Steroids in the Treatment of Group A Streptococcal Necrotizing Soft Tissue Infection

Abstract

Background:

Group A streptococcal necrotizing soft-tissue infection with toxic shock is a life-threatening disease. Corticosteroid use in the treatment of this process has been reported rarely.

Method:

Case reports and review of pertinent literature.

Results:

Two infections caused by the same clonal strain of Streptococcus pyogenes are presented.

Conclusion:

The cases illustrate the possible utility of high-dose steroids in the treatment of this process.

Group A streptococcal (GAS) necrotizing soft-tissue infection with toxic shock syndrome (TSS) is a relatively rare disease that causes significant morbidity and may rapidly be fatal [1]. Streptococcal TSS was first described in 1987 and is characterized by hypotension, multiple-organ dysfunction, and an erythematous rash [2]. The reported mortality rate ranges from 20–70% [1,2]. The mainstay of therapy is prompt, aggressive surgical drainage and debridement of necrotic tissue, high-dose beta-lactam and clindamycin therapy, and activated protein C ([APC] or drotregogin alfa) [3,4]. Intravenous immunoglobulin may be considered also, although its efficacy is not clearly established [3]. These therapies have been reviewed recently in the Surgical Infection Society Guidelines for the Treatment of Skin and Soft Tissue Infections and in the Infectious Diseases Society of America guidelines in 2005 [3,4]. However, the utilization of high-dose corticosteroids in the treatment of GAS infections with TSS was not discussed because of the small number of relevant published reports.

Two cases of GAS necrotizing soft-tissue infection with TSS caused by the same clonal strain of Streptococcus pyogenes, one community-acquired and the other hospital-acquired, allow at least a partial comparison of the clinical courses with and without high-dose steroid therapy. In the index and the hospital-acquired cases, the therapeutic approaches were similar and provided by the same surgical intensivist. In both cases, initial clinical improvement was followed by progressive soft-tissue necrosis. In the index case, high-dose steroids were not given, and despite early clinical improvement, progressive tissue necrosis led to increasing organ dysfunction and eventual death. In the subsequent, hospital-transmitted, case, high-dose steroid therapy was initiated after an initial clinical response was followed by progressive tissue loss. During steroid therapy, soft tissue inflammation and tissue necrosis resolved rapidly.

Case Reports

Case 1

A 55-year old man with non-insulin dependent diabetes mellitus presented to the emergency department with a chief complaint of severe bilateral leg pain, left greater than right. Four days prior to admission, he had suffered bilateral posterior thigh contusions with hematoma formation secondary to a blunt force injury while working. He returned to work the following day but complained of not feeling well that evening. On the evening prior to admission, he developed fever and malaise, with lethargy appearing the day of admission.

At presentation to the emergency department, his blood pressure was 109/65 mm Hg, the heart rate was 126 beats/min, and the ventilatory rate was 22 breaths/min with an oxygen saturation of 90% on room air. He was alert, afebrile (97.4°F/36.3°C), and tachypneic with mild respiratory distress and had normal palpable pulses. Skin examination was notable for a 20 × 15-cm area of ecchymosis with a single bullous lesion over the left posterior-medial thigh and a 15 × 10-cm area of ecchymosis without bullous changes over the right posterior thigh.

Admission laboratory evaluation revealed a white blood cell count of 17 × 10⁹/L, hemoglobin 18.3 g/dL, hematocrit 54%, platelet count 179 × 10⁹/L, international normalized ratio (INR) 1.5, serum sodium 127 mEq/L, potassium 6.8 mEq/L, chloride 94 mEq/L, CO₂ 8 mmol/L, blood urea nitrogen (BUN) 37 mg/dL, serum creatinine 2.73 mg/dL, and serum glucose 265 mg/dL. Non-contrast computed tomography of the lower extremities revealed mild bilateral subcutaneous edema with prominent edema in the fascial layers and muscle tissues in all compartments of the left thigh.

