N ecrotizing lesions of soft tissue are infrequently encountered in routine surgical practice. The term necrotizing fasciitis unites different syndromes of progressive gangrenous infections of the skin and subcutaneous tissue into a single category.1 It is a rare, rapidly progressive infection that affects the fascia and subcutaneous tissue concomitantly with the development of thrombosis of skin microcirculation, resulting in necrosis of skin and soft tissue, destruction of muscles, and liquefaction of fats.1,2 The treatment is complex. The priority lies in an urgent surgical debridement with a targeted application of broad-spectrum antibiotics. Often, the combined surgical-antibiotic treatment is insufficient, prompting the use of auxiliary measures, such as negative pressure wound therapy (NPWT) or hyperbaric oxygenation.3,4 When the extremities are affected, amputations are required with a frequency of up to 25%.2 Mortality in these patients is between 50% and 80%, depending on the comorbid factors in the patient, characteristics of surgical incision, and the development of complications.5–11 Severe complications are acute renal insufficiency with a frequency of 31.6% and mortality of 50%, acute respiratory distress syndrome (ARDS) with a frequency of 29% and mortality of 59%, and multiorgan failure (MOF) with a frequency of 21% and mortality of 77.5%.4 Case Report Clinical status and course of treatment. A 63-year-old woman was hospitalized initially for prospective surgical treatment of an umbilical hernia. The patient’s status was characterized by elevated blood pressure and diabetes mellitus, which were both controlled with medication. Physical parameters and laboratory values were within normal limits. Hysterectomy with adnexectomy was performed due to carcinoma corporis uteri (Ib/grII) and followed by radiation therapy 3 years prior to presentation. The patient did not consume alcohol or smoke. In the course of primary hospitalization, the authors performed plastic surgery of the umbilical hernia with partial resection of the omentum magnum. Antimicrobial therapy was not administered. The operation and the postoperative course were normal, and the patient was released to home care on the fourth day. Three days after release, during a control visit, a normal clinical status of the abdomen and postoperative wound was established. On the second control visit, 10 days after the operation, the patient was urgently hospitalized with clinical symptoms of phlegmona and abscess of the abdominal wall. At the time of hospitalization, the patient was fully conscious, mobile, and febrile at over 39oC with a broad phlegmona of the lower half of the abdominal wall spreading toward the groin with the presence of partial fluctuation. The values of laboratory parameters were as follows: leukocytes 16.9 x 109/L, erythrocytes 3.9 x 1012/L, thrombocytes 273 x 109/L, serum glucose 26.6 mmol/L, urea 22.2 mmol/L, creatinine 104 mmol/L, and C-reactive protein (CRP) > 400 mg/L. Lung radiography revealed infiltrate of unknown etiology of the middle and lower right lung lobe. The physical examination revealed adiposity (160 cm/96 kg) with a body mass index of 37.5 kg/m2 (normal physiological values are 18–25 kg/m2). Other physiological functions were normal, with the exception of mild incontinence of urine and skin erosions in the perineal region. Immediately upon hospitalization, the infected abdominal wall was incised and the abscess evacuated. The abscess cavity was cleansed with 3% hydrogen peroxide and physiological solution, and drains were placed in the cavity. Empirical parenteral antimicrobial therapy was administered simultaneously with surgical intervention. A daily dose of combined penicillin G (20 x 106 U), gentamycin (1 x 240 mg), and metronidazole (3 x 500 mg) was administered. During the operation, targeted samples were taken for microbiological and histopathological examination; the content was aspirated and the tissue biopsied. Histopathological examination of the biopsy of subcutaneous tissue revealed partially destroyed epidermis, hyperemia of the blood vessels, and a mixed perivascular inflammatory infiltrate of the dermis. The following day, despite surgical intervention and administration of antibiotics, sepsis developed with a significant progression of infection and the development of necrosis. The wound was revisited, necrotized tissue was excised, and additional drainage was applied to the abdominal wall. After the following 24 hours in therapy, piperacillin with tazobactam (4 x 4.5 g daily) replaced gentamycin and penicillin G according to progression of the clinical signs of infection. Twenty-four hours later, the patient’s clinical status deteriorated, showing clinical and laboratory signs of shock and the development of cardiac arrest. After resuscitation, the patient was placed on a respirator for 24 hours. The primary samples of aspirate and tissue biopsy yielded anaerobic bacteria as etiologic agents of infection in a quantity > 106 CFU/g of tissue. The species Bacteroides spp, Aerococcus viridans, and