Invasive Malassezia infections

INTRODUCTION — Malassezia (formerly known as Pityrosporum) species are members of human cutaneous commensal flora, which are associated with a wide spectrum of clinical manifestations from benign skin conditions, such as tinea versicolor and folliculitis, to fungemia in the immunocompromised host [1-4].

The mycology, epidemiology, clinical manifestations, diagnosis, and treatment of invasive Malassezia infections will be discussed here. The clinical manifestations, diagnosis, and treatment of tinea versicolor and Malassezia folliculitis are discussed elsewhere. (See "Tinea versicolor (pityriasis versicolor)" and "Infectious folliculitis", section on 'Fungal folliculitis'.)

MYCOLOGY — Malassezia are lipophilic yeasts that are constituents of the normal human skin flora. Studies have revealed that many Malassezia species produce a biofilm that is used during attachment to host and other surfaces [5]. A recent study showed that invasive Malassezia isolates are more likely to develop biofilms than isolates associated with pityriasis versicolor [6]. These organisms have been classified into at least 17species, including M. furfur, M. pachydermatis, M. sympodialis, M. slooffiae, M. obtusa, M. globosa, and M. restricta, based upon polymerase chain reaction and restriction endonuclease analysis [2,7-11]. A study has reported reliable species identification by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry following the development of a MALDI-TOF database [12]. In another study evaluating 392 clinical isolates (identified by sequencing) from patients with Malassezia folliculitis and pityriasis versicolor, 68 percent were M. furfur and 19 percent were M. globosa [13].

EPIDEMIOLOGY — Malassezia species mainly colonize the skin and occasionally the respiratory tract [9,14]. The organisms appear to become part of the normal skin microbiota by three to six months of age. M. furfur was recovered from the skin in 32 to 64 percent of neonates in neonatal intensive care units in two separate series [15,16]. In one study, duration of stay in the unit and gestational age were factors favoring skin colonization [15].

Colonization of the skin with Malassezia and subsequent extension to central venous catheters appears more common in neonates than adults. Studies using scanning electron microscopy have demonstrated that some Malassezia spp produce significant biofilms [5]. M. furfur was recovered from the lumen in 32 percent of percutaneous central venous catheters in a neonatal intensive care unit in one series [16] but not from the insertion sites in 928 adults receiving total parenteral nutrition [17].

This fact may account for the observation that Malassezia central venous catheter-related infections are more common in preterm neonates than adults. High temperature and humidity may facilitate colonization of catheters, and lipid infusions appear to predispose to both catheter colonization and infections [18-20]. Additional risk factors for Malassezia catheter-related infections in newborns include low birthweight, severe comorbidities, and prolonged arterial catheterization [21]. In a report from a single neonatal intensive care unit, the emergence of M. furfur was associated with the introduction of fluconazole prophylaxis [22].

Both localized skin and mucosal infections and systemic infections have been reported in hematopoietic cell transplant recipients [23], patients with underlying hematologic malignancies, those receiving monoclonal antibody therapy for cancer [24], and in patients with other immunodeficiency states (eg, solid organ transplantation, diabetes mellitus, prolonged glucocorticoid therapy, HIV) [25]. Unlike many of the other more common opportunistic fungal infections in immunocompromised patients, neutropenia and the use of broad-spectrum antimicrobials do not appear to be significant risk factors for Malassezia infections in hematopoietic cell transplant recipients [23]. In addition, despite the presence of fungemia, disseminated fungal infection is uncommon.

Outbreaks — Hospital outbreaks of Malassezia infection have been described [20,21,26]. In one outbreak, there was simultaneous occurrence of M. furfur infection in three patients in neighboring beds in an intensive care unit [26]. In a second outbreak, the organism was isolated from the hands of health care workers and the health care workers' pet dogs; all isolates had an identical pattern of restriction fragment length polymorphisms [21]. An outbreak in a neonatal intensive care unit, which was caused by multiple Malassezia genotypes, has also been described [27]. Although a source was not identified, effective infection prevention methods included removal of a lipid-rich moisturizing hand cream used by staff.

