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Vibrio vulnificus septicemia in Korea: Clinical and epidemiologic findings in seventy patients
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Vibrio vulnificus septicemia in Korea: Clinical and epidemiologic findings in seventy patients Seek Don Park, MD, PhD, a Hyung Sun Shon, MD, PhD, a and Nam Joong Joh, MD, PhD b'*
Iri City and Kwangju City, Korea We studied the clinical characteristics and the epidemiologyof primary septicemia associated with Vibrio vulni/icus in 70 patients. All patients came from the western and southern coastal areas of Korea. Most cases (96%) occurred during the summer months, in men (96%), and in persons 40 or more years of age (90%). The illness in 46 patients (66%)began with septicemia, often within 2 days of the consumption of raw seafood. Forty-seven patients (67%) had preexisting hepatic disease, and 49 (70%) had a history of alcoholism. Of the 70 patients, 45 (79%) died. The cutaneous lesions that were present on admission in 64 patients (91%) appeared on the legs in 51 of the cases. V. vulnificus was isolated from the blood of 65 patients tested and from the skin lesionsof 51 of 55 patients tested. The histopathologic findings differed according to the clinical stage of lesions, Because V. vulnificussepticemia is a highly fatal disease, persons with liver disease or alcoholism should avoid eating or handling raw seafood. (J AM ACAD DERMATOL 1991;24:397-403.)
Vibrio vulnificus is a halophilic, gram-negative, motile, marine rod whose pathogenic potential for humans has been recently recognized.t Blake et al. 2 divided the illnesses caused by K vulnificus into two distinct groups. The first, which carries a good prognosis, comprises previously healthy persons with wound infections acquired while handling raw shellfish or after exposure of a preexisting wound to seawater. The second, which is characterized by high mortality, consists of persons with preexisting chronic hepatic disease in whom primary septicemia develops after consumption of raw seafood. Other features of V. vulnificus infection (e.g., gastroenteritis, pneumonia, endocarditis, meningitis, peritonitis, myositis, cellulitis, and necrotizing fasciitis) have also been reported. 2-I~ Cases of fulminating gangrene, intractable shock, and hepatic disease have been reported as "mysterious disease" in Korea every summer since 1979. From the Department of Dermatology, Wonkwang University School of Medicine, lri City,a and Department of Internal Medicine, Chonnam University Medical School, Kwangiu City.b Presented at the Seventeenth World Congre~ of Dermatology, Berlin, May 25, 1987. Accepted for publication April 20, 1990. Reprint requests: Seek Don Park, MD, PhD, Department of Dermatology, Wonkwang University School of Medicine, 344-2, ShinyongDong, Iri City, Chonbuk 570-749, Republic of Korea. *Now in private practice in Kwangju, Korea. 16/1/21843
Since the first published report of bacteriologically proven infections in 1982,11 many more cases have been reported.12-17 K vulnificus septicemia seems to be more prevalent in Korea than in other countries. This may be due to the frequent consumption of raw seafood, even in inland areas, and the higher prevalence of underlying liver disease. There was only one proven case of wound infection in Korea. 18 PATIENTS AND METHODS
We reviewed 49 patients who were admitted to the Wonkwang University Hospital and the Chonnarn University Hospital in Korea between January 1982 and December 1986. Information about an additional 21 patients was obtained from ease reports published in the medical literature in Korea between 1982 and December 1986.1 H7 Primary septicemia was defined as the abrupt onset of symptoms and signs suggestive of septic shock without a focus of infection and the isolation of K vulnificus from either the blood and/or cutaneous lesions or peritoneal fluid. Clinical and laboratory data were abstracted from the hospital records of the 49 patients and the 21 case reports. When data on a particular feature were not known for all 70 patients, the proportion of the patients with available data who had the feature was calculated. RESULTS Clinical features Of 70 patients with primary sepsis, 54% had fever, 33% had chills, 20% had vomiting, 33% had di397
Journal of the American Academy of Derma tology
398 Park et aL
Table I. Clinical features associated with Vibrio vulnificus septicemia Primary septicemia (n = 70)
Feature
Cases
%
Fever Chills Vomiting Diarrhea Abdominal pain Headache Dizziness Dyspnea Oliguria Secondary skin lesions Pain and tenderness of skin lesion Peritonitis Hypotension* Death
38 23 14 23 26 7 3 7 4 64 49
54 33 20 33 37 10 4 10 6 91 70
4 38 55
6 54 79
*Systolic blood pressure of --<80 mm Hg on admission.
Fig. 1. The earliest lesion. Erythematous, painful swelling like bee sting.
arrhea, 37% had abdominal pain and 70% had painful and tender skin lesions, 91% had secondary skin lesions, and 54% had hypotension on admission. Fifty-five patients (79%) died (Table I). Forty-seven of 65 patients (67%) had preexisting hepatic disease (cirrhosis, chronic hepatitis, and fatty liver). Five patients (7%) had an underlying chronic illness (malignant lymphoma, pulmonary tuberculosis, rheumatoid arthritis, duodenal ulcer, diabetes mellitus). Of 49 patients with a history of alcoholism, 30 (43%) had liver disease. Fifty-two patients (76%) had consumed alcoholic beverages before the onset of illness. Secondary skin lesions were present in 64 patients (91%) on admission. The type of skin lesions included vesicles and/or buUae (42%), peripheral edema (41%), localized swelling (33%), gangrene (27%), cyanosis (25%), purpura (22%), macules and)/or patches (16%), papules, wheals, and pustules (Figs. 1 through 5). The skin lesions were present on the legs in 51 (80%) of the 64 cases. Other areas of involvement included the arms (20%), entire body surface (13%), abdomen (9%), face and buttock (8%), back (5%), flank, chest, and scrotum.