Vancomycin and piperacillin-tazobactam were administered intravenously. Emergency general surgery consultation was obtained approximately 4 h after presentation. Over the subsequent hour, the patient became confused, lethargic, and hypotensive with a decreased level of consciousness. He underwent urgent endotracheal intubation, volume resuscitation with crystalloid, and blood pressure support with norepinephrine. Repeat coagulation studies revealed an INR of 3.7. He was admitted urgently to the surgical intensive care unit (SICU) for stabilization prior to operative intervention with placement of central venous access, fluid resuscitation, infusion of fresh-frozen plasma, and treatment with 1.2 g of clindamycin and high-dose penicillin G. He underwent emergency operative debridement 1 h after intubation.

At operation, all fascia and muscles within the left thigh compartment were necrotic, and a left hip disarticulation was performed. The right posterior thigh was explored, and the fascia was necrotic, but all muscle was viable. Surgical sites were dressed with mafenide acetate-soaked dressings. Postoperatively, he underwent further aggressive resuscitation to correct ongoing and disseminated intravascular coagulopathy and treatment with intravenous immune globulin (Gamunex, Talecris Biotherapeutics, Inc., Research Triangle Park, NC; 1 g/day for one day followed by 0.5 g/day for 2 days). Additionally, he was started empirically on stress-dose steroid (hydrocortisone 100 mg every 8 h) because of his profound septic shock that required high-dose vasopressor support. Several hours postoperatively, he developed abdominal compartment syndrome necessitating a decompressive laparotomy in the ICU, takedown of his dressing, and incision exploration with control of bleeding at the bedside secondary to profound coagulopathy. After his coagulopathy improved, he was given a course of drotrecogin alfa. Preoperative blood cultures and intraoperative tissue cultures all were positive for Streptococcus pyogenes.

His hospital course was characterized by an initial improvement of organ dysfunction but recurrent organ system decline that paralleled slow, progressive soft-tissue necrosis in the right leg. He was returned to the operating room daily for the next four days for irrigation and debridement and was weaned off inotropic support. His steroid therapy was discontinued following resolution of shock, and he achieved negative fluid balance and closure of his abdomen. Muscles within the posterior right thigh compartment remained viable throughout this period. Over the following three days, he had improvement of his pulmonary function with the ability to be weaned to minimal support. He underwent a percutaneous tracheostomy seven days after his initial surgery and progressed to intermittent tracheostomy collar trials. However, despite the improvement of organ function, he had recurrent progression of necrosis of muscle and skin within the posterior right thigh and developed progressive renal failure. All blood and tissue cultures remained negative. He required the institution of continuous veno-venous hemodialysis eight days after his initial operation. Nine days after his initial operation, he had rapid onset of marked clinical deterioration with hypotension necessitating high-dose norepinephrine and vasopressin. Serum cortisol assays and a cosyntropin stimulation test were performed with a normal response (serum cortisol 112 micrograms/dL after stimulation), and steroids were not reinitiated. Examination of the tissue within the right thigh revealed marked progression of necrosis that would require significant debridement resulting in loss of function or amputation. Following discussions with family, comfort measures were initiated, and he subsequently died.

Case 2

A 47-year old healthy, physically active, male surgeon with a history of a right total hip arthroplasty secondary to a sports injury experienced in-hospital exposure to the index patient while assisting with the left hip disarticulation. He was asymptomatic for the following eight days, during which time, he remained active. He developed marked fatigue on the evening of the eighth day post-exposure and awoke with myalgias the following morning. On post-exposure day 10, his myalgias worsened, and he developed fever and chills. Erythema over his right foot emanating from a site of chronic tinea pedis interdigitalis and right medial thigh swelling had developed, and he presented to his orthopedic surgeon for evaluation.

Physical examination demonstrated erythema and discoloration of the skin between the right third and forth metatarsal heads and tenderness over the dorsum of the right foot. Right inguinal tender adenopathy was noted. Musculoskeletal examination revealed full range of motion of his right hip without tenderness. Laboratory evaluation showed a white blood cell count of 10 × 10⁹/L, hemoglobin 13.5 g/dL, hematocrit 40%, serum sodium 137 mEq/L, potassium 4.1 mEq/L, chloride 101 mEq/L, CO₂ 26 mmol/L, blood urea nitrogen 22 mg/dL, serum creatinine 1.88 mg/dL, an elevated erythrocyte sedimentation rate of 38 mm/h, and an elevated C-reactive protein concentration of 284 mg/L. Magnetic resonance imaging of the right leg revealed no effusion of the hip but did show edema surrounding the lymphatic drainage of the foot and medial thigh, consistent with cellulitis and lymphangitis. He was admitted to the hospital with infectious disease consultation and begun on intravenous fluid and parenteral piperacillin-tazobactam and vancomycin.

