Vibrio vulnificus infection

INTRODUCTION — Vibrio vulnificus is a gram-negative rod that can cause primary septicemia, wound infection, or diarrheal illness [1-3]. Serious infection due to V. vulnificus is most common among individuals with chronic, underlying illnesses – with particular risks associated with liver disease or hemochromatosis. It is the leading cause of shellfish-associated deaths in the United States.

The epidemiology, clinical features, diagnosis, and treatment of V. vulnificus infections will be reviewed here.

Issues related to cholera (caused by Vibrio cholerae) are discussed separately. (See "Cholera: Epidemiology, clinical features, and diagnosis" and "Cholera: Treatment and prevention".)

Issues related to infection caused by Vibrio parahaemolyticus, as well as illnesses associated with other Vibrio strains and species, are discussed separately. (See "Vibrio parahaemolyticus infections" and "Infections due to non-O1/O139 Vibrio cholerae" and "Minor Vibrio and Vibrio-like species associated with human disease".)

EPIDEMIOLOGY

Geography — Worldwide, Vibrio are found in marine environments, including salt water and brackish water (a mix of salt water and fresh water). Environments where Vibrio may be found include river estuaries and saltwater marshes/wetlands [4,5]. Under optimal conditions it can be relatively common; in the Chesapeake Bay, it has been reported to account for approximately 8 percent of the total aerobic bacterial population [6].

V. vulnificus bacteria thrive in warmer waters – especially during the summer and fall (when water temperatures are highest). V. vulnificus is rarely detected in winter months, in settings in which water temperatures drop consistently below 20°C (68°F). An association between increased temperatures and case numbers has been observed [7,8]. In addition, extreme weather events, such as coastal floods, hurricanes, and storm surges, can force coastal waters into inland areas, putting people who are exposed to these waters at increased risk for Vibrio wound infections [9].

V. vulnificus are concentrated by filter-feeding shellfish; oysters may have V. vulnificus counts up to two orders of magnitude greater than those in the surrounding water.

●United States – Approximately 150 to 200 V. vulnificus infections are reported to the United States Centers for Disease Control and Prevention (CDC) each year and approximately one in five people die, sometimes within one to two days of becoming ill.

In the United States, V. vulnificus infections have been reported most commonly by Gulf Coast states. However, V. vulnificus infections in the Eastern United States increased eightfold between 1988 and 2018, and the northern geographic range of this infection has increased by 48 km per year [10,11]. From July to August 2023, several East Coast states (including Connecticut, New York, and North Carolina) reported severe and fatal V. vulnificus infections, corresponding with increasing sea temperatures [12].

Transmission

●Consumption of raw or undercooked seafood – V. vulnificus may be transmitted via consumption of raw or undercooked seafood (primarily oysters, less commonly other shellfish or fish). More than 90 percent of patients with primary septicemia associated with V. vulnificus infection report consumption of raw oysters prior to onset of illness [13].

●Contact of an open wound with salt water, brackish water, or raw or undercooked seafood – V. vulnificus may be acquired via contamination of an open wound with salt water or brackish water containing the microorganism. Open wounds include those from recent surgery, skin piercing, tattoo, and other cuts or scrapes – including those acquired while handling seafood (such as opening oysters) or in association with recreational water activity (such as swimming or entering, exiting, or launching boats) [14,15].

Risk factors — Individuals with the following conditions are at increased risk for serious infection with V. vulnificus [2,14,16]:

●Alcoholic cirrhosis (present in 31 to 43 percent of patients with primary septicemia)

●Underlying liver disease including chronic hepatitis due to alcohol or other causes (24 to 31 percent of patients)

●Moderate to heavy alcohol use (in the absence of documented liver disease) (12 to 27 percent of patients)

●Hereditary hemochromatosis (12 percent of patients)

●Chronic diseases such as diabetes mellitus, thalassemia, chronic renal failure, rheumatoid arthritis, cancer, lymphoma, or other immunocompromising conditions (7 to 8 percent of patients)

Males (particularly males >40 years of age) appear to be at greater risk for serious infection than females; this may reflect a higher prevalence of liver disease in this group [17].

