INTRODUCTION — Vibrio vulnificus is a gram-negative bacterium that can cause serious wound infections, septicemia, and diarrhea [1-3]. It is the leading cause of shellfish-associated deaths in the United States. Infections due to V. vulnificus are most common in individuals who have chronic, underlying illness; individuals with liver disease or hemochromatosis are at greatest risk.
The pathogenesis, epidemiology, clinical features, diagnosis, and treatment of V. vulnificus infections will be reviewed here. The disease cholera, caused by "epidemic" strains of Vibrio cholerae, infections caused by Vibrio parahaemolyticus, and illnesses associated with other Vibrio strains and species are discussed separately. (See "Cholera: Clinical features, diagnosis, treatment, and prevention" and "Vibrio parahaemolyticus infections" and "Infections due to non-O1/O139 Vibrio cholerae" and "Minor Vibrio and Vibrio-like species associated with human disease".)
EPIDEMIOLOGY — V. vulnificus exists as a free-living bacterium inhabiting estuarine (eg, saltwater marshes/wetlands, river estuaries) or marine environments. Traditionally, three biotypes have been recognized: biotype 1, which accounts for almost all human infections; biotype 2, which consists primarily of eel pathogens; and biotype 3, an apparent hybrid of biotypes 1 and 2 that has been described in tilapia-associated wound infections associated with aquaculture in Israel [4-6]. These biotypes correlate (to a reasonable degree) with phylogenetic studies, which have identified five well-supported V. vulnificus phylogenetic groups or lineages [7]. Biotype 1 strains are found primarily in lineage 1 (but also lineages 2, 4, and 5); biotype 2 strains in lineage 2; and biotype 3 strains in lineage 3.
V. vulnificus accounts for approximately eight percent of the aerobic bacteria in the Chesapeake Bay [8]. Counts peak during summer and late fall (when water temperatures are highest), and an association between increased temperatures and case numbers has been demonstrated [9,10]. Reductions in bacteria counts have been correlated with diminished water salinity [11,12].
Filter-feeding shellfish such as oysters concentrate bacteria and may have counts of V. vulnificus up to two orders of magnitude greater than those in the surrounding water. V. vulnificus can be isolated from virtually all oysters harvested in the Chesapeake Bay and the United States Gulf Coast when water temperatures exceed 20ºC [8,13]. Over 90 percent of patients with "primary" V. vulnificus septicemia (ie, septicemia without an obvious source such as a wound) report having consumed raw oysters prior to the onset of illness [14].
Wound infections generally result from exposure of a wound to salt or brackish water containing the organism, and most often occur in the setting of handling seafood or in association with recreational water activities [15,16]. Wound infections are most common during warm summer months. Rising water temperatures associated with climate change may be contributing to an increase in case numbers, as well as identification of cases further north along the United States Atlantic coast in areas such as Delaware Bay [17]. In individuals with predisposing medical conditions (as detailed below), even minor skin penetrations can result in serious wound infections. In one report, a fish farm hatchery manager with diabetes mellitus and nonalcoholic steatohepatitis developed V. vulnificus necrotizing fasciitis following acupuncture, presumably in the setting of skin contamination [18]; fatal bacteremia and septic shock has also been reported, related to exposure of a "fresh" eight-day-old tattoo to seawater in a 31-year-old patient with alcoholic cirrhosis [19].
Individuals with the following conditions are at increased risk for serious infection with V. vulnificus [2,15,20]:
●Alcoholic cirrhosis (present in 31 to 43 percent of patients with primary septicemia)
●Underlying liver disease including cirrhosis and chronic hepatitis (24 to 31 percent of patients)
●Alcohol abuse without documented liver disease (12 to 27 percent of patients)
●Hereditary hemochromatosis (12 percent of patients)
●Chronic diseases such as diabetes mellitus, rheumatoid arthritis, thalassemia major, chronic renal failure, and lymphoma (7 to 8 percent of patients)
Interestingly, men, and particularly older men, appear to be at much greater risk for serious infection than women [21].
In population-based studies in coastal areas in the United States, the estimated incidence of V. vulnificus infections is approximately 0.5/100,000 population per year [22-24]. The estimated national incidence, based on reports to surveillance programs, is substantially lower at 0.04 to 0.05 per 100,000 persons per year [25]. However, this rate has increased dramatically since 1996. In 2014 (the last year for which complete United States Centers for Disease Control and Prevention (CDC) data have been published), 124 V. vulnificus cases were reported to the Centers for Disease Control and Prevention; among these individuals, 79 percent were hospitalized and 18 percent died [26].
