Fungal Infections in Burn Patients

Abstract

Background:

Fungal burn wound infections are among the most devastating complications in patients who are severely burned. Increasing incidence of burn wound infections caused by fungi led to new challenges in diagnostic and therapeutic approaches. The wide use of broad-spectrum antibiotic agents, an increased prevalence of molds and non-Candida albicans spp., and the variety of available antifungal agents underline the importance of identifying the causative species, to initiate adequate therapy within an adequate timeframe.

Methods:

Review of the pertinent English and German literature.

Results:

Fungal burn wound infections go along with a delay of identifying the causative fungus species and can be mistaken for early bacterial burn wound infection. Recently, an increase of uncommon fungal pathogens and fungi resistance against antifungal agents has been reported. Amphotericin B and voriconazole remain the antifungal drugs used most commonly.

Conclusions:

Adequate therapy remains challenging. Early radical debridement and wound closure play an imperative part, particularly in preventing infections caused by yeasts and molds or any other agent. Prophylactic empiric pharmacologic treatment is reserved for those highly at risk for invasive burn wound infection only. Because of the emergence of drug-resistant fungi, the development of new antifungal drugs is essential for the battle against fungal burn wound infections.

Complications caused by infections are the primary reason for late onset morbidity and high mortality in burn patients [1,2]. The risk for infections is increased because of loss of the barrier-function against microbial species, downregulation of the immune system, and the use of invasive devices such as central lines or urinary catheters [3]. Advancements in burn care over the last decades, such as early radical surgical excision of burn eschar and the use of antibiotic agents, increased the chances of survival of patients who were severely burned [1,4]. Topical and systemic antibacterial treatment, as well as controlled intensive care unit (ICU) procedures have focused on bacterial species, which led to a decrease in bacterial burn wound infections (BWI). However, this led to an increased incidence in fungal infections [5,6]. Since the introduction of topical antibacterial therapy and the establishment of early broad-spectrum antibiotics in the 1960s, a 10-fold increase of fungal burn infections has been observed [7]. The early diagnosis of fungal infections is challenging because their clinical appearance is similar to low-grade bacterial infections [8]. In this review, we discuss the most common fungal pathogens causing burn wound infections, incidence and risk factors, diagnostic approaches, current state-of-the art local and systematic therapeutic options, and put the latest research in context.

Epidemiology and Fungal Pathogens

Prior to the use of the topical antimicrobial agent mafenide acetate, gram-negative bacterial wound infections were the leading cause of death in patients who were severely burned [6]. Over the last decades, the incidence of yeasts and molds in burn wound infections has increased and is reported to ranges from 6.3% to 40% worldwide [6,9,10].

In several studies, Candida albicans is reported to be the most common fungal pathogen causing infections in burn patients [2,11]. Furthermore it is the fourth most frequent pathogen in blood cultures in ICU patients (12).

Mold infections are rare and uncommon but seem to have become more frequent in burn patients over the last decades. In general they are associated with higher risk for morbidity and mortality and are associated with poor prognosis. (12)

Aspergillus species are the most common non-Candida pathogens, with an incidence reported of approximately 14%–17% in patients who are severely burned [5,11]. Furthermore, they are correlated more closely with lethal infections, resulting in high morbidity and mortality rates of up to 33% [1,12 –15]. A retrospective single-cohort study reviewed 1,849 burned patients with a positive filamentous culture. Mold infection was present in 1.7% (1.2% for aspergillosis (ASP), 0.5% for mucormycosis (MMC), and 0.2% for fusariosis (FUS). This study highlighted that most were cutaneous and occurred in patients with mean total body surface area (TBSA) of 55% and mean full thickness burn area of 45%, which was higher than in burned patients without filamentous fungal infection (FFI). Of the FFI, infection caused by Aspergillus was more lethal (30%) and seems to be more serious than other FFI [16].

