Topical Liposomal Amphotericin (Ambisome®) for the Treatment of Cutaneous Fusarium in a Burn-Injured Patient

Design

Case presentation

A 34-year-old female patient with 28% total body surface area (TBSA) partial and full thickness burn in her face, bilateral upper extremities, trunk, back, and bilateral lower extremities was admitted to a burn center in Sacramento, California. Following intubation, bronchoscopy revealed a Grade 4 inhalation injury. After surgery was performed for tangential excision (TE) and split-thickness skin grafts (STSG) to her bilateral upper extremities and lower extremities, reintubation was required due to respiratory distress and she was treated with antibiotics due to pneumonia. Despite several attempts to treat her paralysis after day 8, another operation was performed on hospital day 18 to have further TE and STSG to her shoulder, arm, back, flank, and leg (approximately 15% TBSA) for failed grafts. Although antibiotics were started for methicillin-susceptible Staphylococcus aureus (MSSA), mold was noted on her arm graft and cultures reported Fusarium species.

Based on the hospital-resistant pattern for Fusarium with high minimum inhibitory concentration (MICs), voriconazole and amphotericin B were determined as the drugs of choice. After switching irrigation solutions from Dakin’s 1/4 (0.125%) to topical amphotericin in addition to systemic amphotericin treatment, liposomal amphotericin (Ambisome®) 5 mg/L sterile water was compounded for topical use due to shortage of amphotericin deoxycholate. Topical treatment with amphotericin was continued for 14 days and finally, she was discharged on day 60 after continuous care and support to improve her grafts.

Study Author Conclusions

There are limited alternatives to amphotericin B deoxycholate topical irrigation published in the literature for invasive mold infections. We describe a case of the successful management of a Fusarium infection in a burn-injured patient with a combination of topical liposomal amphotericin B (Amibsome®), systemic amphotericin, and surgical source control.

Liposomal amphotericin B is an attractive option in these circumstances because it maintains broad-spectrum fungal coverage while reducing the risk of keratinocyte toxicity observed with other topical agents. It can easily be prepared from the intravenous solution and risks appear to be minimal for systemic absorption. It is unclear if its absorption into wounds and the dermis would be greater or equal to that of amphotericin B deoxycholate. Given the liposomal nature, one could speculate that it may penetrate better, but there is no data to support this hypothesis. Given the morbidity and mortality associated with invasive Fusarium infections in burn-injured patients, having alternative options available in drug shortage scenarios is crucial.

A fungal burn infection

Design

Case presentation

A 54-year-old man with third-degree burns to 50% of his body surface area presented with septic shock on day 5 after injury. The patient received broad-spectrum antibiotics, burn excision, and resurfacing with allograft. Still, two weeks later the patient presented with a suspected opportunistic fungal infection, with a differential diagnosis including multiple pathogenic yeast and mold species. Analysis of a tissue sample and wound culture confirmed presence of Aspergillus spp, although fungal cultures are considered to be unreliable without an extended incubation time (up to 2 weeks).

The patient was successfully treated with a pulse lavage device with Amphotericin B solution for wound irrigation, in addition to surgical excision and systemic voriconazole.

Study Author Conclusions

Infection with Aspergillus spp is associated with an especially high mortality. When compared to other (non-mold) mycotic infections found in burn patients, Aspergillus spp are independently associated with a nearly 12-fold increase in the odds ratio of death.

Black Plaques and White Nodules in a Burn Patient

Design

Case presentation

A man in his 20s presented with 92% total body surface area, full thickness burn and was intubated upon arrival to the emergency department. He underwent emergent chest, bilateral upper and lower extremity escharotomies, as well as a decompressive laparotomy due to abdominal compartment syndrome. He required left upper extremity amputation 13 days after admission due to development of nonviable muscle tissue that showed black plaques and white nodules.

He was taken to the operating room when hemodynamically stable to undergo four operations for debridement and grafting (initial was 10 days after admission). He had recurrent polymicrobial aspiration pneumonia due to various bacteria, all of which were treated with antibiotics. Wound and blood cultures grew Fusarium species as well as Mucormycosis species. Treatment with both intravenous amphotericin and amphotericin soaks was started immediately. Due to nephrotoxicity, amphotericin was changed to Ambisome (liposomal amphotericin B).

The patient was noted to have septicemia with elevated white blood cell count, hypotension, and persistent acidosis. The patient's bilateral lower extremities became necrotic with extensive regions of black plaques and white nodules. The patient died 31 days after admission, despite multiple debridements and antibiotic therapy, due to pulmonary failure, hypotension, and acidosis. 