The mean incubation period was 2 days and ranged from 3 hours to 6 days. The mean interval between the onset of illness and death was 4.2 days (13 hours to 22 days). Leukopenia was noted in 14 of 59 patients, and 20 had leukocytosis. Differential WBC counts showed a shift to the left in 27 (69%) of the 39 patients with recorded differential counts. Twenty-six (69%) of 38 patients tested had thrombocytopenia. Serum aminotransferase (aspartate and alanine) and 3'-glutamryl transpeptidase (~/-GTP) levels were elevated in many tested cases. V. vulnificus was isolated' from the blood of 49 (75%) of the 65 patients, from secondary skin lesions in 51 (93%) of 55 patients, and from blood and skin lesions in 32 patients. In addition, V. vulnificus was isolated from the peritoneal fluid in four patients, from cerebrospinal fluid in one patient, from the stool in one patient, and from the urine in one patient. The histopathologicfindings differed according to the clinical stages of the lesions. The lesions with localized swelling or cellulitis-like appearance revealed extravasation of RBCs and massive infiltration of neutrophils in the dermis and subcutis (Fig. 6). The bullous skin lesions showed subepidermal bullae and perivascular infiltration of neutrophils and lymphocytes. Microscopic examination of gangrenous lesions showed necrosis of the entire skin and nonleukocytoclastic, transmural, necrotizing vasculitis with or without thrombosis in the subcu-
Volume 24 Number 3 March 1991
Vibrio vulnificus septicemia
399
Fig. 2. Purpuric patches and edema.
tis. Gram-negative bacilli were seen, especially around the blood vessels on hematoxylin-and-eosin and Gram's stains.
Epidemiologie features Ninety percent of the patients were 40 years of age or older (mean age 51 years), and 96% were men. There was marked seasonal distribution of the dates of onset of illness. Most cases in Korea (96%) occurred during the summer months. All patients came from western and southern coastal Korea. Forty-four patients (63%) had consumed raw seafood within 1 week of the onset of illness; 12 (19%) reported no ingestion of seafood before illness, and relevant data were not recorded for the remaining 14 cases studied. Seafood consumed raw or undercooked included various kinds of fish and shellfish. In all cases, the K vulnificus organism was sensitive to ampicillin, tobramycin, and chloramphenicol and resistant to penicillin, methicillin, and coilstin. DISCUSSION
K vulnificus, a recently identified marine bacte-
Fig. 3. Reddishand/ornecroticmaculopatchesontrunk
rium, is capable of causing wound infection in otherwise healthy persons and a syndrome of primary septicemia in persons with underlying chronic disease, particularly liver disease. 2 V. vulnificus has been isolated from a wide range of environmental sources, including seawater, brackish water, sediment, plankton, fish and shellfish, and estuaries. 19-22 There is little doubt that the gastrointestinal tract is
a portal of entry for V. vulnificus in primary septicemia. K vulnificus has been shown to survive between pH 3.6 and 12.5 when incubated at 37 ~ C for 1 hour and grows best between pH 7 and 9, 23 Therefore, although the stomach normally serves as an important barrier to bacterial overgrowth, after
and edema of right upper extremity.
400
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Park et al.
Fig. 4. Advanced lesion. Cellulitis-like lesion with vesicles and erosions.
Fig. 5. Gangrenous lesion. Extensive gangrene, edema, vesicobullae, and ulcer. the ingestion of seafood contaminated with V. vulnificus, the bacterium can survive as it passes through the stomach. Id. vulnificus multiplies rapidly during its pass through the small bowel because the intraluminal pH is maintained well above 7.0, V. vulnificus invades the gastrointestinal mucosa at the level of the proximal small bowel into the systemic circulation, thereby producing sepsis. 24 The organism also invades the intestinal wall into the ascitic fluid (produces bacterial peritonitis in patients with liver cirrhosis). 6, 16 The mechanism of increased susceptibility to V. vulnificus infection in patients with liver disease and/or alcohol consumption has not yet been clarified. However, these patients are more susceptible
to bacterial infection. Our study corroborates the association of chronic hepatic disease (67% of cases), particularly liver cirrhosis, with V. vulnificus septicemia. However, alcohol abusers (defined as persons who consume 1 ounce of 100% ethanol equivalence daily) were more susceptible to V. vulnificus infection than the patients in our study with liver cirrhosis. V. vulnificus is known to produce virulence factors, such as cytolysin, hemolysin, protease, phospholipase A2, collagenase, lipase, chondroitinase, hyaluronidase, sulfatase, deoxyribonuclease, siderophores, antiphagocytic surface antigen, and capsular materialsY -38 By having capsular materials and antiphagocytic antigen, the K vulnificus organisms
Volume24 Number 3 March 1991 acquire resistance to serum bactericidal action and antiphagocytic activity. 37"39 Production of collagenase and lipase can contribute to invasion of healthy tissue.34, 35 V. vulnificusproteases invade tissues that contain elastin and collagen and elicit rapidly extensive dermal necrosis. 3~ Protease causes edema by enhancing vascular permeability through histamine release and activation of the plasma kallikrein-kinin system, which generates bradykinin.4~ 41 ExtracelIular cytolysin possesses four toxic activities including cytolytic, cytotoxic, vascular permeability-increasing, and lethal activities25' 26, 39; hemolysin is probably identical to the lethal toxin. 42 Intradermal infection with V. vulnificus and intradermal injection of the cytolysin produced acute cellulitis in mice characterized by edema and necrosis of cells. 39 Although none of the exoenzymes appeared to correlate with the ability of K vulnificus to produce lethality in mice,35 the production of cytolysin, protease, and hemolysin is significant in the pathogenesis of V. vulnificus septicemia, thereby implicating them in the pathologic features of V. vulnificus infections (edema, bulla formation, tissue necrosis, purpura, and death). However, Bowdre et al.43 have suggested that local edema or lethality in V. vulnificus infection might not be attributable to a diffusable toxin and might require contact between host cells and viable Vibrio cells. Park et al. 15 classified histopathologic findings of skin lesions according to clinical manifestations into three stages. The initial (inflammatory) stage of erythema and localized swelling revealed edema, massive infiltration of pol~aorphonuclear leukocytes, and extravasation of RBCs.The second (bullous) stage showed subepidermal bullae and vasculitis. The third (gangrenous) stage showed necrosis of the entire skin surface and nonleukocytoclastic, transmural, necrotizing vasculitis with or without thrombosis in the subcutis. Bacteria were present throughout the dermis, and numerous bacteria were found within the bullous fluid and centered around the dermal vessels. Most notable among laboratory abnormalities in V. vulnificus septicemia was the elevation of hepatoceUular enzymes. Leukocytosis was observed more commonly than leukopenia, in contrast to another report. 2 Thrombocytopenia was common in our patients, as was varying degrees of disseminated intravascular coagulation. Other laboratory abnormalities reflected specific organ involvement as a result of septicemia and septic shock. V. vulnificus was
