Vibrio Infections

Background

Vibrio infections are a significant public health concern, with Vibrio cholera and noncholera Vibrio species causing illnesses. The prevalence of noncholera Vibrio infections, categorized based on their halophilic or nonhalophilic nature, has risen in the United States.^[1]  Data from the CDC indicates that approximately 80,000 cases of Vibrio infections occur annually in the United States, with V parahaemolyticus being the primary causative agent in 40% of cases.^{[2, 3]} However, V vulnificus is responsible for a considerable proportion of noncholera Vibrio-related deaths, highlighting the severity of infections caused by this species.^{[4, 5]}

The incidence of Vibrio infections has shown a notable increase over the years, contrasting with the decreasing trends observed for other foodborne illnesses. FoodNet data from 2021 reported significant increases in Vibrio infections, along with other pathogens such as Cyclospora and Yersinia, underlining the need for continued vigilance and surveillance of these pathogens.^{[6, 7]} Challenges in identifying Vibrio gastroenteritis cases persist due to the limited use of specific culture mediums in clinical settings, which may lead to an underestimation of the true burden of these infections.

In addition to foodborne transmission, Vibrio infections can occur through exposure to contaminated water, particularly following natural disasters like hurricanes. The aftermath of Hurricane Ian in 2022 resulted in a considerable uptick in V vulnificus infections, emphasizing the importance of monitoring and managing such outbreaks in disaster-affected areas.^[8]

Overall, the evolving epidemiology of Vibrio infections underscores the need for enhanced surveillance, timely diagnosis, and targeted public health interventions to mitigate the impact of these potentially severe and life-threatening illnesses.^[6]

Etiology

Vibrio are gram-negative bacteria that inhabit warm, salty marine environments such as saltwater and brackish water. They can cause vibriosis, a potentially serious illness in humans. More than 20 species of Vibrio have been identified as pathogens, with V parahaemolyticus, V vulnificus, and V alginolyticus being the most prevalent in cases of vibriosis in the United States.^[9]

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Pathophysiology

The Vibrionaceae family includes the genera Vibrio, Plesiomonas, and Aeromonas. Members of the family Vibrionaceae are natural inhabitants of sea water but can also be found in fresh water. Vibrio species are oxidase-positive, gram-negative bacilli. With the exception of nonhalophilic Vibrio species, such as Vibrio cholerae and Vibrio mimicus, all Vibrio species require saline for growth.

Vibrio species can produce multiple extracellular cytotoxins and enzymes that are associated with extensive tissue damage and that may play a major role in the development of sepsis.

Table 1. Noncholera Vibrio Species and Associated Clinical Presentations

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V vulnificus lives in areas where the temperature exceeds 18°C. In the United States, it is found in the coastal waters of the Gulf of Mexico,^[10] New England, and the northern Pacific. Low-to-moderate salinity (15-25 parts per thousand) provides the most favorable growing condition for V vulnificus, and, conversely, high salinity (>25 parts per thousand) adversely affects its survival. Similar to the effect of high salinity, low seawater temperature (< 10°C) significantly inhibits the growth of V vulnificus. V vulnificus is ingested by filter-feeding mollusks such as oysters, mussels, clams, and scallops. During the warmer months, the concentration of bacteria can be as high as 1 X 10⁶ bacteria per gram of oyster.^[11]

It is hypothesized that high salinity supports the proliferation of Bacteriovorax, the predatory bacterium that may infect and kill Vibrio bacteria, particularly V parahaemolyticus and V vulnificus.^[12]

Several mechanisms contribute to the virulence of V vulnificus. Iron is an important growth factor. However, because free iron is virtually absent in humans, the organism produces siderophores that acquire iron from transferrin or lactoferrin and deliver it to the bacteria. Conversely, the inability to produce siderophores leads to reduction of virulence. Hepcidin, a natural cysteine-rich peptide, has recently been suggested to possess important antibacterial activity. It is possible that inadequate expression of hepcidin in patients with liver disease predisposes them to serious infections, including those caused by Vibrio species.^{[13, 14]}

Clinical conditions associated with increased free iron, such as hemochromatosis or hemolytic anemia, represent a major risk factor for disseminated Vibrio infections. In addition, V vulnificus produces several other virulence factors, including proteases, hemolysins, and cytolysins. One in particular, a thermolysin-like metalloprotease, activates the bradykinin pathway, causing an increase in vascular permeability. This metalloprotease is far more efficient at activating human enzymes than those of other Vibrio species, possibly explaining why V vulnificus causes severe skin damage and necrotizing fasciitis.^[15]

A study in mice, however, has shown that metalloprotease is not necessarily fundamental for the virulence of V vulnificus. The absence of protease activity resulted in increased cytolysin activity that may have contributed to the enhanced virulence.^[16] On animal models, a protease-deficient mutant of V vulnificus was as virulent as the wild-type strain.

