Topical Nystatin Treatment for Candida Infection Following Wound Reconstruction

Introduction. Wound infection is an important cause of nonhealing wounds and graft rejection. Objective. A series of 5 patients (4 females, 1 male; median age, 50; age range, 1.5–83 years) with nosocomial Candida infection of burns and chronic wounds that were reconstructed with split-thickness skin grafts is presented. Materials and Methods. This case series was carried out between February 2011 and June 2014. Based on tissue cultures, wounds were treated with 100 000 units/mL of nystatin and 25 mg in 500 cc normal saline of mafenide acetate, which resulted in regression of wound infection symptoms and improvement of skin graft take. Conclusions. The authors propose this simple, nontoxic, and economic topical treatment for wounds and skin grafts with positive Candida cultures. 

Infection is a common local factor that impedes wound healing. Hence, a topical antimicrobial dressing is frequently used to control bacterial proliferation.¹ Since the introduction of effective topical antibacterial therapy, fungal infections have become more prevalent, especially in burn patients.² Bacteria causes 70% of burn wound infections (BWIs), followed by fungi (20%–25%) and anaerobes and viruses (5%–10%). The propensity for fungal infection increases the longer the wound is present. Patients may present with signs and symptoms such as fever, separation of eschar, partial-thickness defect converting into full thickness, blackening of the tissue, or progression to cellulitis or fasciitis despite antibiotic intake. However, most fungal infections are missed due to lack of clinical awareness and similar presentation to bacterial infection, and it is necessary to perform tissue biopsy in order to diagnose and appropriately treat these patients. 

Local treatment with mafenide acetate 5% solution combined with nystatin, a topical antifungal, has been suggested⁴ for Candida spp infections as well as Aspergillus and other fungi. Nystatin is a polyene antibiotic obtained from Streptomyces noursei. It is both fungistatic and fungicidal in vitro. It has a strong antifungal effect by binding to sterols in the fungal cell membrane with resultant change in permeability. Lower concentrations inhibit C albicans, but higher concentrations may be needed to inhibit other species. It has no antibacterial activity and is virtually nontoxic, nonsensitizing, and well tolerated by all age groups. Nystatin is not absorbed by the skin or mucosa but may be absorbed by open wounds.^3,4 Mafenide acetate is a topical agent with a potent broad-spectrum antibacterial activity particularly useful against bacteria such as Pseudomonas, Clostridia, and Enterococcus species. Mafenide acetate is able to penetrate wound eschar and is the only agent capable of suppressing dense bacterial proliferation beneath the eschar surface. The main side effects of mafenide acetate are respiratory alkalosis caused by carbonic anhydrase inhibition, allergic rash, and painful application on the skin. The agent also possesses certain antifungal properties.⁵

A combination of nystatin and mafenide acetate 5% solution may be useful to prevent superinfection and treat concomitant bacterial infections. Prompt debridement remains the gold standard for treatment of invasive fungal infections.⁶

Until now, there has been no consensus regarding the management of nosocomial fungal infection. The effect of topical nystatin therapy has not been documented in human studies. It has been suggested for the treatment of infected burns and chronic wounds based on its antifungal effect in animal models and as prophylaxis in patients with burn injuries.^4,7 The authors present a series of 5 patients with nosocomial Candida infection of burns or chronic wounds that were treated with nystatin and mafenide acetate 5%. Based on the initial findings herein, the authors wish to suggest this simple topical treatment for wounds and skin grafts with a positive Candida culture. 

This study was carried out between February 2011 to June 2014. It included 5 patients (4 females, 1 male; median age, 50; range, 1.5–83 years) hospitalized in the Department of Plastic and Reconstructive Surgery at Shaare Zedek Medical Center (Jerusalem, Israel). All patients had wound cultures with Candida spp and were treated with nystatin 100 000 units/mL and mafenide acetate 25 mg in 500 cc normal saline. Wound cultures were obtained from chronic and burn wounds at the bedside or during surgical debridement to target antimicrobial therapy. Wounds were cleaned with chlorhexidine gluconate 0.05%, a sterile aqueous solution that has antiseptic properties for wound care. Then, gauze soaked with nystatin 100 000 units/mL and mafenide acetate 25 mg in 500 cc normal saline were applied to the wound. Dressings were changed twice daily. Wound healing was clinically assessed on a daily basis until complete recovery.