PATHOGENESIS — Virulence of V. vulnificus has been associated with a variety of potential factors: (1) production of an anti-phagocytic polysaccharide capsule [27]; (2) MARTX and other toxins [28,29]; and (3) iron availability and iron acquisition systems [30-32].
Capsule — V. vulnificus produces a capsular polysaccharide that provides protection against phagocytosis and opsonization [27]. Strains are able to undergo phase variation, shifting between encapsulated forms (opaque colony morphology) and unencapsulated forms (translucent colony morphology). Unencapsulated strains are avirulent in mouse models. When these strains are taken up by oysters, there is a high rate of shift to the capsulated phenotype, suggesting that oyster passage selects for the encapsulated, virulent form of the organism [33].
Anticapsular antibodies are protective, but appear to be type-specific rather than cross-reactive [34]. The type-specific nature of protective antibodies is significant since V. vulnificus has great diversity in capsular types. In one study of 120 strains, for example, 96 different capsular types ("carbotypes") were identified [35].
V. vulnificus contains a lipopolysaccharide (LPS) but, in contrast to Escherichia coli and other members of the Enterobacteriaceae, the LPS of V. vulnificus is not a strong trigger for release of tumor necrosis factor (TNF)-alpha and other shock-related cytokines. However, capsular polysaccharide itself may directly trigger some cytokine responses, contributing to the development of the shock syndrome [36]; TNF-alpha was detected in mice up to 12 hours after inoculation of an encapsulated V. vulnificus strain, while an unencapsulated strain was rapidly cleared. Both capsular polysaccharide and LPS provoked cytokine release in vitro from human peripheral blood mononuclear cells.
Toxins — V. vulnificus produces a variety of extracellular toxins, including the metalloprotease VvpE, the cytolysin/hemolysin VvhA, and the multifunctional autoprocessing repeats-in-toxins (MARTX) toxin. While both VvhA and MARTX toxin contribute to virulence, in vivo studies in mice suggest that the MARTX toxin is a major driver for bacterial dissemination from the intestine and subsequent sepsis [29,37].
Iron — Growth of V. vulnificus is dependent in part upon the availability of iron [30-32]. Growth of the organism in human serum is related directly to the percentage saturation of transferrin with iron [30]. When transferrin iron saturation exceeds 70 percent, growth of the bacterium is nearly exponential.
The relationship between iron and virulence in V. vulnificus may account for the enhanced susceptibility to serious infections with this organism in patients with hemochromatosis [38,39]. However, most patients with serious V. vulnificus infections have normal iron and iron saturation levels. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'Susceptibility to infection'.)
Differentiating strains — The number of reported V. vulnificus cases is relatively low, in spite of the frequency with which humans are exposed to V. vulnificus in oysters and in contact with estuarine water (even taking into account differences in host susceptibility). This has led to the hypothesis that certain strain subsets are more likely than others to cause human disease, in keeping with phylogenetic studies, which show evidence of clustering of human isolates in what has been designated lineage 1 [7]. However, in contrast to findings with V. parahaemolyticus and V. cholerae, it has not been possible to identify a single V. vulnificus virulence factor that is almost exclusively present in clinical isolates [40].
CLINICAL MANIFESTATIONS — V. vulnificus causes wound infections and "primary septicemia" (septicemia without a clearly defined source of infection, such as a wound) [1,2,15,20,22,23]. Wound infections may be acquired during handling of shellfish or fish, or after exposure of a preexisting wound to estuarine water. In one case series from Korea, the incubation period for septicemia ranged from three hours to six days [41].
V. vulnificus has also been associated with occurrence of watery diarrhea and other symptoms of gastroenteritis [42]. An etiologic role is difficult to establish when the organism is isolated from stool samples since the bacterium is ubiquitous in both water and shellfish and has been isolated from stool samples of asymptomatic persons.
Wound infections — V. vulnificus may contaminate wounds exposed to estuarine waters, shellfish, or fish. Typical examples include hand injuries related to opening oysters or leg lacerations related to entering, exiting, or launching boats. The cellulitis is usually mild. However, in high-risk individuals, the infection may spread rapidly, producing severe myositis and necrotizing fasciitis reminiscent of gas gangrene (picture 1).