clindamycin-resistant Peptostreptococcus spp (minimum inhibitory concentration [MIC] value > 32 mg/mL) were isolated. Gram-negative rods and gram-positive cocci without visible polymorphonuclear leukocytes were visible on Gram stain. Target samples taken for microbiological examination 48 hours after the first incision isolated new species including Enterococcus faecalis, Escherichia coli, and Morganella morganii in quantities > 106 CFU/g of tissue. These findings proved a mixed aerobic-anaerobic infection caused by 4 types of etiologic agents, probably of endogenous origin. According to the laboratory parameters, clinical signs of infection, and microbiological isolates on the fifth day, antimicrobial therapy was changed to meropenem (3 x 1 g) with metronidazole. This combination of antimicrobial agents was administered during the following 14 days. As the clinical status of the patient and the local findings deteriorated further despite treatment (Figure 1) on the seventh day of hospitalization, a large excision of the lower third of the abdominal wall was undertaken with partial removal of the fascia of the rectus muscle bilaterally (Figure 2). The most pronounced necrotic changes were found in the left lower hemiabdomen with propagation toward the back into the left lumbar region. During the operation, a Schloffer tumor (a reaction to the presence of a foreign body, ie, a surgical suture) was located and removed. The tumor was located under the rectus muscle fascia on the location of the first hernial operation. After reoperation, negative pressure wound therapy (NPWT, V.A.C.® Therapy™ System, KCI, San Antonio, Tex)12–15 was introduced as an auxiliary therapy that closed the newly created opening of the abdominal wall (Figure 3). The device remained in place for 23 days. Dressing foams were changed and necrotic tissue was partially excised every 48 hours. The clinical course of infection was closely and intensively observed daily from the time of admission to the hospital intensive care unit by monitoring the patient’s temperature (Figure 4), physiological functions, and laboratory parameters, such as leukocytes (Figure 5), erythrocytes,thrombocytes, CRP (Figure 6), glucose, and renal and liver functions. These parameters, especially leukocyte and CRP values, were targeted to define the efficiency of combined surgical, antimicrobial, and negative pressure wound therapy. Although leukocyte and CRP values significantly decreased after combined therapy, the patient’s clinical status deteriorated during the first 7 days, most likely as a result of endotoxemia. Targeted samples of tissue were taken for microbiological examination every 48 hours when the NPWT dressing was changed. The isolation of anaerobic bacteria ceased 2 days after the introduction of NPWT. As the patient’s clinical status stabilized, a methicillin-resistant Staphylococcus epidermidis (MRSE) in quantities 0.2 x 101–102 CFU/g of tissue was isolated from targeted samples. Gram-stained preparations revealed few inflammatory cells as well as few individual or clustered gram-positive cocci. The isolates were interpreted as colonization of the wound by the patient’s physiological flora. Tissue samples were taken in a febrile state (>38.2oC), and blood samples were taken simultaneously for hemoculture but remained sterile throughout the course of treatment. During 22 days of intensive combined surgical and antimicrobial treatment with the application of NPWT as auxiliary therapy, the clinical status of the patient stabilized, and the defect of the abdominal wall significantly reduced with the development of granulation tissue. On the 22nd postoperative day, the secondary sutures were placed in the medial area of the wound, followed by sutures on the right lateral side 2 days later and lateral left side 5 days later. Targeted antimicrobial therapy was applied during 28 days and was withdrawn upon the general stabilization of the patient’s clinical status and isolation of physiological flora from the incision. After 45 days of treatment, the patient was released with a normal clinical status (Figure 7). Discussion In 1871, Jones first clearly defined necrotizing soft tissue infection as hospital gangrene.16 Thereafter, other authors described, defined, and grouped this clinical entity in a single category of progressive necrotizing infections.1,17 The term necrotizing fasciitis was first used by Wilson in 1952.18 With regard to expected etiologic agents and means of surgical treatment, necrotizing infection of soft tissue can be divided into necrotizing cellulitis, necrotizing fasciitis, myonecrosis, and the group of nonclostridial or clostridial infections.1,17,19 Currently, division is based on several factors that characterize the soft tissue infection more closely, determine the course of treatment, and, in a way, predict the outcome. These are the predisposing host factors, incubation period, etiologic agents, systemic toxicity, clinical course of infection, particularities of the lesion and tissue coverage, characteristics of gram-stained tissue preparations, and