Vibrio vulnificus septicemia
401
Fig. 6. Photomicrograph of biopsy specimen of erythematous swollenarea (Fig. 1) showsmassive infiltration of neutrophils and extravasation of RBCs throughout dermis and subcutis. (Hematoxylin-eosin stain; • 13.2.) isolated from skin lesions more commonly than from blood. This may be due to the scarcity of growth inhibitors of this bacterium in the skin. The skin lesions were first caused by hematogenous seeding of Vibrio cells to affected sites, as K vulnificus was isolated from both skin lesions and blood simultaneously. There have been few efforts to identify K vulnifieus in stool specimens, 3, 44 probably because of the difficulty in doing so. The predominance of men (96%) and of persons 40 years of age or older (90%) in our study reflects a greater likelihood of these groups eating raw seafood, having underlying hepatic disease, and consumption of liquor. The increased incidence of K vulnificus septicemia in Korea may be because most Korean men ingest various kinds of raw seafood and because the Korean population has a higher incidence of hepatic disease. V. vulnificus has been isolated from a wide range of environmental sources including seawater, brackish water, sediment, plankton, and shellfish (oyster, clam, and crab), and from various locations around
402 P a r k et al. the world. 4, 6, 11-22,27, 45-47 Isolation has been more frequent in w a r m water (20 ~ C) with a salinity of 7% to 29.3%. 19, 21, 47 At higher water temperatures, V. vulnificus, like V. parahemolyticus, m a y be released and rise to surface waters where it attaches to plankton and shore fishes. T h e organism is then taken up by marine animals and concentrated, particularly by filter-feeding mollusks and crustaceans. 48 This suggestion is supported by the fact that 44 patients (63%) in our study had consumed various kinds of raw fish and shellfish before onset of disease. Oliver 49 has suggested that raw oysters kept on ice are not likely to be a major factor in the epidemiology of V. vulnificus infection. However, the viability of the organism was not decreased by mere refrigeration or freezing. 5~ Therefore, cooking seafood at a boiling temperature should destroy bacteria and bacterial toxins. 25, 26, 29.49 Seawater temperature increases to greater than 20 ~ C during the w a r m e r months of year (July to September) in Korea, 16 and most of our reported cases (96%) occurred during these months. Because V. vulnificus infection is life-threatening and can progress rapidly, antibiotic therapy must be initiated as soon as this disease is suspected, even before the organism is identified. All strains of V. vulnificus have been reported to be sensitive to ampicillin, chloramphenicol, tetracycline, and gentamicin, ~,6,~7,53,54 and similar results were shown in our study. Bowdre et al.54 suggested that tetracycline is the therapy of choice. Corticosteroids did not improve the overall survival of the patients with severe late septic shock, but these might be helpful early in the course of the disease. 55 Heparin has been shown to be effective in reducing tissue ischemia in gangrenous erysipelas. 56 However, the use of steroids and heparin has been associated with relatively high mortality in V. vulnificus septicemia. 2 If skin necrosis occurs, surgical debridement m a y be necessary to prevent contiguous spread of infection and further seeding to the bloodstream. However, in general there is not enough time to debride necrotizing tissue because death m a y rapidly ensue. Promising results have been obtained in gram-negative infectious shock with antiserum to endotoxin.57, 58 The high mortality rate in V. vulnificus septicemia warrants clinical trials with antiserum to exotoxin of this organism. For the present, earlier recognition and treatment may allow a more favorable response to therapy and improve the prognosis.
Journal of the American Academy of Dermatology
For prevention of V. vulnificus infections, persons with chronic disease or alcohol abuse should avoid consuming or handling raw seafood and physicians should consider V. vulnificus infection in septicemic patients who have been exposed to raw seafood or seawater.
REFERENCES 1. HollisDG, Weaver RE, Baker CN, et al. Halophilic Vibrio species isolated from blood cultures. J Clin Microbiol 1976;3:425-31. 2. BlakePA, Merson H, Weaver RE, et al. Diseasecaused by a marine Vibrio: clinical characteristics and epidemiology. N Engl J Meal 1979;300:1-5. 3. Johnston JM, Beaker SF, McFarland LM. Gastroenteritis in patients with stool isolates of V. vulnificus. Am J Med 1986;80:336-8. 4. Kelly MT, Avey DM. Lactos~positive Vibrio in seawater: a cause of pneumonia and septicemia in drowning victim. J Clin Microbiol 1980;11:278-80. 5. Truwit JD, Badesch DB, Savage AM, et al. Vibrio vulnificus baeteremia with endocarditis. South Med J 1987; 80:1457-9. 6. Fearrington EL, Rand CH, Mewborn A, et al. Noneholera Vibrio septicemia and meningoencephalitis. Ann Intern Med 1974;81:401. 7. Wongpaitoon V, Sathapatayavongs B, Prachaktam R, et al. Spontaneous Vibrio vulnificus peritonitis and primary sepsis in two patients with alcoholic cirrhosis. Am J Gastroentereol 1985;80:706-8. 8. Kelly MT, McCormick WF. Acute bacterial myositis caused by Vibrio vulnificus. JAMA 1981;246:72-3. 9. Howard R J, Pessa ME, Brennaman BH, et al. Necrotizing soft tissue infections caused by marine Vibrios. Surgery 1985;98:126-30. 10. Howard R J, Lieb S. Soft-tissue infectionscaused by halophilic marine Vibrio. Arch Surg 1988;123:245-9. 11. Goo JS, Kim DW, Hart KS, et al. Lactose-fermenting Vibrio (Vibrio vulnificus) septicemia. Report of five cases. Kor J Pathol 1982;16:463-9. 12. ChongYS, Park MY, Lee SY, et al. Vibrio vulnificus septicemia in a patient with liver cirrhosis. Yonsei Med J 1982;23:146-52. 13. Kim HO, Rhim CH, Chong YS, et al. Four cases of Vibrio vulnificus septicemia, including two misidentifiedcases as Aeromonas hydrophilia infection. Kor J Clin Pathol 1984;4:115-22. 14. Kim HG, Choi EY, Lee ST, et al. Three cases of septicemia by Vibrio vuln~cus. Kor J Intern Med 1985;29:112-8. 15. ParkSD, Sohn HS, Moon HB, et al. Vibrio vulnificus gangrene. J Kor Med Assoc 1985;28:681-91. 16. Joh NJ. Epidemiology and clinical charaeteristics of Vibrio vulnificus infectionsinKorea. J Kor Med Assoc 1986;29:6977. 17. Kim J J, Yoon KJ, Yoon HS, et al. Vibrio vulnificus septicemia: report of four cases. Yonsei Med J 1986;27:307-13. 18. Hur MK. Report of a case of Vibriovulnificus isolated from wound infection. Kor 3 Clin Pathol 1986;6;69-75. 19. Oliver JD, Warner RA, Cleland DR. Distribution of a Vibrio vulnificus and other lactose-fermenting Vibrios in the marine environment. Appl Environ Microbiol I983; 45:985-98. 20. Taeket CO, Barrett TJ, Mann JM, et al. Wound infections
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21. 22. 23. 24.
