ACRT Journal

Introduction

Serratia marcescens

Serratia marcescens, a Gram-negative facultative anaerobic bacterium, is an opportunistic pathogen often found in healthcare settings, belonging to the Enterobacteriaceae family. S. marscecens can cause a wide spectrum of infections involving urinary tract, bloodstream, skin, soft tissue, bones, respiratory tract, eyes, and central nervous system. S. marcescens is a very unusual cause of soft tissue infections, appearing only in the presence of certain risk factors, such as immunosuppression, diabetes mellitus, antibiotic and/or steroid exposure, alcoholism, trauma, and peripheral vascular disease [1].

The mechanism through which S. marcescens induces soft tissue infections remains unclear; however, it could potentially be linked to the release of virulence factors by the microorganism. Serratia sp. releases a variety of compounds, including hemolysin, nuclease, lipases, lecithinase, siderophores, metalloproteases, and notably proteases. These proteases possess characteristics that can enhance vascular permeability, trigger epidermal tissue necrosis, incite dermal inflammation and swelling, and contribute to the infiltration of polymorphonuclear leukocytes into muscle tissue. [2] In addition, vasoconstriction caused by bacterial toxins and immune responses results in fascial spaces not reached by blood vessels, leading to necrosis, and hindering antibiotic penetration into tissues.

Serratia infections are challenging to treat due to their frequent resistance to multiple antibiotics. Resistance mechanisms involve enzymes like cephalosporinase and plasmid-encoded betalactamases. These bacteria often possess inherent or acquired resistance, including inducible chromosomal AmpC β-lactamases, for ampicillin and first-generation cephalosporins. Effective treatment options include aminoglycosides, third- and fourthgeneration cephalosporins, and carbapenems.

Serratia marcescens is also an infrequent yet highly dangerous trigger for a particular type of soft tissue infection such as necrotizing fasciitis, a medical condition also known as “flesheating disease”. [3] Cases of necrotizing fasciitis related to S. marcescens have recently become more prevalent in the published literature [1, 4].

Necrotizing fasciitis

Necrotizing fasciitis, first described in the early 20th century [5, 6], is a life-threatening infection primarily affecting superficial fascia and subcutaneous tissue, causing gradual tissue destruction. It commonly occurs in the lower limbs but can affect other body parts. [7] Typically, it involves a mix of aerobic and anaerobic bacteria, making it a polymicrobial infection.

Early detection is challenging, as it can resemble cellulitis or abscesses. Diagnosis often relies on late signs like crepitus, skin necrosis, and bullae. [8] However, their absence doesn’t rule out the disease [9].

Necrotizing fasciitis has a significant mortality rate, especially when caused by uncommon pathogens like S. marcescens. The first reported case of S. marcescens-associated lower limb necrotizing fasciitis dates back to 1987 [10].

At the beginning, muscle and dermal tissue are unaffected, but necrosis occurs in the fascia and subcutaneous tissue due to skin vessels microthrombosis, leading to devascularization and the formation of necrotic tissue. [11]

Another common finding is blisters, resulting from necrolysis, as consequence of the same ischemia-triggered mechanism.

Histological progression involves gradual declines in neutrophilic response and polymorphonuclear infiltration, alongside heightened bacterial proliferation. This corresponds to increased tissue ischemia, reduced perfusion, and intensified bacterial growth. As histopathological staging advances, mortality rates also rise [12].

Classifications

Two distinct forms exist for necrotizing fasciitis. Type I involves mixed aerobic and anaerobic bacteria, commonly emerging post-surgery in aged and diabetic patients. Type II signifies monomicrobial infections caused by Group A Streptococcus or Staphylococcus aureus, affecting younger, healthy individuals. Some Authors [1, 13] argue for a third type related to Vibrio vulnificus and gas gangrene, yet scientific consensus varies. Multimicrobial infections are more frequent than monomicrobial, with the latter impacting younger individuals with minor trauma history.

Clinical staging of necrotizing fasciitis proposed by Wang et al. [7] describes symptoms and signs that evolve with the disease as the infection progresses (Table 1). Initial evaluation reveals erythema, tenderness, warmth, and swelling in most patients (stage 1): this early-stage necrotizing fasciitis may be confused with other soft tissue infections. Blistering occurs in only 41% of early-stage patients: as the disease progresses, blisters increase (stage 2), often followed by late-stage indicators such as skin crepitus, anesthesia, and necrosis (stage 3).

Clinical stage	Stage 1 (early)	Stage 2 (intermediate)	Stage 3 (late)
Clinical features	Erythema	Blister/Bullae	Crepitus
	Tenderness		Skin
	Calor		Anesthesia
	Swelling		Necrosis

Table 1: Clinical stages of necrotizing fasciitis. Skin alterations are heterogeneous: the region displaying the most progressed changes should define the clinical stage [7].

The Laboratory Risk Indicator For Necrotizing Fasciitis (LRINEC) score [9] is a helpful tool to differentiate necrotizing fasciitis from milder skin infections. It employs routine lab tests to predict necrotizing fasciitis (Table 2): the maximum score is 13; 6 or higher raises suspicion, while 8 or higher strongly predicts the disease. An elevated LRINEC score (≥ 8 out of 13 points) is reported to have a sensitivity of only 32.4% (95% Confidence interval (CI)

22.0%-45.1%) and specificity of 93.9% (95% CI 80.9%-98.2%) [14], so despite the utility of this score, it’s crucial to emphasize that necrotizing fasciitis is primarily diagnosed through surgical evaluation.

