Magnusiomyces clavatus fungemia treated with combination antifungals including isavuconazole in an immunocompromised pediatric patient: a case report

Abstract

Magnusiomyces clavatus, formerly Saprochaete clavata or Geotrichum clavatum, is an ascomycetous yeast found in the environment as well as the gastrointestinal and respiratory tracts of humans. It has been described as an emerging, albeit rare, cause of invasive fungal disease affecting immunocompromised patients. Intrinsic resistance to fluconazole and echinocandins has been theorized; however, little else is known regarding optimal treatment regimens for this opportunistic pathogen. To our knowledge, only 13 infectious cases have been described in pediatric patients, all of which utilized a combination of antifungals including liposomal amphotericin B (LAmB) and voriconazole with or without flucytosine (5-FC). Here we report a case of a 4-year-old, 12.3 kg, female patient who immigrated from Ukraine and was admitted to our institution for an allogeneic umbilical cord blood transplant in the setting of bone marrow failure secondary to Fanconi anemia. On day +6 after cell transplantation, the patient developed febrile neutropenia found to be because of invasive M. clavatus fungemia on day +7. The patient was empirically treated with LAmB, micafungin, and posaconazole (POS), the latter of which failed to reach therapeutic levels. Ultimately, our patient defervesced and cleared blood cultures after transitioning LAmB to 5-FC, followed by definitive treatment with isavuconazole (ISA) monotherapy. To our knowledge, this is the first case of pediatric M. clavatus ultimately treated with 5-FC plus POS followed by ISA alone.

Introduction

Invasive fungal disease (IFD) can be a life-threatening consequence in immunocompromised patients. Prolonged hospitalization, neutropenia, and the use of immunosuppressive therapies, such as chemotherapeutics and steroids, are among the most notable risk factors for IFD.^1,2 Magnusiomyces clavatus—formerly Saprochaete clavata or Geotrichum clavatum—has been implicated as a rare etiology of IFD, although reported cases are increasing, particularly in the Mediterranean region of Europe, where these infections have primarily been described. Reservoirs for this opportunistic pathogen include environmental sources as well as the microflora of human skin, gastrointestinal, and respiratory tracts. ¹ When implicated in IFD, M. clavatus has been associated with life-threatening sepsis and multi-organ dissemination, carrying a high mortality rate upwards of 60%–80%. ²

Literature pertaining to M. clavatus IFD is primarily limited to case reports, case series, and a handful of retrospective descriptive studies. As such, guidance regarding the optimal treatment approach for these infections is lacking and is instead guided by expert opinion and available microbiologic laboratory data. M. clavatus is an ascomycetous yeast with a hyphal structure. Echinocandins and fluconazole are typically avoided within treatment regimens, as high rates of elevated MICs suggestive of resistance have been previously identified.^2,3 Rather, successful treatment regimens described at this time consist of liposomal amphotericin B (LAmB) in combination with a triazole antifungal, typically voriconazole (VRC), with or without the addition of 5-flucytosine (5-FC). Of the 13 pediatric cases previously described, triazole antifungal use has been limited to VRC.^1,4–14

Herein, we present the case of a 4-year-old female who developed a M. clavatus IFD within days of receiving a hematopoietic cell transplant (HCT) for Fanconi anemia with bone marrow failure. She was ultimately treated with a combination of 5-FC and posaconazole (POS), the latter of which was sub-therapeutic, followed by isavuconazole (ISA) monotherapy. To our knowledge, this is the first pediatric case of M. clavatus IFD that has utilized ISA as a component of the treatment regimen.

Case report

This 4-year-old, 12.3 kg, female patient with past medical history significant for Fanconi anemia was admitted to our institution for an allogeneic umbilical cord blood transplant in the setting of bone marrow failure. Additional relevant past medical history includes VACTERL association, tracheoesophageal fistula previously repaired in infancy, and horseshoe kidneys. The patient received a reduced-intensity conditioning regimen consisting of busulfan, anti-thymocyte globulin, fludarabine, and cyclophosphamide beginning 1 week prior to HCT, which successfully induced profound neutropenia (absolute neutrophil count (ANC) = 10 cells/µL). The patient subsequently started antimicrobial prophylaxis with cefepime, acyclovir, letermovir, pentamidine, and micafungin (MFG).