CLINICAL PRESENTATION — Malassezia infections can be localized and/or systemic in immunocompromised hosts. Malassezia spp can produce the following clinical syndromes:

●Malassezia folliculitis presents with pruritic, monomorphic, follicular papules or pustules on the chest, back, and/or shoulders. Less frequent sites of involvement include the face, neck, and extensor side of the arms. (See "Infectious folliculitis", section on 'Fungal folliculitis'.)

●Catheter-related fungemia, especially in preterm neonates receiving lipid infusions (ie, total parenteral nutrition) through a central venous catheter [20] – The clinical examination, apart from fever, may be unremarkable [23]. Both septic thrombosis of the superior vena cava [28] and peripheral thromboembolism [29] have been described.

●Localized infections, including meningitis and urinary tract infections have been described [21]. Rarely, Malassezia species have been implicated in cases of peritonitis, mastitis, septic arthritis, sinusitis, and hepatic abscess [25,30,31].

DIAGNOSIS — In patients with fungemia, meningitis, peritonitis, or septic arthritis, a definitive diagnosis is made by detection of characteristic yeasts on microscopy in the microbiology laboratory, on histologic or cytologic examination of a biopsy, or needle aspirate specimen or positive culture from a sterile site (picture 1) [32]. The optimal blood culture system for Malassezia has not been determined, but there are reports of positive blood cultures using both the pediatric isolator and the BacT/Alert systems [33]. Prolonged incubation of up to two weeks has been recommended for isolation [34]. The culture of Malassezia spp from urine in the absence of a urinary catheter or from a sinus aspirate is diagnostic of Malassezia urinary tract infection or sinusitis, respectively.

Malassezia require fatty acids for growth and, thus, do not grow on routine laboratory media. If the diagnosis of Malassezia infection is suspected based on the morphologic findings, the specimen should be plated onto specialized media, such as Dixon agar, which contains glycerol mono-oleate, or Sabouraud dextrose agar, covered with a layer of olive oil and incubated at 37ºC [21,23,25,26,28,29,35,36].

On microscopy, Malassezia have characteristic features. The yeast is typically thick walled (3 to 8 microns in diameter), round to oval in shape, with a broad-based bud and collarette at one pole. Hyphae and pseudohyphae are rarely seen [23]. This microscopic finding has been described as the "spaghetti and meatballs" appearance [37]. Identification is usually confirmed on the basis of microscopic appearance and the need for specialized media.

Newer methods of identification of Malassezia spp include matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) [38,39] and multiplex polymerase chain reaction (PCR) [40]. These methods may be useful adjunctive tests for rapid identification, particularly in outbreak settings. With MALDI-TOF, the spectra of most species have not as yet been included in current databases, but this methodology has been successful when the database has been expanded to include numerous Malassezia species [39].

Serum (1,3)-beta-D-glucan was assessed for the diagnosis of invasive yeast infection in 47 neonates in a neonatal intensive care unit but does not appear to be positive in the setting of invasive Malassezia infection [41].

The diagnosis of Malassezia folliculitis is discussed separately. (See "Infectious folliculitis", section on 'Malassezia (Pityrosporum) folliculitis'.)

SUSCEPTIBILITY TESTING — Because Malassezia spp do not grow on the recommended susceptibility media, susceptibility testing has not been standardized for this organism. Reported minimum inhibitory concentrations (MIC) values for terbinafine, amphotericin B, and the azoles vary among species [11,13,42]. Reports have described experience with optimized broth microdilution and E-tests methodologies [43-45]. In vitro, all Malassezia spp appear susceptible to amphotericin B (0.3 to 2.5 mcg/mL) and azole agents, including ketoconazole, itraconazole, voriconazole (0.016 to 0.25 mcg/mL), and posaconazole. However, the MIC for fluconazole are somewhat higher (0.5 to 6.5 mcg/mL) [46,47]. One study, performed in India, reported that itraconazole had the lowest MIC values (0.125 to 1 mcg/ml) [48]. Malassezia spp have variable susceptibility to terbinafine with MICs that range from 0.06 mcg/mL for M. globosa to 32 mcg/mL for M. furfur [46,47]. Synergism has been reported between terbinafine and itraconazole and between tacrolimus and itraconazole, ketoconazole, and terbinafine, although the clinical significance of such synergism is unclear [13]. Echinocandins and griseofulvin appear to have no activity against Malassezia spp [43,49].

