Necrotizing fasciitis is a rapidly progressive, life-threatening soft-tissue infection that involves the superficial fascia and subcutaneous tissue. Early diagnosis, emergency surgical debridement, and broad-spectrum antibiotic therapy are the most effective treatment strategies to reduce the bacterial load and mortality rate associated with this condition1,2. Necrotizing fasciitis is categorized as type I (mixed infection with aerobic and anaerobic bacteria), type II (group-A ß-hemolytic Streptococcus and Staphylococcus aureus), and type III (marine vibrios)1,3-7. Although type-I necrotizing fasciitis, a polymicrobial infection caused by aerobes and facultative anaerobes, constitutes 55% to 90% of all cases, the incidence of monomicrobial infections caused by methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA), especially community-associated MRSA, has increased in the past decade1,3-8.
Vibrio species are endemic to warm coastal waters and are often found in raw seafood. Although Vibrio species often cause epidemic diarrhea, they have been the leading cause of necrotizing fasciitis at our institution. In our previous investigations, the mortality rate associated with Vibrio necrotizing fasciitis has ranged from 35% to 43.75%9-12. Thus, Vibrio necrotizing soft-tissue infection has been categorized as type-III necrotizing fasciitis because of its fulminant clinical presentation and high mortality rate1,3,4,13-15.
Vibrio vulnificus is a gram-negative, halophilic, and rod-shaped bacterium, and it causes fatal soft-tissue infection in immunocompromised patients and those with hepatitis, liver cirrhosis, and diabetes mellitus. Staphylococcus aureus, a gram-positive coccus, is the most common cause of skin and soft-tissue infections reported worldwide, and MRSA has emerged as the most common isolate in emergency departments of the United States2,5,8,16-19. The mortality rate of necrotizing fasciitis caused by MRSA has been reported to range from 0% to 28%2,5,7,20,21.
In our institution, we established a treatment strategy for patients who had a history of contact with seawater or raw seafood and suspected Vibrio fulminant necrotizing fasciitis. This strategy involves emergency fasciotomy or amputation combined with third-generation cephalosporin plus tetracycline or gentamicin antibiotic therapy and intensive unit care9-12,22. Some patients with a Staphylococcus aureus necrotizing soft-tissue infection have clinical signs and symptoms, including hemorrhagic bullae, subcutaneous bleeding, purpura, necrosis, and gangrene, that are similar to those of necrotizing fasciitis caused by Vibrio vulnificus, and thus it is difficult to differentiate the line at the time of presentation in an emergency room. To our knowledge, no publication or literature review to date has described and compared these two causative pathogens of fatal necrotizing fasciitis.
The purpose of the present study was to compare the specific characteristics evident on initial examination of Vibrio vulnificus and Staphylococcus aureus necrotizing soft-tissue infections and to identify risk factors related to outcomes between the two groups. We also compared the clinical characteristics and outcomes of necrotizing infections caused by Vibrio vulnificus, MRSA, and MSSA.
Patient Selection
We reviewed the medical records for 115 patients with surgically and pathologically confirmed necrotizing fasciitis involving the upper and lower extremities, caused by Vibrio vulnificus or Staphylococcus aureus, who were admitted to our hospital from June 2003 to June 2009. Patients with necrotizing fasciitis that involved the neck and trunk were excluded. The most common complaints were pain and swelling of the involved limbs with edematous, patchy, erythematous, and hemorrhagic bullous skin lesions at the time of admission to the emergency department or at the time of consultation in the hospital ward. Broad-spectrum antibiotics were initially administered to all patients, and excisional debridement of the necrotic fascia or immediate limb amputation was performed for all patients with a diagnosis of necrotizing fasciitis.
Clinical Assessment
The study group included eighty men and thirty-five women with a mean age of 62.5 years (median, sixty-three years; range, twenty-five to ninety years). Age, sex, comorbidity, signs and symptoms, the site of infection, the result of bacteriological tests, predisposing factors, laboratory findings at the time of admission, the interval between contact and admission, the interval between diagnosis and the first operative procedure, the length of stay, and clinical outcomes were reviewed for each patient.
