Three Successfully Treated Cases of Lodderomyces elongisporus Fungemia: Case Reports and a Review of the Literature

Fungemia is a fatal systemic infection that can occur in immunocompromised patients. Despite that, antifungal stewardship is spreading widely, but the mortality rate is extremely high, showing 40–60%. Loderomyces elongiporus is a newly morphologically detected pathogen, first described in 1994, followed by isolation in humans in 2008. It has been misrecognized as Candida parapsilosis. Recently, fever attributable to L. elongisporus fungemia cases has been reported, and the etiology and clinical features are still unknown. Here, we present three successfully treated L. elongisporus fungemia cases by echinocandin. In total, 11 cases were reviewed, including ours. Six of the eleven cases (55%) had external devices. All cases had some immunocompromised conditions or underlying diseases, such as diabetes mellitus, lung cancer, etc. Six patients survived, and the remaining five died. Seven patients who had received echinocandin initially survived. Risk factors for L. elongiporus fungemia overlap with those of candidemia. Even though there is no breakpoint for L. elongiporus, echinocandin can be a helpful treatment regimen for L. elongiporus fungemia.


Introduction
With advanced diagnostic methods, such as matrix-assisted laser desorption/ionization mass spectrometry (MALDI-TOF MS), newly detected pathogens have been increasing year by year [1,2]. In addition, various immunosuppressive agents cause the emergence of opportunistic infections. In spite of a global spread in antifungal stewardship, invasive fungal infection such as catheter-associated blood stream infection caused candidemia, still results in critical severe cases that show a high mortality rate of 46-75% [3][4][5].
"Lodderomyces elongisporus was first recovered from Californian citrus concentrate in 1952 and named Saccharomyces elongisporus by Recca and Mrak. It was later renamed as Lodderomyces elongisporus by van der Walt and colleagues in 1966 [6]. L. elongisporus was considered a teleomorph of Candida parapsilosis until sequencing of the 18S rRNA gene differentiated it as a unique species. While it has been recovered from fresh fruit, fruit concentrates, and soft drinks, L. elongisporus has also been recovered from insects [6]". L. elongiporus is an uncommon yeast opportunistic pathogen that can cause a sporadic fungal infection. L. elongisporus is an uncommon yeast opportunistic pathogen that can cause a sporadic fungal infection. This fungus was newly morphologically identified in 1994 [7], followed by its isolation in 2008, as a causative pathogen of human infection [8]. While several fungemia cases caused by this fungus have been reported [6,[9][10][11][12][13][14][15][16], we still know little about its epidemiology, clinical features, risk or prognostic factors. Here, we present three cases of catheter-related bloodstream infection (CRBSI)s caused by L. elongisporus, which were successfully treated. Furthermore, we review all known reports published previously of fungemia caused by L. elongisporus.

Case Presentation
After a cardiac catheter test, a 76-year-old man was admitted to our institute due to an infectious aneurysm in the right inguinal artery. He had a history of poorly controlled diabetes mellitus with hemoglobin A1c 8.6% and angina pectoris. Since the causative pathogen for the disease was Staphylococcus aureus, he received combination antibiotic therapy with sulbactam/ampicillin and daptomycin for 4 weeks. Then, his condition was improved once. During the stay, he had a high fever, and two sets of blood cultures revealed yeast in both aerobic and anaerobic samples (BD, Tokyo, Japan). His central venous catheter (CVC) was removed, and empiric antifungal therapy with micafungin (MCFG) was started simultaneously. The yeast was identified as Lodderomyces elongisporus by MALDI-TOF MS using the VITEK-2 system (BioMérieux, Marcy l'Etoile, France). Since the tip of the CVC also revealed L. elongisporus, he was diagnosed as having a catheter-related bloodstream infection (CRBSI). His condition improved after two weeks of antifungal treatment.
A 12-year-old boy had been admitted due to subarachnoid hemorrhage (SAH), which required a decompressive craniectomy. He had been diagnosed as having autism. On admission day 40, he had a high fever, and we removed the CVC and obtained two sets of blood cultures. Aerobic and anaerobic samples for the tip and two sets of blood culture yielded a yeast identified as L. elongisporus by the VITEK-2. Because of these results, he was diagnosed as having a CRBSI. He became afebrile as soon as the CVC was removed and the MCFG was started. The antifungal therapy had been performed for 2 weeks after the removal of the CVC. Consequently, his condition improved. Both sets of blood culture identified that the yeasts were susceptible to MCFG, as shown in Table 1. An 82-year-old woman had a medical history of diabetes mellitus, Parkinson's disease and cholelithiasis. She was admitted due to cholangitis, which was successfully treated by endoscopic gallbladder stenting (EGBS) and drainage with antibiotic therapy by meropenem. She had a high fever, which was attributable a yeast infection revealed by the two sets of blood cultures as L. elongisporus by the VITEK-2 on day 28. Antifungal therapy with fosfluconazole (F-FLCZ) was started. However, after rechecking the blood cultures seven days after starting F-FLCZ, they continued to show positive results for L. elongisporus. Thus, F-FLCZ was switched to CPFG on day 39. She improved after 2 weeks of antifungal therapy with CPFG.
On CHROMagarTM candida (CHROMagar, Paris, France), there were turquoise blue colonies in all three cases, which looked different from C. albicans and C. parapsilosis, as shown in Figure 1A. Furthermore, a Gram-staining of L. elongisporus from an aerobic blood culture sample exhibited ellipsoidal to elongated ascospores ( Figure 1B). The results of Basic Local Alignment Search Tool (BLAST) analysis showed the internal transcribe spacer (ITS)1 and ITS2 were 100% homologous with those of the L. elongisporus strain (CBS 2605) from GenBank on all three isolates. In total, 11 cases of L. elongisporus fungemia, including ours, have been previously reported, as shown in Table 1. The age of the patients ranges from 9 days to 82 years. Seven patients (64%) were male. Eight patients (73%) had some comorbidities such as diabetes mellitus or lung cancer. The remaining three patients had specific conditions, such as extremely low birth weight, autism, or postoperative trauma. Regarding infection sites, 4 of the 11 patients (36%) had CVCs and 5 patients were diagnosed as having CRBSI. As for the outcomes, 8 of the 11 patients (73%) were treated with echinocandins. Finally, six survived (55%), and five died (45%). Antifungal susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI M27-A3).

