Necrotizing Fasciitis Caused by Serratia marcescens: A Fatal Complication of Nephrotic Syndrome

Abstract

Necrotizing fasciitis is an uncommon complication of nephrotic syndrome. There have been only four cases of necrotizing fasciitis complicating nephrotic syndrome reported in the English literature. We report a 40-year-old woman with minimal-change nephrotic syndrome receiving cyclosporine therapy, who suffered from necrotizing fasciitis of her left leg. Cultures of blood and surgical specimens yielded Serratia marcescens. Despite aggressive treatment, the patient expired shortly after surgery. We review the literature and find eight cases of necrotizing fasciitis caused by S. marcescens. Most of these patients had an immunocompromised background, and the mortality rate was high.

• necrotizing fasciitis
• nephrotic syndrome
• Serratia marcescens

INTRODUCTION

It is well known that infection is an important complication of nephrotic syndrome. A disturbance in the humoral immune defense mechanisms, edematous subcutaneous tissue, and increased fragility of the skin due to stretching predispose nephrotic patients to cellulitis. However, invasive infections of soft tissue such as necrotizing fasciitis rarely complicate nephrotic syndrome. We find only four reports in the English literature.^1–4 Serratia marcescens is a gram-negative bacillus belonging to the family Enterobacteriaceae. This organism is known to cause a variety of infections including bacteremia, pneumonia, urinary tract infection, infective endocarditis, and septic arthritis.⁵ S. marcescens is rarely involved in soft tissue infections such as cellulitis and necrotizing fasciitis.⁶ It has been shown to be normal flora of the colon, but most cases of infection occur via nosocomial or iatrogenic transmission. Community-acquired S. marcescens infections are uncommon and most often occur in immunocompromised or otherwise debilitated individuals. Infections caused by S. marcescens may be difficult to treat because of multiple antibiotic-resistant strains.⁷ Herein, we report a case of community-acquired necrotizing fasciitis due to S. marcescens infection occurring in a patient with minimal-change nephrotic syndrome, which took a rapidly progressive and fulminant course leading to mortality.

CASE REPORT

A 40-year-old woman was admitted because of acute onset of severe pain and erythema in her left calf. Her medical history was relevant for nephrotic syndrome due to minimal-change disease which was diagnosed by renal biopsy 5 years ago. Although steroid responsive, frequent relapses during tapering steroid and steroid dependence were noted. Being intolerant of the side effects of steroids, an alternative immunosuppressive agent was maintained with cyclosporine at a dose of 1.5 mg/kg/day to remain in remission. The patient had been well until 2 weeks earlier, when nephrotic syndrome presenting with leg edema, hypoalbuminemia, and heavy proteinuria occurred. The patient conceded that she had stopped cyclosporine for 3 months before the relapse. Cyclosporine was resumed at a dose of 3 mg/kg/day and diuretic furosemide was prescribed to control edema. One week later, the leg edema did not improve and she complained of severe pain in her left calf.

On arrival, the patient had clear consciousness with stable hemodynamics, except for a body temperature of 38.6°C. There was erythematous swelling with local heat and severe tenderness without crepitus over her left calf. Hematologic analysis revealed a white blood cell count of 5600/μL, hemoglobin of 14.8 g/dL, and platelet count of 305,000/μL. Biochemical studies showed albumin 1.0 g/dL, cholesterol 428 mg/dL, triglyceride 220 mg/dL, urea nitrogen 23 mg/dL, creatinine 0.84 mg/dL, sodium 139 mEq/L, and potassium 4.3 mEq/L. The spot urine albumin/creatinine ratio was 7352.9 mg/g (normal <30 mg/g).

She was initially treated for cellulitis with intravenous antibiotic cefazolin. Despite this antibiotic therapy, the skin lesions with bullae formation rapidly extended to both thighs and lower abdomen, and hypotension developed on the third day of admission. The antibiotic regimen was empirically changed to a combination of piperacillin/tazobactam and vancomycin. Computed tomography showed increased attenuation of the subcutaneous fat from the left calf to both the thighs and lower abdomen (Figure 1). Surgical debridement was performed immediately, and necrotic subcutaneous tissue and fascia were noted during surgery. Cultures of blood and surgical specimens yielded S. marcescens (Table 1). Despite aggressive therapy, the patient expired shortly after surgery.