The enrolled patients were categorized into two groups: the Vibrio vulnificus group and the Staphylococcus aureus group. The patients in the Staphylococcus aureus group were divided in two subgroups: the MSSA group and the MRSA group. Differences in mortality, patient characteristics, clinical presentation, underlying chronic diseases, infection site, first operative procedure, laboratory data, and hospital course were compared between the Vibrio vulnificus group and the Staphylococcus aureus group and between the MSSA subgroup and the MRSA subgroup.
Statistical Methods
We used the Wilcoxon rank-sum test for continuous variables and used the chi-square test and the Fisher exact test for categorical variables to examine significant relationships between these factors among the groups. A value of p < 0.05 was considered significant.
Source of Funding
We did not receive any outside funding or grants in support of our research.
Forty-seven patients had skin lesions involving the upper extremities, and sixty-eight patients had skin lesions involving the lower extremities. The results of culture confirmed that the cause of infection was Vibrio vulnificus in sixty patients and Staphylococcus aureus in fifty-five cases. Nineteen patients (including eleven in the Vibrio vulnificus group and eight in the Staphylococcus aureus group) died, resulting in a mortality rate of 16.5% (Tables I and II).
Vibrio vulnificus specimens were obtained from wounds in twenty-eight cases, from blood in six, and from both in twenty-six. Cases in which Staphylococcus aureus was present in a mixed culture were included in the present study only when the Staphylococcus aureus growth was heavy and predominant. MSSA was found in wound culture specimens from twenty-six patients, and MRSA was found in wound culture specimens from twenty-nine patients. Staphylococcus aureus was isolated from wounds in forty-six cases and from the blood and wound in nine cases. Other pathogens identified were Enterobacter cloacae in five patients, ß-Streptococcus species in four, Escherichia coli in one, Pseudomonas aeruginosa in one, and Proteus species in one.
Patient Characteristics in Vibrio vulnificus Group
The Vibrio vulnificus group included forty-four men and sixteen women with a mean age of 63.8 years (median, sixty-three years; range, thirty-six to eighty-six years). Fifty-eight of the sixty patients had a history of having handled raw seafood or had prolonged occupational exposure to warm seawater. Of the remaining two patients, one had a cut on the right arm and the other had an insect bite on the right hand. Eleven patients with a history of contact with seawater or raw seafood died (at a mean nineteen days after admission), resulting in a mortality rate of 18.3%.
The mean estimated period from the initial contact or injury to presentation in the emergency department was 2.35 days (range, one to seven days). The mean time interval from treatment in the emergency department to the first operation was 11.7 hours.
Ten patients had both hepatic dysfunction and diabetes mellitus, and four of them died. Twenty patients had a history of hepatic dysfunction alone (such as liver cirrhosis, hepatitis B or C, and alcoholic liver disease), and six died. Seven patients had diabetes mellitus without hepatic disease, and one died. Four patients had diabetes mellitus with gout or corticosteroid intake for nephritic syndrome, and one patient had chronic renal insufficiency. Four patients had gout with or without corticosteroid intake for pain relief, and four patients had corticosteroid intake alone because of asthma or the use of Chinese herbal medications containing undeclared prescription drugs. Six patients had other chronic underlying disease; specifically, two patients had valvular heart disease and four patients had chronic obstructive pulmonary disease (one patient), rheumatoid arthritis (one), a history of drug abuse (one), or renal cell carcinoma with metastasis (one). Four patients were in good health.
Twenty-five patients had upper limb skin lesions, and thirty-five had lower limb skin lesions. Fifty-eight patients initially underwent fasciotomy and debridement (Fig. 1), and two patients underwent immediate above-the-knee amputation because of severe skin lesions and sepsis at the time of presentation. Four patients underwent above-the-knee amputation, two patients underwent above-the-elbow amputation, one patient underwent below-the knee amputation, and one patient underwent finger amputation a few days after fasciotomy because of progressive uncontrolled sepsis. Twenty-nine patients received skin grafts, five patients underwent flap reconstruction, seven patients underwent further debridement, and nine patients did not undergo any surgery following the fasciotomy.