MICROBIOLOGY AND PATHOGENESIS

●Microbiology – V. vulnificus exists as a free-living gram-negative rod. Three biotypes of V. vulnificus have been recognized. Biotype 1 accounts for almost all human infections. Biotype 2 consists primarily of eel pathogens. Biotype 3 is an apparent hybrid of biotypes 1 and 2 that has been described in tilapia-associated wound infections associated with aquaculture in Israel [18-20].

These biotypes correlate (to a reasonable degree) with phylogenetic studies, which have identified five well-supported V. vulnificus phylogenetic lineages [21]. 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.

●Pathogenesis – The virulence of V. vulnificus has been associated with a variety of potential factors; these include production of an anti-phagocytic polysaccharide capsule [22], toxin production [23,24], and iron availability and iron acquisition systems [25-27].

•Capsule – V. vulnificus produces a capsular polysaccharide that provides protection against phagocytosis and opsonization [22]. Strains are able to shift between encapsulated forms (opaque colony morphology) and unencapsulated forms (translucent colony morphology). When these strains are taken up by oysters, there is a high rate of shift to the encapsulated phenotype, suggesting that oyster passage selects for the encapsulated, virulent form of the organism [28].

Anticapsular antibodies are protective, but appear to be type-specific [29]. This 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 [30].

V. vulnificus contains a lipopolysaccharide (LPS); however, 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 shock [31].

•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 [24,32].

•Iron – Growth of V. vulnificus is dependent in part upon the availability of iron [25-27]. When transferrin iron saturation exceeds 70 percent, growth of the organism is nearly exponential [25].

The relationship between iron and V. vulnificus virulence may account for enhanced susceptibility to serious V. vulnificus infections among patients with hemochromatosis [33,34]. However, most patients with serious V. vulnificus infection have normal iron and iron saturation levels. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'Susceptibility to infection'.)

•Differentiating strains – Certain strain subsets may be more likely to cause human disease; this is in keeping with phylogenetic studies, which demonstrate clustering of human isolates in lineage 1 [21]. However, it has not been possible to identify a single V. vulnificus virulence factor present in all clinical isolates [35].

CLINICAL MANIFESTATIONS — Clinical manifestations of V. vulnificus include primary septicemia (45 to 60 percent of cases), wound infection (30 to 45 percent of cases), and diarrhea (5 to 10 percent of cases) [3,36].

Primary septicemia — Primary septicemia due to V. vulnificus (ie, septicemia with no clear localizing source such as a wound) is associated with ingestion of raw or undercooked seafood; patients may or may not have antecedent gastrointestinal illness [36]. Patients with primary septicemia nearly always have an underlying comorbidity (often cirrhosis). (See 'Risk factors' above.)

Onset of hypotension is rapid; approximately one-third of patients with primary septicemia present with shock or become hypotensive within 12 hours of hospital admission [37]. (See "Evaluation and management of suspected sepsis and septic shock in adults".)

Acute skin findings usually appear within 24 hours of sepsis onset. These usually involve the lower extremities, are frequently bilateral, and manifest as severe cellulitis with fluid-filled bullae, which then may become hemorrhagic (picture 1 and picture 2). The lesions may progress rapidly to necrotic ulceration, gangrene, and necrotizing fasciitis with myonecrosis. (See "Necrotizing soft tissue infections", section on 'Clinical manifestations'.)

Thrombocytopenia is common, and often there is evidence of disseminated intravascular coagulation. Complications such as gastrointestinal bleeding can occur.

Persons who survive acute shock often require prolonged hospitalization. While there may be recovery from V. vulnificus infection, there may be ongoing morbidity due to associated multiorgan system failure.

Primary septicemia due to V. vulnificus is a serious illness with a high mortality rate. (See 'Outcomes' below.)

Wound infection — V. vulnificus may be transmitted via contact of an open wound with salt water or brackish water containing the microorganism. (See 'Transmission' above.)

