Necrotizing Fasciitis caused by Streptococcus pyogenes: A case report and literature review of disease diagnosis and management

Treatment and Follow-up: Broad-spectrum antibiotics given at outset were extended with additional antibiotics. Treatment consisted of fi ve separate surgeries involving extensive debridement of necrotic tissue amounting to approximately 55 to 65 percent of the patient’s body surface area. The patient was eventually released to a burn center for skin grafting and wound closure and in less than three months, he expired. Case Report


Background
Group A beta-hemolytic streptococcus (GABS), also known as Streptococcus pyogenes, is a non-motile, Gram-positive coccus shaped bacteria. This adaptive human pathogen is wellknown for infecting the oropharynx resulting in pharyngitis. It can also contribute to more serious invasive diseases such as toxic-shock syndrome and necrotizing soft-tissue infections [1][2][3][4]. Several serotype strains, M1 and M3 being the most prevalent within the United States, are known to cause NF [1][2][3][4]. This infection is generally community acquired and primarily occurs in the extreminities [2]. The fi rst account of NF dates back to 1783, when Claude Pouteau fi rst described the disease [1,3]. Similar cases have been documented throughout the nineteenth and twentieth centuries, specifi cally in military hospitals during war times [3,4]. The actual term necrotizing fasciitis didn't come about until 1952 [3,4].
Studies show that NF can occur despite health status and current research has created speculations about the role of host immunological factors in relation to disease protection or predisposition [5]. Still, risk factors exist such as peripheral vascular disease, diabetes, malignancy, obesity, trauma, surgery, intravenous drug use, or insect bites [5]. Conversely, reports of pediatric cases are rare with the exception of countries where the disease is widespread [1,5]. Within the United States, an estimated 10,000 cases of NF caused by GABS occur annually, 1500 of them resulting in death [5].
In addition to GABS and Staphylococcus aureus, other aerobic and anaerobic pathogens may be present in NF cases, including Bacteroides and Clostridium. Facultative aerobic organisms grow because polymorphonuclear neutrophils (PMNs) exhibit decreased function under hypoxic wound conditions, thus, lowering the oxidation/reduction potential and enabling more anaerobic proliferation resulting in acceleration of the disease process [6]. Spread of the infection from the subcutaneous tissue to the deep fascial planes is facilitated by bacterial enzymes and toxins. This causes vascular occlusion, ischemia, and tissue necrosis [4,6]. Superfi cial nerves are damaged, producing the characteristic localized anesthesia. Septicemia ensues with systemic toxicity. NF soft-tissue infections involve rapid and extensive necrosis of the superfi cial fascia that results in high morbidity and mortality despite prompt treatment [3].

Pathogenesis
Most necrotizing infections, approximately 80%, occur secondary to trauma or a surgical process in which the external defense system is breached [7,8]. Cases arising from minor injuries, such as scratches and insect bites are often due to GABS [4,5,8] Pathogenesis can be attributed to several molecular functions that allow the organism to quickly adapt to the host environment [6,9]. First, they can alter their transcriptome in response to changes in the environment, the growth conditions, and their stage of growth [6,9]. Second, their expression of virulence factors facilitates tissue invasion and vascular dissemination [6,9]. cleaving immune molecules [6,9]. Third, these organisms produce proteins designed to subvert the body's immune system [6,9]. For instance, the protein Mac1 accomplishes this by both mimicking a host cell receptor and cleaving IgG, ultimately enhancing survival [6,9].
Additionally, pathogenesis may be contingent on the molecular genetics of the host.
Evidence shows that the same strain of GABS can produce exceedingly different clinical manifestations in separate individuals [4,5,10]. Aside from the previous risk factors mentioned, it is speculated that both host immunological and genetic factors infl uence the development and outcome of invasive GABS infections [10]. In relation, certain HLA class II haplotypes may confer protection from severe systemic disease, whereas other haplotypes increase risk [10].

Clinical Presentation
The rarity of this disease combined with its initial clinical similarity to cellulitis makes prompt diagnosis diffi cult [2][3][4]10]. History of trauma, severe localized pain, heat and swelling, fl u-like symptoms, and redness are all common early indications of NF [1]. Additionally, signs of sepsis, such as increased heart or respiratory rates, along with local symptoms or signs, such as severe spontaneous pain, skin pallor, or muscle weakness may indicate NF when skin necrosis is not yet apparent [1]. Cellulitis, edema, and skin discoloration or gangrene are observed at the site of infection in 90, 80, and 70% of cases, respectively [10].
Unlike cellulitis, in which the subcutaneous tissues are easily palpitated, NF wound infections have a wooden-hard feel [8]. Direct inspection during surgery will reveal swollen, dull gray fascia, a brownish exudate and despite deep dissection, no pus will be present [8]. Ultimately, clinical judgment and observance of the subcutaneous tissue or facial planes during operation are essential in the diagnosis of NF [8].