Study Author Conclusions

This patient’s burn wounds were likely inoculated with the fungi during the burn injury and manifested within the initial 2 weeks after admission. Current recommendations for treatment include surgical debulking, removal of catheters, correction of neutropenia, and systemic and topical antifungal therapy, such as amphotericin B, amphotericin B lipid complex, voriconazole, and caspofungin. 

Diagnosis is usually made by tissue and blood cultures, histopathologic characteristics, and clinical manifestations. Owing to the infrequency of these 2 infections in burn patients, most literature reports are anecdotal or retrospective, and clinical trials are difficult to conduct. To date, there have been no standardized diagnostic or treatment protocols for Fusarium species or Mucormycosis species.

Aspergillus tamarii: an uncommon burn wound infection

Design

Case presentation

A 53-year-old woman presented with an accidental thermic burn injury to a hospital in Gabon (Africa). At post-burn day 8, a wound infection was suspected, with swab cultures identifying Enterobacter cloacae and Stenotrophomonas maltophilia, leading to intravenous antibiotic treatment with piperacillin-tazobactam plus amikacin along with topical mafenide acetate.

A new wound infection manifested on day 15 in the same region, with cultures finding an unidentified Aspergillus species. Meanwhile, the initial microbiological identification for the first wound was found to be incorrect, instead being concluded to be related to Aspergillus tamarii. Susceptibility testing revealed minimum inhibitory concentrations (MICs) for amphotericin B of 1 μg/mL, itraconazole of 0.03 μg/mL, voriconazole of 0.25 μg/mL, posaconazole of 0.03 μg/mL, and caspofungin of 0.25 μg/mL. Intravenous antifungal therapy was initiated with voriconazole, then liposomal amphotericin B accompanied by topical amphotericin B solution irrigation 0.1 mg/mL.

Although antigen levels decreased within 8 days, along with negative detection, the patient deteriorated into severe multiple organ failure, with complete wound healing requiring several surgeries. Eventually, with aggressive surgical debridement of infected tissues and both local and systemic antifungal therapies, the patient was finally discharged to a rehabilitation facility after 117 days.   

Study Author Conclusions

This is the first description of A. tamarii responsible for burn wound injury. Despite clinical severity, the patient survived due to surgical and medical aggressive therapies. Strategy of treatment for A. tamarii’s infection is similar to other filamentous burn wound injury. However, attention should be given to the risk of misidentification with other species.

Effective Treatment of Invasive Aspergillus fumigatus Infection Using Combinations of Topical and Systemic Antifungals in a Severely Burned Patient

Design

Case presentation

A 33-year-old male was admitted one hour after an accidental blast for 92% total body surface area (80% full-thickness) burns and inhalation syndrome. Escharotomies were performed on the patient's neck, thorax, abdomen, and upper and lower limbs upon admission. Same-day laparotomy was required due to acute abdominal compartment syndrome after initial resuscitation. His hospital stay was also complicated by rhabdomyolysis and acute renal failure due to severe shock, which required prolonged continuous renal replacement therapy. Hydrotherapy and surgical debridement were initiated after abdominal closure on day 7; parenteral administration of nutrients was required due to persistent digestive tract malabsorption.

The burn wounds were covered with silver sulfadiazine and pig skin. By day 15 the patient had increased systemic inflammatory response syndrome requiring an increase in norepinephrine dose due to nosocomial septic shock originating from a deep-burn wound infection due to multiple identified bacteria which was treated with antibiotics (piperacillin-tazobactam, amikacin, and vancomycin). Antibiotics were escalated to meropenem on day 21 due to relapse of septic shock without identification of infection focus; empiric caspofungin was initiated on day 25 and on day 28 a wound biopsy showed Aspergillus fumigatus infection, along with a rise in galactomannan titers; invasive aspergillosis was confirmed.

On day 27, caspofungin was changed to intravenous voriconazole dosed to maintain blood levels of 2 to 4 mg/L. Additionally, topical treatment was applied once daily from day 40 to day 190; as topical preparations of amphotericin B and voriconazole were not commercially available, 1% terbinafine cream (Lamisil®; Novartis, Basel, Switzerland) was applied to the patient's wounds as the minimum inhibitory concentration for terbinafine was lower than expected. Skin grafts failed due to concomitant Enterococcus spp. burn wound infection, and a locally compounded cream (250 g 1% terbinafine [10 mg/g; 2,500 mg terbinafine] and 250 g of 0.1% gentamicin ointment [1 mg/g; 250 mg gentamicin]) was used to treat both infections. This formulation, along with systemic voriconazole and vancomycin, controlled the burn wound infection to facilitate successful skin grafting; both galactomannan antigen assays and wound biopsies were negative for A. fumigatus from day 120. 

