Surgical-site mucormycosis infection in a solid-organ transplant recipient and a concise review of the literature

Abstract

Surgical-site mucormycosis infections in solid-organ transplant recipients are rare conditions, with only 15 previously reported cases. We describe a case of a 49-year-old man who received a liver transplant due to alcoholic cirrhosis. On postoperative day 14, necrosis was noticed at the surgical site. After mucormycosis was diagnosed, monotherapy with amphotericin was started along with surgical debridements. Due to continued clinical deterioration, triple antifungal therapy was started with amphotericin, micafungin and posaconazole. Treatment with a granulocyte-macrophage colony-stimulating factor was also started. Despite therapy, the patient expired on postoperative day 31. We review the risk factors for mucormycosis infection in solid-organ transplant recipients as well as evidence for current treatment options. We also review the 15 previously reported cases of surgical-site mucormycosis infections in solid-organ transplant recipients, including time to infection, infecting organisms, mortality and treatments.

Background

Mucormycosis refers to a group of potentially lethal fungal infections that can occur in solid-organ transplant recipients due to potent immunosuppressive medications that are given to these patients.¹ Incidents of mucormycosis infections in solid-organ transplant recipients vary by region but have been reported at 0.4%–16.0%.¹ Rhizopus is the most common species of mucormycosis isolated from infection sites.² Cutaneous mucormycosis is a rarer subset of solid-organ transplant-associated infections, as evidenced by a recent review showing only 24 reported cases of primary cutaneous mucormycosis.³ Cutaneous mucormycosis can result from either local invasion or haematogenous spread.³ Here, we review surgical-site cutaneous mucormycosis infections by reporting a rare case after a liver transplant and present a concise literature review of the 15 previous cases in solid-organ transplant patients. We highlight the risk factors and treatments for this rare disease.

Case presentation

A 49-year-old man presented with weakness, jaundice and altered mental status, as evidenced by slurring of speech. His medical history revealed hypertension and heavy alcohol abuse. The initial evaluation revealed that the patient had suffered both liver and renal failure and required emergency dialysis. The patient was also found to have macrocytic anaemia, requiring large transfusions of packed red blood cells. He subsequently went into hypovolemic shock, necessitating intravenous dopamine. When the patient stabilised, he underwent a liver biopsy consistent with cirrhosis with no evidence of recent alcohol activity. He subsequently underwent an orthotopic liver transplant in a procedure deemed difficult for several reasons: large body habitus, hepatorenal syndrome, portal hypertension and severe coagulopathy. The patient required many transfusions, including packed red blood cells, fresh frozen plasma and platelets, both intraoperatively and postoperatively. Despite the difficulties, the procedure was performed without complications.

Postoperatively, he was given three doses of antithymocyte globulin, and he was started on an immunosuppressive regimen that included mycophenolic acid, tacrolimus and a prednisone taper. He was also started on antifungal prophylaxis with 400 mg of fluconazole daily, which is the standard protocol for liver transplant patients in our institution. His postoperative course was initially complicated by a biliary leak. On postoperative day 8, the patient went back to the operating room (OR) for an uneventful biliary reconstruction. The patient’s total and direct bilirubin decreased over the next few days. On postoperative day 14, the abdominal surgical site became necrotic and oozed serosanguinous fluid. The wound measured approximately 18×12 cm (figure 1).

Figure 1.

Lateral view of the abdomen. Necrosis and drainage at the surgical site is apparent. The black necrotic tissue extends into the subcutaneous tissue.

Investigation

Laboratory studies from when the necrotic tissue developed revealed a white blood cell count of 4.06×10³/μL with a left shift of 85%. No bandaemia was present in the initial white blood cell count. The blood glucose level was 119 mg/dL. Wound cultures from the necrotic tissue as well as peripheral blood cultures were collected. The patient was investigated for disseminated disease with a CT scan of the brain, chest, abdomen and pelvis. The abdomen scan showed a new 10 cm subcapsular fluid collection in the left lobe of the liver, and the chest scan showed atelectasis. The CT scans of the brain and pelvis were unremarkable.