Case 1

An 83-year-old man presented to the Department of Plastic and Reconstructive Surgery with second-degree and third-degree fire burns of his right lower limb and bilateral palms, with a total body surface area (TBSA) of 13%. Burns were caused by flames while lighting his fireplace. Medical history included hyper- tension, chronic atrial fibrillation, and chronic obstructive pulmonary disease. During hospitalization, he was treated locally with silver sulfadiazine dressings, and after a few days, the burn to his right lower limb was partially excised (due to a large burn surface area) and grafted. Skin graft take was uneventful. Remaining burn areas were treated with mafenide acetate 5% dressing. Twenty-three days following surgery, the burn area seemed to worsen, with a deeper-looking burn and offensive smell. Burn wound tissue cultures demonstrated C albicans, Escherichia coli, Enterococcus spp, and Staphylococcus aureus growth. Systemic antibacterial treatment with Fortum (GlaxoSmithKline UK, Middlesex, UK) and Flagyl (Pfizer, New York City, NY) was initiated along with topical treatment with nystatin and mafenide acetate 5%. Five days after the application of the dressing, local infection signs improved and debridement and skin graft reconstruction was successfully performed (Figure 1). 

Case 2

A 63-year-old, healthy woman was hospitalized in hypotensive shock after she had been run over by a truck. Upon arrival at the hospital, she was rushed to the operating room with a mangled left lower limb and multiple rib and pelvis fractures. She underwent a below-the-knee amputation of the left leg, and a skin flap from the amputated part was transferred as a full-thickness skin graft to reconstruct the stump. She was transferred to the intensive care unit (ICU) for further stabilization and care for the following 9 days. After extubation, she was transferred to the Department of Plastic and Reconstructive Surgery for further treatment due to skin graft failure. She underwent debridement of the stump and regrafting with a split-thickness skin graft (STSG). Tissue cultures collected at surgery demonstrated Enterococcus species and C glabrata. Topical dressing containing nystatin and mafenide acetate 5% was initiated to improve graft take. Oral fluconazole treatment was recommended by an infective disease specialist. The dressing was removed after 3 days with successful graft take (Figure 2). 

Case 3

A 56-year-old woman with type 2 diabetes mellitus, hyperlipidemia, essential hyper- tension, chronic kidney disease, and ischemic heart disease presented with post coronary bypass sternal dehiscence due to infection. Upon arrival, the patient had sepsis with purulent discharge from the surgical wound, a fever, and an elevated white blood cell count. She had been treated conservatively for a long period in another hospital. Empirical treatment with intravenous vancomycin was initiated and she underwent debridement of soft tissue, sternum, and several ribs. Tissue cultures demonstrated P aeruginosa, E coli, Enterococcus spp (vancomycin resistant), Acinetobacter baumannii, C albicans, and C parapsilosis growth. Antibacterial treatment was changed to ampicillin-sulbactam (Unasyn; Pfizer) and colistin and a topical dressing with nystatin and mafenide 5% was applied. Three weeks after hospitalization, the wound was clean and the patient successfully underwent reconstruction with an omental flap and skin graft (Figure 3). 

Case 4

A 48-year-old woman was referred to the Department of Plastic and Reconstructive Surgery from the General Surgery Department for treatment of a skin defect in her abdominal wall. She suffered from an infected mid abdominal (5 cm x 10 cm) skin defect following gastric bypass surgery. Medical history included severe morbid obesity, multiple ventral hernias with a large apron, hypertension, and type 2 diabetes mellitus. Tissue culture demonstrated C albicans and P aeruginosa. Antibacterial treatment with piperacillin- tazobactam and topical treatment with nystatin and mafenide acetate 5% dressing was initiated. Following clinical improvement of the wound and a negative tissue culture, she underwent debridement and reconstruction with a STSG that was unsuccessful due to her severe comorbidities. She was then discharged for conservative treatment with secondary wound healing as an outpatient. 

Case 5

An 18-month-old, previously healthy girl was hospitalized in the pediatric intensive care unit (PICU) with 50% TBSA scald burns. She underwent 5 sessions of debridement and allografting and autografting. During her stay in the PICU, burn wounds seemed to worsen despite optimal wound care. Tissue cultures from the burn initially demonstrated bacterial contamination with S aureus and coagulase-negative staphylococci. Cefuroxime treatment was initiated. A month into her PICU hospitalization, tissue cultures demonstrated C albicans and Fusarium growth; also, she had C parapsilosis from repeated blood cultures. Systemic antifungal treatment with Amphotericin B was initiated as well as local treatment with nystatin and mafenide acetate 5% dressing, resulting in improvement in burn wound healing and successful graft take. Further tissue cultures were negative.