Cutaneous mucormycosis, in particular zygomycetes, shows an increase in infection rate that can lead to a wide spectrum of diseases. In contrast to Candida, which is part of the healthy human skin flora, zygomycetes are soil fungi. Zygomycetes typically are parasites of plants, insects, and small animals and in general, are rare and uncommon. In burn patients they are likely to occur only in those patients who are severely immunocompromised [16,17]. They are associated with a high mortality rate of 54%, which has not improved in the last decades, as reported in the review by Ledgard et al. [18]. Although Candida plays a major role in fungal burn wound infections, there is a recognized increasing prevalence of non-Candida albicans spp., such as Candida tropicalis, Candida parapsilosis, Candida krusei, and Candida glabrata. They are associated with higher mortality rates and a decreased susceptibility to the widely used fluconazole and other antifungal agents [8,19,20]. A recently published retrospective observational study reviewed 410 patients who were severely burned with a TBSA of more than 40%. Thirty-nine (9.51%) were diagnosed with candidemia. There was a dominance of non-Candida albicans spp., namely Candida parapsilosis (28.21%), followed by Candida tropicalis and Candida albicans (15.38%) [21]. The wide use of fluconazole and its impact on the epidemiology of invasive Candida has been described, as studies reported the emergence of Candida krusei [22,23].

Risk Factors

There exist multiple risk factors for invasive fungal infections in burns. The infections usually occur after the second week of thermal injury. Immunodeficiency in the patient who is severely burned has the most impact on development of fungal infections. Also inhalation injury, renal dysfunction, and replacement therapy as well as gastrointestinal complications are major risk factors [21]. Furthermore, broad-spectrum antibiotic treatment and being on a ventilator for longer than 48 hours increase susceptibility to fungal infections [2]. The single most important risk factor for fungal infections however, is the burn wound itself [1,2,11]. A larger TBSA burned and the early usage of broad-spectrum antibiotic agents were found to increase the risk for invasive fungal infections further [24]. A recently published prospective study reviewed 50 patients with burns over 20%–60% TBSA [9]. The incidence for fungal infections was 26%. The incidence was directly proportional to TBSA, which increased to 63.6% with burns larger than 51%–60% TBSA. These findings agree with other studies [6,7,11,25]. Furthermore, in the study by Sharma et al. [9] an increase of incidence was observed in patients of third-degree burns, which was agreed with the findings in the study by Bruck et al. [25]. However, according to a recently published retrospective cohort study of 130 patients who were severely burned with Candida spp. colonization and at least one episode of sepsis or septic shock, only the duration of recent antibiotic therapy was independently associated with higher risk for fungal wound infection [26].

Furthermore, there are environmental risk factors, especially for true fungal infections (i.e., zygomycetes), which occur in the early phase of hospitalization. Characteristically, burn victims are exposed to spores at the time of the injury because of exposure to contaminated surface water or rolling on the ground during their attempt to extinguish the fire [27]. Contamination of waters systems has also been reported to be a source of infections caused by Aspergillus and other molds [28).

Diagnosis of fungal infections

The diagnosis of fungal infections is particularly difficult, especially in the early phase of an infection because they can mimic early low-grade bacterial infections. Several different culture media are necessary to identify the specific genome. Nevertheless, it requires several weeks to obtain laboratory confirmation, which may result in delay of adequate treatment. Furthermore, laboratory tests may have limited impact. Despite the low sensitivity of 50%–70%, obtaining fungal cultures is still the gold standard and identifying the exact fungal strain causing the burn wound infection has become increasingly important. Similar to treating bacterial infections after resistance testing, there are new antifungal treatments available that are used specifically for particular strains [2,29 –32]. Histologic evaluation of burn wound biopsies is the only tool by which a fungal invasion can be identified precisely [1]. However, because of its invasive character, this method is usually avoided and not performed routinely. Moreover, a study by Schofield et al. (31) showed that there is inconsistency in correlation between histopathologic and culture identification of fungi. Furthermore, this study showed that histopathologic samples alone are inadequate in order to specify the right antifungal agent and highlighted the importance of taking histopathologic samples as well as cultures to determine the fungi species and further initiate the adequate antimycotic treatment.