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38. 39.
caused by Vibrio vulnificus, a marine Vtbrio, in an inland area of the United States. J Clin Microbio11984; 19:197-9. Tamplin M, Rodrick GE, Blake N J, et al. Isolation and characterization of Vibrio vulnificus from two Florida estuaries. Appl Environ Microbiol 1982;44:1466-70. Chong YS, Chung MS, Chung HK, et al. Isolation of Vibrio vulnificus from shellfish. J Kor Soc Microbiol 1984;19:73-7. Park SD, Sohn HS, Koh JW. Effect of hydrogen ions on the growth of Vibrio vulnificus. Kor J Dermatol 1986;24: 354-7. Pool MD, Oliver JD. Experimental pathogenicity and mortality in ligated ileal loop studies of the newly reported halophilic lactose-positive Vibrio sp. Infect Immun 1978; 20:126-9. Gray LD, Kreger AS. Purification and characterization of an extracellular cytolysin produced by Vibrio vulnificus. Infect Immun 1985;48:62-72. Kreger A, Lockwood D. Detection of extracellular toxin(s) produced by Vibrio vulnificus. Infect Immun 1981;33:58390. Johnson DE, Calia FM. Hemolytic reaction of clinical and environmental strains of Vibrio vulnificus. J Clin Microbiol 1981;14:457-9. Shinoda S, Miyoshi S, Yamanaka H, et al. Some properties of Vibrio w~hzificus hemolysin. Microbiol Immunol 1985;29:583-90. Park SD, Kim HR. Studies on the purification and characterization of an extracellular hemolysin by Vibrio vulnificus. J Kor Meal Assoc 1986;29:662-7. Kothary MH, Kreger AS. Production and partial characterization of an elastolytic protease of Vibrio wdnificus. Infeet Immun 1985;50:534-40. Miyoshi N, Shimizu C, Miyoshi SI, et al. Purification and characterization of Vibrio vulnificus protease. Microbiol Immunol 1987;31:13-25. Kothary MH, Kreger A. Purification and characterization of an elastolytic protease of Vibrio vulnificus. J Gen Microbiol 1987;133:1783-91. Testa J, Daniel LW, Kreger AS. Extracellular phospholipase A2 and lysophospholipase produced by Vibrio vulnificus. Infect Immun 1984;45:458-63. Smith GC, Merkel JR. Collagenolytic activity of Vibrio vulnificus: potential contribution to its invasiveness. Infect Immun 1982;35:1155-6. Oliver JD, Wear JE, Thomas MB, et al. Production of extracellular enzymes and cytotoxicity by Yibrio vulnificus. Diagn Microbiol Infect Dis 1986;5:99-1 ] l. Simpson LM, Oliver JD. Siderophore produced by Vibrio vulnificus. Infect Immun 1983;41:644-9. Kreger A, DeChatelet L, Shirley P. Interaction of Vibrio vulnificus with human polymorphonuclear leukocytes: association of virulence with resistance to phagocytosis. J Infeet Dis 1981;144:244-8. Yoshi SI, Ogawa M, Mizuchi Y. Relation of capsular materials and colony opacity to virulence of Vibrio vulnificus. Infect Irnmun 1985;47:446-51. Gray LD, Kreger AS. Mouse skin damage caused by cytolysin from Vibrio vulnificus and by Vibrio vulnificus infection. J Infect Dis 1987;155:236-41.
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40. Miyoshi S, Sugiyama K, Furuta H, et al. Histamine release from rat mast cells by Vibrio vulnificus protease. FEMS Microbiol Lett 1986;34:301-4. 41. Miyoshi N, Miyoshi S, Sugiyama K et al. Activation &the plasma Kalllkrein-kinin system by Vibrio vulnificus protease. Infect Immun 1987;55:1936-9. 42. Okada K, Mitsuyama M, Miake S, et al. Monoclonal antibodies against the hemolysin of Vibrio vulnificus. J Gen Mierobiol 1987;133:2279-84. 43. Bowdre JH, PoNe MD, Oliver JD. Edema and hemoconcentration in mice experimentally infected with Vibrio vulnificus. Infect Immun 1981;32:1193-9. 44. Pollak SJ, Parrish III EF, Barrett T J, et al. Vibrio vulnificus septicemia. Isolation of organism from stool and demonstration of antibodies by indirect immunoftuorescence. Arch Intern Med 1983;143:837-8. 45. Bonner JR, Coker AS, Berryman CR, et al. Spectrum 9f Vibrio vulnificus in a gulf coast community. Ann Intern Med 1983;99:464-9. 46. Tacket CO, Brenner F, Blake PA. Clinical features and epidemiological study of Vibrio vulnificus infections. J Infeet Dis 1984;149:558-61. 47. Kelly MT. Effect of temperature and salinity on Vibrio (Beneckea) vulnificus occurrence in a gulf coast environment. Appl Environ Microbiol 1982;44:820-4. 48. Kelly MT, Dinuzzo A. Uptake and clearance of Vibrio vulnificus from gulf coast oysters Crassostrea virginica. Appl Environ Microbiol 1985;50:1548-9. 49. Oliver JD. Lethal cold stress of Vibrio vulnificus in oysters. Appl Environ Microbiol 1981 ;41:710-7. 50. Johnston JM, Andes WA, Flasser G. Vibrio vulnificus. A gastronomic hazard. JAMA 1983 ;249:1756-9. 51. Koh JW, Sohn HS, Park SD. The bacteriologic characteristics of Vibrio vulnificus. Kor J Dermatol 1985;23: 36-7. 52. Chung SS, Park CI--I,Rhee JH. Study on the bacteriological properties of Vibrio vulnificus. Infection 1986;18:5562. 53. Farmer JJ lII, Hickman-Brenner FW, Kelly MT. Vibrio. In: Lennette EH, Balows A, Hausler WJ Jr, et al, eds. Manual of clinical microbiology. Washington, DC: American Society for Microbiology, 1985:282-301. 54. Bowdre JH, Hull JH, Cocchetto DM. Antibiotic efficacy against Vibrio vulnificus in the mouse: superiority of tetracycline. J Pharm Exp Ther 1983;225:595-8. 55. Sprung CL, Caralis PV, Marcial EH, et al. The effects on high-dose corticosteroids in patients with septic shock. N Engl J Med 1984;311:1137-43. 56. Hammar H, Wanger L. Erysipelas and neerotizing fasciitis. Int J Dermatol 1977;96:409-19. 57. Zeigler EJ, McCutchan JA, Fierer J, et al. Treatment of gram-negative bacteremia and shock with human antiserum to a mutant Escherichia coil N Engl J Med 1982; 307:1225-30. 58. Warren HS, Novitsky TJ, Bucklin A, et al. Endotoxin neutralization with rabbit antisera to Escherichia coli J~ and other gram-negative bacteria. Infect Immun 1987;55:166873.