Differential diagnosis

Surgical-site infections complicate approximately 11.9% of surgeries.⁴ The microbes responsible for these infections are usually on the surrounding skin or the associated structures in the OR. The most common infectious organisms include Staphylococcus aureus, coagulase-negative Staphylococci, Escherichia coli, Enterococcus faecalis and Pseudomonas aeruginosa.⁵ Due to the potent T-cell suppression medications used after solid-organ transplants, patients are more susceptible to invasive fungal infections.¹ Fungal microbes, such as mucormycosis, have been found on objects in hospital environments, including tongue depressors, cotton stockinettes and cloth tape.³ Such microbes have many virulence factors, such as iron acquisition from host organisms despite sequestration mechanisms, extensive angioinvasion leading to necrosis that prevents leucocyte delivery and antifungal agents that lead to infection foci.⁶

Clinical signs of bacterial surgical-site infections typically include localised swelling, erythema, pain, tenderness or purulent drainage.⁵ The initial presentation for cutaneous mucormycosis includes a lesion that can be an erythematous plaque or nodule, an open ulcer or a necrotic eschar.⁷ Other presentations include targetoid lesions, tender nodules, ulcers, purpuric lesions and swollen or scaly plaques.⁸ Surgical-site mucormycosis can mimic a wide variety of infections, including ecthyma gangrenosum, cutaneous aspergillosis or cutaneous fusariosis.³ When targetoid lesions appear, other diagnoses—such as autoimmune disorders, drug reactions, infiltrative diseases and neoplastic disorders—need to be ruled out.⁸ Diagnosis of mucormycosis is made by direct examination of the fluid or tissue, culture of a sterile site and a biopsy.¹ Early detection can be made by direct potassium-hydroxide microscopic examination revealing non-septated hyaline hyphae with irregular branching at right angles.⁸

Treatment

On postoperative day 15, the patient was taken to the OR for debridement of the wound and drainage of the subcapsular liver fluid. The entire visible necrotic area was debrided to healthy tissue, biopsy was taken and primary closure was achieved. The initial antimicrobial regimen started after the appearance of necrosis included intravenous vancomycin, meropenem and micafungin at a dose of 100 mg/day. On postoperative day 17, localised necrosis of the abdominal wall returned, and the patient’s vital signs deteriorated, necessitating the use of intravenous norepinephrine. The patient was subsequently taken back to the OR for further debridement of the wound, after which the wound was left open. On postoperative day 18, biopsy results returned revealing skin necrosis, active inflammation and numerous fungal hyphae with features consistent with Rhizopus-species mucormycosis (figure 2A–B). Subsequent blood cultures revealed vancomycin-resistant E. faecium bacteraemia, and wound cultures grew both Rhizopus-species mucormycosis and E. faecium. The patient’s treatment was subsequently changed from intravenous vancomycin to intravenous linezolid and from micafungin to intravenous liposomal amphotericin B at a dose of 6 mg/kg daily. All antirejection medications, including prednisone, tacrolimus and mycophenolic acid, were stopped at this time.

Figure 2.

(A) Light microscopy of tissue obtained from abdominal wound. Fungi can be seen dissecting through necrotic skeletal and fibrofatty tissue with widespread dystrophic calcifications. Periodic acid–Schiff stain used. (B) Light microscopy of tissue obtained from abdominal wound. Numerous fungal hyphae with features consistent with zygomycetes are present. Extensive vascular invasion is present. Periodic acid–Schiff stain used.

On postoperative day 18 and 19, the patient was taken back to OR for further debridements of the abdominal wall wound with the abdomen being left open in both procedures. The patient’s condition deteriorated, requiring the use of multiple pressors. On postoperative day 20, it was decided to start triple antifungal therapy with intravenous amphotericin B at 6 mg/kg daily, intravenous micafungin at 100 mg/day and intravenous posaconazole at 300 mg/day. The patient was also put on a granulocyte-macrophage colony-stimulating factor (GM-CSF) in an effort to reverse prednisone-related immunosuppression. Despite all of this, the necrotic wound continued to spread (figure 3), and on postoperative day 25, the patient returned to the OR for further debridement.