Topical Treatment Approaches

Because of natural barrier loss, immunosuppression, and the use of broad-spectrum antibiotic agents and catheters in patients who are severely burned, the treatment of this specific patient cohort is problematic. Fungal growth prophylaxis, especially Candida, can be provided by topical treatment, using nystatin. It is a highly potent topical equivalent to amphotericin B and can be applied in low doses of 100,000 U/g as cream, lotion, or ointment. The topical application of pure nystatin powder at a higher concentration of 6,000,000 U/g was proved to be effective in exterminating invasive fungi [8]. The powder does not only eradicate fungi superficially but also in deep burned tissue. This type of application does not cause pain or discomfort and is easy to use. For prevention of oral or perineal overgrowth of yeast and fungi, liquid nystatin “swish and swallow” is used commonly in combination with topical therapy. On the other hand, it must be considered that the effect of topical treatment is limited to the wound and might mask manifestations of systemic fungal infections [2,8,33].

Mafenide acetate ointment (Sulfamylon^®, Mylan Institutional, Canonsburg, PA) was introduced in the 1960s and was used as topical treatment against BWI. It is effective and shows excellent bacteriostatic activity in both gram-negative and gram-positive micro-organisms, however, it lacks antifungal activity. A solution of the combination of amphotericin B with mafenide acetate, commonly known as SMAT, has been shown to provide antifungal activity against species including Candida, Fusarium, and Aspergillus. However, a recent published study showed that the stability of amphotericin B in SMAT is impacted by the storage conditions regarding the temperature. This report emphasized that SMAT should refrigerated while stored and applied at room temperature to provide antifungal activity against Candida spp. yeasts. (34)

Systemic Treatment Approaches

The antimycotic pharmacologic armamentarium includes a limited number of drug groups (azoles, polyenes, and echinocandin) with different susceptibility to fungi. However, it must be remembered that these antifungal agents cause adverse effects. The antifungal agents commonly used in fungal burn infections are illustrated in Table 1.

Table 1.

Commonly Used Antifungal Agents in Fungal Burn Wound Infection

Drug	Doses	Application	Side effects and notes
Amphotericin B deoxycholate (AmBd)	0.3–1.5 mg/kg over 1–4 h	IV	Widely used antifungal agent; nephrotoxicity is the main side effect, which limits the use of AmBd. Additional side effects are: fever, chills, and myalgia.
Amphotericin B lipid complex	5 mg/kg	IV	Similar to AmB but nephrotoxicity is less frequent than AmB; new standard for treating invasive molds.
Fluconazole	∼6 mg/kg/d	IV/oral	Widely used antifungal agent; well tolerated
Voriconazole	2 × 200 mg/d oral or 3–6 mg/kg every 12 h IV	IV/oral	Visual disturbance in various forms has been reported. Approved for invasive Aspergillus and Fusarium spp.
Caspofungin	For IA: 35–70 mg/d, begin with 70 mg on day one, 50 mg/d from day 2 onwards	IV	Mild side effects (nausea, vomiting, diarrhea, fever, skin rush or itching, headache)

Data from Cambiaso-Daniel et al. [8] and drfungus.org [44].

AmB = amphotericin B; IV = intravenous; IA = invasive aspergillosis.

The prophylactic and empiric use of antifungal agents should not be done routinely, because it leads to emerging antifungal resistance and there is no existing evidence to support this strategy. However, there are reports of prophylactic treatment in burn patients with high risk for invasive candidiasis and presenting with more than 50% TBSA and inhalation injury [2,11,35].

Amphotericin B and fluconazole are widely used antifungal agents applied in fungal BWI. Amphotericin B has a broad-spectrum antifungal activity and covers most Candida and Aspergillus species, however, its use is limited by its nephrotoxicity. This side effect manifests in acetonia, decreased glomerular filtration rate, loss of sodium and potassium, and loss of urinary concentration [36]. The lipid formation reduces the toxicity, but it is not a first-line therapy option and there is no evidence that it is superior to amphotericin B deoxycholate in the treatment of candidiasis [37].