Intravenous voriconazole was discontinued on day 43 due to hepatotoxicity and changed to intravenous anidulafungin along with the topical terbinafine and gentamicin treatment. On day 70, anidulafungin was changed to voriconazole to treat breakthrough invasive aspergillosis infection indicated by positive galactomannan antigen assay and skin biopsy, which was stopped again on day 76 due to severe cholestasis and topical terbinafine was continued.

Oral voriconazole was started from day 92 which resulted in both galactomannan antigen assays and skin biopsies remaining negative; no recurrence of aspergillosis was seen during topical terbinafine and systemic voriconazole maintenance treatment. For probable breakthrough invasive candidiasis, caspofungin was started from day 132 to 152 and from day 168 to 172. After multiple bacterial infections, the eventually died on day 214 from a refractory septic shock and multiple organ failure due to a pan-resistant Pseudomonas aeruginosa ventilator-associated pneumonia. 

Study Author Conclusions

To our knowledge, this is the first known successful control of an invasive A. fumigatus deep-burn wound infection by using the combination of topical terbinafine and systemic voriconazole treatments. This case report demonstrates that a multimodal strategy is recommended to successfully manage difficult-to-treat, potentially lethal, invasive forms of aspergillosis in severely burned patients. Effective treatment was achieved by combining an aggressive diagnostic approach (antigen assay and biopsy) with long-lasting topical terbinafine and systemic voriconazole.

Invasive Conidiobolomycosis Can Be Successfully Treated on Burn Survivors

Design

Case presentation

A 36-year-old man with a history of heroin abuse presented with third-degree burns to 88% of his total body surface area surgically treated the day before, with excision of burned skin. Five days after injury, the patient developed methicillin-resistant Staphylococcus aureus pneumonia, followed by Stenotrophomonas maltophilia pneumonia 1 week later. Both were treated with vancomycin and trimethoprim/sulfamethoxazole. However, at 6 weeks after injury, the patient developed small abscesses under skin grafts, at sites of heron injection. Within 3 days, these developed into small necrotic nodules and the patient developed sepsis, with cultures growing an unidentified mold and S. maltophilia. The patient was initiated on voriconazole and cefepime, in addition to topical wound irrigation with amphotericin and mafenide solutions. 

At 8 weeks post-injury, the mold was identified as Conidiobolus spp.; by this time, arm nodules progressed substantially, requiring extensive surgical excision. Antifungal therapy with voriconazole was continued. The patient required continued surgical treatment due to recurring and spreading masses, nearly requiring bilateral arm amputations. Systemic antifungal therapy was changed from voriconazole to liposomal amphotericin B and posaconazole after the final surgery. After 2 weeks, amphotericin B was discontinued in favor of systemic posaconazole and topical amphotericin. 

After susceptibility results of Conidiobolus were reported, posaconazole was discontinued, and no further systemic antifungal therapy was given, but amphotericin topical therapy was continued along with twice daily wound care. Eventually, at 14 weeks post-surgery, continued observation revealed no further recurrence of masses, and the patient underwent grafting. The arms healed without further evidence of infection, along with improved clinical status allowing for discharge to rehabilitation facility at 23 weeks. 

Study Author Conclusions

Burn patients can survive Conidiobolus infections. Invasive Conidiobolus may be monitored by measuring serum levels of BDGs because unlike most Zygomycetes it does release detectable levels of BDG in human serum. Successful treatment of invasive Conidiobolomycosis may be achieved with aggressive multimodality therapy, combining serial surgical resections of nonviable and infected tissues and meticulous wound care in the burn unit with anti-fungal therapy.

Mucormycosis of the Face

Design

Case presentation

A 25-year-old obese female presented to the trauma center after extensive flame burn injury; she was previously healthy with no past medical history. She sustained 45% total body surface area burns, of which two-thirds were obvious full-thickness burns; she was intubated, resuscitated, and then transferred to a regional burn unit. Escharotomies of the bilateral upper extremities and thorax were performed; starting postburn day (PBD) 1 extensive debridement of the bilateral upper extremities, chest, and shoulders was performed.

