Successful Treatment of Refractory Candida auris Ventriculitis With Intraventricular Liposomal Amphotericin B

ABSTRACT

We report on a case of a patient in their early 60's with a history of traumatic brain injury, decompressive cranioplasty, and chronic ventriculoperitoneal (VP) shunt who presented from a nursing home with altered mental status and status epilepticus. He was found to have Candida auris growing from his cerebrospinal fluid (CSF) cultures. Initial management included removal of the VP shunt, placement and two exchanges of external ventricular drains (EVD), and treatment with various antifungal regimens, including intraventricular liposomal amphotericin B. Despite these measures, the patient had a persistent ventriculitis that lasted over 4 weeks. Due to the refractory infection, we also performed therapeutic drug monitoring to determine the degree of antifungal penetration into the CSF. In this report, we aim to describe our approach in treating a challenging case of C. auris ventriculitis.

Summary.

• Candida auris is a multidrug‐resistant pathogen that can cause nosocomial infections that are difficult to eradicate.

• Our case illustrates the possibility of using adjunct intraventricular liposomal amphotericin B as part of a salvage regimen for the treatment of refractory Candida auris ventriculitis.

1. Background/Introduction

Candida auris is a nosocomial pathogen that is often multidrug‐resistant and difficult to eradicate. Risk factors for developing C. auris infections include colonization with C. auris , prolonged exposure to the health care setting, presence of tracheostomies or percutaneous endoscopic gastrostomy (PEG) tubes, and disruption of the gut microbiome after use of broad‐spectrum antimicrobials [1]. While there are limited official guidelines for the management of C. auris infections, echinocandins are recommended as first‐line treatment. However, for certain site infections where drug penetration may be suboptimal (e.g., central nervous system [CNS] infections), alternative agents such as triazoles, polyenes, and flucytosine have been considered [2, 3]. Additionally, adjunct intraventricular and intrathecal antifungals have been used in a few published cases of CNS “non‐auris” Candida infections [4, 5, 6]. Here we describe our experience successfully treating refractory C. auris ventriculitis with adjunct intraventricular liposomal amphotericin.

2. Case Presentation

A 63‐year‐old man was brought to the emergency department (ED) from a long‐term skilled nursing facility for stroke alert, altered mental status, and status epilepticus. His past medical history was notable for severe traumatic brain injury (TBI) status post bilateral decompressive craniotomies, post traumatic hydrocephalus, ventriculoperitoneal (VP) shunt, chronic tracheostomy, and gastrostomy tube. Additionally, hospitalization from 5 months prior showed colonization with C. auris from surveillance skin swab and carbapenem‐resistant Pseudomonas aeruginosa from sputum culture. Upon arrival, the patient's vitals were: blood pressure 93/69 mmHg, heart rate 126 beats/min, respiratory rate 30 cycles/min, and temperature 39.4°C. Neurologic exam showed a non‐cachectic, alert man, oriented to self and place but not time, with non‐bizarre delusions. Attention was intact; however, the patient had significant memory impairment with 2 attempts needed for immediate recall, 1/5 on delayed recall, and 3/5 with prompting. Speech was fluent with no dysarthria or aphasia. He followed multistep commands. Gait was wide‐based and unsteady. The rest of the neurological examination, including strength, sensation, cranial nerve exam, and coordination, was intact. In the ED, the patient exhibited persistent seizures and fevers, and required emergent intubation for airway protection. Pertinent laboratory tests were as follows: Complete blood count showed leukocytosis of 14,600 per microliter with 90% neutrophils; lactic acidosis of 2.7 mmol/L. Urinalysis was abnormal, and chest X‐ray showed right middle lobe infiltrates and bibasilar infiltrates versus atelectasis. He underwent reservoir puncture of his VP shunt and the cerebrospinal fluid (CSF) culture grew C. auris . Computed tomography (CT) brain without contrast was performed 7 days after the initial CSF was collected and this showed mild dilatation of the ventricular system (Figure 1). Two weeks later, follow up CT brain without contrast demonstrated severe hydrocephalus (Figure 2a) with surrounding edema (Figure 2b). After VP shunt removal and external ventricular drains (EVD) placement, CSF cultures remained persistently positive (Table 1).

FIGURE 1.

Coronal view CT brain without contrast showing mild dilatation of the ventricular system.

FIGURE 2.

Coronal view CT brain without contrast obtained 2 weeks after Figure 1 demonstrated severe hydrocephalus (a) with surrounding edema (b).

TABLE 1.