Azoles are widely used for fungal infections. Fluconazole especially is widely used for treating candidiasis because of its low toxicity, but it lacks in activity against Candida krusei and has limited or no activity against molds. Furthermore, the high frequent use and long-term exposure to fluconazole led to the emergence of drug-resistant strains of Candida albicans [30,37,38]. As a result of the increasing prevalence of non-Candida albicans spp. such as Candida glabrata (with known low susceptibility to fluconazole) and Candida krusei (an inherently fluconazole-resistant species), the use of echinocandins for prophylaxis and treatment has increased. This led to increased rates of echinocandin resistance [40,41]. However, recent published guidelines strongly recommend caspofungin as first choice, followed by fluconazole, in patients who are considered unlikely to have a fluconazole-resistant Candida species [42]. Voriconazole is approved to be the first choice in non-Candida infections, followed by liposomal Amphotericin B. An echinocandin, as caspofungin can be considered in combination with voriconazole against invasive aspergillosis and Fusarium in severe or refractory cases [1,2,43]. The best therapy, however, is the prevention of BWI via radical surgical debridement and earliest possible wound closure via autografts. The fungal pathogens and the reported resistances to antifungal drugs are illustrated in Table 2.

Table 2.

Antifungal Drugs, Spectrum, and Reported Resistance

Drugs	Spectrum	Proven clinical and in vitro resistance	Fungi with reports of clinical resistance or decreased in vitro susceptibility
Polyene Amphotericin B	Most yeasts and molds Initial drug of choice for zygomycosis	Aspergillus terreus, Scedosporium (Pseudallescheria) species, Candida lusitaniae	Fusarium, Trichosporon
Azoles Fluconazole Itraconazole Voriconazole	Most yeasts Most yeasts and molds Most yeasts and molds (primary for the treatment of aspergillosis and invasive mold infections)	Most molds, Candida krusei Zygomycetes Zygomycetes	Candida glabrata, Candida krusei, Fusarium, Aspergillus fumigatus
Echinocandin Caspofungin	Candidal yeasts and Aspergillus (combination treatment of Aspergillus and Fusarium spp.)	Trichosporon, Zygomycetes	Candida parapsilosis, Candida guilliermondii

Data from Branski et al. [2], Ledgard et al. [18], Schofield et al. [31], Malani et al. [45], and Sanglard [46].

Summary

Fungal burn infections remain a challenging complication in patients who are severely burned in terms of the diagnostic and therapeutic approaches. The precise identification of the species is difficult in clinical practice because fungal BWI mimics low-grade bacterial infections, which results in delay of proper treatment.

Candida albicans remains the most fungal pathogen found most often, however, the incidence of other fungal species has increased. Molds, such as Aspergillus and zygomycetes are still rare but the infection caused by these fungi is associated with higher risk of lethal infections. An increased incidence of non-Candida albicans spp. has been reported, which also show more resistance to azoles and other antifungal agents. Amphotericin B and voriconazole are the most commonly used antifungal pathogens. They differ in spectrum of susceptibility and side effects. Because of the reported increase of resistance to these antifungal agents the development of new drugs plays an imperative part in the battle against fungal BWI.

Footnotes

Funding Information

The authors received no financial support for the research, authorship, or publication of this review.

Author Disclosure Statement

No competing financial interests exist for any of the authors.

References

Norbury

, Herndon

, Tanksley

, et al. Infection in burns. Surg Infect, 2016; 17:250–255.

Branski

, Al-Mousawi

, Rivero

, et al. Emerging infections in burns. Surg Infect, 2009; 10:389–397.

Matthaiou

, Blot

, Koulenti

. Candida burn wound sepsis: The “holy trinity” of management. Intensive Crit Care Nurs, 2018; 46:4–5.

Houschyar

, Tapking

, Duscher

, et al. Antibiotic treatment of infections in burn patients—A systematic review. Handchir Mikrochir Plast Chir, 2019; 51:111–118.

Sarabahi

, Tiwari

, Arora

, et al. Changing pattern of fungal infection in burn patients. Burns, 2012; 38:520–528.