Laboratory role in diagnosis
Acidosis, anemia, electrolyte abnormalities, coagulopathy, and an elevated white blood cell count are commonly present in patients with NF [3,4]. Early on, laboratory results for C-reactive protein (CRP) and creatine kinase (CPK) are helpful in differentiating GABS NF from cellulitis. Both test values are typically elevated in patients with GABS NF [3]. Gram stain of the exudate collected during surgery can provide physicians with information about the pathogen and therefore treatment options [4,8] However, tissue cultures or positive blood cultures are typically used for defi nitive bacteriologic diagnosis. Still, some fi nd that tissue biopsies for frozen section analysis are necessary to defi nitively diagnose NF [2,8]. If tissue biopsies are collected for diagnosis they should not be collected from areas of necrosis, but from the deep tissues in order to avoid bacterial misrepresentation due to the presence of superfi cial contaminates [2,8]. Along with chemistry and microbiology results, complete blood count and manual differential also indicate when a bacterial infection is present. Neutrophilia or a left shift, toxic granulation, vacuolization, and Dohle bodies can all be present in cases of bacterial infection [4].

Treatment
Patients with symptoms of NF should immediately be placed on intravenous antibiotics, which can be adjusted later based on the microbiological identifi cation and sensitivities [4,5]. Clindamycin and penicillin are the drugs of choice in patients with GABS NF [4,5,8]. The basis for selecting these two antibiotics is as follows: clindamycin has been shown (by in vitro studies) to suppress toxins and control cytokine production more effi ciently than penicillin and -lactam antibiotics; however, increasing resistance of GABS to macrolides necessitates administration of penicillin [4,5,8].
Prompt fasciotomy and surgical debridement are the primary means of treatment following the diagnosis of NF [7,8].
Failure to respond to antibiotics or progressive toxicity, fever, or hypotension while receiving antibiotics therapy signify the need for surgical intervention [7,8]. During surgery, the extent of debridement is determined based on the amount of necrotic tissue. Easy dissection along the fascia by a blunt instrument and/or gas in the affected tissue suggests necrotic tissue and both require additional incision and drainage [8]. Multiple surgical procedures and even amputation may be necessary to contain the disease [3,7,8]. Medications can be administered to raise blood pressure and in some cases, a hyperbaric oxygen chamber may be helpful [2,4,5].
Lastly, aside from isolating patients with NF, individuals exposed to the patient should undergo preventative treatment with clindamycin [5]. After the disease process is controlled, patients should be transferred to a burn center for splitthickness skin grafting for wound closure [7,8]. The outcome of NF following surgical intervention closely resembles full thickness burn injuries and therefore, burn centers are best equipped to care for NF patients [7,8].

Case Conclusion
The patient initially demonstrated clinical signs of left arm compartment syndrome. Following surgical treatment, he developed severe shock requiring administration of phenylephrine and norepinephrine to constrict blood vessels and to raise blood pressure. Additionally, progressive symptoms of erythema became evident in his left arm and left chest. Subsequently, he was returned to surgery where the actual diagnosis of NF was determined. Concurrently, his fi rst preliminary blood culture bottles were positive for GPC. Along with a combination of piperacillin and tazobactam and vancomycin covered from outset, the patient was given ciprofl oxacin hydrochloride and clindamycin. His differential results correlated to his diagnosis with a left shift, toxic granulation, vacuolization, and Dohle bodies. Final identifi cation and sensitivity determined that the organism present in the blood cultures, aerobic wound culture, tissue cultures and brownish exudate collected during surgery, was penicillin sensitive GABS.
Throughout surgical treatment, the patient received large amounts of fl uids and at one point required platelet transfusion and fresh frozen plasma due to thrombocytopenia thought to be secondary to sepsis. After the disease process was contained and the patient was considered hemodynamically stable he was transferred to a burn center. Unfortunately, during recovery he expired.

Conclusion
This case study confi rmed that NF is diffi cult to diagnose due to its general initial clinical presentation and rare incidence. It further established that the invasive nature of GABS softtissue infections directly correlates to the importance of prompt diagnosis and antimicrobial and surgical treatments. Future research is still needed to solidify the signifi cance of risk factors and microbial and host factors in the molecular pathogenesis of the disease.