Signs and symptoms of V. vulnificus wound infection range from mild cellulitis (skin redness, warmth, swelling, and pain) to severe infection resulting in muscle involvement and widespread tissue destruction. Manifestations may include swelling, ecchymosis, blister formation, ulceration, hemorrhagic bullae, and abscess. They may progress rapidly to necrotizing fasciitis and myonecrosis, especially among individuals with an underlying comorbidity. (See 'Risk factors' above and "Necrotizing soft tissue infections", section on 'Clinical manifestations'.)

These manifestations are localized, at least initially, to the area of the initial wound and therefore may be differentiated from the bilateral lower extremity pattern of skin findings in the presentation of primary sepsis (see 'Primary septicemia' above). Patients with primary wound infection are at high risk for development of bacteremia, sepsis, and limb loss.

Diarrhea — There are reports of isolation of V. vulnificus from patients with mild to moderate diarrhea, frequently in association with a history of seafood consumption. The relative importance of V. vulnificus as a cause of isolated diarrheal illness is uncertain, and cases, when identified, tend to be mild and self-limited [38].

EVALUATION

Clinical suspicion — V. vulnificus infection should be suspected in the following circumstances, particularly in the context of relevant risk factors (see 'Risk factors' above):

●Septic shock in the context of characteristic bullous skin lesions (picture 1 and picture 2) and a history of raw oyster consumption.

●Wound infection associated with contact with salt or brackish water during warm summer months, in an area where water temperatures exceed 20°C and V. vulnificus is present in the environment.

History and physical examination

●History – The history should include asking about relevant epidemiologic exposures, including (see 'Transmission' above):

•Contact of an open wound to salt or brackish water

•Consumption of raw or undercooked seafood (primarily oysters, less commonly shellfish or fish)

In addition, a detailed past medical history should be obtained, to assess for risk factors associated with severe infection. (See 'Risk factors' above.)

●Physical examination – Patients should be evaluated for clinical manifestations described above, including a careful skin and soft tissue examination. (See 'Clinical manifestations' above.)

Obtaining diagnostic specimens — The following specimens should be obtained:

●Blood cultures (for patients with signs of sepsis, hemorrhagic bullae, and/or clinical findings suggestive of an infected wound associated with seawater exposure)

●Culture of hemorrhagic bullae (if present)

●Wound culture (for patients with wound infection)

●Stool culture or culture-independent stool testing (for patients with diarrhea in addition to other manifestations suggestive of V. vulnificus infection)

DIAGNOSIS — The diagnosis of V. vulnificus infection is established by culture or molecular identification systems.

V. vulnificus grows readily 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.

Identification of V. vulnificus in stool is generally done via molecular identification systems; depending on the system used, it may or may not be possible to identify Vibrios to the species level. Microbiologic isolation from stool requires use of a specific selective culture media (thiosulfate citrate bile-salts sucrose [TCBS]) on which the organism produces characteristic blue-green colonies. For these reasons, the laboratory should be notified V. vulnificus infection is suspected.

If V. vulnificus is detected by an culture-independent tests (such as a stool multiplex panel) specimens should be set up for reflex culture to obtain antimicrobial susceptibility data.

DIFFERENTIAL DIAGNOSIS

●Sepsis – Sepsis may be caused by a broad array of pathogens. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis".)

●Soft tissue infection associated with water exposure – Soft tissue infection due to a broad array of organisms can occur in patients with traumatic injury associated with water exposure (table 1). (See "Soft tissue infections following water exposure".)

●Bullous lesions – Bullous lesions may be observed in other conditions including pemphigus, pemphigoid, Steven-Johnson syndrome, toxic epidermal necrosis, and drug reaction. (See "Approach to the patient with cutaneous blisters".)

●Necrotizing soft tissue infection – Necrotizing soft tissue infection may be caused by other microorganisms in addition to V. vulnificus; these include group A Streptococcus, Staphylococcus aureus, Aeromonas, Pseudomonas, and Clostridium perfringens (table 2). (See "Necrotizing soft tissue infections".)