On the day of HCT (day +0), the patient developed non-infectious diarrhea secondary to grade 1 mucositis. On day +5 after HCT, the patient developed fever (Tmax = 38.7°C) associated with tachycardia and tachypnea in the setting of neutropenia (ANC 20 cells/µL; Figure 1). An infectious workup was initiated, including blood cultures drawn from the patient’s tunneled central venous catheter (CVC). Vancomycin was added to her original antibiotic prophylaxis regimen. Additional antifungals were not started, and prophylactic MFG was continued per institutional protocol (Table 1).

Figure 1.

Patient’s fever curve and ANC throughout full hospital course.

5-FC, flucytosine; ANC, absolute neutrophil count; CVC, central venous catheter; ISA, isavuconazole; LAmB, liposomal amphotericin B; MFG, micafungin; POS, posaconazole.

Table 1.

Antifungal dosing regimens.

Antifungal agent	Dose
MFG, prophylaxis	1 mg/kg IV every 24 h
MFG, treatment	3 mg/kg IV every 24 h
LAmB	5 mg/kg IV every 24 h
POS*	Load: 8 mg/kg PO every 12 h × 2 doses, Maintenance: 8 mg/kg PO every 24 h
5-FC	25 mg/kg PO every 6 h
ISA	Load: 149 mg PO every 8 h × 6 doses, Maintenance: 149 mg PO every 24 h

^*POS delayed-release tablets utilized.

5-FC, flucytosine; ISA, isavuconazole; LAmB, liposomal amphotericin B; MFG, micafungin; POS, posaconazole.

On day +7, the patient reported a new cough and left lower lobe posterior chest pain. Growth was observed on the patient’s initial aerobic bacterial blood culture 34.1 h after being drawn, with Gram-positive cocci in pairs and chains as well as fungal elements being noted following review of the blood culture Gram stain. The sample was then evaluated using the BioFire^® Blood Culture Identification-2 (BCID-2) (Salt Lake City, Utah, USA) polymerase chain reaction assay, which did not detect any organisms contained within the panel. Antibacterial coverage was then expanded to include ampicillin for coverage of less common Gram-positive bacteria not included on BCID-2. Broad antifungal coverage was additionally initiated due to the ambiguous appearance of fungal elements, consisting of treatment-dosed MFG, POS, and LAmB (5 mg/kg/dose IV every 24 h) for yeast, mold, and resistant fungal coverage, respectively (Table 1).

By the next day (day +8), the Gram-positive cocci seen on Gram stain were identified via matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) as an Abiotrophia species, for which antibiotics were transitioned to levofloxacin to minimize the risk of acute kidney injury while on LAmB. Further microbiologic workup of the fungal elements noted on the Gram stain remained vague with a broad differential. Karius^® (Redwood City, California, USA) microbial cell-free DNA blood test sample was sent, which resulted in positive for G. adiacens (77,039 MPM), human adenovirus A (685 MPM), and herpes simplex virus type 1 (121 MPM), but no fungal pathogen. Concurrent fungal workup included negative serum Aspergillus galactomannan antigen (Aspergillus galactomannan index 0.03) and positive (1,3) beta-d-glucan (237 pg/mL).

Secondary to the patient’s cough and chest pain, the highest concern was a pulmonary source. Computed tomography (CT) chest with contrast showed limited pulmonary expansion without a focal abnormality. A CT abdomen pelvis with contrast was also performed to investigate a potential enteric source of infection; findings were overall unremarkable. Finally, the patient’s CVC was considered a potential source of infection and, following the unimpressive imaging workup, her CVC was removed on day +9.

During this time, the patient’s daily blood cultures, which were sampled from the patient’s tunneled CVC on days +7–9 and peripheral venipuncture on day +10, remained persistently positive for fungal elements. The patient remained febrile despite broad anti-fungal coverage (Figure 1). On the morning of day +12, the repeat (1,3) beta-d-glucan level increased to >500 pg/mL.

