Invasive para-aortic Candida glabrata: a multidisciplinary management challenge
- 1 General Medicine, Royal Devon and Exeter Hospital, Exeter, UK
- 2 Geriatrics, Royal Devon and Exeter Hospital, Exeter, UK
- 3 Microbiology, Royal Devon and Exeter Hospital, Exeter, UK
- 4 Pharmacy, Royal Devon and Exeter Hospital, Exeter, UK
- Correspondence to Dr Robert Miller; robmiller@doctors.org.uk
Abstract
A 69-year-old man was admitted with recurrent fungal bloodstream infection on a background of abdominal aneurysm, diabetes and chronic obstructive pulmonary disease. Investigations revealed a para-aortic mass, previously thought to be lymphoma, which was culture positive for Candida glabrata on biopsy. Diagnosis and management involved multidisciplinary teamwork, diagnostic uncertainty and significant risk taking.
Background
Multidisciplinary input is vital for complex cases involving multiple organ systems, especially where there is significant diagnostic and management uncertainty. This report describes the diagnostic process and management of a rare complication of systemic microbial infection. This case required the patient and medical teams to accept uncertainty and take risks.
We report a case of persistent Candida glabrata bloodstream infection (BSI) associated with a mycotic complication of an aortic aneurysm.
Infections involving C. glabrata, the second most prevalent yeast pathogen in humans, are increasing and its unique virulence factors and antifungal resistance patterns make it a growing threat.1 2
Multidisciplinary working between the departments of medicine, microbiology, vascular surgery, pharmacy, radiology and anaesthetics, as well as cross-site liaison, was required to enable effective patient care.
Case presentation
A 69-year-old man presented in 2016 with a left ureteric stone. He had a medical history of type 2 diabetes mellitus, chronic obstructive pulmonary disease (COPD), obstructive sleep apnoea and autoimmune nephritis. In addition, he had a juxtarenal abdominal aortic aneurysm under surveillance.
He had a ureteroscopy and stent insertion. He re-presented 2 days later with fevers and rigours; blood cultures grew C. glabrata. He was managed with anidulafungin 100 mg intravenously for 14 days. However, repeat blood cultures demonstrated continued candidal growth. He was treated with fluconazole 400 mg, initially intravenous, converting to oral after 3 days, for a total course of 24 days. The stone was removed, and stent replaced, while on fluconazole.
Three weeks later, the patient developed right flank pain, CT and subsequent MRI did not show renal stones but revealed para-aortic lymphadenopathy, retrocrural and retrocaval soft tissue masses and an increase in the size of his abdominal aortic aneurysm from 5 to 5.4 cm in 8 months. The radiological diagnosis was of possible lymphoma. A CT-guided biopsy was considered but not performed due to proximity of the mass to the aortic aneurysm. The decision was for radiological surveillance unless he became symptomatic. This surveillance also showed a right upper lobe lung nodule.
The patient remained well for over 2 years until March 2019 when he developed night sweats and weight loss, an outpatient CT of thorax abdomen and pelvis was arranged. While awaiting the scan, the patient had a short admission with an exacerbation of COPD. Blood cultures taken on that admission became positive at 48 hours, growing C. glabrata, and in May 2019, the patient was urgently recalled for admission.
He was clinically stable, and on examination, there were no stigmata of endocarditis or invasive candidiasis.
Differential diagnosis
The differential diagnosis was of either the known para-aortic mass representing a tumour such as lymphoma and the focus of Candida infection being separate, or the para-aortic mass being the source of fungal infection.
Investigations
CT scan demonstrated an increase in size of the para-aortic mass and lymphadenopathy (figure 1). The previously demonstrated nodule in the upper lobe of the right lung was unchanged since previous scanning in 2018. No alternative source of the fungal infection was identified on CT. A positron emission tomography (PET) scan (figure 2) and radiolabelled white cell scan were performed. Neither identified any abnormal intra-abdominal uptake, nor evidence of an infective focus elsewhere, despite the patient continuing to have rigours and positive blood cultures.
Contrast-enhanced CT image demonstrating the para-aortic mass and abdominal aneurysm.
Positron emission tomography–CT scan demonstrating very little uptake in the para-aortic mass.
A CT-guided biopsy of the para-aortic mass was performed (figure 3). This demonstrated that the soft-tissue mass consisted of connective tissue containing high numbers of yeast cells (figure 4). These yeast cells were cultured and identified to be C. glabrata by mass spectrometry (Biomerieux matrix-assisted LASER desorption ionisation–time of flight).
CT image of biopsy needle entering the para-aortic mass.