Summary of CSF studies and cultures.

Hospital day	Specimen source	Isolated pathogen	Fluid analysis	Antifungal regimen
12	CSF	C. auris	Glu 42, protein 57, RBC 10, total nucleated count 10	None
17	CSF	C. auris	Glu 51, protein 55, RBC 0, total nucleated count 55	IV amphotericin 5 mg/kg lipid complex + PO flucytosine 25 mg/kg q6h
20	CSF	No growth	Glu 36, protein 243, RBC 2100, total nucleated count 1	IV amphotericin 5 mg/kg lipid complex + PO flucytosine 25 mg/kg q6h
22	CSF	No growth	Glu 45, protein 174, RBC 7468, total nucleated count 96	IV amphotericin 5 mg/kg lipid complex + PO flucytosine 25 mg/kg q6h
25	CSF	No growth	Glu 39, protein 111, RBC 39, total nucleated count 48	IV amphotericin 5 mg/kg lipid complex + PO flucytosine 25 mg/kg q6h
28	CSF	C. auris	Glu 47, protein 124, RBC 882, total nucleated count 35	IV amphotericin 5 mg/kg lipid complex + PO flucytosine 25 mg/kg q6h
32	CSF	No growth	Glu 36, protein 97, RBC 433, total nucleated count 1	IV amphotericin 7.5 mg/kg lipid complex + IV micafungin 150 mg daily
37	CSF	No growth	Glu 40, protein 93, RBC 750, total nucleated count 3	IV amphotericin 6 mg/kg liposomal + IV micafungin 150 mg daily
39	CSF	C. auris	Glu NA, protein NA, RBC 119, total nucleated count 26	IV amphotericin 6 mg/kg liposomal + IV micafungin 150 mg daily
40	CSF	No culture work‐up	Glu 35, protein 103, RBC 21, WBC 2	IV amphotericin 6 mg/kg liposomal + IV posaconazole 300 mg q12h
41	Blood	C. auris	—	IV amphotericin 6 mg/kg liposomal + IV posaconazole 300 mg daily
42	CSF	No growth	Glu 47, protein 95, RBC 6, total nucleated count 1	IV amphotericin 6 mg/kg liposomal + IV posaconazole 300 mg daily
46	CSF	No growth	Glu 40, protein 107, RBC 853, total nucleated count 33	IV amphotericin 7.5 mg/kg liposomal + IV Micafungin 150 mg + posaconazole 300 mg daily
	EVD catheter tip	C. auris	—
50	CSF	No growth	Glu 42, protein 118, RBC 0, total nucleated count 20	IV amphotericin liposomal 7.5 mg/kg + IV Micafungin 150 mg + IT amphotericin 1 mg
53	CSF	No growth	Glu 59, protein 93, RBC 0, WBC 0	IV amphotericin liposomal 7.5 mg/kg + IV Micafungin 150 mg + IT amphotericin 1 mg

Abbreviations: CSF ‐ Cerebrospinal fluid; Gluc‐ Glucose; IV ‐ Intravenous administration; IVT ‐ Intraventricular administration; kg ‐ kilogram; mg ‐ milligram; PO ‐ Oral administration; RBC ‐ Red blood cell; WBC ‐ White blood cell.

3. Differential Diagnosis

The patient's initial presentation was altered mental status and seizures. Evaluation showed fever, tachycardia, leukocytosis, and lactic acidosis. Infectious and non‐infectious causes were considered as possible differential diagnoses. Infectious possibilities included urinary tract infection, bacterial or viral pneumonia, aspiration pneumonitis, community‐acquired meningitis or encephalitis, and VP shunt infection. Non‐infectious causes included severe hydrocephalus secondary to malfunctioning VP shunt, post‐traumatic seizure with postictal phase (since seizure activity can also result in leukocytosis and lactic acidosis), as well as thromboembolism. After confirmed growth of C. auris in the CSF, the diagnosis of fungal ventriculitis was made.