Primary septicemia — Primary V. vulnificus septicemia is associated with ingestion of raw or undercooked shellfish, particularly raw oysters. Patients with primary septicemia generally have underlying liver disease, alcoholism, hereditary hemochromatosis, or a chronic disease as noted above.
Approximately one-third of patients with primary septicemia present in shock or become hypotensive within 12 hours of hospital admission. Three-fourths of patients have distinctive bullous skin lesions (picture 2). Thrombocytopenia is common, and often there is evidence of disseminated intravascular coagulation. Complications such as gastrointestinal bleeding can occur.
Primary V. vulnificus septicemia is a serious illness with a high mortality rate. Among all reported foodborne infections in the United States, V. vulnificus is associated with the highest case fatality rate (39 percent) [43]. Mortality rates exceeding 40 percent have been reported in case series, with a case fatality rate of more than 90 percent among those who are hypotensive when they present for medical care [2,15,20,44]. Advanced liver disease with model for end-stage liver disease (MELD) scores of >20 has also been associated with high mortality (64-fold increased odds of death), as have hypoalbuminemia and severe anemia [45].
Persons who survive the acute shock event often require prolonged hospitalization in intensive care. While there may be complete recovery from the actual V. vulnificus infection, there may be ongoing morbidity due to associated multiorgan system failure.
DIAGNOSIS — Given the potential severity of the infection, a presumptive diagnosis of V. vulnificus septicemia should be made in any person with fever, hypotension, or symptoms suggestive of septic shock, characteristic bullous skin lesions, and risk factors for acquiring infection as noted above. The infection should also be suspected in persons from these risk groups who have rapidly progressive wound infections associated with exposure to estuarine waters.
The diagnosis is confirmed by culture or by non-culture-based identification systems, which are becoming increasingly common in clinical microbiology laboratories. If traditional culture techniques are used, V. vulnificus will grow without difficulty in standard blood culture media or on nonselective media (such as blood agar) routinely used for wound cultures; identification and speciation of the organism is possible via any standard, commercially available microbiology identification system. Isolation of the organism from stool generally requires the use of a specific selective culture media (thiosulfate citrate bile-salts sucrose [TCBS]), on which V. vulnificus, V. parahaemolyticus, and some other Vibrio species produce blue-green colonies, in contrast to the yellow colonies produced by V. cholerae.
TREATMENT
Severe infections — Case fatality rates for V. vulnificus septicemia and serious wound infections have been shown to increase with greater delays between onset of illness and initiation of antibiotic treatment [15,22]. Thus, patients with a presumptive diagnosis of V. vulnificus septicemia should be started immediately on antibiotic therapy and managed aggressively in an intensive care unit to minimize the possible consequences of hypotension, septic shock, and the risk of multiorgan system failure.
We favor treatment of patients with septicemia or serious wound infections using combination therapy with a third-generation cephalosporin (eg, cefotaxime 2 g intravenously every eight hours or ceftriaxone 1 g intravenously daily) plus either a tetracycline (eg, doxycycline 100 mg orally twice daily or minocycline 100 mg orally twice daily) or a fluoroquinolone (eg, ciprofloxacin 500 mg orally twice daily). Doses should be appropriately adjusted for underlying renal or hepatic disease.
In high-risk patients, more serious wound infections may require aggressive debridement in addition to parenteral antibiotics. In a series of 121 patients in Taiwan who presented with necrotizing fasciitis, surgery within 12 hours of admission resulted in a significant improvement in survival [46]. Among 423 V. vulnificus wound infections reported in the United States, 10 percent of patients required amputation of some type [15].
Use of combination antibiotic regimens is supported by several observational studies. In a retrospective study from Korea that included 218 patients with V. vulnificus septicemia, the combinations of a third-generation cephalosporin plus either doxycycline or ciprofloxacin were associated with largely comparable survival rates in the overall and propensity score-matched analysis, which were higher than those associated with other monotherapy regimens [47]. Similarly, in a retrospective study of 89 patients with histologically and microbiologically confirmed V. vulnificus necrotizing fasciitis who underwent prompt surgical debridement, those treated with either a third-generation cephalosporin plus minocycline, or ciprofloxacin with or without minocycline had lower mortality rates than those who received a third-generation cephalosporin alone (14, 14, and 61 percent, respectively) [44,48]. In one case report, the combination of tigecycline and cefpirome was reported to be efficacious as "salvage" therapy in a child with V. vulnificus necrotizing fasciitis who was not responding well clinically to ceftazidime and minocycline [49].