Concern for persistent fungemia secondary to a yeast-like fungus with high tolerance to LAmB was considered, leading to the patient being transitioned from LAmB to flucytosine (5-FC) the afternoon of day +12. A sample of the fungal elements was sent to the Fungus Testing Laboratory at the University of Texas Health Science Center (UTHSC) for identification and susceptibility testing at this time.

Following the transition to the new combination antifungal regimen of MFG, POS, and 5-FC, the patient’s fever curve began to improve (Figure 1), and follow-up blood cultures showed no growth of fungal elements.

On day +14, 7 days after initiating POS, the trough level result was subtherapeutic (181 ng/mL, treatment goal >1000 ng/mL). A 5-FC level was additionally drawn, which was found to be non-toxic at 13 µg/mL. On the same day that therapeutic drug monitoring results became available, fungal susceptibility results from UTHSC were received without organism identification (Table 2). MFG was discontinued secondary to susceptibility results. Due to the low POS trough and anticipated delays in reaching therapeutic values, combined with low ISA minimum inhibitory concentration (MIC), the patient was transitioned to ISA on day +20. 5-FC was continued for an additional 7 days until the patient was determined to be therapeutic on ISA (trough: 1.5 mcg/mL, goal: >1 mcg/mL), ¹⁵ at which point 5-FC was discontinued, leaving the patient on ISA monotherapy.

Table 2.

M. clavatus isolate susceptibility results.

Antifungal agent	MIC (mcg/mL)
LAmB	1
5-FC	0.125
MFG	2
POS	0.5
VRC	0.06
ISA	0.125

5-FC, flucytosine; ISA, isavuconazole; LAmB, liposomal amphotericin B; MFG, micafungin; POS, posaconazole; VRC, voriconazole

On day +27 after cell transplantation, UTHSC Fungus Testing Laboratory identified the fungal pathogen as M. clavatus. The patient continued ISA monotherapy and was discharged from the hospital on day +43. She continued antifungal treatment with ISA through day +127, and at that time had not experienced any recurrent or additional fungal infections, nor any adverse effects associated with antifungal therapy.

Discussion

In recent years, significant therapeutic advances have been made in the fields of hematology and oncology. While these advances have improved malignancy survival rates, they have also led to increasing rates of IFD.^1,2 Not only has the incidence of invasive candidiasis and aspergillosis been on the rise, but case reports on rare etiologies of IFD, such as M. clavatus, have also increased. With < 120 cases described in the literature, the majority of which are in adult patients with leukemia, M. clavatus appears to be an emerging cause of IFD in patients with severe immunocompromise.^1,2 Similar to previous reports, our patient was profoundly neutropenic at the time of IFD onset; she was D + 6 after receiving an HCT with an ANC of 0 cells/µL.

M. clavatus is a yeast-like ascomycetous fungus found in a variety of environmental sources, including soil, water, wood, and even air, given its spore-producing capabilities. ² Given its non-specific environmental reservoirs, M. clavatus has been found within the microbiota of human respiratory and gastrointestinal systems as well as on the skin. Outside of immunodeficiency as a risk factor, this fungus has only been noted to cause invasive disease in the setting of penetrating trauma involving soil contamination. ¹⁶ Historically, reports of invasive M. clavatus have been concentrated within the Mediterranean region of Europe, suggesting a geographical risk factor for exposure. However, a growing number of cases outside of this region have been noted. In 2023, the first known occurrence of an invasive M. clavatus infection in North America was reported—a 6-year-old female living in Oregon, USA, with B-cell acute lymphoblastic leukemia. ¹² The exact origin of exposure for our patient—opportunistic infection secondary to colonization or a novel exposure while immunocompromised—is unclear. To our knowledge, this is the second M. clavatus case reported in North America (CO, USA), potentially representing an early signal that opportunity exists for environmental exposure in the Pacific Northwest region of the United States. Further reports are needed to strengthen this association. Notably, however, our patient originated from Ukraine before immigrating locally, so there is also the distinct possibility that she was exposed to M. clavatus during her time there, becoming colonized prior to entering the United States. Regardless of where she was exposed to this pathogen, it is our impression that her profound neutropenia, presence of a central venous catheter, and mucositis were potentially key factors in the development of her concomitant fungal and bacterial infections, as they provided the proper immune state and a point of entry for these pathogens.