4. Treatment

On hospital day 1, vancomycin and cefepime were started empirically for sepsis with suspected urinary and pulmonary sources of infection. The infectious diseases team was consulted, and antibiotics were switched to trimethoprim/sulfamethoxazole plus ertapenem to treat pneumonia caused by Klebsiella pneumoniae carbapenemase (KPC)‐producing Klebsiella pneumoniae and urinary tract infection caused by extended‐spectrum beta‐lactamase (ESBL)‐producing Proteus mirabilis . On hospital day 12, the VP shunt was tapped by neurosurgery to rule out infection. CSF cultures returned with heavy growth of C. auris . On hospital day 16, intravenous amphotericin B (AmB) lipid complex 5 mg/kg (formulation selected based on hospital formulary) plus flucytosine 25 mg/kg q6h oral suspension was initiated. The following day, repeat CSF cultures were sent, which remained positive for C. auris . The entire left VP shunt system, which was the presumed source for infection, was removed and a frontal EVD was placed. The day after the initial EVD placement (hospital day 20), new CSF was extracted from the EVD, and this did not grow C. auris. Serial repeat CSF was performed approximately every 3 days while the EVD was in place to trend pleocytosis and hypoglycorrhachia. On hospital day 29, flucytosine was stopped due to a national drug shortage. After three negative CSF cultures, the patient's CSF cultures became positive again for C. auris on hospital day 32 (See Table 1). AmB lipid complex dose was increased to 7.5 mg/kg and high‐dose micafungin 150 mg daily was added. Despite having poor CNS penetration, micafungin was added because this was the only drug with confirmed susceptibilities at that time. Further susceptibility testing for alternative antifungals was requested as a send‐out to a national reference center. On hospital day 33, the patient's EVD was exchanged for the first time by the neurosurgery team. Three days later, intravenous AmB lipid complex was switched to liposomal AmB due to a national shortage of the lipid complex formulation. Send‐out antifungal susceptibilities returned with the following Minimum inhibitory concentration (MIC) results: amphotericin = 1, posaconazole < 0.03, isavuconazole < 0.03. Micafungin was then discontinued and replaced with posaconazole. CSF cultures remained positive on hospital day 39; so liposomal AmB dose was increased to 7.5 mg/kg, and the EVD was exchanged for the second time. The EVD catheter tip subsequently grew C. auris , and on hospital day 44, blood cultures returned positive with C. auris for the first time. Micafungin was restarted at a dose of 150 mg since the patient also had axillary and branchial veins thrombi and the decision was to treat for septic thrombophlebitis.

On hospital day 45, we conducted therapeutic drug monitoring to assess the CNS penetration of the two antifungals being used to treat the patient's ventriculitis. Drug levels were measured with the following results: serum amphotericin (8.05 mcg/mL), CSF amphotericin (undetectable), serum posaconazole (1.5 mcg/mL), CSF posaconazole (undetectable). Due to having undetectable levels in the CSF, posaconazole was stopped, and intraventricular liposomal AmB was initiated at a dose of 1 mg/3 mL of Dextrose 5% Water on hospital day 48. Four days later, CSF cultures remained sterile, and there were significant improvements in CSF white blood cells, glucose, and protein levels. See Table 1 for a full summary of CSF studies and cultures.

5. Outcome and Follow up

Intraventricular liposomal AmB was continued for 3 additional days after negative C. auris CSF cultures and improving CSF parameters. Intravenous liposomal AmB was continued for an additional 7 days after negative CSF cultures. Intravenous micafungin 150 mg daily was provided for a total of 4 weeks after negative blood cultures to target C. auris fungemia with suspected septic thrombophlebitis. Even though the patient's VP shunt infection and candidemia resolved, it was difficult to measure the impact of infection clearance on the patient's mental status given significant impairment in brain functionality related to his underlying TBI. The patient's EVD was removed prior to discharge, but no shunt replacement was done due to refinement of goals of care. The patient was discharged from the hospital with palliative services and eventually transitioned to hospice care.

6. Discussion

We share our experience using adjunct intraventricular liposomal AmB for the treatment of refractory C. auris shunt‐associated ventriculitis. Our patient had risk factors for developing this type of infection due to the history of C. auris skin colonization and living in a long‐term nursing home with a chronic tracheostomy and VP shunt [7]. Our case illustrates the challenges of eradicating C. auris from the CSF, particularly due to the organism's ability to form biofilms and the questionable penetration of antifungals into the CNS. Currently, the recommended treatment for Candida meningitis is intravenous AmB ± oral flucytosine for 4–8 weeks; however, we resorted to using multiple antifungal combinations for the treatment of this persistent infection [8]. It took over 4 weeks to sterilize our patient's CSF.