Figure 3.

Lateral view of the abdomen. Extensive necrosis can still be seen and is spreading despite numerous debridement operations. Extent of the debridement can be clearly seen. The open-abdomen dressing is covering abdomen.

Outcome and follow-up

Despite five debridement operations, triple antifungal therapy, broad-spectrum antibiotics and treatment with a GM-CSF, the patient continued to deteriorate. The patient’s condition was complicated by acute renal failure and acute respiratory distress syndrome secondary to overwhelming septic shock. Blood cultures continued to be positive for E. faecium and, later, Acinetobacter baumannii. The patient had labile blood pressure, despite being put on multiple vasopressors. The patient was given full ventilator support, antimicrobials and continuous veno-venous haemodialysis. Even so, on postoperative day 31, he developed worsening hypoxia and metabolic acidosis. The patient suffered bradycardic arrest secondary to his hypoxia and acidosis. Spontaneous circulation was achieved after one round of resuscitation with the advanced cardiac life-support protocol, but the patient went into asystole shortly afterwards. The patient could not be resuscitated and subsequently expired.

Discussion

Surgical-site mucormycosis infections after solid-organ transplants are rare, with only 15 previously reported cases (table 1). Of the 15 previous cases, one occurred after a lung transplant, one after a heart transplant, nine after liver transplants and four after kidney transplants.^{3 9–21} The median time to presentation of all mucormycosis infections in solid-organ transplant patients is reported to be approximately 60 days.³ In cases with primary cutaneous mucormycosis after interventions such as biopsy or surgery, the median time to presentation was 23 days.³ In our review of surgical-site mucormycosis infections after solid-organ transplants, the median time to infection was 18 days, with our patient presenting signs of infection on postoperative day 14.

Table 1.

Summary of the previous 15 reported cases of surgical-site mucormycosis infections in solid-organ transplant recipients

Patient #	Paper	Demographics	Transplanted organ	Risk factors for infection	Time to infection	Disseminated disease	Infecting species	Primary treatment	Secondary treatment	Outcome	Mortality risk factors
1	Srivastava et al 9	60-year-old man	Liver	Malnutrition, immunosuppression, blood transfusions	Postoperative day (POD) 10	No	Mucor species	Surgical debridement	Amphotericin	Survived	Acute liver rejection, renal injury, pancytopenia, cytomegalovirus infection
2	Page et al 3	43-year-old man	Lung	Immunosuppression, multiple operations, concomitant bacterial infection	POD 14	Yes	Rhizopus microsporus	Surgical debridement	Amikacin, oral posaconazole, and amphotericin B-soaked bandages	Withdrawal of care	Renal failure, neutropenia, sepsis
3	Woods and Elewski10	37-year-old woman	Liver	Immunosuppression	n/a	No	Rhizopus arrhizus	Intravenous amphotericin B and topical amphotericin B lotion	Fluconazole and surgical debridement	Survived	n/a
4	Uckay et al 11	47-year-old woman	Liver	Immunosuppression	POD 23	No	Rhizopus species	Extensive surgical debridement, concomitant IV amphotericin B and peritoneal amphotericin B lavage	None	Survived	Acute liver rejection
5	Marco del Pont et al 12	2-year-old girl	Liver	Immunosuppression, multiple operations, concomitant bacterial infection	POD 1	No	Mucor species	Amphotericin	None	Died 12 days post-transplant	Acute liver failure, hepatic artery thrombosis
6	Nordén et al 13	40-year-old man	Kidney	Immunosuppression, renal failure	POD 12	No	Rhizopus rhizopodiformis	Surgical debridement	Repeat surgical debridement and addition of naftifine	Survived	Renal injury
7	Wilson14	9-year-old girl	Kidney	Immunosuppression, renal failure, diabetes, multiple operations, concomitant bacterial infection	n/a	No	Rhizopus arrhizus	Surgical debridement	Amphotericin	Survived	n/a
8	Wajszczuk et al 15	n/a	Liver	n/a	POD 7	n/a	Mucor species	n/a	n/a	Died	n/a
9	Davuodi et al 16	66-year-old man	Kidney	Renal failure, diabetes, immunosuppression	POD 7	No	Mucor species	Surgical debridement and antibiotics	Amphotericin	Died 52 days post- transplant	Septic shock
10	Zhao et al 17	59-year-old man	Kidney	Immunosuppression, renal failure, concomitant bacterial infection	POD 4	No	Rhizopus oryzae	Surgical debridement	Amphotericin	Survived, lost transplant	Renal failure
11	Kerbaul et al 18	61-year-old man	Heart	Immunosuppression, diabetes, concomitant bacterial infection	POD 17	No	Rhizopus oryzae	Amphotericin	Surgical debridement	Died 118 post-transplant	Acute bacterial peritonitis, renal injury
12	Jiménez et al 19	50-year-old man	Liver	Immunosuppression, diabetes, multiple operations	POD 16	No	Rhizopus oryzae	Surgical debridement	Amphotericin	Survived	Acute liver rejection
13	Jiménez et al 19	48-year-old man	Liver	Immunosuppression, diabetes	POD 60	No	Rhizopus species	Amphotericin	Surgical debridement	Survived	Acute renal failure, malnutrition, ascites
14	Chen et al 20	38-year-old man	Liver	n/a	POD 30	n/a	Rhizopus species	Amphotericin	Surgical debridement	Survived	n/a
15	Klimova et al 21	39-year-old man	Liver	Immunosuppression, renal failure, multiple operations, concomitant bacterial infection, use of antibiotics	POD 35	No	Mucor species	Amphotericin	Surgical debridement and posaconazole	Survived	n/a