types of treatment.20 Accordingly, the clinical entity is differentiated as necrotizing fasciitis, anaerobic streptococcal myositis, progressive bacterial synergistic gangrene, polymicrobial synergistic necrotizing fasciitis, nonclostridial crepitant cellulitis, and Fournier’s gangrene.5,20 Necrotizing fasciitis is an acute surgical condition. Early recognition and prompt, aggressive surgical debridement of necrotic tissue are extraordinarily important and significantly influence the course of treatment and patient survival.21–24 Inadequate surgical intervention (ie, insufficient debridement or inadequate repetition of debridement) significantly influences mortality (50% mortality, p4 In reaching an early diagnosis, the use of magnetic resonance is helpful,25,26 as well as the pathohistological analysis of the biopsy specimens,27 but neither of these determines the nature and extent of surgical intervention.25 During initial examination, necrotizing fasciitis is not recognized in as many as 85% of cases2 due to the fact that the clinical presentation is masked by abscess or cellulitis (non-necrotic soft tissue infections). In some instances, it is possible for the patient to present with what appears to be only a mild form of cellulitis, while necrotizing fasciitis is rapidly progressing through the fascia and the muscles.24 In these patients, the correct diagnosis is reached only when the infection rapidly progresses with a migrating edge of edema and indurations of the skin despite intravenous application of broad-spectrum antibiotics. Physical examination and laboratory and radiographic parameters predictive of necrotizing fasciitis are edema and skin bullae, leukocytes > 14 x 109/L, serum Na 15 mg/dL. In 39% of cases, radiography reveals the presence of gas. Leukocyte values > 30 x 109/L are a good predictive factor for postoperative mortality.27 Severe infections of the skin and soft tissue are characterized by clinical presentation followed by systemic manifestations and, consequently, the treatment strategies. These infections are usually secondary, because they manifest after skin lesions due to any kind of trauma or surgical intervention.5,28 The contributing factors are excessive pre-operative hospitalization, shaving the day before operation, elective operation in the presence of covert or apparent infection, and delayed debridement.29,30 Infection may develop as a consequence of chemotherapy or from macerated tissue, decubitus ulcers, a dog bite, or a cat scratch.4,31 The initial lesion can be so small that 20% of patients have no visible lesion at all.5,31 Of the total number of acute soft tissue infections, two-thirds of patients acquire them outside of the hospital as a result of endogenous comorbid diseases5 and factors that significantly reduce the host defenses, such as advanced age (over 65), obesity, malnutrition, cirrhosis, uremia, diabetes mellitus, AIDS, burns, splenectomy, use of corticosteroids and cytostatics, blood transfusion, or acute infection of any etiology and localization.32 The clinical presentation of necrotizing fasciitis takes an acute course and develops within 1 to 4 days. There is usually a triad of symptoms: severe pain, swelling, and elevated temperature. Tenderness of the skin, erythema, and locally elevated temperature are often the only symptoms present in the early phase of necrotizing fasciitis. The characteristics of the advanced clinical presentation are systemic intoxication followed by febrility, hemorrhagic skin bullae, cellulitis in 90% of cases, edema in 80% of cases, skin necrosis, fluctuation, crepitation, and sensory and motor deficit.7 The pathophysiological process involves the skin, subcutaneous tissue, fascia, and muscles and is characterized by angiothrombotic microbial invasion or liquefactious necrosis. Histologically apparent is the necrosis of the surface fascia of the muscles, infiltration of polymorphonuclear leukocytes into the deep dermis and fascia, thrombosis and suppuration of veins and arteries that pass through the fascia, and, finally, the proliferation of microorganisms within the damaged fascia.4,33 Microbiologically, the condition is a severe polymicrobial infection caused by mixed aerobic-anaerobic microflora. Etiologic agents are predominantly aerobic and anaerobic bacteria but can also be systemic fungi. The dominant species are Streptococcus spp, Staphylococcus spp, Peptostreptococcus spp, Peptococcus spp, Bacteroides spp, members of the Enterobacteriacea family, and Pseudomonas aeruginosa.34–36 Additionally, necrotizing fasciitis can be caused by rare or bizarre agents, particularly in an immunocompromised host. These include Mycobacterium ulcerans, Stenotrophomonas maltophilia, Bacillus cereus, Vibrio vulnificus, and fungi, such as Curularia brachyspora, Alternaria spp, or Apophysomyces elegans subtype mucormycosis, as well as combinations of bacteria and fungi.5,6,25,30,37–40 Multiple etiologic agents can be involved.40 The treatment of necrotizing fasciitis is complex, consisting of an aggressive surgical debridement of the