The ability of V vulnificus to express a capsular polysaccharide on its cell surface also corresponds to an increased virulence. It allows the bacteria to circumvent the host’s immune system and to cause extensive tissue damage and septicemia. Besides environmental factors such as temperature and aeration, V vulnificus can alter the amount of capsular polysaccharide displayed on its surface.^[17]

The gene pyrH is essential for in vivo survival and growth of V vulnificus in infected mice and is likely associated with its virulence. Clinical isolates of V vulnificus, but not environmental isolates, caused extensive damage to macrophages in animal models, possibly explaining the lethal effects of this infection. PyrH plays a significant role in catalyzing the phosphorylation of UMP to UDP, which subsequently is used in the synthesis of pyrimidines. The numerous attempts to uncover the biochemical profile of pyrH may lead to a novel set of antimicrobial agents.^[18] In addition, photodynamic therapy (PDT) with toluidine blue in mice has been found to be curative in otherwise-fatal V vulnificus wound infections.^[19]

HlyU is a transcriptional regulator required for the activation of various virulence genes in Vibrio species. In V.vulnificus, HlyU regulates the expression of the major pore-forming toxins (PFT), induces the expression of vvhA, rtxA, and plpA encoding hemolysin, multifunctional-autoprocessing repeats-in-toxin (MARTX), and phospholipase A2 by directly binding to the promoter region. A non-toxic small molecule such as f ursultiamine hydrochloride (FTH) or CM14 inhibits HlyU-regulated toxin genes and enhances survival of mices infected with V vulnificus.^{[20, 21]}

Two major virulence factors in pathogenic V parahaemolyticus strains include a thermostable direct hemolysin (TDH) and a thermostable direct hemolysin-related hemolysin (TRH). TDH induces beta-hemolysis termed the Kanagawa phenomenon on a Wagatsuma blood agar and possesses both enterotoxic and cytotoxic effects, which gives rise to the watery diarrhea associated with V parahaemolyticus infection.^{[22, 23]}

For additional information on cutaneous V vulnificus infections, see the article Vibrio Vulnificus.

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Epidemiology

Frequency

United States

Between 1998 and 2010, the incidence of Vibrio infections increased by more than 115%. The CDC estimates that 80,000 Vibrio infections (100 V vulnificus, 45,000 V parahaemolyticus) and approximately 100 deaths related to Vibrio infections may occur annually in the United States.^[24]

Of the 1,252 vibriosis cases reported to CDC in 2014, 325 (26%) were reported from Gulf Coast states, 425 (34%) from Pacific Coast states, 325 (26%) from Atlantic Coast states, and 177 (14%) from non-coastal states. The Vibrio species reported most frequently from Gulf Coast states were V alginolyticus 91 (28%), V vulnificus 64 (21%), and V parahaemolyticus 62 (20%). The Vibrio species reported most frequently from non-Gulf Coast states were V parahaemolyticus 543 (59%), V alginolyticus 148 (16%), and V vulnificus 60 (7%).^[25]

Vibrio infections are acquired through consumption of contaminated raw or undercooked shellfish such as oysters, clams, mussels, or crabs. Exposure of wounds to contaminated seawater, injury caused by contaminated seashells, and shark and alligator bites are potential alternative sources of infection (see Table 2).

V parahaemolyticus is the leading cause of seafood-associated gastroenteritis in the United States.^[26] During a large outbreak of gastroenteritis in July 2004 in the Gulf of Alaska, V parahaemolyticus caused illness in almost one third of cruise ship passengers who consumed Vibrio-contaminated oysters. From May to July 2006, health departments of New York City, New York state, Oregon, and Washington state reported a total of 177 cases of V parahaemolyticus gastroenteritis. Of these reported cases, 113 (64%) involved residents of Washington state.^[27]