Discussion
Candidemia has emerged as an important nosocomial infection, showing a high mortality rate of 30-50%. "It is the fourth most common nosocomial bloodstream infection (BSI) in the United States, and the seventh most common nosocomial BSI in Europe and Japan. Previously reported risk factors for candidemia include central venous catheterization (CVC), neutropenia, malignancy, abdominal surgery within the previous 30 days, immunosuppressant use and admission to an intensive care unit (ICU)". However, the etiology and the clinical features of L. elongisporus fungemia are still unknown. Although few L. elongisporus fungemia cases have been reported, they might have been misdiagnosed as C. parapsilosis fungemia. The widespread use of MALDI-TOF-MS makes it possible to diagnose L. elongisporus fungemia correctly, and the number of cases is estimated to increase. The etiology and the clinical features of this fungemia are still unknown. We found all the cases had either external devices or immunocompromised conditions. Thus, the risk of L. elongisporus fungemia might be similar and overlap with that of candidemia. The current Infectious Diseases Society of America (IDSA) guidelines favor the therapeutic use of echinocandins to treat C. parapsilosis [17,18]. Since there are no evidence-based breakpoints for antifungal susceptibility testing for L. elongisporus, those for C. parapsilosis are often used as an alternative [9,19]. In this review, five of the seven patients who received initial antifungal therapy with MCFG survived, including ours. Furthermore, all microorganisms isolated in our study showed that the MIC values for MCFG were ≤0.06, which were interpreted as susceptible, as shown in Table 2. Despite starting F-FLCZ, case 3 had persistent fungemia, shown by the positive blood cultures of L. elongisporus. Finally, switching to CPFG improved fungemia. Unfortunately, we could not find any reason for persistent fungemia while receiving F-FLCZ. Echinocandin might be the first choice for L. elongisporus fungemia.
As for a predictive tool for fungemia, we previously reported that combined sequential organ failure assessment (SOFA) and Charlson Comorbidity Index (CCI) scores could predict the outcomes among candidemia patients [4]. Multiple organ failure conditions and comorbidities contribute to a poor prognosis among candidemia patients. In our reports, all three cases displayed the combined SOFA (scores: 0-2) and CCI (scores: 1-3) scores of 2-3 on diagnosis as the fungemia, which were considered low, and eventually, all survived. This suggested that the combined score can be useful to predict the outcome of this fungemia, although the disease severity of the cases could be just not severe. We need more cases to evaluate whether this prognostic tool is helpful in the treatment of L. elongisporus fungemia.
All patients with L. elongisporus fungemia had immunocompromised conditions and/or an external device. Thus, we hypothesize that these risk factors for L. elongisporus fungemia overlap with those of candidemia. More cases need to be accumulated to clarify the clinical features and epidemiology of L. elongisporus fungemia. Moreover, the clonal relationship of the three strains of L. elongisporus isolated should be analyzed for the prevention of nosocomial outbreaks in further analysis.
"Biofilm formation of C. albicans and C. parapsilosis in catheter or other implanted de vices in patients with weakened immune host defenses most often leads to the development of candidemia with serious repercussions for the health of these patients [20]. As early catheter removal may not always improve outcome, an effective antibiofilm treatment is of great clinical importance." Echinocandins previously demonstrated a potent antibiofilm. Echinocandins previously demonstrated a potent antibiofilm formation activity in C. albicans and C. parapsilosis both in vitro and vivo studies [21]. L. elongiporus may have a potential to form a biofilm same as C. albicans and C. parapsilosis. Thus, L. elongiporus fungemia might have been persistent, even though antifungal agent therapy with F-FLCZ started in in the case 11. CPFG, is a fungicidal, water-soluble semisynthetic echinocandin that inhibits synthesis of β-1,3-D-glucan, a main structural component of the fungal cell wall, showing an antibiofilm formation activity. In a vitro study, Simitsopoulou et al. demonstrated that CPFG had a strong antibiofilm activity against C. albicans. This antifungal agents can be a useful treatment option for the treatment of L. elongiporus fungemia [22].
In conclusion, we experienced three successfully treated cases of L. elongisporus fungemia by MCFG. The risk factors of L. elongisporus fungemia may overlap with those of candidemia, and echinocandin can be a useful antifungal treatment for L. elongisporus fungemia.

Institutional Review Board Statement:
The Ethics Committee at Aichi Medical University ruled that no formal ethical approval was required for reporting a case study.
Informed Consent Statement: Written informed consent was obtained from the patients for publication of this case series. Data Availability Statement: All authors meet the International Committee of Medical Journal Editors (ICMJE) authorship criteria for this article.