In vitro and in vivo studies in mice have demonstrated an apparent synergism between cefotaxime and minocycline in the treatment of serious V. vulnificus infections [50]. Mouse studies have also highlighted the efficacy of combination therapy with cefepime in combination with doxycycline or ciprofloxacin [51], ciprofloxacin plus cefotaxime [52], and tigecycline plus cefotaxime [53].
Mild infections — Mild wound infections in patients who do not have significant underlying diseases generally respond well to local care and oral antibiotics (such as a tetracycline or a fluoroquinolone). Duration of therapy is dictated by severity of the initial infection and clinical response; patients with mild to moderate infections generally respond to five to seven days of antibiotics.
PREVENTION — Given the high mortality associated with V. vulnificus infection, individuals in high-risk groups should avoid eating raw or undercooked shellfish, particularly oysters. Post-harvest treatments (mild heat treatment, freezing, hydrostatic pressure) can reduce V. vulnificus counts in raw oysters, potentially reducing disease risk [54]. Individuals with increased susceptibility to V. vulnificus infections should also avoid situations in which estuarine-associated wounds are likely to occur. Should such a wound occur, there are no specific preventive measures beyond basic wound care. However, immunocompromised patients and those with liver disease, in particular, should be advised that if any signs or symptoms of infection (eg, fever, erythema, tenderness, or drainage) develop, they should contact their clinician or present to medical care immediately for further evaluation and initiation of antibiotics. (See 'Treatment' above.)
SUMMARY AND RECOMMENDATIONS
●Vibrio vulnificus is a gram-negative bacterium that can cause serious wound infections, septicemia, and diarrhea. It is the leading cause of shellfish-associated deaths in the United States. Serious infections due to V. vulnificus are most common in individuals who have chronic, underlying illness; those with liver disease or hemochromatosis are at greatest risk. (See 'Introduction' above and 'Clinical manifestations' above.)
●V. vulnificus can be isolated from virtually all oysters harvested in the Chesapeake Bay and the United States Gulf Coast when water temperatures exceed 20ºC. Over 90 percent of patients with "primary" V. vulnificus septicemia (ie, septicemia without an obvious source such as a wound) report having consumed raw oysters prior to the onset of illness. (See 'Epidemiology' above.)
●Growth of V. vulnificus in human serum is related to the percentage saturation of transferrin with iron. The relationship between iron and virulence in V. vulnificus may account for the enhanced susceptibility to serious infections in patients with hemochromatosis. However, most patients with serious V. vulnificus infections have normal iron and iron saturation levels. (See 'Iron' above.)
●Wound infections generally result from exposure of a wound to salt or brackish water containing the organism, and most often occur in the setting of handling seafood or in association with recreational water activities. In high-risk individuals, the infection may spread rapidly, producing severe myositis and necrotizing fasciitis reminiscent of gas gangrene (picture 1). (See 'Epidemiology' above and 'Wound infections' above.)
●Primary V. vulnificus septicemia is a serious illness with a high mortality rate. Approximately one third of patients with primary septicemia present in shock or become hypotensive within 12 hours of hospital admission. Three-fourths of patients have distinctive bullous skin lesions (picture 2). Thrombocytopenia is common, and often there is evidence of disseminated intravascular coagulation. (See 'Primary septicemia' above.)
●A presumptive diagnosis of V. vulnificus septicemia should be made in any person with fever, hypotension, or symptoms of septic shock, characteristic bullous skin lesions, and risk factors for infection. The diagnosis is confirmed either by non-culture-based methods or by traditional culture; V. vulnificus will grow without difficulty in standard media. Isolation of the organism from stool generally requires the use of a specific selective culture media (thiosulfate citrate bile-salts sucrose [TCBS]). (See 'Diagnosis' above.)
●Patients with a presumptive diagnosis of V. vulnificus septicemia should be started immediately on antibiotic therapy and managed aggressively in an intensive care unit, pending laboratory confirmation of the infection. We suggest treatment with a third-generation cephalosporin plus either a tetracycline or fluoroquinolone (Grade 2C).
●Mild wound infections in patients who do not have significant underlying diseases generally respond well to local care and oral antibiotics; we suggest a tetracycline or fluoroquinolone (Grade 2C). (See 'Treatment' above.)
