifungal therapy, nor primary Malassezia infection in bone marrow transplant recipients having recovered granulocyte counts (7).

In another series of Malassezia folliculitis among 11 orthotopic heart transplant recipients, the time to onset of folliculitis from transplant ranged from 2 weeks to 21 months (mean 5.4 mo; median 2.5 mo). Neutrophil count was not specified, however, all 11 cases were receiving cyclosporine. Six cases were deemed to have responded favorably to topical application of a combination of selenium sulfide lotion and clotrimazole lotion twice daily for 1 month. Two of these cases were identified as M. furfur; 2 cases as M. pachydermatis; and 2 cases were not identified by species. Of 5 cases considered failing the topical regimen, oral fluconazole 100 mg daily for 3-4 weeks was used to successfully treat 3 patients and another patient received 200mg/ day orally for 1 week with successful outcome. Three of these 4 cases had no relapse within a 1-year follow-up period. One patient responded rapidly to 100mg/day and therapy ceased after 14 days; however this case relapsed 3 and 5 months later, each time receiving an additional 1-month course of fluconazole before being considered cured at the 1-year follow-up. Among these patients, M. pachydermatis was implicated in 1 case; the Malassezia species in the other 3 cases were not identified, including the latter, relapsing case. The fifth case of inadequate response to topical therapy, suffering from chronic rejection and a wider distribution of lesions, however, was identified as M. furfur and was the most refractory among all 11 cases. This case was categorized as the lone failure at one year. This patient received topical clotrimazole 1% (lotion) therapy BID for 1 month, then starting oral fluconazole 100 BID x 3 weeks followed by 200 mg QD, cited as "chronic", for nearly 2.5 years at which time he received a second heart transplant. Of note, with respect to serum cyclosporine levels influenced by fluconazole administration, no constant, adverse event was noted. Cyclosporine serum levels could best be summarized as unpredictable as post-fluconazole cyclosporine levels rose, decreased, or remained relatively constant in these 5 cases (37).

Fluconazole may have a larger role in the treatment of cutaneous infections due to other Malassezia species, especially M. pachydermatis, which differs significantly from M. furfur in respect to physiologic lipid dependence. The failure of the fifth M. furfur case mentioned above and the limited effectiveness of fluconazole in HIV-positive subjects on cryptococcal maintenance therapy presenting with seborrheic dermatitis may be indicative of an adverse influence of fluconazole’s limited penetration into lipid-rich sites such as the epidermis and sebum (37, 40). Thus, as it does in tinea versicolor, systemic ketoconazole may have a role in the treatment of these infections in patients with normal hepatic function (48). Other azole and antifungal compounds on the horizon possessing lipophilic properties may also be useful.

Cutaneous M. furfur infections often respond to topical, or a combination of topical and oral systemic antifungal therapy. The patient s underlying immune status appears to strongly influence the rapidity and extent of response. Those patients with profound immunosuppression may especially warrant the added consideration of systemic antifungal therapy. Whether or not this is added to topical therapy, treatment of a lengthened duration - to halt progression of disease or effect cure, is common until there is recovery of host defenses.

ADJUNCTIVE THERAPY

Findings coincident with the initial presentation of illness may be as influential in guiding therapy as those findings that arise during treatment. Indeed, treatment of antibiotics are adjuncts to other interventions in treating this opportunistic infection.

In cases of M. furfur fungemia where a central venous access device is in place, assessment of the immediate and long-term needs for the device should be taken. Whether or not the device can or should be removed permanently -or subsequently replaced are the same questions applying to intravenous lipid administration. Intravenous lipids should be immediately discontinued whenever possible and only resumed with caution in instances of absolute necessity.

Also at this time, a review of the utilization of antibacterial antimicrobials is warranted. The discontinuation of these agents, or change to a narrower spectrum of activity can help facilitate resolution of the patient’s normal microbial flora, limiting superinfection.

As with other infectious diseases, adjunctive therapeutic measures arise in response to various host factors, the site of infection and preventing or limiting the degree of damage inflicted by the organism. In the case report of M. furfur fungemia accompanied by a septic thrombus that extended into the patient s right atrium, debridement and excision of the mass was required (41).

ENDPOINTS FOR MONITORING THERAPY

The endpoints for monitoring greatly rely upon the clinician s close observations, patient risk factors for M. furfur infection, and related clinical findings. In cases of fungemia, following a course of systemic antifungal therapy, the resolution of clinical signs and symptoms, especially when accompanied by normal neutrophil counts, can signal a good clinical outcome or cure. If the patient s central venous access device has been left in place or changed, clinicians should seek additional objective measurement through the recovery of subsequent negative central blood cultures.

Attention should be given to intravenous lipid administration. Discontinuing lipid administration or noting their discontinuation date with temporal association to positive blood culture is warranted. The patient’s endogenous lipid levels may give clues as to the ability of the organism to sustain growth.

Following M. furfur fungemia, a high index of suspicion for reinfection should be maintained if the central venous access device is either retained or replaced or lipid therapy resumes shortly after "curative" therapy. In the uncommon presentation of end-organ infections, the added value of obtaining subsequent histopathologic evidence versus the invasiveness of the procedure must be weighed. Serial radiographic and other diagnostic examinations may help in aiding this decision.

VACCINES

There are no vaccines for this fungus.