The evening of admission, his heart rate remained elevated, ranging from 90–100 beats/min, considerably above his resting baseline (45–55 beats/min), and his systolic blood pressure consistently remained between 90–100 mm Hg. He had no spontaneous urination that evening and by morning developed nausea, vomiting, and diarrhea. His erythema had progressed somewhat on the dorsum of the foot and, more importantly, along the lymphatic channels of the medial right thigh. He developed oliguria. Two liters of crystalloid was given, high-dose clindamycin was initiated, and he was transferred to the SICU. Nearly simultaneously, he developed hypotension with systolic blood pressure in the 70s, fever to 38.4°C, and a rash consistent with streptococcal TSS. He had a marked change in his serum laboratory values: White blood cell count 5.8 × 10⁹/L, hemoglobin 10.6 g/dL, hematocrit 31%, platelet count 140 × 10⁹/L, INR 1.7, serum sodium 133 mEq/L, potassium 4.1 mEq/L, chloride 108 mEq/L, CO₂ 17 mmol/L, BUN 34 mg/dL, and serum creatinine 3.57 mg/dL.

On his arrival in the SICU, his systolic blood pressure was as low as 58 mm Hg. Central venous access was achieved, and norepinephrine was initiated, requiring doses of as much as 20 mcg/min to maintain adequate systemic pressure. Intravenous immune globulin was initiated (1 g/day the first day and 0.5 g/day for two days), and he was resuscitated with 6 L of fluid. A serum cortisol stimulation test was performed per protocol for the management of septic patients with shock refractory to fluid and inotropic support and was found to be normal (baseline serum cortisol 18.0 mcg/dL; post-stimulation 37.2 mcg/dL), and stress-dose steroids were withheld. His serum lactate concentration was elevated (2.9 mEq/L) at this time. Blood cultures obtained at the time of admission yielded Streptococcus pyogenes. Computed tomography of the leg and abdomen revealed diffuse edema in the foot, thigh, and retroperitoneum along the lymphatic channels but no suggestion of fluid collections. Erythema remained limited to areas of lymphatic channels in the medial right thigh, and his adenopathy improved, with a decline in both the tenderness and the size of his palpable nodes. Operative intervention was believed not to offer benefit at this time, and therapy with drotrecogin alfa was initiated. He initially had a good clinical response, with a decrease in erythema, reduction in tenderness, improvement in his urine output, and marked reduction in his vasopressor requirement.

The following morning, his serum lactate concentration, INR, BUN, and creatinine had all improved, but he had some mild progression of erythema of the medial thigh. However, by that evening, he had progression of erythema, with increased warmth and tenderness and significant changes in the skin of the medial thigh. His laboratory values had worsened again with the development of acute lung injury (P:F ratio < 300), acute renal failure (oliguria, BUN 39 mg/dL, creatinine 3.75 mg/dL), and elevation of bilirubin (4.0 mg/dL) and INR. He was taken to the operating room for incision, drainage, and debridement. Operative exploration revealed fascial necrosis along the medial thigh with fluid collections, edema, and separation of the muscle compartments on the medial surface from the mid-thigh to just above the popliteal fossa. The skin, subcutaneous tissues, and muscle were all viable. He had his incisions packed with mafenide acetate dressings and went back to the SICU.

