Does parental nutrition increase the risk for fungemia?

Comment by InpharmD Researcher

Available literature presents conflicting findings regarding whether parenteral and lipid nutrition increases the risk of fungemia. While some prospective studies and case reports suggest that parenteral nutrition may contribute to the development of fungemia, other literature indicates that factors such as the pH and osmolarity of the parenteral nutrition, presence of hyperglycemia, and increased manipulation of the bag may play a more significant role in increasing the risk of fungal infections rather than parenteral nutrition alone. Overall, further research is needed to fully understand the relationship between fungemia and parenteral nutrition.

Background

A 2017 report aimed to describe factors associated with fungemia in patients with parenteral nutrition. The recommendation from multiple organizations such as the Infection Control Practices Advisory Committee and the European Society for Clinical Nutrition & Metabolism is to remove or change lipids for every 24 hours to decrease the risk of fungal infections, although the authors argue this recommendation may be based on outdated information. While thought to pose a risk of increased fungal infection when added to parenteral nutrition, the review notes that literature supporting this claim is ambiguous, lacking sufficient recent, good-quality evidence. Ultimately, the authors suggest that lipids in parenteral nutrition do not increase the risk of fungal infections and that withholding parenteral nutrition for this specific reason may actually result in patient harm. Strict protocols regarding catheter placement and utilization of a nutrition support team to educate medical personnel may help reduce overall risk of infection due to parenteral nutrition in general. Future studies are still needed to fully elucidate the relationship between fungemia and parenteral nutrition, with the author suggesting that factors such as the pH and the osmolarity of the parenteral nutrition, presence of hyperglycemia, and increased manipulation of the bag may play a bigger role in increased risk of fungal infections rather than from the parenteral nutrition alone. [1]

Other related discussion articles also argue that the risk of increased fungal infections due to lipid emulsions is erroneous, likely due to outdated information compiled from a time period when parenteral nutrition administration may not have been conducted with proper equipment and protocols, such as inadequate catheter care and poor techniques for achieving glucose control. The sole presence of a central venous catheter (CVC) and its connection point is associated with increased infection, even with ideal standard of care. Additionally, animal models suggest the very absence of enteral feeding may increase risk of fungal infection due to resulting gut atrophy and translocation of microorganisms. Authors discuss the lack of clinical studies specifically investigating Candida-related bloodstream infections associated with lipid-containing or lipid-free parenteral nutrition, hypothesizing that such a comparison may not be viable due to ethical reasons associated with forgoing a vital component such as lipids from parenteral nutrition. Some data demonstrates that Candida species can proliferate in all parenteral nutrition solutions, regardless of presence of lipids, and an in vitro study was discussed, which demonstrated that inclusion of lipid emulsion was not found to impact growth of C. albicans, further suggesting concerns regarding increased risk of fungal infection with modern day compounded practices is unfounded. Furthermore, recent advances such as use of multi chamber bags and peripherally inserted central catheters have been shown to decrease rates of bloodstream infections, as well as standards of care such as hand hygiene and maximal barrier precautions during insertion of catheters. Ultimately, if bloodstream infections occur in a patient receiving parenteral nutrition, currently available data suggests that the cause is likely to be independent of the infusates contained within the product, lipid or otherwise. [2]

A 2016 systematic review and meta-analysis assess the effect of lipid emulsion on microbial growth in parenteral nutrition. A total of 24 studies were included; notably, the authors discussed that some guidelines related to microbial growth and use of parenteral nutrition utilized more limited and weaker data. Amongst the included studies for the present review, compositions of infusates varied widely and compositions of lipid parenteral nutrition rarely matched that of lipid-free parenteral nutrition. Lipid concentrations, energy density, pH, osmolarity, and other factors may have also varied. The effects of nutrients on growth ratio (GR) was assessed, finding that presence of lipid in parenteral nutrition at fixed glucose concentrations did not significantly increase GR of Candida albicans (p= 0.352). [3]

Additionally, a 2012 comparative retrospective study may be insightful, despite not specifically assessing incidence of fungemia. The study included 4,669 patients to compare use of commercially available premixed parenteral nutrition with or without lipids and risk of incident bloodstream infections. Data regarding use of nutrition was compiled via charge codes. Lipid emulsions were administered through a separate line or piggybacked through the parenteral nutrition line. After adjusting for patients baseline characteristics, risk factors, and potential confounders, results indicated that no significant differences were observed in overall risk of bacterial infections (51.4% vs. 53.5%; odds ratio [OR] 1.11, 95% confidence interval [CI] 0.96 to 1.27) or bloodstream infections (19.6% vs. 19.2%; OR 0.97, 95% CI 0.81 to 1.16) for patients receiving nutrition without lipids vs. those with lipids, respectfully. Unfortunately, a subgroup analysis investigating risk of Candida related infections was not conducted. [4]

References:

[1] Quesada, C., Aceituno, J., Suárez, R., & Mazariegos, C. (2017). Fungemia Related to Parenteral Nutrition. Current Tropical Medicine Reports, 4(3), 172–177. doi:10.1007/s40475-017-0120-8
[2] Sriram K, Meguid MM. Addition of lipids to parenteral nutrition does not cause fungal infections. Nutrition. 2015;31(11-12):1443-1446. doi:10.1016/j.nut.2015.05.010
[3] Austin PD, Hand KS, Elia M. Systematic review and meta-analyses of the effect of lipid emulsion on microbial growth in parenteral nutrition. J Hosp Infect. 2016;94(4):307-319. doi:10.1016/j.jhin.2016.08.026
[4] Pontes-Arruda A, Liu FX, Turpin RS, Mercaldi CJ, Hise M, Zaloga G. Bloodstream infections in patients receiving manufactured parenteral nutrition with vs without lipids: is the use of lipids really deleterious?. JPEN J Parenter Enteral Nutr. 2012;36(4):421-430. doi:10.1177/0148607111420061

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Does parental nutrition increase the risk for fungemia?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→



Please see Tables 1-3 for your response.


 

Risk factors for candidal bloodstream infections in surgical intensive care unit patients: the NEMIS prospective multicenter study. The National Epidemiology of Mycosis Survey

Design

Prospective, multicenter study

N= 4,276

Objective

To assess risk factors for the development of candidal bloodstream infections (CBSIs)

Study Groups

All patients (N= 4,276)

Inclusion Criteria

Patients admitted to surgical intensive care unit (SICU) for >48 h

Exclusion Criteria

Not explicitly stated 

Methods

Clinical and epidemiological data were collected daily for all patients enrolled in the study. Case patients were identified as individuals with a Candida species recovered from blood culture 148 hours after admission to the SICU. Risk factor analysis for case patients included data up to CBSI development, while non-case patients' data were analyzed for the entire SICU stay.

In the first year of the study, all azole drug use was recorded as a single variable, while in the second year, specific information about the administered azole drugs (e.g., fluconazole, itraconazole, ketoconazole, miconazole, or clotrimazole) was documented. Severity-of-illness measures, such as American Society of Anesthesia (ASA) scores, Acute Physiology and Chronic Health Evaluation (APACHE) II scores, and McCabe-Jackson scores, were calculated for all patients upon SICU admission. Rectal swabs and urine specimens were collected upon SICU admission and weekly thereafter for fungal surveillance culture.

Duration

October 1993 to November 1995

Outcome Measures

Incidence of CBSIs and risk factors associated

Baseline Characteristics

 

All patients (N= 4,276)

Age, years

4–24

25–44

45–64

≥65

 

331 (8%)

1118 (26%)

1558 (36%) 

1269 (30%)

Female

1632 (38%)

McCabe and Jackson disease score

Nonfatal

Ultimately fatal

Rapidly fatal

 

1848 (43%)

1468 (34%)

948 (22%)

APACHE II score

0–11

12–17

18–24

25–47

 

946 (22%)

991 (23%)

1157 (27%)

1159 (27%)   

ASA score*

1–2

3

4–5

 

600 (14%)

1434 (35%)   

947 (23%)

Abbreviations: APACHE= Acute Physiology and Chronic Health Evaluation; ASA= American Society of Anesthesia 

*Surgery patients only

Results

Endpoint

All patients

RR (95% CI)

p-Value

Incidence of CBSIs

42 of 4,276 - -

Case patients who received central venous catheter*

41 of 42 (98%)

8.1 (1.1–59.6)

0.04

Treatments/drugs received by case patients*

Parenteral nutrition

Intralipid agents

Vancomycin

Anti-anaerobic agents

 

30 of 42 (71%)

22 of 42 (52%)

27 of 42 (64%)

32 of 42 (76%) 

 

3.8 (1.9–7.6)

2.2 (1.2–4.0)

1.5 (0.8–2.8)

2.2 (1.1–4.6) 

 

<0.001 

0.02

0.26

0.03

Any antifungal agent
administered to case patients*

16 (38%)

0.6 (0.3–1.1)

0.09

Abbreviations: CBSIs= candidal bloodstream infections; CI= confidence interval; RR= relative risk 

*n= 42 

Total of 42 CBSIs occurred (9.82 CBSIs per 1000 admissions). The overall incidence was 0.98 CBSIs per 1000 patient days and 1.42 per 1000 SICU days with a central venous catheter in place.

Adverse Events

N/A

Study Author Conclusions

In summary, this report demonstrates that the wide variation in the rate of CBSI between institutions is likely due to the underlying risk factors of the different patient populations served by the geographically dispersed institutions, and it defines a number of risk factors that are independently associated with increased risk of CBSI.

InpharmD Researcher Critique

Although the study suggests that parenteral nutrition is a risk factor for candidal bloodstream infections this finding may not be generalizable to all patients receiving parenteral nutrition, as the study specifically focused on surgical intensive care unit patients.