H&E staining of biopsy demonstrating lighter-coloured connective tissue with clusters of darker fungal cells (marked).
Treatment
The details of antimicrobial therapies are illustrated in figure 5. The patient was initially started on anidulafungin 100 mg intravenously. After 48 hours, he continued to have frequent rigours and blood cultures remained positive so liposomal amphotericin B (Ambisome, hereafter referred to as LAmB) was added; unfortunately, he experienced an adverse reaction at the time of infusion. Therefore, intravenous flucytosine, initially at 5 mg two times per day, was started. However, due to national supply issues, this drug was switched to voriconazole 600 mg two times per day while continuing anidulafungin. Due to ongoing positive blood cultures on day 7, the decision was made to rechallenge with LAmB which was successful. The goal was for dual therapy with LAmB and either flucytosine or voriconazole, but due to difficulties in drug supply, there were breaks in treatment. Additionally, deterioration in renal function also required breaks in LAmB therapy. Finally, because of further positive blood cultures, anidulafungin was reintroduced on day 22 and given with flucytosine when available and LAmB when renal function permitted.
A diagram demonstrating antimicrobial use during the inpatient episode, red vertical lines demonstrate positive blood cultures. PO, orally; IV, intravenously; OD, once per day; BD, two times per day; QDS, four times per day.
Rigours were frequent, they were distressing for the patient and a challenge to manage. During a rigour, his observations were deranged with National Early Warning Scores (NEWS) of 11 or more. Despite repeated reviews by the medical emergency team (MET), there was no clear way to manage his clinical deterioration during rigours. He was admitted to the intensive care unit (ICU) for observation. Rigours lasted 10–15 min and each time the patient recovered spontaneously. Following ICU admission, the plan was that his high NEWS would only trigger a MET call if the high score was sustained for more than 20 min.
Rigours with positive blood cultures continued despite antifungal therapy for 7 weeks. Source control was carefully considered. The vascular surgical opinion was that surgical removal of the para-aortic mass could only be undertaken with a plan to repair the aortic aneurysm at the same procedure if it was found that the mass was integral to the aortic wall. The aneurysm was complex, even without the addition of possible mycotic transformation, requiring an endovascular fenestrated repair in order to preserve renal perfusion. Operative prognosis was worsened by the fact that the patient had been septic for 6 weeks with depletion of his physiological reserve. If he did survive surgical intervention, given the ongoing fungaemia, there was a risk that his prosthesis would become infected. During these discussions, the patient was showing some signs of improvement on anidulafungin 100 mg intravenously and flucytosine 2.5 g orally. A decision was made to pursue medical therapy with a review of the options if his physiological fitness for surgery improved.
Outcome and follow-up
After day 49, the patient’s rigours ceased, and C-reactive protein (CRP) fell to 36 mg/L. The patient was discharged to continue treatment through ambulatory care.
Triple antifungal therapy continued as an outpatient including daily attendances for intravenous anidulafungin 100 mg with oral voriconazole 200 mg two times per day and oral flucytosine 2.5 g four times per day (four times a day) until day 82. His CRP continued to decrease and he was maintained on oral vorizonazole and flucytosine with no recurrence of fevers. After a further month and due to side effects, flucytosine was reduced to 1.25 g four times a day.
Future management requires minimising risk factors for invasive candidiasis. The diabetologists are endeavouring to achieve optimum control of type 2 diabetes mellitus and respiratory physicians are managing his COPD with a plan to try to avoid steroid therapy to reduce the risk of reactivating the mycotic infection.
After prolonged discussions with all the teams involved, including regional vascular surgeons, the current plan is to maintain the patient on long-term antifungal therapy and not to proceed to surgery. The extremely high risks of operating on a stable aortic aneurysm less than 6 cm in diameter with the complications of a fungal mass were felt to be too high. At the time of submission, the patient remains on dual antifungal therapy, free from rigours and at home.
Discussion
Candida glabrata
C. glabrata, a haploid budding yeast, is a common human commensal and increasingly prevalent opportunistic pathogen.2 C. glabrata BSIs are most commonly found in elderly individuals, patients with diabetes and solid organ transplant recipients. UK data have shown that C. glabrata accounts for 50% of critical care fungal BSIs and 29% of total Candida BSIs.2 3 Multiple virulence factors enable the microorganism to thrive in the host by readily forming biofilms, reducing and evading host immune responses, and developing antimicrobial resistance.4
C. glabrata expresses a large number of adhesins which enable it to adhere to both biotic and abiotic surfaces; these adhesins are upregulated in urine, helping make C. glabrata the most common Candida isolated from urine.5 C. glabrata forms very compact biofilms which confer antifungal resistance and further reduce the host immune response.6
Immune evasion is a key strategy in the pathogenicity of C. glabrata. In contrast to Candida albicans, C. glabrata induces monocyte rather than neutrophil migration to the site of infection.7 Furthermore, when C. glabrata is phagocytosed, it is adapted to survive and replicate in monocytes without leading to cell destruction and cytokine release, therefore limiting recruitment of other immune cells.8 C. glabrata has been shown to persist in immunocompetent mice for several weeks, eliciting only mild immune responses and pathology.9 In our case, we postulate that the infection remained dormant for 2 years and, even when the infection was active, PET and radiolabelled white cell scans were normal.