TREATMENT — Central venous catheter-related Malassezia infections are usually treated with catheter removal, discontinuation of the lipid infusion (ie, total parenteral nutrition), and administration of antifungal therapy [23]. However, there are reports of successful eradication of infection with antifungal therapy without catheter removal [25] and with catheter removal without systemic antifungal treatment [23].

For treatment of most patients with Malassezia infection, we use a lipid formulation of amphotericin B (3 to 5 mg/kg intravenously [IV] daily); Malassezia are lipophilic yeasts and it has been suggested that lipid formulations of amphotericin may have more activity against Malassezia than nonlipid formulations but this is unproven [34]. An exception is the rare occurrence of urinary tract infection for which we use amphotericin B deoxycholate (0.3 to 0.5 mg/kg IV once daily) in adults because lipid formulations of amphotericin B do not achieve adequate concentrations in the urine. (See "Candida infections of the bladder and kidneys", section on 'Fluconazole-resistant Candida'.)

In neonates with Malassezia infection, amphotericin B deoxycholate (0.7 mg/kg IV once daily) is used rather than a lipid formulation.

Therapy with voriconazole, posaconazole, or itraconazole is an alternative option, based on in vitro data rather than clinical studies. Fluconazole should not be used because its in vitro activity is inferior to the in vitro activity of the other azoles. Patients who develop Malassezia bloodstream infections while receiving fluconazole prophylaxis should be treated with a different antifungal agent [34].

There are no reports of treatment of Malassezia with echinocandins, most likely related to the lack of in vitro activity of this class of antifungal agents against Malassezia species. (See 'Susceptibility testing' above.)

The management of folliculitis caused by Malassezia spp is discussed separately. (See "Infectious folliculitis", section on 'Malassezia folliculitis'.)

OUTCOME OF INFECTION — With catheter removal and discontinuation of intravenous lipids (ie, total parenteral nutrition), the outcome is usually favorable, even in transplant patients with fungemia [23].

In 11 cases of folliculitis occurring in heart transplant recipients, six responded to topical applications of clotrimazole (1%) and selenium sulfide, and the remainder responded to fluconazole [35].

SUMMARY AND RECOMMENDATIONS

●Clinical significance – Malassezia species are members of human cutaneous commensal microbiota and are associated with intravascular catheter-related infections and folliculitis in the immunocompromised host. (See 'Introduction' above.)

●Risk factors – Central venous catheter-related bloodstream infections are seen most commonly in premature neonates receiving lipid infusions (ie, total parenteral nutrition [TPN]). Additional risk factors include low birthweight, severe comorbidities, and arterial catheterization for longer than nine days. (See 'Epidemiology' above.)

●Diagnosis – A definitive diagnosis is made by culture from a sterile site. If the diagnosis of Malassezia infection is being considered, Sabouraud dextrose agar must be plated at 37ºC, and the specimen must be covered with a layer of olive oil. (See 'Diagnosis' above.)

●Treatment – For patients other than neonates, we recommend the administration of a lipid formulation of amphotericin B for treatment of central venous catheter-related Malassezia infections (Grade 1B). For neonates, amphotericin B deoxycholate is preferred over the lipid formulations. Therapy with voriconazole, posaconazole, or itraconazole is an alternative option.

We also suggest central venous catheter removal and discontinuation of lipid infusions (ie, TPN) (Grade 2C). (See 'Treatment' above.)