●Diarrhea – A broad array of bacteria, viruses, and parasites may be implicated in acute diarrheal illness. (See "Approach to the adult with acute diarrhea in resource-abundant settings" and "Diagnostic approach to diarrhea in children in resource-abundant settings".)

TREATMENT

Severe infection

Clinical approach — The clinical approach should be guided by the clinical presentation:

●Patients with sepsis that is known or suspected to be due to V. vulnificus (see 'Clinical suspicion' above) require prompt initiation of antibiotic therapy with activity against V. vulnificus, in addition to supportive care in an intensive care unit.

●Patients with severe soft tissue infection that is known or suspected to be due to V. vulnificus require prompt initiation of antibiotic therapy with activity against V. vulnificus, in addition to evaluation for immediate surgical debridement.

In one case series including 62 patients with V. vulnificus infection (38 with primary septicemia and 17 with wound infection), mortality was lowest for patients who received antibiotics within the first 24 hours after illness onset compared with those treated 24 to 48 hours later or >72 hours later (33, 53, and 100 percent, respectively) [39].

Antibiotic therapy

Selection — For patients with primary septicemia or severe wound infection, we treat with combination antibiotic therapy as follows; dosing is summarized in the table (table 3):

●A third-generation cephalosporin (eg, ceftriaxone, cefotaxime, or ceftazidime). Cefepime may provide adequate coverage but clinical data for this newer agent are limited.

PLUS

●A tetracycline (doxycycline or minocycline). A fluoroquinolone (ciprofloxacin or levofloxacin) may be used as an alternative for patients who are not able to tolerate tetracyclines; we prefer ciprofloxacin given limited clinical data for other fluoroquinolones [40].

Antibiotic selection should be tailored to susceptibility data, when available. In particular, treatment may need to be adjusted for strains with decreased susceptibility to certain third generation cephalosporins.

Other antibiotic agents with activity against V. vulnificus include carbapenems, tigecycline, aminoglycosides, and trimethoprim-sulfamethoxazole. Vibrio spp tend to respond poorly to treatment with penicillins and first-generation cephalosporins, regardless of susceptibility test results.

Use of combination therapy is supported by retrospective trials, case reports, and animal data:

●In a retrospective study from Korea including 218 patients with primary septicemia due to V. vulnificus, 30-day survival rates following treatment with a third-generation cephalosporin plus ciprofloxacin or a third-generation cephalosporin plus doxycycline were comparable (54 versus 38 percent) [41].

●In a retrospective study from Taiwan including 89 patients with necrotizing fasciitis due to V. vulnificus who underwent prompt surgical debridement, the case fatality was lower among those treated with combination therapy (either a third-generation cephalosporin plus minocycline, or a fluoroquinolone [with or without minocycline]) compared with those who received monotherapy with a third generation cephalosporin (14, 14, and 61 percent, respectively) [42].

●In a case report of a child in Taiwan with necrotizing fasciitis due to V. vulnificus who was not responding clinically to ceftazidime and minocycline, combination treatment with tigecycline and cefpirome was efficacious as "salvage" therapy [43].

●In vitro and in vivo studies in mice have demonstrated an apparent synergism between cefotaxime and minocycline for treatment of serious V. vulnificus infection [44]. Mouse studies have also highlighted the efficacy of combination therapy with cefepime in combination with doxycycline or ciprofloxacin [45], cefotaxime plus ciprofloxacin [46], and tigecycline plus cefotaxime [47].

Duration — We treat for a duration of at least two weeks, given the potential seriousness of the infection and that most patients have underlying chronic conditions. Beyond that, treatment should be tailored to individual patient circumstances. For patients who are responding well clinically, completion of treatment with an oral tetracycline or fluroquinolone may be reasonable.

Surgical debridement — Patients with serious wound infection require prompt evaluation regarding need for surgical debridement. Skin abscesses should be drained. Severe cases might require aggressive debridement, fasciotomy, or amputation of the infected limb. (See "Surgical management of necrotizing soft tissue infections".)

In one series including 121 patients in Taiwan with necrotizing fasciitis due to V. vulnificus, the mean time between admission and surgery was shorter among survivors than nonsurvivors (14.1 versus 25.7 hours) [48]. In another study including 423 V. vulnificus wound infections, 10 percent of patients required amputation [14].