I
Vibrio vulnificus septicemia in Korea: Clinical and epidemiologic findings in seventy patients Seek Don Park, MD, PhD, a Hyung Sun Shon, MD, PhD, a and Nam Joong Joh, MD, PhD b'*
Iri City and Kwangju City, Korea We studied the clinical characteristics and the epidemiologyof primary septicemia associated with Vibrio vulni/icus in 70 patients. All patients came from the western and southern coastal areas of Korea. Most cases (96%) occurred during the summer months, in men (96%), and in persons 40 or more years of age (90%). The illness in 46 patients (66%)began with septicemia, often within 2 days of the consumption of raw seafood. Forty-seven patients (67%) had preexisting hepatic disease, and 49 (70%) had a history of alcoholism. Of the 70 patients, 45 (79%) died. The cutaneous lesions that were present on admission in 64 patients (91%) appeared on the legs in 51 of the cases. V. vulnificus was isolated from the blood of 65 patients tested and from the skin lesionsof 51 of 55 patients tested. The histopathologic findings differed according to the clinical stage of lesions, Because V. vulnificussepticemia is a highly fatal disease, persons with liver disease or alcoholism should avoid eating or handling raw seafood. (J AM ACAD DERMATOL 1991;24:397-403.)
Vibrio vulnificus is a halophilic, gram-negative, motile, marine rod whose pathogenic potential for humans has been recently recognized.t Blake et al. 2 divided the illnesses caused by K vulnificus into two distinct groups. The first, which carries a good prognosis, comprises previously healthy persons with wound infections acquired while handling raw shellfish or after exposure of a preexisting wound to seawater. The second, which is characterized by high mortality, consists of persons with preexisting chronic hepatic disease in whom primary septicemia develops after consumption of raw seafood. Other features of V. vulnificus infection (e.g., gastroenteritis, pneumonia, endocarditis, meningitis, peritonitis, myositis, cellulitis, and necrotizing fasciitis) have also been reported. 2-I~ Cases of fulminating gangrene, intractable shock, and hepatic disease have been reported as "mysterious disease" in Korea every summer since 1979. From the Department of Dermatology, Wonkwang University School of Medicine, lri City,a and Department of Internal Medicine, Chonnam University Medical School, Kwangiu City.b Presented at the Seventeenth World Congre~ of Dermatology, Berlin, May 25, 1987. Accepted for publication April 20, 1990. Reprint requests: Seek Don Park, MD, PhD, Department of Dermatology, Wonkwang University School of Medicine, 344-2, ShinyongDong, Iri City, Chonbuk 570-749, Republic of Korea. *Now in private practice in Kwangju, Korea. 16/1/21843
Since the first published report of bacteriologically proven infections in 1982,11 many more cases have been reported.12-17 K vulnificus septicemia seems to be more prevalent in Korea than in other countries. This may be due to the frequent consumption of raw seafood, even in inland areas, and the higher prevalence of underlying liver disease. There was only one proven case of wound infection in Korea. 18 PATIENTS AND METHODS
We reviewed 49 patients who were admitted to the Wonkwang University Hospital and the Chonnarn University Hospital in Korea between January 1982 and December 1986. Information about an additional 21 patients was obtained from ease reports published in the medical literature in Korea between 1982 and December 1986.1 H7 Primary septicemia was defined as the abrupt onset of symptoms and signs suggestive of septic shock without a focus of infection and the isolation of K vulnificus from either the blood and/or cutaneous lesions or peritoneal fluid. Clinical and laboratory data were abstracted from the hospital records of the 49 patients and the 21 case reports. When data on a particular feature were not known for all 70 patients, the proportion of the patients with available data who had the feature was calculated. RESULTS Clinical features Of 70 patients with primary sepsis, 54% had fever, 33% had chills, 20% had vomiting, 33% had di397
Journal of the American Academy of Derma tology
398 Park et aL
Table I. Clinical features associated with Vibrio vulnificus septicemia Primary septicemia (n = 70)
Feature
Cases
%
Fever Chills Vomiting Diarrhea Abdominal pain Headache Dizziness Dyspnea Oliguria Secondary skin lesions Pain and tenderness of skin lesion Peritonitis Hypotension* Death
38 23 14 23 26 7 3 7 4 64 49
54 33 20 33 37 10 4 10 6 91 70
4 38 55
6 54 79
*Systolic blood pressure of --<80 mm Hg on admission.