Identification of M. clavatus in the present case was difficult, with definitive identification occurring at D + 25. Additional microbiologic and laboratory tests are thus critical to guiding therapy. Concern for fungal etiology was first raised when fungal elements were detected on our patient’s initial aerobic blood culture, which was drawn at the time of fever onset from her tunneled CVC. Beta-d-glucan was positive, and serum galactomannan was negative, as we would suspect for Magnusiomyces spp., and these results decreased the likelihood of aspergillosis. ¹⁷ Neither the BioFire® BCID-2 Panel nor the Karius® microbial cell-free DNA assay includes M. clavatus as a valid pathogen and thus were negative. This diagnostic workup was ineffective in allowing us to narrow antifungal therapy for our patient, and as such, she remained on our standard local empiric antifungal therapy of micafungin, a mold-active triazole, and LAmB to broadly cover for yeast, mold, and resistant fungi, respectively.

Changes to empiric antifungal therapy were not made until D + 12. Lack of defervescence and persistently positive blood cultures, primarily drawn from the patient’s tunneled CVC but inclusive of one sample drawn via peripheral venipuncture on D + 10 (1 of 2 samples positive), led to concern for persistent fungemia secondary to a yeast-like fungus with suspected high tolerance to LAmB. Susceptibility breakpoints do not exist for M. clavatus due to its rarity and thus lack of extensive data necessary for formalized breakpoint creation. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) does, however, provide some suggested guidance regarding MIC interpretation for rare yeasts lacking breakpoints. Magnusiomyces spp. is included within this guidance, which cautiously suggests LAmB may be considered for therapy in M. clavatus isolates with a LAmB MIC ⩽ 1 mcg/mL. ¹⁸ EUCAST also recommends that isolates whose MIC is close to this “interpretative value” be assessed for susceptibility reproducibility due to the inherent variation associated with MIC determination. Susceptibility results for our isolate, which were only available later in our patient’s course, indicate a LAmB MIC of 1 mcg/mL. This result is the exact interpretative value suggested by EUCAST and may explain our patient’s lack of full response to this therapy. Susceptibility results were not repeated in our patient to confirm this result, as the patient was clinically stable on an alternate therapy by the time initial susceptibility results were available. Regardless, our patient was transitioned to 5-FC because of suspicion of LAmB resistance and the speed of growth of the fungal organism. While there is no suggested interpretative value for 5-FC from EUCAST, unknowingly, our isolate had a subjectively low 5-FC MIC when comparing it to that of similar fungal species. ²

