Diagnosis and Treatment Challenges of Candida guilliermondii in Immunocompromised Patients: A Case Study in a Neutropenic AML Patient

Although fungal infections causing intestinal perforation and necrosis are rare, they can be particularly dangerous in immunosuppressed patients, often leading to increased mortality rates and poor prognoses. Candida species are typically surface fungi, but in patients with compromised immune systems, they can invade the small intestine and cause angioinvasive infections. A case study involving a 30-year-old female with acute myeloid leukemia (AML) illustrates this phenomenon. The patient was presented with symptoms of abdominal pain, fever, diarrhea, recurrent episodes of intestinal necrosis, hematomas due to thrombocytopenia, and subsequent postoperative enterocutaneous fistulas. Extensive testing ruled out other possible causes of intestinal necrosis and enteritis, including Crohn's and CMV diseases. Candida guilliermondi was ultimately identified in blood cultures from the periphery, peritoneal fluid, and intestinal biopsy of respected sections, indicating that it was responsible for intestinal invasion and necrosis. The patient was then treated with amphotericin B, cefepime, and metronidazole. This case highlights the potential severity of fungal infections in immunosuppressed patients, particularly Candida species, and the importance of prompt diagnosis and appropriate treatment.


Introduction
Te Candida guilliermondii complex is a taxonomically complex group consisting of several morphologically indistinguishable species such as C. guilliermondii, Candida fermentati, Candida carpophila, and Candida xestobii [1].After recent taxonomic revisions, the teleomorph (sexual reproductive form) of this yeast has been renamed Meyerozyma guilliermondii.However, infections are commonly caused by the anamorph (asexual reproductive form), which continues to be known as Candida guilliermondii [2].
C. guilliermondii is a relatively rare fungal yeast pathogen that usually acts as a saprophyte in humans.It can lead to serious infections in immunocompromised individuals, especially in those with hematological malignancies.Tis yeast has been isolated from a variety of sources, including human skin and mucosal surfaces, soil, insects, plants, seawater, and tree secretions [3].Tis species is characterized by its production of only pseudohyphae and its ability to grow on Sabouraud dextrose agar (SDA), where it forms small, fat, or smooth colonies that are yellowish or creamish in color, along with short pseudohyphae [4].
In recent years, the number of invasive infections caused by yeasts has increased, and the C. guilliermondii complex accounts for 3.7% of all fungal infections in Latin America [5].Additionally, previous studies have highlighted the reduced susceptibility of C. guilliermondii complex species to common antifungal agents, such as azoles and echinocandins [6].

Case Presentation
A 30-year-old female with a history of arthritis, HPV, irritable bowel syndrome, and COVID-19 was admitted to our institute on November 12, 2021, for induction chemotherapy (7 + 3 regimen with cytarabine, daunorubicin, gemtuzumab, and leuprolide) following a diagnosis of AML.Te patient developed neutropenic fever and streptococcus mitis infection, which resolved.
Tirteen days after the chemotherapy, the patient presented with worsening abdominal pain, nausea, and vomiting.Physical examination revealed a soft, nondistended abdomen with signifcant periumbilical, rebound, and guarding tenderness.Laboratory tests showed neutropenia, with a white blood cell count of 0.3 cells/μL and a platelet count of 7 platelets/μL.Clinical symptoms suggestive of ischemia prompted an immediate abdominal CT scan, revealing an ischemic jejunal segment and enterocolitis (Figure 1).GI surgery was performed, and the patient underwent exploratory laparotomy.Operative fndings included a 3 cm ischemic segment of the proximal jejunum associated with mesenteric hematomas (Figure 2).A 10 cm segment on either side was resected because of vascular compromise and impending perforation.Te underlying etiology was attributed to thrombocytopenia, which led to intestinal and peri-intestinal hematoma.
Te respected specimens were sent for pathological examination, along with peripheral blood cultures.Pathology revealed necrosis and yeast in the vascular bed, and the peripheral blood cultures tested positive for C. guilliermondii (Figure 3).Zosyn and micafungin were initiated.Despite receiving antibiotics and her initial postoperative improvement, her condition declined after two days.Te patient's pain escalated, and a repeat CT was warranted, which demonstrated an edematous small bowel wall proximal and distal to the anastomosis and thickening of the colon, suggesting enterocolitis, with the presence of increased peritoneal fuid with layering hemoperitoneum in the pelvis.Te patient was brought back for a repeat surgery on December 1, 2021.Tirteen areas of bowel compromise, characterized by stenosis, hematomas, and ischemia, were found (Figure 4).Te patient underwent fve partial small bowel resections and hand-sewn end-to-end anastomoses.Cultures from November 30, 2021 to December 2, 2021 remained positive for C. guilliermondii.Fungal culture with a smear of the wound and peritoneal fuid confrmed the presence to be Candida guillermondii.
Te patient developed partial wound dehiscence (Figure 5) (cultures positive for Enterobacter cloacae) and drainage of bilious fuid.A computed tomography (CT) scan on December 20, 2021 revealed an enterocutaneous fstula and loculated pockets of fuid within the abdomen and pelvis (Figure 6).Te patient would not tolerate wound care at the bedside, so she was taken to the operating room on December 21, 2021 for wound debridement and catheter placement for fstula output control.Te enterocutaneous fstula was managed with bowel rest, total parenteral nutrition, and drainage catheters.Tis allowed the patient to undergo three cycles of consolidation chemotherapy (March 4, 30, and April 28, 2022).During this period, the wound around the fstula healed.On June 17, 2022, the patient underwent takedown of the enterocutaneous fstula and ventral hernia repair.All subsequent scans and bone marrow biopsies revealed complete remission.Some of the peritoneal fuid from the perforation settled in the lower pelvis and formed a complex heterogeneous collection that was never removed but resolved in time.Te patient was discharged on posaconazole (Table 1).