Fig. 1. The earliest lesion. Erythematous, painful swelling like bee sting.
arrhea, 37% had abdominal pain and 70% had painful and tender skin lesions, 91% had secondary skin lesions, and 54% had hypotension on admission. Fifty-five patients (79%) died (Table I). Forty-seven of 65 patients (67%) had preexisting hepatic disease (cirrhosis, chronic hepatitis, and fatty liver). Five patients (7%) had an underlying chronic illness (malignant lymphoma, pulmonary tuberculosis, rheumatoid arthritis, duodenal ulcer, diabetes mellitus). Of 49 patients with a history of alcoholism, 30 (43%) had liver disease. Fifty-two patients (76%) had consumed alcoholic beverages before the onset of illness. Secondary skin lesions were present in 64 patients (91%) on admission. The type of skin lesions included vesicles and/or buUae (42%), peripheral edema (41%), localized swelling (33%), gangrene (27%), cyanosis (25%), purpura (22%), macules and)/or patches (16%), papules, wheals, and pustules (Figs. 1 through 5). The skin lesions were present on the legs in 51 (80%) of the 64 cases. Other areas of involvement included the arms (20%), entire body surface (13%), abdomen (9%), face and buttock (8%), back (5%), flank, chest, and scrotum.
The mean incubation period was 2 days and ranged from 3 hours to 6 days. The mean interval between the onset of illness and death was 4.2 days (13 hours to 22 days). Leukopenia was noted in 14 of 59 patients, and 20 had leukocytosis. Differential WBC counts showed a shift to the left in 27 (69%) of the 39 patients with recorded differential counts. Twenty-six (69%) of 38 patients tested had thrombocytopenia. Serum aminotransferase (aspartate and alanine) and 3'-glutamryl transpeptidase (~/-GTP) levels were elevated in many tested cases. V. vulnificus was isolated' from the blood of 49 (75%) of the 65 patients, from secondary skin lesions in 51 (93%) of 55 patients, and from blood and skin lesions in 32 patients. In addition, V. vulnificus was isolated from the peritoneal fluid in four patients, from cerebrospinal fluid in one patient, from the stool in one patient, and from the urine in one patient. The histopathologicfindings differed according to the clinical stages of the lesions. The lesions with localized swelling or cellulitis-like appearance revealed extravasation of RBCs and massive infiltration of neutrophils in the dermis and subcutis (Fig. 6). The bullous skin lesions showed subepidermal bullae and perivascular infiltration of neutrophils and lymphocytes. Microscopic examination of gangrenous lesions showed necrosis of the entire skin and nonleukocytoclastic, transmural, necrotizing vasculitis with or without thrombosis in the subcu-
Volume 24 Number 3 March 1991
Vibrio vulnificus septicemia
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Fig. 2. Purpuric patches and edema.
tis. Gram-negative bacilli were seen, especially around the blood vessels on hematoxylin-and-eosin and Gram's stains.
Epidemiologie features Ninety percent of the patients were 40 years of age or older (mean age 51 years), and 96% were men. There was marked seasonal distribution of the dates of onset of illness. Most cases in Korea (96%) occurred during the summer months. All patients came from western and southern coastal Korea. Forty-four patients (63%) had consumed raw seafood within 1 week of the onset of illness; 12 (19%) reported no ingestion of seafood before illness, and relevant data were not recorded for the remaining 14 cases studied. Seafood consumed raw or undercooked included various kinds of fish and shellfish. In all cases, the K vulnificus organism was sensitive to ampicillin, tobramycin, and chloramphenicol and resistant to penicillin, methicillin, and coilstin. DISCUSSION
K vulnificus, a recently identified marine bacte-
Fig. 3. Reddishand/ornecroticmaculopatchesontrunk
rium, is capable of causing wound infection in otherwise healthy persons and a syndrome of primary septicemia in persons with underlying chronic disease, particularly liver disease. 2 V. vulnificus has been isolated from a wide range of environmental sources, including seawater, brackish water, sediment, plankton, fish and shellfish, and estuaries. 19-22 There is little doubt that the gastrointestinal tract is
a portal of entry for V. vulnificus in primary septicemia. K vulnificus has been shown to survive between pH 3.6 and 12.5 when incubated at 37 ~ C for 1 hour and grows best between pH 7 and 9, 23 Therefore, although the stomach normally serves as an important barrier to bacterial overgrowth, after
and edema of right upper extremity.
400
Journal of the American Academy of Dermatology
Park et al.
Fig. 4. Advanced lesion. Cellulitis-like lesion with vesicles and erosions.