Compared to previous case reports of pediatric M. clavatus fungemia, our choice of triazole antifungal therapy was unique. To our knowledge, there are only 13 other cases of M. clavatus fungemia reported in a pediatric patient, of which all utilized combinations of LAmB, 5-FC, and VRC.^1,4–14 (Table 3) While our voriconazole MIC would end up being relatively low compared to EUCAST’s cautious interpretative value of ⩽1 mcg/mL, and thus VRC may have been an effective therapeutic option, based on local experience with difficulty rapidly reaching therapeutic VRC levels, we opted to utilize ISA as the triazole component of our patient’s treatment regimen. ¹⁹ Again, while interpretative values do not exist for ISA against M. clavatus, our isolate’s MIC appeared relatively low (0.125 mcg/mL). ¹⁹ Retrospectively calculating an AUC/MIC ratio, the widely accepted pharmacodynamic target for triazole antifungals, using our isolate’s MIC and the average pediatric AUC of ISA, we get an AUC/MIC ratio of 826.4. This is reassuring and perhaps underlies the effectiveness of ISA in our patient. Of note, while no reported pediatric cases of M. clavatus have utilized ISA as a component of the treatment regimen, one adult case report in a patient with acute myeloid leukemia has done so. ²⁰ The patient was noted to have died 3 days after beginning antifungal therapy consisting of LAmB and ISA for the treatment of their invasive M. clavatus infection. Of note, antifungal dosing information and microbiologic susceptibility data pertaining to that isolate were not available to compare with our patient’s case. Additionally, the patient described in this case was noted to have potential central nervous system (CNS) involvement, as elucidated through possible infectious foci seen on brain CT and magnetic resonance imaging (MRI). While ISA can penetrate the CNS to some degree, this is an important distinction as it may represent a more severely disseminated disease. Based on these mixed results, more data is needed to better define ISA’s role in the treatment of M. clavatus IFD. However, this case demonstrates its potential therapeutic role, specifically in the setting of pediatric IFD. Aside from mitigating the need for routine therapeutic drug monitoring, ISA confers several other potential advantages over VRC in terms of safety and monitoring. While ISA carries a similar risk for hepatotoxicity as the other azole antifungals—and thus requires periodic monitoring of liver function tests during therapy—it causes QTc shortening rather than QTc prolongation, a potential advantage in patients with a significant cardiac history or those on several other QTc prolonging medications. ²¹ ISA is generally well-tolerated, with adverse effects most commonly involving gastrointestinal upset. ²¹ Additionally, compared to VRC, ISA is not described as having a significant risk of acute kidney injury, dermatologic reactions, or visual disturbances.^21,22 While ISA represents a promising alternative to VRC for the treatment of M. clavatus IFD, more studies are needed to validate its potential role in this context.

Table 3.

Review of prior pediatric M. clavatus case reports.

Study	Country	Sex	Age	Underlying Disease	Clinical Form	Treatment	Outcome
Lacroix et al., 2007	France	M	14	AML	Sepsis	E: L-AMB T: L-AMB + VRC D: VRC + 5-FC	Survived
de Almeida et al., 2016	Brazil	F	6	Hemophagocytic lymphohisiocytosis	Not-Specified	E: L-AMB D: VRC	Deceased
Liu et al., 2018	China	M	10	ALL	Disseminated, non-CNS	E: MFG T: VRC T: MFG + VRC D: MFG + L-AMB	Survived
Leoni et al., 2019	Italy	M	6	Bone marrow failure, s/p allogeneic HSCT x 2	Disseminated	E: L-AMB D: L-AMB + VRC	Survived
Buchta et al., 2019	Israel	F	17	AML	Disseminated, including CNS	E: L-AMB T: L-AMB + 5-FC D: L-AMB + 5-FC + VRC	Survived
Wee et al., 2019	Singapore	M	13	ALL	Disseminated, non-CNS	D: L-AMB + VRC	Survived
Cascio GL et al., 2020	Italy	M	4	AML	Not specified	D: L-AMB	Survived
Goupillou et al., 2022	France	M	9	AML	Sepsis, Chorioretinitis	E: CAS T: L-AMB (IV and intravitreal) D: L-AMB + VRC + 5-FC	Survived
Kraft et al., 2023	Brazil	M	11	ALL	Not specified	E: L-AMB + VRC	Deceased
Mitchell PG, Chang BH & Walker LW, 2023	United States of America (Oregon)	F	6	ALL	Disseminated, including CNS	E: MFG T: L-AMB + VRC D: L-AMB + VRC + 5-FC	Survived
Styczynski T, et al., 2023	Poland	F	14	AML	Sepsis	E: L-AMB T: L-AMB + VRC D: VRC	Survived
Styczynski T, et al., 2023	Poland	F	14	AML	Sepsis	E: L-AMB T: L-AMB + VRC D: VRC	Survived
Akinci et al., 2023	Turkey	M	14	ALL	Sepsis, Skin Lesions	E: L-AMB	Deceased

Conclusion

M. clavatus is an emerging pathogen implicated in IFD within the immunocompromised population. While optimal treatment regimens for this pathogen have not been elucidated, it has most commonly been treated with a combination of LAmB, 5-FC, and VRC. This case report of a pediatric patient with M. clavatus fungemia, however, provides the first known description of successful treatment with ISA within a pediatric patient’s treatment regimen for this rare IFD, providing preliminary evidence for additional triazole antifungal options outside of VRC.