necrotic tissue (fascia and adipose tissue) with skin incisions and initial application of broad-spectrum antibiotics. The wound must be reassessed within 24 to 48 hours to determine the need for additional debridement. Time is of vital importance for the prognosis and outcome of treatment. An optimal timing for the first debridement is within 6 hours after the onset of clinical symptoms. Likewise, the first suture can only be placed on the 12th day after the initial excision of necrotic tissue and drainage.41 Additionally, supportive therapies, such as hyperbaric oxygenation and NPWT, are also appropriate. Negative pressure wound therapy is a novel method in the treatment of wounds and has been applied since 1995.13 It is a mechanism that maintains negative pressure in the wound while draining and isolating the wound from surrounding influences. The purpose of NPWT is to reduce the quantity of microorganisms causing infection, to adsorb toxic products that appear due to tissue degeneration and the activity of microorganisms, and to clean the wound continuously and effectively (removal of smaller tissue fragments by suction). Oxygenation of tissue is increased, which is important, as the tissue is hypooxygenated as a consequence of the 4-fold increase in blood circulation and a significant increase in granulation tissue.14 Edema and pain are reduced, and the size of the wound decreases. The edges of the wound are retracted, and the wound is isolated from the environment. Ultimately, this shortens the time of treatment and hospitalization.12,36,42–49 The bacterial count is significantly reduced 4 days after NPWT application.50 After the treatment of infection, a plastic reconstructive intervention is often necessary to reconstruct and close the created defects.30,35 Although a combined targeted therapy along with adjunctive therapies may be commenced in time, the outcome of necrotizing fasciitis is always uncertain. The factors that determine an unfavorable outcome are delayed incision or delayed surgical exploration 30 hours after the onset of symptoms, spontaneous or post-operative appearance, localization on the trunk, advanced age (over 65), male sex, the presence of endogenous diseases, index of body weight over 40%, infection caused by Streptococcus pyogenes (serogroup A), manifestation of complications, and lack of immunocompetence of any etiology.6–9,15,51 With complications, the expected mortality rate is between 50% and 80%.4,5,11 Conclusion In the described clinical case, the development of necrotizing soft tissue infection was preceded by surgical intervention. Numerous predisposing factors enabled the development of infection, such as diabetes mellitus, index of body mass greater than 40%, skin erosions in the perineal region, and secretion from the area of umbilical hernia before the initial surgical intervention. The development of infection was rapid with clinical signs of intoxication and a later development of sepsis, shock, and cardiac arrest. Etiologic agents were aerobic and anaerobic bacteria including Bacteroides spp, Aerococcus viridans, Peptostreptococcus spp, Enterococcus faecalis, Escherichia coli, and Morganella morganii in a quantity > 106 CFU/g of tissue. Gram stain revealed visible microorganisms with rare inflammatory elements. The diagnosis of necrotizing fasciitis was reached on the basis of clinical symptoms, the particularities of the mixed infection, and predisposing and exposure factors of the patient. Possible differential diagnoses were synergistic necrotizing cellulitis20 or progressive bacterial synergistic gangrene, which typically develops along the sutures or at the drain site after operation in the abdomen or the incision of the abdominal wall.5,51 Intensive surgical debridement with targeted application of broad-spectrum antibiotics for 23 days and the application of NPWT along with other supportive therapy led to the regression of clinical symptoms and the healing of infection. The overall duration of treatment was 45 days with survival prospects uncertain. The authors attribute the development of necrotizing fasciitis in this patient to an immunocompromised status, previous surgery with the development of a Schloffer tumor, and influence of gram-positive anaerobic cocci (Peptostreptococcus spp) during the process of wound healing. Gram-positive anaerobic cocci have a potential role in impaired wound healing.52,53 Additionally, the authors suspect that the absence of prophylactic antibiotic therapy during primary surgery (hernia repair) in this immunocompromised patient contributed to the development of necrotizing fasciitis. Another important contributing factor may have been a lack of recognition of the early signs of necrotizing fasciitis and a delay in primary surgical debridement. Irrespective of the targeted treatment and adherence to all preventative and curative tenets, the outcome of necrotizing fasciitis in an immunocompromised host is still uncertain and demands a prompt and intensive treatment with close monitoring as the patient’s clinical status continues to change.