References:

Blumberg HM, Jarvis WR, Soucie JM, et al. Risk factors for candidal bloodstream infections in surgical intensive care unit patients: the NEMIS prospective multicenter study. The National Epidemiology of Mycosis Survey. Clin Infect Dis. 2001;33(2):177-186. doi:10.1086/321811

 

Case report: nosocomial fungemia caused by Candida diddensiae

Design

Case report 

Case presentation

A 62-year-old woman was admitted to a community hospital in South Korea for multiple contusions from repeated falls. She received treatment including antibiotics, urinary catheterization, and total parenteral nutrition (TPN) with a lipid emulsion. C. diddensiae fungemia was diagnosed based on positive blood cultures on hospitalization days 17, 23, and 24. The patient had a history of systemic lupus erythematosus and chronic leukopenia. She also had a chordoma diagnosed 5 years prior, resulting in multiple cranial nerve neuropathies. Before admission, she had aspiration pneumonia and received antibiotic treatment with piperacillin/tazobactam and levofloxacin for 2 weeks. TPN with a lipid emulsion was started at the beginning of hospitalization, and all infusions were completed within 24 hours of initiating the fluid. On day 8, the patient developed an intermittent fever (peak temperature 38.8 °C) that persisted for 14 days. Catheter-associated urinary tract infection was suspected, and ceftriaxone was initiated after a urine culture was taken. The antibiotic was subsequently changed to vancomycin because the urine culture revealed the presence of ampicillin-resistant, vancomycin-susceptible Enterococcus faecium. Chest and abdominal computed tomography did not reveal any focus of infection or perforation. Because blood cultures obtained on day 17 indicated the presence of a yeast, she was transferred to another hospital for the treatment of fungemia.

Upon physical examination, there were no local inflammatory signs at the peripheral intravenous catheter sites. On arrival to the other hospital (on day 23), a follow-up blood culture was performed, and intravenous (IV) fluconazole was initiated empirically (800 mg loading dose followed by 400 mg/day). The TPN was then discontinued. An ophthalmological examination showed no evidence of endophthalmitis, and transthoracic echocardiography showed no evidence of endocarditis. On day 26, the fluconazole was replaced with micafungin 100 mg/day for 16 days due to the high fluconazole minimum inhibitory concentration in antifungal susceptibility tests. Follow-up blood cultures taken on day 26 were negative. The patient’s condition improved, and she was discharged on day 41 after supportive care and IV echinocandin treatment.

Study Author Conclusions

The use of lipid TPN may potentially contribute to the occurrence of nosocomial fungemia by C. diddensiae, an unusual Candida species. 
References:

Kim SE, Jung SI, Park KH, Choi YJ, Won EJ, Shin JH. Case report: nosocomial fungemia caused by Candida diddensiae. BMC Infect Dis. 2020;20(1):377. Published 2020 May 27. doi:10.1186/s12879-020-05095-3

 

Catheter-related fungemia caused by Candida intermedia

Design

Case series

Case presentation 1

A 99-year-old man with gastric adenocarcinoma underwent total gastrectomy with Billroth’s II anastomosis in January 2007. He was admitted to the hospital in early 2008 due to post-operative adhesion ileus. A broad-spectrum cephalosporin was administered for fever and suspected intra-abdominal infection during his hospital stay. Due to prolonged poor oral intake, a Port-A-Cath was inserted for parenteral nutrition. After receiving parenteral nutrition for two weeks, he developed fever and leukocytosis with left-shift. He had no respiratory or urethral symptoms. Blood cultures from the Port-A-Cath and peripheral vein were both positive for yeasts, identified as C. intermedia. The Port-A-Cath was removed, and culture of the removed catheter tip also tested positive for C. intermedia. Intravenous fluconazole (400 mg daily) was administered, resulting in the resolution of fever, normalization of white blood cell count, and eradication of C. intermedia fungemia after two weeks of treatment.

Case presentation 2

A 37-year-old man with a history of megacolon underwent surgical intervention at birth, resulting in the development of short bowel syndrome. He subsequently received long-term parenteral nutrition via an implantable central venous catheter. Over the years, he underwent multiple replacements of the central venous catheter due to catheter-related infections. One month prior to the recent event, he had an episode of catheter-related infection with Escherichia coli bacteremia, successfully treated with an advanced-generation cephem. In late March 2008, he developed a high fever with chills, without other specific symptoms or physical signs noted. His white blood cell count was within the normal range, but significant left-shift was observed. A chest radiograph showed no abnormalities. Blood cultures from both a peripheral vein and a central venous catheter yielded yeasts, highly suspecting catheter-related candidemia. Although the central venous catheter was replaced, culture of the removed catheter tip was not performed. IV fluconazole (200 mg daily) was administered. The yeast isolates in blood cultures were identified as C. intermedia. Subsequently, his fever subsided, and follow-up blood cultures returned negative.

Study Author Conclusions

In summary, this is the first case report of human bloodstream infections caused by C. intermedia. It raises the possibility that C. intermedia may be a causative pathogen of catheter-related fungemia in patients with long-term parenteral nutrition or intravenous catheters over a long period.
References:

Ruan SY, Chien JY, Hou YC, Hsueh PR. Catheter-related fungemia caused by Candida intermedia. Int J Infect Dis. 2010;14(2):e147-e149. doi:10.1016/j.ijid.2009.03.015