Despite all advances in medical care, wound infection continues to play a major role in patient morbidity and mortality. The propensity for fungal infection increases the longer the wound is present.
C albicans is the fourth most common organism found in blood cultures in ICU burn patients.^8,9 In the severely injured trauma patient, there has been a 10-fold rise in fungal wound infections since 1960 due to the introduction of systemic anti- biotics.¹⁰ It has been estimated that the incidence of fungal burn wound infections ranges from 20% to 44%.¹¹ Hence, invasive wound infection due to fungi has become an important cause of late morbidity. Fungi colonizing the wound are found either in the surrounding environment or in the patient’s own flora. In burn patients, fungal wound infection usually starts in the second or third week following injury. Suspicious local signs include separation of eschar, blackening of the tissue, partial-thickness wounds that turn to full thickness, or a clinical condition that does not improve despite the use of long-term antibiotic therapy. Suspicious clinical signs usually warrant empirical antifungal therapy with fluconazole or Amphotericin B.^11,12 

In these patients, symptoms of clinical wound aggravation began after long-term hospitalization with a median of 4 weeks’ hospital stay. All patients were admitted to the ICU during their hospitalization. Cases 2 and 5 received systemic antifungal treatment. Case 5 had C parapsilosis growth in blood cultures. These patients received systemic and topical antifungal treatment after a consultation with an infectious disease specialist. 

Topical treatment also has proven its benefits and may control local noninvasive wound infections, thus preventing the use of antifungals with their potentially toxic adverse side effects. The results presented herein, as well as previous cases presented in the literature,^3,13 show that the use of effective topical antimicrobial therapy led to a significant decline in morbidity and mortality from fungal infection. Moreover, prophylactic antifungal treatment may be considered in select severe trauma cases. Desai et al⁷ demonstrated the beneficial prophylactic effects of nystatin in their study. They showed a reduction of both wound infection and systemic candidiasis with nystatin prophylaxis.⁷ As previously described, Case 2 was treated prophylactically due to positive tissue cultures during reconstruction in order to improve graft take. This led to a successful reconstruction despite her severe comorbidities and wound colonization. Further studies^3,13 have shown that nystatin was the most effective agent to prevent C albicans from invading deeper tissue and from systemic infection. It was noted that nystatin should be used in combination with a topical antibacterial agent as it has no activity against bacteria.^3,13

The present results demonstrate clinical improvement within a median time of 5 days with nystatin and mafenide acetate 5% treatment. Of the 5 treated cases, 4 were successfully reconstructed. The failure of graft take in Case 4 was attributed to the patient’s severe systemic comorbidities. The patient was class 3 morbidly obese (body mass index, 40), had unbalanced diabetes, and had a large apron and multiple ventral hernias. 

As demonstrated by this case series and previous studies,^3,13 topical nystatin proved beneficial in treating infected wounds refractory to regular antibacterial agents. Fungal infection should be suspected early after treatment failure and prophylactic nystatin may be initiated (as it is nontoxic) until the results of wound cultures are received. However, there are no available, prospective, evidence-based trials comparing wound healing with nystatin to the standard treatment. It is important for clinicians to be familiar with this treatment option as it may help salvage failed reconstructions.    

In this case series, a topical nystatin dressing showed effectiveness in the treatment of wounds and improvement of skin graft take in patients with Candida wound cultures. Topical nystatin is a simple, nontoxic, and fairly economic agent that should be considered for the treatment of wound infections refractory to other topical agents and for wounds infected by Candida. 

Affiliations: Department of Plastic & Reconstructive Surgery, Shaare Zedek Medical Center, Jerusalem, Israel; Infectious Disease Unit, Shaare Zedek Medical Center; and Pediatric Intensive Care Unit, Shaare Zedek Medical Center

Correspondence: Adi Maisel Lotan, MD, Department of Plastic & Reconstructive Surgery, Shaare Zedek Medical Center, P.O. Box 3235, Jerusalem 91031, Israel; lotan.adi@gmail.com 

Disclosure: The authors disclose no financial or other conflicts of interest.