Our patient was on AmB lipid complex for over 2 weeks, followed by liposomal AmB for approximately 1 week before the addition of intraventricular liposomal AmB. In hindsight, there may have been advantages to starting with the liposomal formulation upfront. Liposomal AmB is two orders of magnitude smaller than the lipid complex and therefore is anticipated to have better CNS penetration [9]. However, animal models have demonstrated that liposomal AmB is able to reach good concentrations in the brain tissue but not necessarily in the CSF. A study comparing four different amphotericin formulations showed that none of these drugs could actually surpass the lower limit of CSF quantification [10]. This is similar to what we observed in our case, where we measured undetectable levels of AmB in the CSF despite having adequate serum levels. Therefore, it still remains unclear if utilizing the liposomal formulation of AmB would have been more effective for the treatment of C. auris ventriculitis.

After performing therapeutic drug monitoring, we decided to add on intraventricular liposomal AmB as a salvage approach; this type of approach is limited due to its safety profile, as drug‐related adverse effects have been reported [11]. With the intraventricular route, headaches, fever, nausea, and vomiting can occur. Direct effects of neurotoxicity presenting as ophthalmoplegia, hearing loss, ataxia, paraplegia, and neurogenic bladder have also been reported [12]. For our case, we administered the liposomal formulation of AmB via the intraventricular route and this was well tolerated by our patient. The dosage we used for our patient was extracted from a study by Toprak D and colleagues, where intraventricular liposomal AmB 1 mg per 3 mL of D5W was also used to treat a recurrent Candida albicans ventriculitis in a 4‐year‐old boy [13].

Data to support intraventricular amphotericin is limited, with a majority of studies using the intrathecal route to treat non‐ C. auris infections [14, 15, 16, 17]. A retrospective study of 18 patients with HIV and cryptococcal meningitis received intrathecal AmB and demonstrated a trend towards improved survival [14]. Intrathecal liposomal AmB was also successfully used to treat a 44 year‐old man with refractory coccidioidal meningitis [15]. For data in Candida‐specific species, the outcomes have been mixed [4, 5, 6, 16, 17]. A case series by Nguyen MH and colleagues described 5 neurosurgical patients with Candida meningitis treated with intravenous and intrathecal AmB. Of the 3 patients who had implanted CNS devices, only 1 patient achieved cure; the remaining two patients had persistent infection and achieved cure only after adding flucytosine. There was another case report of Candida meningitis secondary to Gliadel wafer placement where the patient was successfully treated with intrathecal amphotericin for 14 days in combination with intravenous amphotericin B for 27 days [17]. For our case, we attempted to add on intraventricular amphotericin because we had EVD access, confirmed amphotericin susceptibility for C. auris , and an undetectable AmB level in the CSF even after prolonged systemic administration. We believe the addition of intraventricular liposomal AmB may have contributed to the overall improvement of our patient's CSF studies.

Another unique aspect of our patient case was utilizing posaconazole as part of our treatment regimen. Posaconazole is not considered first‐line for the treatment of C. auris or CNS infections; however, we attempted to use it based on a murine model that demonstrated posaconazole to be equivalent to amphotericin B for the treatment of CNS aspergillosis [16, 18]. Few studies have investigated posaconazole's penetration into the CSF, with the results showing low to undetectable drug levels [3, 19, 20]. Therefore, it is not surprising that for our case, we measured undetectable posaconazole levels in the CSF. From our experience, CSF drug level monitoring was a useful tool to guide our treatment decision‐making; it led to the discontinuation of posaconazole and the decision to add‐on intraventricular amphotericin.

In conclusion, we believe that intraventricular amphotericin B should be considered as a safe and effective adjunct treatment option for the management of C. auris ventriculitis. Furthermore, therapeutic drug monitoring should be considered as a strategy to help guide the management of cases where penetration may be suboptimal. Future studies are needed to correlate CNS drug levels and clinical outcomes. Finally, more research is needed to determine the best strategies for the treatment of refractory C. auris infections.

Author Contributions

Christine A. Vu: conceptualization, data curation, writing – original draft, writing – review and editing. Kelsey Ladd: data curation, writing – original draft, writing – review and editing. Folusakin O. Ayoade: supervision, writing – review and editing.

Consent

The authors were unable to obtain written consent as the patient was deceased and every effort to reach the next of kin was unsuccessful. A signed Waiver of Consent was therefore obtained and data has been anonymized to exclude any patient identifiers.

Conflicts of Interest

The authors declare no conflicts of interest.

Vu C. A., Ladd K., and Ayoade F. O., “Successful Treatment of Refractory Candida auris Ventriculitis With Intraventricular Liposomal Amphotericin B,” Clinical Case Reports 13, no. 9 (2025): e70798, 10.1002/ccr3.70798.

Data Availability Statement

The anonymized data from this case report may be available from the corresponding author upon reasonable request.