Fig. 5. Gangrenous lesion. Extensive gangrene, edema, vesicobullae, and ulcer. the ingestion of seafood contaminated with V. vulnificus, the bacterium can survive as it passes through the stomach. Id. vulnificus multiplies rapidly during its pass through the small bowel because the intraluminal pH is maintained well above 7.0, V. vulnificus invades the gastrointestinal mucosa at the level of the proximal small bowel into the systemic circulation, thereby producing sepsis. 24 The organism also invades the intestinal wall into the ascitic fluid (produces bacterial peritonitis in patients with liver cirrhosis). 6, 16 The mechanism of increased susceptibility to V. vulnificus infection in patients with liver disease and/or alcohol consumption has not yet been clarified. However, these patients are more susceptible
to bacterial infection. Our study corroborates the association of chronic hepatic disease (67% of cases), particularly liver cirrhosis, with V. vulnificus septicemia. However, alcohol abusers (defined as persons who consume 1 ounce of 100% ethanol equivalence daily) were more susceptible to V. vulnificus infection than the patients in our study with liver cirrhosis. V. vulnificus is known to produce virulence factors, such as cytolysin, hemolysin, protease, phospholipase A2, collagenase, lipase, chondroitinase, hyaluronidase, sulfatase, deoxyribonuclease, siderophores, antiphagocytic surface antigen, and capsular materialsY -38 By having capsular materials and antiphagocytic antigen, the K vulnificus organisms
Volume24 Number 3 March 1991 acquire resistance to serum bactericidal action and antiphagocytic activity. 37"39 Production of collagenase and lipase can contribute to invasion of healthy tissue.34, 35 V. vulnificusproteases invade tissues that contain elastin and collagen and elicit rapidly extensive dermal necrosis. 3~ Protease causes edema by enhancing vascular permeability through histamine release and activation of the plasma kallikrein-kinin system, which generates bradykinin.4~ 41 ExtracelIular cytolysin possesses four toxic activities including cytolytic, cytotoxic, vascular permeability-increasing, and lethal activities25' 26, 39; hemolysin is probably identical to the lethal toxin. 42 Intradermal infection with V. vulnificus and intradermal injection of the cytolysin produced acute cellulitis in mice characterized by edema and necrosis of cells. 39 Although none of the exoenzymes appeared to correlate with the ability of K vulnificus to produce lethality in mice,35 the production of cytolysin, protease, and hemolysin is significant in the pathogenesis of V. vulnificus septicemia, thereby implicating them in the pathologic features of V. vulnificus infections (edema, bulla formation, tissue necrosis, purpura, and death). However, Bowdre et al.43 have suggested that local edema or lethality in V. vulnificus infection might not be attributable to a diffusable toxin and might require contact between host cells and viable Vibrio cells. Park et al. 15 classified histopathologic findings of skin lesions according to clinical manifestations into three stages. The initial (inflammatory) stage of erythema and localized swelling revealed edema, massive infiltration of pol~aorphonuclear leukocytes, and extravasation of RBCs.The second (bullous) stage showed subepidermal bullae and vasculitis. The third (gangrenous) stage showed necrosis of the entire skin surface and nonleukocytoclastic, transmural, necrotizing vasculitis with or without thrombosis in the subcutis. Bacteria were present throughout the dermis, and numerous bacteria were found within the bullous fluid and centered around the dermal vessels. Most notable among laboratory abnormalities in V. vulnificus septicemia was the elevation of hepatoceUular enzymes. Leukocytosis was observed more commonly than leukopenia, in contrast to another report. 2 Thrombocytopenia was common in our patients, as was varying degrees of disseminated intravascular coagulation. Other laboratory abnormalities reflected specific organ involvement as a result of septicemia and septic shock. V. vulnificus was
Vibrio vulnificus septicemia
401
Fig. 6. Photomicrograph of biopsy specimen of erythematous swollenarea (Fig. 1) showsmassive infiltration of neutrophils and extravasation of RBCs throughout dermis and subcutis. (Hematoxylin-eosin stain; • 13.2.) isolated from skin lesions more commonly than from blood. This may be due to the scarcity of growth inhibitors of this bacterium in the skin. The skin lesions were first caused by hematogenous seeding of Vibrio cells to affected sites, as K vulnificus was isolated from both skin lesions and blood simultaneously. There have been few efforts to identify K vulnifieus in stool specimens, 3, 44 probably because of the difficulty in doing so. The predominance of men (96%) and of persons 40 years of age or older (90%) in our study reflects a greater likelihood of these groups eating raw seafood, having underlying hepatic disease, and consumption of liquor. The increased incidence of K vulnificus septicemia in Korea may be because most Korean men ingest various kinds of raw seafood and because the Korean population has a higher incidence of hepatic disease. V. vulnificus has been isolated from a wide range of environmental sources including seawater, brackish water, sediment, plankton, and shellfish (oyster, clam, and crab), and from various locations around
402 P a r k et al. the world. 4, 6, 11-22,27, 45-47 Isolation has been more frequent in w a r m water (20 ~ C) with a salinity of 7% to 29.3%. 19, 21, 47 At higher water temperatures, V. vulnificus, like V. parahemolyticus, m a y be released and rise to surface waters where it attaches to plankton and shore fishes. T h e organism is then taken up by marine animals and concentrated, particularly by filter-feeding mollusks and crustaceans. 48 This suggestion is supported by the fact that 44 patients (63%) in our study had consumed various kinds of raw fish and shellfish before onset of disease. Oliver 49 has suggested that raw oysters kept on ice are not likely to be a major factor in the epidemiology of V. vulnificus infection. However, the viability of the organism was not decreased by mere refrigeration or freezing. 5~ Therefore, cooking seafood at a boiling temperature should destroy bacteria and bacterial toxins. 25, 26, 29.49 Seawater temperature increases to greater than 20 ~ C during the w a r m e r months of year (July to September) in Korea, 16 and most of our reported cases (96%) occurred during these months. Because V. vulnificus infection is life-threatening and can progress rapidly, antibiotic therapy must be initiated as soon as this disease is suspected, even before the organism is identified. All strains of V. vulnificus have been reported to be sensitive to ampicillin, chloramphenicol, tetracycline, and gentamicin, ~,6,~7,53,54 and similar results were shown in our study. Bowdre et al.54 suggested that tetracycline is the therapy of choice. Corticosteroids did not improve the overall survival of the patients with severe late septic shock, but these might be helpful early in the course of the disease. 55 Heparin has been shown to be effective in reducing tissue ischemia in gangrenous erysipelas. 56 However, the use of steroids and heparin has been associated with relatively high mortality in V. vulnificus septicemia. 2 If skin necrosis occurs, surgical debridement m a y be necessary to prevent contiguous spread of infection and further seeding to the bloodstream. However, in general there is not enough time to debride necrotizing tissue because death m a y rapidly ensue. Promising results have been obtained in gram-negative infectious shock with antiserum to endotoxin.57, 58 The high mortality rate in V. vulnificus septicemia warrants clinical trials with antiserum to exotoxin of this organism. For the present, earlier recognition and treatment may allow a more favorable response to therapy and improve the prognosis.
Journal of the American Academy of Dermatology
For prevention of V. vulnificus infections, persons with chronic disease or alcohol abuse should avoid consuming or handling raw seafood and physicians should consider V. vulnificus infection in septicemic patients who have been exposed to raw seafood or seawater.