Discussion
Tis case highlights the importance of the early identifcation and management of fungal infections in patients with AML undergoing induction chemotherapy.In this case, we observed a 30-year-old female patient with Acute Myeloid Leukemia (AML) undergoing chemotherapy who developed a rare Candida guilliermondii infection that led to necrosis of the bowel wall and peritonitis.A critical contributor to the patient's vulnerability to Candida guilliermondii infection was neutropenia, which can be attributed to both AML and chemotherapy regimen.It is well established that neutropenia signifcantly diminishes the body's ability to fend of infections, and in this context, provides a favorable milieu for Candida guilliermondii to thrive.Our patient had neutropenic enterocolitis, which was identifed by the presence of acute abdominal symptoms, neutropenia, and bowel wall thickening, which was evident from several radiological tests.Te pathophysiology behind this type of invasive fungal infection is believed to be due to direct cytotoxicity on the intestinal wall caused by chemotherapy, followed by neutropenia and thrombocytopenia, which lead to spontaneous intramural hemorrhage or microvascular thrombosis [7].
Systemic candidiasis is a notable complication among patients with neutropenia and those undergoing cancer therapy [8].Te incidence of this infection has been on a consistent upward trajectory over the last 30 years and now constitutes a major cause of morbidity and mortality in highrisk demographics [9].In the reviewed articles, the mortality rates range of 3.4-66.6%.In this regard, this infection had mortality rates of 11.76-66.6%,13.6-54%, 16.66-18.8%,59.25%, and 3.4% in Japan, Spain, Taiwan, United States, and Italy, respectively [10].
Te factors that render neutropenic patients with hematological malignancies susceptible to systemic candidiasis vary depending on the extent of immune suppression and intricacies of the underlying malignancy.
It is important to recognize the digestive tract as a critical entry point for Candida species, especially in patients with acute neutropenia and leukemia [11,12].Being rich in endogenous microfora, the digestive tract is vulnerable to Candida ingress into the bloodstream through compromised anatomical barriers.Te manifestations of Candida infections vary, including oropharyngeal candidiasis, esophagitis, candidemia, and acute or chronic disseminated candidiasis [4,12].