He returned to the operating room roughly 12 h later for his second debridement and was found to have progression of erythema over the anterior and lateral thigh necessitating a second incision on the anterior thigh. He had progression of fascial necrosis and the development of an area of skin and subcutaneous fat necrosis measuring 10 × 8 cm. These tissues were débrided and sent for touch preparation, gram stain, and quantitative cultures. His pulmonary function had deteriorated significantly with the development of acute respiratory distress syndrome (P:F 89). Both gram stain and cultures were negative for streptococcal spp. On the basis of the input from a senior infectious disease consultant and the consultant's anecdotal experience with higher-dose steroids (as opposed to stress-dose steroids for refractory septic shock) in a series of patients with necrotizing streptococcal infections, a 10-mg intravenous dexamethasone load followed by 4 mg q 6 h for 48 h was initiated.

The patient returned to the operating room the morning after the initiation of steroid therapy for his third exploration and debridement. He was found to have full resolution of erythema of the leg and no further progression of fascial or soft tissue necrosis. The appearance had improved to allow closure of the subcutaneous tissue over a drain on the anterior thigh. He had partial closure of his posterior thigh incision with drains and application of a vacuum-assisted closure device in another 48 h. The patient had resolution of his acute respiratory dysfunction syndrome, acute renal failure, hepatic dysfunction, and coagulopathy and was weaned from mechanical ventilation on hospital day nine and discharged to home with a vacuum-assisted closure device in place on hospital day 12. The patient underwent elective delayed primary closure of his thigh wound approximately seven days after discharge and had an uneventful recovery.

Discussion

In general, the risk of soft tissue infection (including surgical site infections) can be conceptualized by the following relation [5]: \documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland,xspace}\usepackage{amsmath,amsxtra}\pagestyle{empty}\DeclareMathSizes{10}{9}{7}{6} \begin{document} \begin{align*} \frac {\hbox{Bacterial inoculum} \times \hbox{bacterial virulence}} {\hbox{Resistance of the host}}\\ \quad = \hbox{Risk of soft tissue infection} \end{align*} \end{document}

Group A Streptococcus is a particularly virulent pathogen with a rapid growth rate and numerous virulence factors that enable invasion of intact skin and healthy, well-vascularized soft tissues. Its virulence and ability to cause rapidly progressive necrotizing soft-tissue infections has led to the term “flesh-eating bacteria” [1]. Whereas Staphylococcus aureus requires > 10⁵ colony-forming units (cfu) in vascularized tissues to cause infection, group A streptococci require 10² cfu or fewer. The portal of entry cannot be identified in at least one-half the infections; identified portals frequently are in areas of minor trauma or breaks in the skin [1]. Group A Streptococcus may cause a variety of clinical syndromes, including pharyngitis, non-necrotizing cellulitis and erysipelas, necrotizing cellulitis, necrotizing fasciitis, and myositis. Patients who develop streptococcal TSS may report symptoms consistent with a virus infection for two or three days prior to progressive signs of invasive infection. Nausea, emesis, and diarrhea also may occur. This syndrome occurs secondary to streptococcal protein and toxin production (M1 protein, SPE-A, -B, and -C) that act as superantigens causing direct activation of as much as 20%–30% of the host T-cell population (conventional antigen presentation activates roughly 0.01% of cells) and pronounced cytokine production [1,2,6]. The epidemiologies of GAS soft-tissue infection and TSS are both complex, but the infections remain rare: The estimated incidence of invasive GAS infections ranges from < 5–20 cases per 100,000 population. The incidence of TSS in invasive GAS infections ranges from 5%–14% overall but is about 50% in necrotizing soft-tissue infections [2]. The mortality rate for necrotizing GAS infections and TSS ranges from 20–70% in most reports.

The two cases presented here clearly differed in the severity of illness at the time of presentation. However, the two were caused by the same pathogen, as determined by DNA typing, both patients had signs and symptoms of streptococcal TSS, and the patients were treated with similar regimens that included high-dose penicillin and clindamycin, drotrecogin alpha, and intravenous immunoglobulin. Each case was characterized by initial clinical improvement but continuing tissue necrosis despite negative cultures after the initial operative debridement. In the index case, originally viable muscle became completely necrotic several days after the initial debridement and days after negative tissue and blood cultures. Of note, the recurrence of tissue necrosis despite negative cultures followed discontinuation of empiric steroid therapy initiated for refractory septic shock. In the second case, steroid therapy was not given initially, as this patient had an appropriate response to cosyntropin stimulation, and his vasopressor requirement diminished fairly rapidly with other therapeutic interventions. However, steroid therapy was initiated when marked progression of organ dysfunction, erythema, and fascial necrosis with new-onset skin and fat necrosis was noted at the time of the second operative intervention. This decision was based on observations in an unreported case series of a senior infectious disease expert. The dosing regimen selected for this patient was roughly two to three times that of the equivalent hydrocortisone regimen indicated for sepsis. After the initiation of steroids, all of the erythema resolved, and cessation of tissue necrosis was noted within 24 h.