Nineteen patients (31.7%) had a body temperature of =38.5°C. Thirty-two patients (53.3%) were hypotensive, with a systolic blood pressure of =90 mm Hg. Forty patients were admitted to the intensive care unit initially. The mean hospital stay for patients with Vibrio infection was 31.4 days (range, two to eighty days).
All Vibrio vulnificus isolates were susceptible to ampicillin, amikacin, ceftazidime, ceftriaxone, cefuroxime, ciprofloxacin, gentamicin, imipenem, piperacillin, and sulfamethoxazole-trimethoprim. Broad-spectrum antibiotic therapy with a third-generation cephalosporin plus tetracycline was initially administered to forty-seven patients, and antibiotic therapy comprising penicillin or oxacillin plus gentamicin was administered in thirteen patients.
Patient Characteristics in Staphylococcus aureus Group
The Staphylococcus aureus group included thirty-six men and nineteen women with a mean age of 61.2 years (median, sixty-two years; range, twenty-five to ninety years). Of the fifty-five patients with Staphylococcus aureus infection, twenty-one sustained abrasion wounds while working (and one died); nineteen had previous chronic ulcers (four died); three had a previous surgical wound infection (one died); one had a cut on the hand; one had a nail penetrating injury in the foot; and ten did not recall any injuries (two died). Eight patients died at a mean of 20.5 days after admission, and the mortality rate was 14.5%.
The mean interval from injury to presentation at the emergency department was 5.51 days (range, two to twenty-one days). The mean interval between treatment in the emergency department and the first operation was forty-four hours.
Five patients had both hepatitis B or C and diabetes mellitus. One patient who died had liver cirrhosis and diabetes mellitus. Eight patients had a history of hepatic dysfunction alone; of these, two had liver cirrhosis, four had hepatitis C, one had hepatitis B and C, and one had alcoholic liver disease. Twenty-four patients had diabetes mellitus alone, and five of them died. One patient had diabetes mellitus with corticosteroid intake for nephritic syndrome, and one patient had both diabetes mellitus and gout. Six patients had gout with or without steroid intake, and one of these patients, who used corticosteroids for pain relief, died. One patient had corticosteroid intake alone because of the use of Chinese herbal medications containing undeclared prescription drugs. One patient had chronic renal insufficiency and died. One patient had a history of hypertension, and one patient had human immunodeficiency virus infection. Five patients were healthy before the infection occurred.
Twenty-two patients had upper limb skin lesions, and thirty-three had lower limb skin lesions. Fifty-three patients initially underwent fasciotomy with debridement, one patient had an immediate below-the-elbow amputation, and one patient underwent an immediate above-the-knee amputation. Eighteen patients had turbid pus accumulation in the fascial plane (Fig. 2). Three patients underwent below-the-knee amputation and two underwent above-the-knee amputation because of progressive skin involvement following fasciotomy. Thirteen patients received skin grafts, six underwent a flap reconstruction, twenty underwent debridement with repair, and nine received only wound care after the initial fasciotomy.
Six patients (10.9%) were febrile (body temperature, =38.5°C), and eight patients (14.5%) had a systolic blood pressure of =90 mm Hg at the time of presentation in the emergency department. The mean duration of hospital stay for the patients was 28.8 days (range, one to eighty-five days).
Broad-spectrum antibiotics were administered initially in the emergency department to patients with a Staphylococcus aureus infection; twenty-eight patients received oxacillin plus gentamicin, eight received ceftriaxone plus gentamicin, seven received penicillin plus gentamicin, six received cefazolin plus gentamicin, four received vancomycin plus ceftriaxone, and two received vancomycin alone.
Comparison of Vibrio vulnificus and Staphylococcus aureus Groups
The two groups did not differ significantly in terms of age, sex, wound location, first operative procedure, or the number of lymphocyte forms of white blood cells (Tables I and II). However, we found significant differences between the two groups with regard to exposure to raw seafood or warm seawater, a systolic blood pressure of =90 mm Hg, a body temperature of =38.5°C, the interval between contact and admission, the interval between diagnosis and the first operative procedure, and admission to the intensive care unit (Tables II, III, and IV). There were significant differences between the surviving patients in the two groups with regard to a systolic blood pressure of =90 mm Hg, a body temperature of =38.5°C, the interval between contact and admission, and admission to the intensive care unit.