The Pacific Northwest (PNW) strain that caused illness in 104 persons from 13 states during May-September 2013 consisted of the V parahaemolyticus serotypes O4:K12 and O4:K(unknown). Illness was associated with consumption of raw shellfish and seafood from harvest areas in Connecticut, Massachusetts, New York, Virginia, Maine, and Washington.^[26] According to the CDC, the PNW strain is becoming endemic in an expanding area of the Atlantic Ocean, and clinicians, health departments, and fisheries departments should be prepared for this foodborne infection in spring 2014.^[28]

The CDC reported that as of September 18, 2018, 26 patients with illnesses due to V parahaemolyticus were reported from Colorado, Delaware, the District of Columbia, Louisiana, Maryland, New York City, Pennsylvania, and Virginia. Illnesses in this outbreak started from April 1 to July 19, 2018. Nine patients were hospitalized but no deaths were reported. FDA and regulatory officials in Maryland traced back the source of the crab meat from restaurants and grocery stores and identified potential multiple Venezuelan suppliers of crab meat linked to the outbreak.^[29]

During June–August 2023, widespread heat waves and above-average sea surface temperatures occurred in the United States. Eleven persons infected with V. vulnificus were reported to health officials in North Carolina (seven), Connecticut (two), and New York (two). Nine out of these cases had at least one underlying condition such as diabetes mellitus, cancer, or heart disease. Waterborne transmission of V. vulnificus resulting from wound exposure to marine or estuarine water along the US Atlantic coast was the route of infection in six cases, or from exposure to a cut on the hand while handling raw seafood in two cases. Four patients had septic shock; five patients died.^[30]

With around 40 cases reported to the CDC each year since 2000, non-O1 and non-O139 V cholerae are the third most commonly reported group of Vibrio infections. Non-O1 and non-O139 infections are seasonal, with a peak in the late summer and early fall. Diarrhea is the most common presentation. However, non-O1 V cholera has been reported with disseminated infections and high mortality rate due to necrotizing fasciitis and primary sepsis.^[31]

Based on probable incidence of Vibrio infections and the related costs, V vulnificus ($233 million) and V parahaemolyticus ($20 million) are the first and third most costly marine-borne pathogens.^[32]

Table 2. Clinical Presentation Rates of Pathogenic Vibrio Infections

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International

Noncholera Vibrio infections are commonly reported in areas such as Japan, Taiwan, China, Hong Kong, Korea, Italy, and Israel. The high prevalence of hepatitis B infections in areas such as China and Taiwan may also contribute to the high incidence of severe noncholera Vibrio infections.

Contrary to epidemiologic patterns of Vibrio infections, only sporadic cases were reported among survivors and injured individuals following the tsunami that devastated Thailand, Indonesia, and India in December 2004.

A 2013 study conducted across 4 Southeast Asian countries (Thailand, Vietnam, Malaysia, Indonesia) found that about half of marketed seafood was contaminated with V parahaemolyticus. The prevalences were 49% in Thailand and Indonesia, 50% in Malaysia, and 70% in Vietnam. V parahaemolyticus markers were found in all types of examined seafood, including fish, shrimp, squid, crab, and molluscan shellfish. Of such, the molluscan shellfish had the highest prevalence of contamination, ranging from 63% (Thailand) to 89% (Vietnam).^[33]

Asian countries consume seafood at a higher rate than the global average because of their coastal locations and abundant seafood supply, making them more susceptible to V vulnificus infections.^{[10, 26]} The highest prevalence was reported in Japan, where 47.6% of the seafood samples tested positive for V vulnificus. A meta-analysis of the eligible studies estimated the overall prevalence of seafood-borne V vulnificus in Asia to be 10.47%, with bivalve shellfish, such as oysters, mussels, clams, and cockles being the most contaminated seafood.{ref 68}

Despite a high annual estimated incidence of V vulnificus septicemia in Japan (425 cases), a survey of registered emergency physicians in Japan surprisingly revealed that only 15.7% of responding physicians had a basic knowledge of this frequently fatal infection.^[34]

In contrast to Asian countries and the USA, non-cholera Vibrio infections are less often reported in Europe. In the UK, only 57cases of V. parahaemolyticus infection were reported between 2004 and 2005, and mostly involved infections obtained via foreign travel to endemic regions. Despite sporadic infections and large outbreaks associated with V parahaemolyticus and V vulnificus have been reported in many European countries in the last several years, both of these pathogens are poorly understood in Europe because of the lack of a systematic surveillance program for non-cholera Vibrio infections together with a lack of standardized, validated methodologies and limited environmental data on the prevalence, distribution, and virulence characteristics.^[35]  