Whereas well-accepted mainstays of therapy for streptococcal necrotizing soft-tissue infections include surgical debridement of necrotic tissue, high-dose penicillin and clindamycin, volume resuscitation, and inotropic support, the use of intravenous immunoglobulin and drotrecogin alfa are less widely accepted; and few data exist regarding the value of high-dose steroids in this setting [3,4]. Intravenous immunoglobulin may be considered in streptococcal TSS (2C) largely on the basis of case reports and case series in view of its theoretic ability to neutralize superantigens associated with streptococcal infections [3]. However, inadequate data exist to make firm recommendations either for or against its use [3]. Drotrecogin alfa is indicated for patients with severe sepsis but has not been studied specifically in streptococcal TSS. The indications for steroids in septic shock remain controversial [7,8]. The guideline utilized in the ICU at the time these cases were seen is consistent with the recommendations put forth in the consensus statements of the American College of Critical Care Medicine [7]. Steroid replacement was utilized in the first patient during the period of septic shock refractory to fluid resuscitation and inotropic support. In the second patient, steroid replacement was not used early during the patient's course, as baseline cortisol and cosyntropin stimulation tests did not support its use, and inotropic therapy was withdrawn rapidly after resuscitation and antibiotic therapy. Steroid therapy was subsequently initiated on the basis of the experience of a senior infectious disease consultant. Steroid therapy for streptococcal TSS also has strong theoretical rationale but limited data to demonstrate its benefit. A literature search revealed four references reporting the use of steroids in the setting of TSS [9 –12].

The first description of steroid use in treating streptococcal TSS was in a case series during a streptococcal outbreak in 11 consecutive patients with either respiratory or skin infections [12]. Ten patients received hydrocortisone in a dose of ≤400 mg/day. Whether any of these patients experienced a necrotizing infection is unclear. Two other reports note the successful use of high-dose steroids in pediatric patients with streptococcal TSS, one with pharyngitis and the other with septic arthritis [9,10]. As in our second patient, both cases were characterized by progression of organ dysfunction despite aggressive antibiotic therapy with resolution following steroid therapy. The final reference reports the successful use of steroids in postoperative toxic shock secondary to an S. aureus infection [11]. The initial decision to administer steroids was based on an unreported case series of a senior consultant. Four cases of streptococcal necrotizing soft-tissue infections (three adults and one child) and one of severe cellulitis all had slow or inadequate responses to initial antibiotic therapy followed by good clinical responses to steroid administration.

Glucocorticoids are a well-accepted component of therapeutic regimens in other infection settings, including meningitis in children and adults [13]. Through a variety of mechanisms, glucocorticoids are potent inhibitors of T-cell activation and the production of a number of cytokines [14]. Given the dramatic T-cell activation and cytokine production caused by the superantigen effects of GAS toxins, the value of glucocorticoids has substantial biologic plausibility. Short courses of steroids are relatively well tolerated with few complications. In this case, both erythema and progression of tissue necrosis resolved immediately after initiation of higher-dose steroids in the second patient. No other therapies coincided with this clinical change. The wounds improved to the extent that primary closure could be accomplished at the subsequent two operative procedures. Given the prompt response to steroid therapy reported here and the high mortality rate in most series of necrotizing GAS soft-tissue infections with TSS, we believe that steroid therapy should be studied in animal models of streptococcal soft-tissue infections and considered for human trials. The authors now consider steroids as a rescue therapy in this setting but, given the lack of appropriate studies, cannot make formal recommendations.

Footnotes

Author Disclosure Statement

No conflicting financial interests exist.

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