Mild infection

Wound infection — The approach to treatment of mild wound infection should be guided by whether risk factors for severe disease are present. (See 'Risk factors' above.)

●Presence of risk factors for severe disease – For patients with mild wound infection in the presence of risk factors for severe disease, treatment with combination antibiotic therapy including a third-generation cephalosporin plus a tetracycline (as for severe infection) is appropriate, at least until the infection appears to be resolving and there is minimal risk of associated bacteremia and sepsis. (See 'Severe infection' above.)

●Absence of risk factors for severe disease – For patients with mild wound infection in the absence of risk factors for severe disease, management consists of local wound care and oral antibiotic therapy with a tetracycline (doxycycline or tetracycline) (table 3). A fluoroquinolone may be used an alternative for patients who are not able to tolerate tetracyclines; we prefer ciprofloxacin given limited clinical data for other fluoroquinolones.

Antibiotic selection should be tailored to susceptibility data, when available.

The duration of antibiotic therapy should be guided by the clinical response to treatment; five to seven days is generally sufficient.

Diarrhea — For patients with isolated mild to moderate diarrhea, symptoms are generally self-limited. Treatment should focus on volume repletion in the absence of antibiotic therapy.

OUTCOMES — V. vulnificus infection is a serious illness with a high mortality rate. The case-fatality rate is 50 percent for primary septicemia and approximately 15 percent for wound infection [3]. Among patients who are hypotensive when they present for medical care, a case fatality rate >90 percent has been reported [2,14,16,49]. Advanced liver disease with model for end-stage liver disease (MELD) score >20 has also been associated with high mortality (64-fold increased odds of death) [50].

PREVENTION

●Regarding wounds and cuts:

•Individuals (particularly those with increased susceptibility to V. vulnificus infection) who have open wounds should avoid situations in which wound exposure to salt or brackish water during warm summer or fall months are likely to occur.

•For high-risk individuals with an open wound that could come in contact with salt or brackish water during warm summer or fall months, the wound should be covered completely with a waterproof bandage.

•Any open wounds or cuts that come into contact with salt or brackish water should be washed thoroughly with soap and clean, running water.

●Regarding seafood handling and consumption:

•Use gloves or wash hands after handling raw shellfish.

•Individuals (particularly those with increased susceptibility to V. vulnificus infection) should avoid eating raw or undercooked shellfish, particularly oysters, during warm summer or fall months.

•Post-harvest treatment of raw oysters (such as freezing or mild heat treatment) can reduce counts of V. vulnificus and other Vibrio species, potentially reducing disease risk [51].

SUMMARY AND RECOMMENDATIONS

●Introduction – Vibrio vulnificus is a gram-negative rod that can cause primary septicemia, wound infection, or diarrheal illness. Serious infection occurs most commonly among individuals with underlying comorbidities. (See 'Introduction' above.)

●Epidemiology

•Geography – Vibrio vulnificus can be relatively common in marine environments, including salt water and brackish water (a mix of salt water and fresh water). V. vulnificus bacteria thrive in warmer waters, and the geographic range is expanding with rising sea temperatures. The organisms are concentrated by filter-feeding shellfish (such as oysters). (See 'Geography' above.)

•Transmission – Transmission of V. vulnificus infection occurs via the following mechanisms (see 'Transmission' above):

-Consumption of raw or undercooked seafood (primarily oysters, less commonly shellfish or fish)

-Contact of an open wound with salt or brackish water

•Risk factors – Factors conferring increased risk for serious infection include (see 'Risk factors' above)

-Alcoholic cirrhosis

-Underlying liver disease including chronic hepatitis due to alcohol or other causes

-Moderate to heavy alcohol use (in the absence of documented liver disease)

-Hereditary hemochromatosis

-Chronic diseases such diabetes, thalassemia, renal failure, and immunocompromising conditions

●Clinical manifestations (See 'Clinical manifestations' above.)