REFERENCES 1. HollisDG, Weaver RE, Baker CN, et al. Halophilic Vibrio species isolated from blood cultures. J Clin Microbiol 1976;3:425-31. 2. BlakePA, Merson H, Weaver RE, et al. Diseasecaused by a marine Vibrio: clinical characteristics and epidemiology. N Engl J Meal 1979;300:1-5. 3. Johnston JM, Beaker SF, McFarland LM. Gastroenteritis in patients with stool isolates of V. vulnificus. Am J Med 1986;80:336-8. 4. Kelly MT, Avey DM. Lactos~positive Vibrio in seawater: a cause of pneumonia and septicemia in drowning victim. J Clin Microbiol 1980;11:278-80. 5. Truwit JD, Badesch DB, Savage AM, et al. Vibrio vulnificus baeteremia with endocarditis. South Med J 1987; 80:1457-9. 6. Fearrington EL, Rand CH, Mewborn A, et al. Noneholera Vibrio septicemia and meningoencephalitis. Ann Intern Med 1974;81:401. 7. Wongpaitoon V, Sathapatayavongs B, Prachaktam R, et al. Spontaneous Vibrio vulnificus peritonitis and primary sepsis in two patients with alcoholic cirrhosis. Am J Gastroentereol 1985;80:706-8. 8. Kelly MT, McCormick WF. Acute bacterial myositis caused by Vibrio vulnificus. JAMA 1981;246:72-3. 9. Howard R J, Pessa ME, Brennaman BH, et al. Necrotizing soft tissue infections caused by marine Vibrios. Surgery 1985;98:126-30. 10. Howard R J, Lieb S. Soft-tissue infectionscaused by halophilic marine Vibrio. Arch Surg 1988;123:245-9. 11. Goo JS, Kim DW, Hart KS, et al. Lactose-fermenting Vibrio (Vibrio vulnificus) septicemia. Report of five cases. Kor J Pathol 1982;16:463-9. 12. ChongYS, Park MY, Lee SY, et al. Vibrio vulnificus septicemia in a patient with liver cirrhosis. Yonsei Med J 1982;23:146-52. 13. Kim HO, Rhim CH, Chong YS, et al. Four cases of Vibrio vulnificus septicemia, including two misidentifiedcases as Aeromonas hydrophilia infection. Kor J Clin Pathol 1984;4:115-22. 14. Kim HG, Choi EY, Lee ST, et al. Three cases of septicemia by Vibrio vuln~cus. Kor J Intern Med 1985;29:112-8. 15. ParkSD, Sohn HS, Moon HB, et al. Vibrio vulnificus gangrene. J Kor Med Assoc 1985;28:681-91. 16. Joh NJ. Epidemiology and clinical charaeteristics of Vibrio vulnificus infectionsinKorea. J Kor Med Assoc 1986;29:6977. 17. Kim J J, Yoon KJ, Yoon HS, et al. Vibrio vulnificus septicemia: report of four cases. Yonsei Med J 1986;27:307-13. 18. Hur MK. Report of a case of Vibriovulnificus isolated from wound infection. Kor 3 Clin Pathol 1986;6;69-75. 19. Oliver JD, Warner RA, Cleland DR. Distribution of a Vibrio vulnificus and other lactose-fermenting Vibrios in the marine environment. Appl Environ Microbiol I983; 45:985-98. 20. Taeket CO, Barrett TJ, Mann JM, et al. Wound infections
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40. Miyoshi S, Sugiyama K, Furuta H, et al. Histamine release from rat mast cells by Vibrio vulnificus protease. FEMS Microbiol Lett 1986;34:301-4. 41. Miyoshi N, Miyoshi S, Sugiyama K et al. Activation &the plasma Kalllkrein-kinin system by Vibrio vulnificus protease. Infect Immun 1987;55:1936-9. 42. Okada K, Mitsuyama M, Miake S, et al. Monoclonal antibodies against the hemolysin of Vibrio vulnificus. J Gen Mierobiol 1987;133:2279-84. 43. Bowdre JH, PoNe MD, Oliver JD. Edema and hemoconcentration in mice experimentally infected with Vibrio vulnificus. Infect Immun 1981;32:1193-9. 44. Pollak SJ, Parrish III EF, Barrett T J, et al. Vibrio vulnificus septicemia. Isolation of organism from stool and demonstration of antibodies by indirect immunoftuorescence. Arch Intern Med 1983;143:837-8. 45. Bonner JR, Coker AS, Berryman CR, et al. Spectrum 9f Vibrio vulnificus in a gulf coast community. Ann Intern Med 1983;99:464-9. 46. Tacket CO, Brenner F, Blake PA. Clinical features and epidemiological study of Vibrio vulnificus infections. J Infeet Dis 1984;149:558-61. 47. Kelly MT. Effect of temperature and salinity on Vibrio (Beneckea) vulnificus occurrence in a gulf coast environment. Appl Environ Microbiol 1982;44:820-4. 48. Kelly MT, Dinuzzo A. Uptake and clearance of Vibrio vulnificus from gulf coast oysters Crassostrea virginica. Appl Environ Microbiol 1985;50:1548-9. 49. Oliver JD. Lethal cold stress of Vibrio vulnificus in oysters. Appl Environ Microbiol 1981 ;41:710-7. 50. Johnston JM, Andes WA, Flasser G. Vibrio vulnificus. A gastronomic hazard. JAMA 1983 ;249:1756-9. 51. Koh JW, Sohn HS, Park SD. The bacteriologic characteristics of Vibrio vulnificus. Kor J Dermatol 1985;23: 36-7. 52. Chung SS, Park CI--I,Rhee JH. Study on the bacteriological properties of Vibrio vulnificus. Infection 1986;18:5562. 53. Farmer JJ lII, Hickman-Brenner FW, Kelly MT. Vibrio. In: Lennette EH, Balows A, Hausler WJ Jr, et al, eds. Manual of clinical microbiology. Washington, DC: American Society for Microbiology, 1985:282-301. 54. Bowdre JH, Hull JH, Cocchetto DM. Antibiotic efficacy against Vibrio vulnificus in the mouse: superiority of tetracycline. J Pharm Exp Ther 1983;225:595-8. 55. Sprung CL, Caralis PV, Marcial EH, et al. The effects on high-dose corticosteroids in patients with septic shock. N Engl J Med 1984;311:1137-43. 56. Hammar H, Wanger L. Erysipelas and neerotizing fasciitis. Int J Dermatol 1977;96:409-19. 57. Zeigler EJ, McCutchan JA, Fierer J, et al. Treatment of gram-negative bacteremia and shock with human antiserum to a mutant Escherichia coil N Engl J Med 1982; 307:1225-30. 58. Warren HS, Novitsky TJ, Bucklin A, et al. Endotoxin neutralization with rabbit antisera to Escherichia coli J~ and other gram-negative bacteria. Infect Immun 1987;55:166873.