Murray

, Loo

, Hospenthal

et al. Incidence of systemic fungal infection and related mortality following severe burns. Burns, 2008; 34:1108–1112.

Capoor

, Gupta

, Sarabahi

et al. Epidemiological and clinico-mycological profile of fungal wound infection from largest burn centre in Asia. Mycoses, 2012; 55:181–188.

Cambiaso-Daniel

, Gallagher

, Norbury

, et al. Treatment of infection in burn patients. In: Herndon DN (ed): Total Burn Care, 5th ed. Philadelphia, PA: Elsevier,, 2018:93–113

Sharma

, Bajaj

, Sharma

. Fungal infection in thermal burns: A prospective study in a tertiary care centre. J Clin Diagnostic Res, 2016; 10:PC05–7.

10.

Lawrence

, Soothill

. Burn wound infection. Burns, 1989; 15:342.

11.

Ballard

, Edelman

, Saffle

, et al. Positive fungal cultures in burn patients: A multicenter review. J Burn Care Res, 2008; 29:213–221.

12.

Wisplinghoff

, Bischoff

, Tallent

, et al. Nosocomial bloodstream infections in US hospitals: Analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis, 2004; 39:309–317.

13.

Perlroth

, Choi

, Spellberg

. Nosocomial fungal infections: Epidemiology, diagnosis, and treatment. Med Mycol, 2007; 45:321–346.

14.

Wilson

, Reyes

, Stolpman

, et al. The direct cost and incidence of systemic fungal infections. Value Health, 2002; 5:26–34.

15.

Fournier

, Pantet

, Guerid

, et al. Effective treatment of invasive aspergillus fumigatus infection using combinations of topical and systemic antifungals in a severely burned patient. J Burn Care Res, 2015; 36:e85–89.

16.

Schaal

, Leclerc

, Soler

, et al. Epidemiology of filamentous fungal infections in burned patients: A French retrospective study. Burns, 2015; 41:853–863.

17.

Kyriopoulos

, Kyriakopoulos

, Karonidis

, et al. Burn injuries and soft tissue traumas complicated by mucormycosis infection: A report of six cases and review of the literature. Ann Burns Fire Disasters, 2015; 28:280–287.

18.

Ledgard

, Van Hal

, Greenwood

. Primary cutaneous zygomycosis in a burns patient: A review. J Burn Care Res, 2008; 29:286–290.

19.

Hope

, Morton

, Eisen

. Increase in prevalence of nosocomial non- Candida albicans candidaemia and the association of Candida krusei with fluconazole use. J Hosp Infect, 2002; 50:56–65.

20.

Katz

, Wasiak

, Cleland

, et al. Incidence of non-candidal fungal infections in severe burn injury: An Australian perspective. Burns, 2014; 40:881–886.

21.

Zhou

, Tan

, Gong

, Li

, Luo

. Candidemia in major burn patients and its possible risk factors: A 6-year period retrospective study at a burn ICU. Burns, 2019; 45:1164–1171.

22.

Girmenia

, Martino P

. Breakthrough candidemia during antifungal treatment with fluconazole in patients with hematologic malignancies. Blood, 1996; 87:838–839.

23.

Wingard

, Merz

, Rinaldi

MG et al

. Increase in Candida krusei infection among patients with bone marrow transplantation and neutropenia treated prophylactically with fluconazole. N Engl J Med, 1991; 325:1274–1277.

24.

Fochtmann-Frana

, Freystätter

, Vorstandlechner

, et al. Incidence of risk factors for bloodstream infections in patients with major burns receiving intensive care: A retrospective single-center cohort study. Burns, 2018; 44:784–792.

25.

Bruck

MHM

, Nash

, Foley

, et al. Opportunistic fungal infection of the burn wound with phycomycetes and aspergillus: A clinical-pathologic review. Arch Surg, 1971; 102:476–482.

26.

Dudoignon

, Alanio

, Anstey

, et al. Outcome and potentially modifiable risk factors for candidemia in critically ill burns patients: A matched cohort study. Mycoses, 2019; 62:237–246.