Figure 1.  Computed tomography showing increased attenuation of the subcutaneous fat over both the thighs (arrows).

Table 1.  Antibiotic susceptibility of Serratia marcescens in the present case.

Agent	Sensitivity
Ampicillin	Resistant
Cefazolin	Resistant
Cefuroxime	Resistant
Flomoxef	Susceptible
Ceftazidime	Susceptible
Cefotaxime	Susceptible
Cefepime	Susceptible
Gentamicin	Susceptible
Amikacin	Susceptible
Ciprofloxacin	Susceptible
Meropenem	Susceptible
Piperacillin	Susceptible
Piperacillin/tazobactam	Susceptible

DISCUSSION

There is an increased tendency for infections in nephrotic syndrome due to immunological changes secondary to proteinuria. Patients have an increased susceptibility to infection because of low serum IgG concentrations, reduced complement activity, and depression of T-cell function.⁸ Together with the use of corticosteroids and other immunosuppressive agents, all these factors increase the risk for infection in nephrotic patients. With respect to the spectrum of infections, a variety of infectious complications have been reported in patients with nephrotic syndrome, particularly bacterial infections. Earlier reports described that peritonitis and bacteremia without a focus are the most common and serious infections in hospitalized nephrotic children, usually caused by encapsulated organisms (e.g., Streptococcus pneumoniae) and gram-negative enteric organisms, predominantly Escherichia coli.^9–11 Edema may predispose to entry and spread of infection and increase the probability of soft tissue infections such as cellulitis, but necrotizing fasciitis has been very rarely reported in the literature. There have been only four cases of necrotizing fasciitis complicating nephrotic syndrome reported in the English literature (Table 2).^1–4 The glomerulopathies included two minimal-change disease, one diabetic nephropathy, and one steroid-sensitive idiopathic nephrotic syndrome. The causative infectious organisms included one S. marcescens, one Streptococcus agalactiae, one methicillin-resistant Staphylococcus aureus, and one Pseudomonas.

Table 2.  Clinical characteristics of nephrotic patients afflicted with necrotizing fasciitis described in the literature.

Case no. [reference]	Age (year)/gender	Underlying condition and risk factor	Site of infection	Isolated organism	Outcome
1 ^1	73/M	Nephrotic syndrome (MCD), corticosteroids use	Right leg	Serratia marcescens	Died
2 ^2	50/F	Nephrotic syndrome,^a diabetes	Right leg	Streptococcus agalactiae	Recovered
3 ^3	58/F	Nephrotic syndrome (MCD), renal transplant, tacrolimus, MMF, corticosteroids use	Right leg	MRSA	Recovered
4 ^4	1/M	Nephrotic syndrome,^b corticosteroids use	Both legs	Pseudomonas	Recovered
5 [our case]	40/F	Nephrotic syndrome (MCD), cyclosporine use	Left leg	Serratia marcescens	Died

Notes: MCD, minimal-change disease; MMF, mycophenolate mofetil; MRSA, methicillin-resistant Staphylococcus aureus.

^aNo renal biopsy and clinical diagnosis as diabetic nephropathy.

^bNo renal biopsy and clinical diagnosis as steroid-sensitive idiopathic nephrotic syndrome.

Table 3.  Clinical characteristics of patients with necrotizing fasciitis caused by Serratia marcescens described in the literature.