Multidrug antimicrobial resistance is an important problem in C. glabrata.10 It is intrinsically less susceptible to azole antifungals and, when exposed, develops increasing resistance.11 In 2018, data for England showed resistance levels of C. glabrata isolates to fluconazole and voriconazole at 9% and 10%, respectively.12 Widespread azole use may establish a selective pressure for C. glabrata against C. albicans. Resistance to echinocandins has also been demonstrated. Crucially, antifungal resistant forms of C. glabrata demonstrate increased pathogenicity compared with less resistant forms.13
Combined, these features make C. glabrata a growing threat.
Importance of source location and control
Source control is the most important strategy in the management of infection.14 In this case, we considered removal of a para-aortic mass in an operation that carried a high risk of mortality. Therefore, unequivocal evidence that the para-aortic mass was the source of infection was required. Multiple imaging modalities failed to prove the source, so it was necessary to proceed to biopsy. The proximity of the mycotic collection to the aneurysmal wall and their potential interaction meant that even biopsy could prove fatal.
Having proved the source and, when it appeared that the patient would not stabilise on antimicrobial therapy alone, surgery was carefully considered. Vascular surgery discussions were elevated to national level and concluded that the risk of operating was too great. Even if the patient survived the operation, he was to likely require an aortic graft in an infected field and was almost certain to be anephric with poor predicted survival on dialysis.
Diagnostic uncertainty
Mycotic abdominal aortic aneurysms are rare entities which account for 0.65%–2% of aortic aneurysms, a challenging diagnosis requiring a high degree of suspicion.15 However, this aneurysm did not exhibit the characteristic fast growth and radiological appearance of a truly mycotic aneurysm. If this is a mycotic transformation of an abdominal aortic aneurysm, we believe this to be the first such published case.
Variable response to multiple antifungals as well as renal impairment and procurement difficulties made antifungal choice a day-to-day management decision. Antifungal choice was guided by local microbiology and regional mycology departments who recommended anidulafungin initially due to the high tendency of C. glabrata to have resistance to fluconazole.1 Rigours continued and so LAmB was added; however, the patient experienced a severe reaction following the initial dose therefore it was stopped and voriconazole was added. Unfortunately, supply of flucytosine was quickly exhausted due to national shortages and his rigours and inflammatory markers increased after flucytosine was stopped. In this difficult situation, the prognosis was so poor that other options had to be considered. After careful discussion, it was decided by the multidisciplinary team (MDT) that a further attempt at LAmB was the best course of action. We decided to give the medicine at a slower rate and monitor for any reaction. We concluded that his first dose reaction was either due to the infusion rate or a coincident rigour as he did not have further infusion reactions, but he did have LAmB therapy interrupted several times due to transient deterioration in renal function.
Multidisciplinary working
MDT working is a focal strength in the management of this case. Teams at the ward level were required to work closely to manage his frequent rigours, take blood cultures but not escalate his care to peri-arrest calls inappropriately. At the specialty level, physicians, surgeons, microbiologists, pathologists, anaesthetists and radiologists were involved in his care and required to work closely together to decide on the best course of treatment. Pharmacy continues to have a vital role in sourcing antifungal medicines including sourcing drugs internationally. A regional videoconference was arranged to discuss the case and the best management between local centres. At a national level, several tertiary and specialist surgical centres are involved in his care. At a local level, his ongoing care is managed by a general physician in liaison with microbiology, supported by respiratory physicians and endocrinologists.
Pharmacy perspective: Hannah Burnett
This is a complex case combining all aspects of pharmacy and working closely in an MDT. During the inpatient stay, pharmacy helped advise the team about the reaction to LAmB and ensured therapeutic drug monitoring of voriconazole. We sourced intravenous flucytosine which was on a European-wide manufacturing delay, initially looking into the possibility of sourcing it from Australia and then buying stock from other hospitals across the UK.