The mucormycosis species most frequently associated with infections in solid-organ transplant patients is Rhizopus, isolated in approximately 73% of cases.¹ In our review of surgical site mucormycosis infections, Rhizopus was isolated in 9 out of the 15 cases. Our patient was also infected with Rhizopus-species mucormycosis.

Risk factors for fungal infections in solid-organ transplant recipients include the use of T-cell-depleting drugs or antibodies, renal failure, diabetes mellitus and iron overload.¹ Risk factors for fungal infections specifically in liver transplant patients include preoperative steroid use, prolonged duration of transplant or post-transplant operations, bacterial infections and prolonged use of postoperative antibiotics.¹⁵ Transfusion of blood products has also been noted as an independent risk factor for invasive fungal infections in the population of critically ill patients.²² Our patient had numerous risk factors for mucormycosis, including prolonged duration of transplant and post-transplant operations, concomitant bacterial infection, prolonged use of antibiotics, blood transfusions and T-cell suppression treatment.

The overall mortality rate for mucormycosis infections among solid-organ transplant recipients is 38%–48%.¹ In our review of surgical site mucormycosis infections, the mortality rate was 33%, which is similar to the mortality rate for patients with cutaneous mucormycosis, reported at 25%–31%.⁸ The lower mortality rate in our review is consistent with the fact that localised mucormycosis infections have a lower mortality rate than disseminated infections.⁸ Patients in our review who were diagnosed greater than 5 days postoperatively had a higher mortality rate of 36%, indicating poorer prognosis with delayed treatment. Another indicator of poor prognosis is renal failure.¹ Our patient initially presented with hepatorenal syndrome; this resolved after his liver transplant, but after the development of mucormycosis infection, he went into acute renal failure again.