•Primary septicemia – Primary septicemia due to V. vulnificus (ie, septicemia with no clear localizing source such as a wound) is associated with ingestion of raw or undercooked seafood; patients may or may not have antecedent gastrointestinal illness. Patients with primary septicemia nearly always have an underlying comorbidity (often cirrhosis).

Onset of hypotension is rapid. Acute skin findings usually appear within 24 hours of sepsis onset. These usually involve the lower extremities, are frequently bilateral, and manifest as severe cellulitis with fluid-filled bullae, which then may become hemorrhagic (picture 1 and picture 2). The lesions may progress rapidly to necrotic ulceration, gangrene, and necrotizing fasciitis with myonecrosis.

•Wound infection – Signs and symptoms of wound infection range from mild cellulitis (skin redness, warmth, swelling, and pain) to severe infection resulting in muscle involvement and widespread tissue destruction. Manifestations may include swelling, ecchymosis, blister formation, ulceration, hemorrhagic bullae, and abscess. These may progress rapidly to necrotizing fasciitis and myonecrosis, especially among individuals with an underlying comorbidity.

•Diarrhea – V. vulnificus has been associated with isolated cases of mild to moderate self-limited diarrhea.

●Evaluation

•Clinical suspicion – V. vulnificus infection should be suspected in the following circumstances, particularly in the context of relevant risk factors (See 'Clinical suspicion' above.):

-Septic shock in the context of characteristic bullous skin lesions and a history of raw oyster consumption.

-Wound infection associated with contact with salt or brackish water during warm summer months, in an area where water temperatures exceed 20°C and V. vulnificus is known to be present in the environment.

•Obtaining diagnostic specimens – The following specimens should be obtained (see 'Obtaining diagnostic specimens' above)

-Blood cultures (for patients with fever, hemorrhagic bullae, or signs of sepsis)

-Culture of hemorrhagic bullae (if present)

-Wound culture (for patients with wound infection)

-Stool samples for culture or analysis by culture-independent tests (for patients with diarrhea in addition to other manifestations suggestive of V. vulnificus infection)

●Treatment of severe infection

•Clinical approach (see 'Clinical approach' above):

-Patients with sepsis that is known or suspected to be due to V. vulnificus require prompt initiation of antibiotic therapy with activity against V. vulnificus, in addition to supportive care in an intensive care unit.

-Patients with severe soft tissue infection that is known or suspected to be due to V. vulnificus require prompt initiation of antibiotic therapy with activity against V. vulnificus, in addition to evaluation for immediate surgical debridement.

•Antibiotic therapy – For patients with primary septicemia or severe wound infection, we suggest treatment with combination antibiotic therapy including a third-generation cephalosporin plus a tetracycline (table 3) (Grade 2C). We treat for at least two weeks duration, tailored to individual patient circumstances. For patients who are responding well clinically, completion of treatment with an oral tetracycline or fluroquinolone may be reasonable. (See 'Antibiotic therapy' above.)

●Treatment of mild infection (See 'Mild infection' above.)

•Wound infection

-Presence of risk factors for severe disease – For patients with mild wound infection in the presence of risk factors for severe disease, we suggest initial treatment with combination antibiotic therapy including a third-generation cephalosporin plus a tetracycline (as for severe infection) (table 3) (Grade 2C), at least until the infection appears to be resolving and there is minimal risk of associated bacteremia and sepsis.

-Absence of risk factors for severe disease – For patients with mild wound infection in the absence of risk factors for severe disease, management consists of local wound care and oral antibiotic therapy; we suggest treatment with a tetracycline (table 3) (Grade 2C). A fluoroquinolone may be used as an alternative for patients who are not able to tolerate tetracyclines; we prefer ciprofloxacin given limited clinical data for other fluoroquinolones.

Antibiotic selection should be tailored to susceptibility data, when available. The duration of antibiotic therapy should be guided by the clinical response to treatment; five to seven days is generally sufficient.

•Diarrhea – For patients with isolated mild to moderate diarrhea, symptoms are generally self-limited. Treatment should focus on volume repletion in the absence of antibiotic therapy.