Patients with hepatic dysfunction were significantly more likely to have Vibrio vulnificus infection, and those with diabetes mellitus with or without gout or corticosteroid intake were significantly more likely to have Staphylococcus aureus infection. Vibrio vulnificus infection had a significant association with a history of contact with seawater or seafood. Staphylococcus aureus infection had a significant association with a history of a previous abrasion injury, surgical wound infection, or chronic ulcers (Table III).
Patients in the Vibrio vulnificus group had significantly lower total and segmented white blood-cell counts, higher banded white blood-cell counts, and lower platelet counts in comparison with patients in the Staphylococcus aureus group at the time of arrival to the emergency department (Table IV).
Comparison of MSSA and MRSA Subgroups and Vibrio vulnificus Group
The MSSA group included fifteen men and eleven women with a mean age of 61.2 years, and nineteen patients had monomicrobial necrotizing fasciitis. The MRSA group included twenty-one men and eight women with a mean age of 62.3 years, and twenty-four patients had a monomicrobial infection.
The patients in the Vibrio vulnificus group had significantly lower total white blood-cell counts, higher banded white blood-cell counts, lower platelet counts, lower systolic blood pressure, a greater likelihood of high body temperature (=38.5°C), and a shorter interval between contact and admission than the MRSA and MSSA subgroups. However, the MRSA and MSSA subgroups did not differ significantly with regard to age, sex, body temperature, mortality rate, interval between injury and admission, and interval between diagnosis and the first operative procedure. There were significant differences with regard to systolic blood pressure of =90 mm Hg between the MRSA subgroup and the MSSA subgroup (Table V).
Necrotizing fasciitis is a true medical and surgical emergency. In the past decade, Staphylococcus aureus was reported to be the most common cultured pathogen4,6,17,18. The Panton-Valentine leukocidin (PVL) toxin and several clones carrying different staphylococcal cassette chromosome (SCC) mecA gene cassette types have been reported in association with Staphylococcus aureus skin and soft-tissue infections23-26. MRSA has been reported to have a prevalence of 59% to 75% in soft-tissue infections and 29% to 39% in necrotizing fasciitis1,2,5,8,16-19,27. The mortality rate for MRSA necrotizing fasciitis has been reported to range from 0% to 28%2,5,7,20,21,27. US300 (ST8) is now confirmed as the community-acquired MRSA (CA-MRSA) clone in the United States25,26,28.
Vibrio vulnificus, endemic to warm seawaters and raw seafood, can cause a distinctive clinical syndrome of rapidly progressive necrotizing fasciitis and has been categorized as type-III necrotizing fasciitis because of its fulminant clinical presentation and high mortality rate (25% to 100%)9-13,29,30. Vibrio vulnificus can produce many extracellular toxins, especially hemolysin and protease, which frequently disrupt various eukaryotic erythrocytes and mast cells and enhance vascular permeability, resulting in hemorrhagic bullae and severe skin necrosis31,32.
Angoules et al. performed a systematic review of necrotizing fasciitis affecting the upper and lower extremities and found that the most common predisposing factor was a history of drug abuse and multiple needle punctures in an affected limb4. The predominant underlying disease for the development of necrotizing fasciitis was diabetes mellitus (31%). In addition, hepatic dysfunction, including alcohol abuse, cirrhosis, chronic liver disease, and hepatitis, was found to be a factor in 28% of patients4. Although erythema, pain, and edema of the limb are the most common clinical signs, a lack of specific disease characteristics and similarities to cellulites during the initial examination may delay the diagnosis of necrotizing fasciitis and result in failure to initiate aggressive operative intervention.