Case no. [reference]	Age (year)/gender	Underlying condition and risk factor	Site of infection	Positive culture	Outcome
1 ^15	74/M	NSAIDs use	Right arm	Bullae, blood	Died
2 ^16	55/F	Diabetes	Right leg	Tissue	Recovered
3 ^1	44/M	SLE, ESRD on PD, corticosteroids use	Left leg	Tissue, blood	Recovered
4 ^1	73/M	Nephrotic syndrome (MCD), corticosteroids use	Right leg	Tissue, blood	Died
5 ^17	66/F	None	Left leg	Bullae, tissue, blood	Died
6 ^18	2/F	None	Neck	Tissue, blood	Died
7 ^19	49/M	Cancer on chemotherapy, diabetes, alcoholism	Right leg	Bullae, tissue, blood	Died
8 ^20	51/M	Diabetes, ESRD	Left leg	Tissue, blood	Died
9 [our case]	40/F	Nephrotic syndrome (MCD), cyclosporine use	Left leg	Tissue, blood	Died

Note: NSAIDs, nonsteroidal anti-inflammatory drugs; SLE, systemic lupus erythematosus; ESRD, end-stage renal disease; PD, peritoneal dialysis; MCD, minimal-change disease.

Necrotizing fasciitis is a deep-seated infection of the subcutaneous tissue and is frequently characterized by its rapid progression and a high rate of mortality. One of the most important predictors of mortality is a delay in the diagnosis of necrosis. One specific imaging sign of necrotizing fasciitis is the presence of gas in the subcutaneous tissues. However, gas is not observed in all cases, and clinical correlation is crucial.¹² Accurate diagnosis and appropriate treatment must include early surgical intervention. Two types exist according to bacteriologic cultures: type I is a mixed infection caused by aerobic and anaerobic bacteria and occurs most commonly after surgical procedures and in patients with old age and diabetes. Type II refers to a monomicrobial infection caused by group A Streptococcus and can occur in young and previously healthy individuals. Occasionally, other organisms have also been singly incriminated as the cause of necrotizing fasciitis. A recent report emphasized community-acquired methicillin-resistant St. aureus infection as an emerging clinical problem.¹³ S. marcescens has rarely been reported as a pathogen causing soft tissue infections.⁶ In addition, the majority of infections caused by this organism are nosocomial in origin.¹⁴ However, the monomicrobial nature of our patient’s community-acquired necrotizing fasciitis makes this case exceptional. We find only eight cases of necrotizing fasciitis caused exclusively by S. marcescens reported in the English literature (Table 3).^1,15–20 The mean age was not old (50 years), but the majority of patients had an immunocompromised background. The bacteria were isolated from bullae and/or tissue in all patients and from blood cultures in the majority of patients. Outstandingly, despite aggressive therapy, the mortality rate was extremely high (six of the eight patients died).

Treatment of necrotizing fasciitis due to S. marcescens does not differ from that of the same due to other pathogens and includes antibiotics and surgical debridement. However, antibiotic treatment of S. marcescens may be complicated by its high rate of resistance to a variety of drugs, including ampicillin and first- and second-generation cephalosporins.⁷ Aminoglycosides have good activity against S. marcescens, but resistant strains have also been reported.²¹ Third-generation cephalosporins, fluoroquinolones, and imipenem/cilastatin are recommended antibiotic choices for serious infections caused by S. marcescens. Other useful choices depending on susceptibility are aztreonam, aminoglycosides, and piperacillin/tazobactam. The mechanism of resistance may be the production of the enzyme cephalosporinase by the gene in the bacterial chromosome or production of plasmid-encoded enzyme beta-lactamase.⁵ In the present case, failure to cover the resistant strains of S. marcescens with the initial antibiotic cefazolin might have led to the fulminant course.

In conclusion, necrotizing fasciitis is a life-threatening infectious disease that requires prompt recognition and aggressive treatment including appropriate antibiotic therapy and early surgical intervention. Although rare, necrotizing fasciitis can complicate nephrotic syndrome. Our case and a review of the literature suggest that S. marcescens should be included in the bacteriologic differential diagnosis of community-acquired necrotizing fasciitis, particularly in immunocompromised patients. Initiation of broad-spectrum antimicrobial therapy is essential and should cover potential antibiotic-resistant strains of S. marcescens.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.