As the MDT started to discuss discharging the patient, oral formulations of the antifungals were sought. Specialist advice was sought from pharmacist colleagues, through clinical networks, regarding unlicensed oral flucytosine as limited data were available regarding dosing. Funding and ongoing supplies were discussed with the clinical team as antifungals are ‘hospital only medicines’ that general practitioners would not prescribe.
Now as an outpatient, pharmacy continues to manage antifungal supplies and have been sourcing alternatives during multiple manufacturers’ delays to both oral agents; this has presented complex challenges that we have overcome as a MDT.
Managing physician’s perspective: Dr Harris
I was responsible for the care of this patient in my role looking after medical outliers on a surgical ward. We had recently made changes to improve continuity of care for our outliers and this was very helpful in management of a complex case. It is always a privilege when you can manage a patient closely throughout a prolonged illness.
After I discussed the very bleak prognosis with him, the patient asked me what difference it made, and I said now we can take risks. I realise now these are the sort of risks many of my colleagues particularly those in vascular surgery are very familiar with.
It enabled me to retry administration with LAmB despite us thinking that he had an anaphylactic reaction to his first dose. He was already on anidulafungin, both voriconazole and flucytosine were proving very difficult to acquire and he was continuing to have rigours and positive blood cultures. In retrospect, it seems likely that his severe adverse reaction following the first dose of LAmB was a combination of him having a non-anaphylactoid infusion reaction and a simultaneous rigour. He went on to tolerate intravenous LAmB at a reduced infusion rate, although deterioration in renal function required frequent breaks in treatment.
I was able to openly discuss and then arrange a potentially life-threatening biopsy with the patient and his son.
I have increased respect for all of my colleagues. My radiology colleague who performed the biopsy. The vascular surgeons who investigated every avenue for removal of the fungal mass and repair of the aneurysm. The pharmacist and microbiologists who continue to work extremely hard to source antifungal agents for this patient, and for the patient who put his trust in us while questioning what we did in a way that gave us increased opportunity to do the right thing.
I experienced yet again the age-old conundrum of arguing for surgery while the patient was unfit for it and then, when the surgeons felt the risks were as low as they were going to get, arguing that it was probably safer not to proceed.
Microbiology perspective: Dr Porter
C. glabrata BSIs carry a significant mortality risk and are often seen in patients with significant comorbidities. Source control is a key dogma in achieving cure, but it took a significant period of time to finally prove the source of the infection in this patient.
Once we had proved the source on histology and culture from the tissue biopsy, and with no evidence of improvement on multiple antifungals, we were keen to push source control, with a real concern that this was his only hope of surviving. However, the considerable complexity with any surgical approach meant that enough time passed for us to begin to see signs of improvement.
Alongside this, we had challenges with a voriconazole-resistant organism and significant supply issues with other antifungals. All antifungal options were considered including the newer azole isavuconazole with close liaison with national mycology reference laboratory in Bristol.
We remain challenged by the long-term approach to this patient’s care. A review of antifungals with a view to stopping them would seem the most attractive option, with lifelong suppression as an alternative.
Patient’s perspective
Prior to hospital admission, I had thought the rigors to be severe chills and so tried to manage the situation at home for some weeks. The actual rigor attacks, and the constant not knowing when the next rigor would occur, were very draining, and the threat was debilitating and depressing.
The severe reaction I had to the first dose of intravenous Ambisome was startling and extremely painful; facing the second dose was a challenge. Antifungal prescriptions are a constant battle, the worry of being without medication causes stress to me and my family. I was without one of the medications for a week and experienced a possible rigor.
During my admission I was unable to taste food, had no appetite and a constant dry mouth which made me rapidly lose weight and feel physically exhausted. The involvement of so many different medical disciplines made the information flow difficult at times. However, I greatly appreciated the team’s communication, as I felt that I was being kept informed and that I was able to contribute to the discussion. I am still able to contact my consultant, which gives me a link to the medical team. I am happy to say that I have recovered sufficiently to re-start a more or less normal life, including cycling and fishing.
Learning points
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Candida glabrata is a growing threat due to a combination of virulence factors, widespread antifungal resistance and increasing prevalence.
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Management of this case required multidisciplinary team (MDT) working and close relationships between disciplines and hospitals facilitate the best MDT working.
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Unusual cases present a management challenge as they fall outside the evidence base. In this case, it necessitated a willingness to take risks.
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Difficulties in medicines procurement can threaten good patient care, even in established health systems in developed countries, and can be extremely time-consuming and expensive to overcome.
Ethics statements
Footnotes
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Contributors Supervised by SH. Patient was under the care of SH. Additionally, RP, HB and RM were involved in the care of this patient. Perspective and review were provided by SH, RP and HB. Report was written by RM.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.
References
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