Surgical debridement and monotherapy with amphotericin are considered first-line treatments for cutaneous mucormycosis.⁸ Infected tissue is excised and examined to ensure surgical margins.⁸ Treatment with posaconazole is considered a salvage treatment in patients with refractory disease or those with an intolerance to amphotericin.⁸ Small retrospective studies have shown improved outcomes in mucormycosis patients treated with a combination of echinocandin and amphotericin.²³ Murine models have also shown synergy between echinocandin and amphotericin.²⁴ Preclinical studies have shown that a combination of posaconazole and amphotericin may also be beneficial.²³ Amphotericin, echinocandins and posaconazole all have different action mechanisms: amphotericin binds ergosterol, altering cell membrane permeability and causing leakage of cell components; echinocandins inhibit 1,3-beta-d-glucan synthase, leading to decreased cell-wall production; and posaconazole interferes with fungal cytochrome P450 activity.²³

Although in vitro studies and animal models have shown a possible antagonism between antifungal classes, there has never been a clinical study showing that combination antifungal therapy leads to increased mortality. On the contrary, there have been numerous clinical studies in which dual antifungal therapy showed decreased mortality compared with monotherapy.²⁵ A possible explanation for this is that the methodologies used for in vitro studies are highly variable and animal models do not simulate human infection well and are usually inadequately powered.²⁵ With mucormycosis specifically, only 2 out of 25 in vitro studies showed possible antagonism with combination therapy. The combinations in these studies were isavuconazole with amphotericin and isavuconazole with micafungin. All other in vitro studies showed either synergy or indifference.²⁶

To our knowledge, there has been no study addressing the efficacy of combining amphotericin, echinocandin and posaconazole in mucormycosis. There has only been one report of an adolescent who was treated for osteosarcoma, developed disseminated mucormycosis and was successfully treated with triple antifungal therapy.²⁷ The decision was made to start our patient on triple antifungal therapy due to the rapid progression of abdominal-wall necrosis despite multiple surgical debridements and amphotericin. Since no clinical study has shown harm in using combination antifungal therapy and the overwhelming majority of in vitro and animal studies have shown either synergy or indifference, it was decided there could be potential benefit in combination antifungal therapy for our patient. Unfortunately, the therapy was still ineffective. It should be noted that our patient was on prophylactic fluconazole, but this was unlikely to have helped, since many azole antifungals are ineffective against mucormycosis.²³

GM-CSFs have also been used to treat mucormycosis, as they enhance the ability of granulocytes to damage mucormycosis and have been successful when used with amphotericin B.²⁸ Animal studies have shown that GM-CSFs mitigate the corticosteroid-induced suppression of cytokines and reverse macrophage suppression.²⁹ Administration of GM-CSFs has been shown to augment host responses and antifungal effects even in non-neutropenic patients.²³ Our patient was started on a GM-CSF due to his refractory mucormycosis as well in an effort to reverse macrophage suppression.

In our review of the previous 15 cases of surgical site mucormycosis infection, no patients received GM-CSFs or triple antifungal therapy. Due to the relative rarity of the disease, no large-scale randomised controlled trial has been done to compare the efficacy of combination antifungal therapy to monotherapy with amphotericin.²⁴ The current standard for treating mucormycosis is surgical debridement and amphotericin monotherapy, with the treating physician having discretion on which additional therapy to use. Due to the high mortality rate, particularly with delayed diagnosis, clinicians must have a high index of suspicion as early treatment is paramount. More research is needed to determine the optimal treatment of mucormycosis surgical-site infections in solid-organ transplant recipients.

Learning points.

• Surgical-site mucormycosis infections in solid-organ transplant recipients are rare, with only 15 previously reported cases.

• The standard treatment for mucormycosis is surgical debridement and monotherapy with amphotericin.

• Risk factors for fungal infections in liver transplant patients include preoperative steroid use, prolonged duration of transplant and post-transplant operations, bacterial infections, prolonged use of postoperative antibiotics, use of T-cell-depleting drugs or antibodies, renal failure, diabetes mellitus, iron overload and blood-product transfusions.

• Due to the high mortality rate of surgical-site mucormycosis infections, particularly with delayed diagnosis, early treatment is paramount.

• No large-scale randomised controlled trial has been done to compare the efficacy of combination antifungal therapy to monotherapy with amphotericin in treating mucormycosis.