Variable (units)	Score
C-reactive protein (mg/L)
< 150	0
≥ 150	4
Total white cell count (x10,000/µL)
< 15	0
15-25	1
> 25	2
Hemoglobin (g/dL)
> 13.5	0
11-13.5	1
< 11	2
Sodium (mEq/L)
≥ 135	0
< 135	2
Creatinine (µmol/L)
≤ 141	0
> 141	2
Glucose (mmol/L)
≤ 10	0
> 10	1

Table 2: The Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score [9].

Case Presentation

We present the case of a 57-year-old man of Filipino origin on vacation in Switzerland who arrived from Manila two weeks earlier. He came to our Emergency Department for worsening pain in his left leg, associated with local oedema and dyspnoea for about 24 hours. His past medical history included arterial hypertension, hiatus hernia, dyslipidemia, and recurrent tonsillitis, without hospitalization during the last year. The patient stated that he had not used alcohol or intravenous drugs in the past or at present, that he had not suffered any recent trauma, and that he had not recently undergone any dental work.

Physical exam at presentation revealed a tympanic temperature of 36°C, blood pressure of 88/50 mmHg, heart rate 100 bpm, and SpO₂ 100% in room air. The patient showed no wounds on his leg. Laboratory values included creatinine 291 µmol/L, C-reactive protein 312 mg/L, platelets 95x10⁹/L, white blood cells 0.5x10⁹/L, neutrophils 0.23x10⁹/L, pH 7.33, lactates 3.9 mmol/L, hemoglobin 150 g/L, sodium 130 mmol/L, glycemia 7.8 mmol/L, creatine kinase 6073 IU/L. The calculated LRNEC score was 8 out of 13 (high risk for necrotizing soft tissue infection). Leptospirosis, HIV, and Treponema pallidum infection were ruled out.

Given the clinic, a Revised Geneva Score of 12 points (high risk for pulmonary embolism) and a Wells Score of 6 points (moderate risk), a CT angiography was performed which excluded pulmonary embolism; an ultrasound of the left lower limb excluded vascular occlusions. Therefore, in the suspicion of necrotizing fasciitis, broad-spectrum antibiotic therapy with Vancomycin, Clindamycin, and Imipenem/Cilastatin was immediately set up after obtaining blood cultures.

Due to the high suspicion of necrotizing fasciitis, the patient was urgently taken to the operating room where he underwent a fasciotomy of the left leg. Necrosis of the soleus muscle, lateral and medial gastrocnemius muscle was observed during the operation, without pus leakage, but with compartment syndrome of the leg. Subsequently, histopathology confirmed the diagnosis of necrotizing fasciitis. For hypotension with hyperlactatemia and anuria, in the setting of septic shock, crystalloids and everincreasing doses of Norepinephrine were administered.

Following surgery, the patient was admitted to the Intensive Care Unit.

Due to superimposed hypovolemic shock, resulting from capillary leak and hemorrhage after the fasciotomies, the patient required massive transfusions. A multi-organ failure was therefore outlined, with persistent lactic acidosis and associated severe consumption coagulopathy, requiring supplementation with coagulation factors and plasma.

The PiCCO advanced cardiac output monitoring results were consistent with a mixed shock form (septic and hypovolemic), requiring massive fluid administration and high doses of catecholamines.

Continuous hemodiafiltration was started, due to renal failure and impending combined metabolic acidosis.

Given the progressive worsening of the multiorgan failure, the patient underwent above-the-knee amputation on the first day of hospitalization and, given the subsequent clinical worsening, hip disarticulation surgery on the same day.

Eight hours after hospital admission, the cultures turned positive for Serratia marcescens without any other pathogens in biopsies performed in the operating room and in blood cultures (Table 3). The antibiotic therapy was changed to Vancomycin, Meropenem, and Ceftazidime/Avibactam.

Table 3: Antibiotic susceptibilities of Serratia marcescens isolated from biopsies and blood cultures.

Our patient received hydrocortisone in the setting of septic shock, to treat critical illness-related corticosteroid insufficiency, and intravenous immunoglobulin, prior to microbiological results. Despite massive volume replacement, high doses of amines, multiple transfusions, rapid surgery and appropriate antibiotic therapy, the patient died of overwhelming septic shock 27 hours after hospital admission.

Discussion

We performed a literature search in PubMed spanning from 1966 up to 2023. Our search terms included “Serratia marcescens” and “necrotizing fasciitis”. Furthermore, reference lists from identified articles were reviewed for potential additional cases. We identified 28 cases of necrotizing fasciitis due to S. marcescens (Table 4), with a mortality of 46.4% (13 patients out of 28) and a mean age of 49.1 years (standard deviation ±23.8 years). 18 patients (64.3%) contracted the infection in the community, while 10 (35.7%) in a hospital setting: 21 patients (75%) presented comorbidities or were immunocompromised, while only 7 (25%) were healthy or immunocompetent. No healthy or immunocompetent patient receiving extensive care like our patient died: thus, to the best of our knowledge, our patient represents the first fatal case of community-acquired necrotizing fasciitis due to Serratia in an immunocompetent patient.

Table 4: Necrotizing fasciitis due to Serratia marcescens cases, from 1966 to 2023. AKA, above-the-knee amputation; CA, community-acquired infection; CAD, coronary artery disease; CHF, chronic heart failure; CKD, chronic kidney disease; CML, chronic myelomonocytic leukemia; DM, diabetes mellitus; ESRD, end-stage renal disease; HA, health-care-associated infection; LAMA, left against medical advice; SD, surgical debridement; PVD, peripheral vascular disease; SLE, systemic lupus erythematosus; T2DM, type II diabetes mellitus. (Adapted from Roberts et al. [13]).