PREVENTION OR INFECTION CONTROL MEASURES

Numerous reports and studies are in agreement regarding the relatively high rates of skin colonization among hospitalized neonates and infants, and healthy adults (1, 20, 39). Correlation of skin colonization to central venous access device colonization and either of these two conditions as a predictor of systemic disease has not been demonstrated with sufficient power. Among two prospective studies examining the devices among neonates in intensive care units, the incidence of M. furfur central venous access device colonization was 2.7% and 32% (3, 47). The studies differed with regard to type of device utilized, placement of the device and duration of use, brand of lipid administered, culture technique of the device, and finally, selection of culture media.

In contrast to the colonization rates found in ambulatory adults, in one study 928 samples of central line skin-site cultures from 149 adults receiving TPN and intravenous lipids were negative (18).

The question of patient-to-patient as well as healthcare worker-to-patient transmission has been raised (2,6, 38). However, the present level of sophistication for methods of definitive typing was not available at the time and these assertions were made on the basis of epidemiologic evidence.

Growth of M. furfur in intravenous lipid preparations has been discounted (19) and demonstrated (33) in laboratory models supporting the contention that the lipid aspect of parenteral nutrition can also serve as a reservoir for infection. However, to our knowledge, no case of M. furfur fungemia has resulted from such circumstances. Still, as certain lipids are necessary to support growth of M. furfur, an in vitrostudy has demonstrated that intravenous lipid preparations comprised of 50% medium-chain triglycerides (MCT) and medium-chain free-fatty acids prohibit M. furfur growth (31). With concerns over non-infectious issues, such a composition of lipids in commercially-available preparations are not utilized in the United States. However, when compared to long-chain preparations, if issues such as metabolic demands and infusion rates can be resolved these MCT preparations may warrant clinical study for prevention of fungemia in at-risk populations.

The need for routine skin surveillance cultures and whether or not M. furfur fungemia is underdiagnosed, given the organism's need for lipid supplementation for growth and to culture, are also subject to varied opinion (18, 43, 53). Given the incidence of M. furfur fungemia, we do not believe that routine skin surveillance cultures should be performed, given the present absence of correlation between rates of colonization and infection. However, in an attempt to better understand any association between the two, or in the event of a suspected outbreak of M. furfur infection, it seems this exercise could be useful.

We should not discount the possibility that M. furfur infection could be transmitted from patient-to-patient as well as between healthcare worker and patient, and vice-versa. In the hospital environment, such associations leading to infection have been reported with Candida (17, 45). For this reason, as always, we support frequent handwashing and rigid adherence for all other therapeutic manipulations relating to technique and infection control. Obeying the tenets of universal precautions should help minimize the incidence of M. furfur infections as well as other infectious diseases.

CONTROVERSIES AND CAVEATS

We are mindful of the limitations of the existing literature regarding M. furfur infection and M. furfur fungemia. The fastidious requirements of this yeast appear to have influenced its appearance as an opportunistic pathogen among two distinct populations: 1) premature or early neonates receiving intravenous lipid administration, and; 2) immunocompromised, hospitalized or ambulatory care adults who may or may not be receiving intravenous lipids. Overwhelmingly, there is a tendency of either of these two populations to be receiving broad-spectrum antibacterial antibiotics concurrent with first positive blood culture.

There is a lack of uniformity regarding culture media and requirements, susceptibility testing and perhaps, most importantly, a varied adherence to infection control precautions from individual to individual as well as between institutions. Still, presently, we do not believe M. furfur fungemia to be vastly underreported. The incidence of M. furfur fungemia is relatively small. That management of sepsis can sometimes be accomplished through interventions without the use of directed antifungal therapy, we do not discount, nor trivialize the severity of infection. A high index of suspicion should be maintained for those patients at risk, or seemingly without explanation of infection from a more typical bacterial etiology. We favor treating immunocompromised patients having M. furfur-associated catheter infection with a course of antifungal antibiotics and the discontinuation of intravenous lipids. Similar to fungemia caused by other yeasts, these patients should have their central venous access device removed whenever possible and be closely observed.

Hopefully, the NCCLS guidelines will include provisions for the requisite lipids needed in culture to support growth of M. furfur yeast cells. If this is accomplished, despite the low incidence of M. furfur fungemia, a standardized, prospective, multicenter study may yet be able to accrue a number of cases large enough for meaningful comparative analysis. Presently, suspected clusters or outbreaks of systemic or cutaneous M. furfur infections can be subjected to analysis by sophisticated typing methods that can support or refute hypotheses regarding the mode of transmission. As always, paralleling the lessons learned from other historical nuisances, of relatively low pathogenicity such as coagulase-negative staphylococci, clinicians must be aware of the influence exerted by the ever-changing hospital environment. The growing popularity of peripherally-inserted central catheters (PICC lines) may be one such example. Although, they too, have been associated with M. furfur and other fungemias (43), their relative ease of change and carefully selected sites for insertion will hopefully decrease the incidence of M. furfur fungemia.

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Table 1.

Source	Amphotericin B	5-flucytosine	Miconazole	Ketoconazole
Blood/Catheter tip	0.6-2.5 (0.6)	>100	0.4-1.5 (0.8)	0.05-0.4 (0.05)
Skin	0.3-0.6 (0.3)	>100	0.4-1.5 (0.8)	0.025-0.05 (0.5)

*defined as: lowest concentration of drug inhibiting obvious visible growth

Note: NCCLS recommends a growth inhibition standard of 80% (MIC80) for antifungal susceptibility testing