27.

Pham

, Gibran

, Heimbach

. Evaluation of the burn wound: management decisions. In: Herndon DN (ed): Total Burn Care, 3rd ed. Philadelphia, PA: Elsevier,, 2012:125–130.

28.

Patterson

, Thompson

, Denning

, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the infectious diseases society of America. Clin Infect Dis, 2016; 63:e1–60.

29.

Clancy CJ

. Finding the “missing 50%” of invasive candidiasis: How nonculture diagnostics will improve understanding of disease spectrum and transform patient care. Clin Infect Dis, 2013; 56:1284–1292.

30.

Gallagher

, Williams-Bouyer

, Villarreal

et al. Treatment of infection in burns. In: Herndon DN (ed): Total Burn Care, 3rd ed. Philadelphia: Elsevier, 2007:136–176.

31.

Schofield

, Murray

, Horvath

, et al. Correlation of culture with histopathology in fungal burn wound colonization and infection. Burns, 2007; 33:341–346.

32.

Schmiedel

, Zimmerli

. Common invasive fungal diseases: An overview of invasive candidiasis, aspergillosis, cryptococcosis, and Pneumocystis pneumonia. Swiss Med Wkly, 2016; 146:w14281.

33.

Desai

, Rutan

, Heggers

, Herndon

. Candida infection with and without nystatin prophylaxis: An 11-year experience with patients with burn injury. Arch Surg. 2015; 127:159–162.

34.

Rizzo

, Martini

, Pruskowski

, et al. Thermal stability of mafenide and amphotericin B topical solution. Burns, 2018; 44:475–480.

35.

Moore

, Padiglione

, Wasiak

, et al. Candida in burns: Risk factors and outcomes. J Burn Care Res, 2010; 31:257–263.

36.

Meyer

. Current role of therapy with amphotericin B. Clin Infect Dis, 1992; 4(Suppl 1):S154–S160.

37.

Bochud

, Bonten

, Marchetti

, et al. Antimicrobial therapy for patients with severe sepsis and septic shock: An evidence-based review. Crit Care Med, 2004; 32(11 Suppl):S495–S512.

38.

Rahimi

, Roudbarmohammadi

, Hamid Delavari

, et al. Antifungal effects of indolicidin-conjugated gold nanoparticles against fluconazole-resistant strains of Candida albicans isolated from patients with burn infection. Int J Nanomedicine, 2019; 14:5323–5338.

39.

Youngsaye

, Hartland

, Morgan

, et al. ML212: A small-molecule probe for investigating fluconazole resistance mechanisms in Candida albicans. Beilstein J Org Chem, 2013; 9:1501–1507.

40.

Alexander

, Johnson

, Pfeiffer

, et al. Increasing echinocandin resistance in Candida Glabrata: clinical failure correlates with presence ofFKS mutations and elevated minimum inhibitory concentrations. Clin Infect Dis, 2013; 56:1724–1732.

41.

Lortholary

, Desnos-Ollivier

, Sitbon

, et al. Recent exposure to caspofungin or fluconazole influences the epidemiology of candidemia: A prospective multicenter study involving 2,441 patients. Antimicrob Agents Chemother, 2011; 55:532–538.

42.

Pappas

, Kauffman

, Andes

, et al. Clinical practice guideline for the management of candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis, 2015; 62:e1–50.

43.

Tejada

, Campogiani

, Ferreira-Coimbra

, et al. Levels of evidence supporting clinical practice guidelines on invasive aspergillosis. Eur J Clin Microbiol Infect Dis, 2020; 39:903–913

44.

drfungus.org. www.doctorfungus.org/drugs/index.htm (Last accessed March 14, 2020).

45.

Malani

, Kerr

, Kauffman

. Voriconazole: How to use this antifungal agent and what to expect. Semin Respir Crit Care Med, 2015; 36:786–795.

46.

Sanglard

. Emerging threats in antifungal-resistant fungal pathogens. Front Med, 2016; 3:1–10.