Our institution is situated on the western coast of southern Taiwan. Because nearly forty patients with necrotizing fasciitis have presented to our institution annually, with as many as 25% of them having a Vibrio infection, early recognition of and surgical intervention for necrotizing fasciitis has become an important practice in our emergency department. Hsiao, the chief of our emergency department, and colleagues retrospectively reviewed 128 patients with necrotizing fasciitis during a four-year period and reported that Staphylococcus aureus and Vibrio species were the most common pathogens in blood and wound cultures19. However, Vibrio species and Aeromonas species were significantly associated with an increase in mortality19.
Our previous reports have suggested that hypotensive shock, leukopenia, a higher proportion of band forms of leukocytes, a decreased platelet count, and severe hypoalbuminemia at the time of presentation to the emergency department were associated with mortality in cases of Vibrio necrotizing fasciitis10,11. In the present study, we used these clinical indicators and laboratory risk factors to compare the specific clinical characteristics and surgical outcomes of Vibrio vulnificus and Staphylococcus aureus necrotizing fasciitis.
While the clinical signs and symptoms of necrotizing fasciitis caused by these two organisms are characteristically indistinguishable at the time of presentation, the present study identified some differences between Vibrio vulnificus and Staphylococcus aureus infections. First, the underlying chronic disease and the contact mechanism for the two infections differ. Vibrio vulnificus infection had a significant association with hepatic dysfunction and a history of contact with seawater or seafood. Staphylococcus aureus infection had a significant association with diabetes mellitus and a history of an abrasion injury or a chronic ulcer. Second, the overall clinical characteristics of Vibrio vulnificus infection developed more rapidly and were more fulminant than those of Staphylococcus aureus. The interval between contact and admission to the emergency department and the interval between diagnosis and the first operative procedure were significantly shorter for the patients in the Vibrio vulnificus group than for those in the Staphylococcus aureus group. We also observed that the pus that accumulated in patients with Staphylococcus aureus infection following fasciotomy was markedly more yellow and had a foul odor as compared with that in patients with Vibrio vulnificus infection. Patients with Vibrio vulnificus infection were more likely to be hypertensive and had lower white blood-cell counts, higher counts of band forms of leukocytes, decreased platelet counts, and a need for more intensive unit care than did patients with Staphylococcus aureus infection. Finally, the clinical course of necrotizing fasciitis caused by Vibrio vulnificus was more fulminant than the clinical course of necrotizing fasciitis caused by MRSA. However, the mortality rate and the duration of hospital stay did not differ between the Vibrio vulnificus, MRSA, and MSSA groups.
The present study had several limitations. First, it was a retrospective study. Although we conducted an electronic search for a discharge diagnosis of necrotizing fasciitis (International Classification of Diseases, Ninth Revision, code 72886) to identify patients, many patients, especially those with Staphylococcus aureus necrotizing fasciitis, were initially diagnosed as having cellulitis, and their medical records did not include accurate clinical descriptions or the variables in which we were interested. Now, we have set up a registration database to record the details on patients who have been confirmed as having necrotizing fasciitis at the time of surgery. The second limitation of the present study is that eight infections in the MRSA group could not be confirmed as community-associated MRSA infections. These patients were treated for cellulitis at other local clinics with oral or intravenous antibiotics, and they were referred to our emergency department following the failure of conservative treatment. A third limitation is that we did not perform genetic and phenotypic characterization for the MRSA isolates. Chen and Huang reported that isolates of sequence type 59 (US1000) appear to be the major clone of CA-MRSA, and isolates of sequence type 239 have been shown to be the major clone of nosocomial MRSA, by the multilocus sequence typing method in northern Taiwan33. In the future, we plan to confirm the sequence type of MRSA with use of the pulsed-field gel electrophoresis method for the detection of necrotizing fasciitis caused by CA-MRSA.
In conclusion, necrotizing fasciitis caused by Vibrio vulnificus and Staphylococcus aureus is a surgical emergency. Patients with hepatic dysfunction are at increased risk for Vibrio vulnificus infection, and those with diabetes mellitus are at an increased risk for Staphylococcus aureus infection. The clinical characteristics of Vibrio vulnificus infection were more rapidly progressive and fulminant than those of Staphylococcus aureus infection, either MRSA or MSSA.