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Case Reports in Infectious Diseases In our patient, the proliferation of the Candida fungus can be attributed to her neutropenic state, which was compounded by the chemotherapy regimen.Te therapy was instrumental in the breakdown of the intestinal mucosal barriers, paving the way for seeding of the fungus.However, a striking aspect of this case was the identifcation of Candida guilliermondii as the likely cause of necrosis in the bowel segments.
Intriguingly, the identifcation of Candida guilliermondii as the culprit behind necrosis of the bowel segments deviates from the usual suspect, Candida albicans.Candida guilliermondii, which is part of the normal fora of human skin and mucosal surfaces, is involved in a range of infections, including chronic onychomycosis, acute osteomyelitis, septic arthritis, endocarditis, fungemia, and disseminated invasive infections [13].It is one of the opportunistic fungi that recover most frequently in severely immunocompromised patients.
Our literature review confrmed that C. guilliermondii is a more common cause of candidemia in patients with cancer than in general hospital populations; however, it is rarely implicated in bloodstream infections occurring in other high-risk categories, such as intensive care unit patients [14].Previously, the incidence of C. guillermondii in cancer patients appeared to be quite low.A review of 37 reports published between 1952 and 1992 revealed that C. guilliermondii was responsible for only 0.8% of all systemic Candida infections in this high-risk group [15].Te largest reported series included nine cases (two-thirds occurring in leukemia patients) observed over 11 years (1988-1998) at the M. D. Anderson Cancer Center [16].However, recent studies of over 68 patients with over 79 episodes of infection with non-Candida species of C. guillermondii occurring in over 41% of patients with hematological malignancies showed that there has been an increase in the number of infections caused by non-Candida species from 3.6% (1998-2005) to 7.2% (2006-2013; p � 0.0004).[4].
Initial diagnostic evaluations in this case were challenging because of the absence of culture and biopsy results, making it difcult to ascertain the etiology of intestinal necrosis.Upon receiving the biopsy, tissue smear, and deep wound culture results, a clearer picture emerged showing focal necrosis and stenosis, edema, microhematoma, and the presence of fungal organisms in vascular spaces and perivascular tissues, similar to fndings in an autopsy case series  [ [17][18][19][20][21][22] investigating gastrointestinal candidiasis where colonic involvement was identifed in 20% of cases (22 out of 109).Among these, 82% (18 of 22) displayed multisite involvement in the gastrointestinal tract.Te pathology report showed ulcers in 60% (15 of 25), plaque in 24% (6 of 25), erosion in 12% (3 of 25), and polyps in 4% (1 of 25) of cases.
Dissemination, or widespread distribution of the disease, is a frequent occurrence, noted in 71% (5 out of 7) of cases, illustrating the invasive nature of the condition in immunocompromised patients.
Another concern is the resistance pattern of this fungus.Pfaller Madiekema Djmesser et al. [23,24] recently assessed the recovery of rare Candida bloodstream isolates from various parts of the world, including 150 isolates of C. guilliermondii.Te majority (85%-100%) was fully susceptible to amphotericin B, fucytosine, fuconazole, voriconazole, and ravuconazole, but susceptibility to itraconazole was much less common (10%).C. guilliermondii seems intrinsically resistant to echinocandins.High caspofungin MICs (>1 μg/ml) have been reported for more than 95% of the tested isolates [25,26], suggesting that this drug is unlikely to be efective against C. guilliermondii infections.A recent study showed that C. guilliermondii is also among the Candida species that are the least susceptible to echinocandin and anidulafungin [27].Our data confrmed high rates of susceptibility to amphotericin B (100%), voriconazole (95%), fuconazole (90%), and fucytosine (86%); however, our isolates displayed lower rates of resistance to itraconazole (24%) and caspofungin (66%) than those observed in previous studies.Te Candida parapsilosis  [28][29][30][31].A growing number of breakthrough infections with Candida species that have low susceptibility to echinocandins have been reported in patients receiving echinocandin therapy [32][33][34][35][36][37][38][39][40] Tis is also true in our case: despite being on the micafungin regimen, the patient developed necrosis and vascular bed invasion.Fortunately, in  Case Reports in Infectious Diseases our case, the non-Candida fungus was susceptible to most of the antifungal therapy except for anidulafungin and was able to resolve the infection while on amphotericin B. Tere have been reports of single cases of C. guilliermondii infection displaying in vitro resistance to amphotericin B and/or fuconazole [41][42][43][44].

Conclusions
Tis case highlights the increasing incidence of systemic candidiasis in patients with hematological malignancies and the emergence of nonalbicans Candida species, such as Candida guilliermondii.Diagnostic challenges in early-stage intestinal necrosis emphasize the need for vigilant monitoring and prompt diagnostic investigations.
Te observed resistance of Candida guilliermondii to echinocandins, necessitates careful selection of antifungal therapy.Te patient's positive response to amphotericin B illustrates the importance of individualized treatment plans based on susceptibility patterns.
In conclusion, this case underscores the necessity for a comprehensive approach to managing Candida guilliermondii infections in immunocompromised patients.It reinforces the need for high suspicion of invasive fungal infections, tailored antifungal therapy, and continuous epidemiological surveillance.Tis case contributes valuable insights into resistance patterns and treatment responses, aiding in the optimization of treatment strategies and improvement of patient outcomes.

Consent
Written informed consent was obtained from the patient for the publication of this case report and any accompanying images.All eforts were made to ensure patient privacy and confdentiality.Identifable information was anonymized, and no identifable personal health information was disclosed.

Figure 1 :
Figure1: Necrosis of the small bowel.Initially reported as typhlitis but later reported as multiple segments of small bowel ischemia, possible anastomotic breakdown, small bowel obstruction, and enterocolitis.Te CT scan shows an ischemic jejunum segment and enterocolitis.

Figure 2 :
Figure 2: Te ischemic segment (3 cm long) of the proximal jejunum, associated with mesenteric hematomas at the base of the ischemic segment.

Figure 4 :
Figure 4: During surgical exploration, 13 skip areas of compromised small bowel were found, characterized by combinations of stenosis, hematomas, and ischemia.Tis fgure shows stenosed segments of jejunum and necroses of the small intestine.

Figure 6 :
Figure6: Persistent areas of wall thickening, consistent with enteritis; some areas appear to be slightly improved from the prior study.Layering hemoperitoneum in the pelvis seen in abdomen/pelvis soft view.

Table 1 :
Susceptibility for our patient Candida guillermondii fungus.