A split-thickness skin graft was placed at the neck for tracheostomy which was performed on PBD 9; she was taken to the operating room 15 times for additional debridement and cadaver allografting. Despite aggressive early excision and allografting, she started having fevers on PBD 2; blood cultures grew Candida glabrata for which caspofungin was initiated. On PBD 9, tissue cultures from the right upper extremity grew Mucor spp., and caspofungin was changed to liposomal amphotericin B. Repeated surgical debridement of the right upper extremity, and twice daily topical infusions were performed through dressings to all burn areas at a concentration of 50 mg liposomal amphotericin B diluted in 1 L of sterile water. 

Due to facial swabs growing Candida albicans on PBD 13 despite topical and intravenous treatment, the patient was brought back to the operating room on PBD 16 for re-excision cadaver allografting and facial burn wounds; two areas were noted to have gross fungal colonization. Histopathology showed invasion of both Mucor and Candida into viable tissue, confirming a diagnosis of cutaneous mucormycosis. Intravenous liposomal amphotericin B was continued and topical soaks were discontinued due to desiccating effect on the cadaver allograft.

On PBD 25 additional debridement of the lower face and ears was performed with another replacement of cadaver allograft. On PBD 30 complete facial autografting with split-thickness skin grafting was performed and full-thickness skin grafts were placed on both eyelids; all grafts healed well indicating eradication of the cutaneous mucormycosis. 

Study Author Conclusions

We report invasive cutaneous mucormycosis involving the face of an extensively burned patient with no prior medical history that would otherwise predispose her to such infection. There is no definitive data regarding treatment of facial cutaneous mucromycosis. However, we believe that a combination of liposomal amphotericin B systemic antifungal therapy, 5% (by solution) liposomal amphotericin B dressing soaks twice daily, and repeat surgical debridement were key to the successful cure of this patient and prevention of the development of rhinocerebral mucormycosis or amputation of the patient's right upper extremity.

Widespread Lichtheimia Infection in a Patient with Extensive Burns: Opportunities for Novel Antifungal Agents

Design

Case presentation

A 63-year-old man with history of type 2 diabetes mellitus and myocardial infarction was brought to regional burn center after a workplace explosion which produced full-thickness burns of approximately 47% of total body surface, mainly involving the head, torso, and upper extremities. He was intubated,, stabilized, and taken the operating room for escharotomy of the extensively burned left arm. On hospital day (HD) 3 debridement of the chest and placement of an Integra™ bilayer burn dressing was performed. On HD 6 debridement and Integra coverage of his arms was done and on HD 9 another debridement of his face and split-thickness dermal allografting of the flanks and back were done. He had intermittent fevers and rising white blood cell (WBC) count for which vancomycin and piperacillin-tazobactam were initiated for bacterial pneumonia; bronchoalveolar lavage grew Streptococcus pneumonia, and antibiotics were subsequently changed to ceftriaxone to complete 10 days of therapy. 

A small white plaque was seen by the surgical team on HD 10 on his left arm; fungal cultures were obtained and posaconazole was started for possible fungal infection. Upon clinical improvement, on HD 12 flank allografts were removed, he was extubated and posaconazole was discontinued on HD 13; 4 days after tissue samples were obtained, the culture grew Lichtheimia spp. for which posaconazole was restarted.

His WBC count rose and required reintubation and eventual tracheostomy due to respiratory failure; on HD 20 multiple new white plaques were seen on the Integra covering his bilateral upper extremities and torso; the dressing was removed from chest and flanks, and autologous split-thickness skin grafting was performed. Small residual plaques remained on the underlying tissue of the abdomen despite removal of the Integra; cultures from multiple sites all grew Lichtheimia spp. Due to rising serum creatinine intravenous isavuconazole, rather than systemic amphotericin B, was started along with topical amphotericin B washes.

A decrease in fungal burden was noted and fungal organisms were not recovered from cultures after subsequent debridements; the last positive culture was on HD 48. A total of 6 weeks of isavuconazole (through HD 62) and 13 days of topical amphotericin B washes (through HD 35) were completed. No recurrence of Lichtheimia spp. was noted despite requiring ongoing skin grafting with revisions. He was discharged to an inpatient rehabilitation facility after HD 119.

Study Author Conclusions

Although there are limited published clinical data in burn patients, our experience combining the newer systemic antifungal isavuconazole alongside topical amphotericin B washes suggests this combination holds promise for effective Mucorales treatment with a reduced toxicity profile. Whether the potential therapeutic benefits of isavuconazole compared with posaconazole or amphotericin B are broadly clinically relevant in the burn patient population is an understudied issue that deserves further attention.