A multicenter case-series study reported Vibrio infections in 67 patients from 8 hospitals in the Bay of Biscay, France, over a 19-year period (2001-2019). Infections mainly were caused by V alginolyticus (34%), V parahaemolyticus (30%), non-O1/O139 V cholerae (15%), and V vulnificus (10%). Infections were contracted at the beach in 55.3%, 39.5% by handling or eating seafood, and 5.3% while abroad. Most infections (82%) occurred during June–September.^[36]

According to the European Environment Agency the rise of global sea surface temperature (SST) is one of the major physical impacts of climate change.^[10] However, SST in coastal European seas has increased 4–7 times faster over the past few decades than in the global oceans. This local increase in SST has been linked to outbreaks of Vibrio-associated human illness caused by Vibrio cholerae non O1-non-O139, V parahaemolyticus, and V. vulnificus in several European countries.^[35]

Mortality/Morbidity

According to CDC estimates, foodborne diseases cause approximately 48 million illnesses, 128,000 hospitalizations,^[24]  and 3000 deaths annually in the United States.^[1]

Foodborne noncholera Vibrio infections may occur at rate of 0.2-0.3 case per 100,000 population. In 2011, CDC estimates 4,500 cases of V parahaemolyticus infection annually, resulting in 129 hospitalizations and 5 deaths. Two hundred and seven cases of V vulnificus infection are estimated to occur annually, resulting in 200 hospitalizations and 77 deaths.^[24]

Although Vibrio infections are not as common as Campylobacter, Salmonella, or Listeria infections, more patients with Vibrio infections die because of the high mortality rate (35-50%) associated with V vulnificus septicemia.

Among all foodborne diseases, V vulnificus infection is associated with the highest case fatality rate (39%).

Patients with cirrhosis who consumed raw oysters were 80 times more likely to develop V vulnificus infection and 200 times more likely to die of the infection than those without liver disease who consumed raw oysters.^[37]  A 2017 case study reported V vulnificus cellulitis in a patient with a recent leg tattoo who was infected while swimming in the Gulf of Mexico. The patient had underlying chronic liver disease and died of Vibrio septic shock despite early identification of the infection and aggressive initial empiric treatment with doxycycline and ceftriaxone.^[38]

A meta-analysis of 12 studies with 1157 patients wih V vulnificus necrotizing skin and soft tissue infections (VNSSTI) revealed a mortality rate of 53.9% in patients with hepatic disease (HD), and 16.1% in non-HD patients. Patients with HD contracted VNSSTIs were more than twice as likely as non-HD patients to die (risk ratio, 2.61).^[39]

Of the 75 cases of V vulnificus infection reported by the FDA between 2002 and 2007, it appears that the number of oysters consumed (one oyster vs more than 24 oysters) does not relate to the interval before symptom development (0-7 days) or patient outcomes (mortality, 33% vs 25%).^[40]

A 10-year retrospective study reported that an APACHE II score of 20 or more on the first day of admission is an accurate and reliable predictor of ICU mortality among patients with V vulnificus necrotizing fasciitis (sensitivity, 97%; specificity, 86%; NPV, 98%.^[41]

In a retrospective study of 34 patients with V vulnificus infection, the initial arterial pH levels obtained upon hospital admission were found to be an important and more accurate prognostic indicator than the APACHE II score. Regardless of whether emergency surgery was performed and appropriate antimicrobial drug therapy administered, all 9 patients with an admission arterial pH < 7.2 died, whereas all 18 patients who had an initial arterial pH ≥7.35 survived. A pH level < 7.35 was an accurate predictor of death (sensitivity, 100%; specificity, 83%; PPV, 84%; NPV, 100%).^[42]

Regardless of pre-existing conditions, the mortality risk increases in patients with V vulnificus infection who are hospitalized more than 2 days after symptoms develop (odds ratio, 2.9).^[43]

A delay in performing the first fasciotomy (>24 h) after development of clinical symptoms in patients with V vulnificus necrotizing fasciitis was associated with 5-fold increase in the mortality risk.

Race

Vibrio infections have no racial predilection. Because Vibrio species are natural inhabitants of sea water, Vibrio infections are more commonly reported in states or countries bordered by large bodies of sea water. Persons with underlying medical conditions, such as alcoholism, cirrhosis, or malignancy, and recipients of organ transplants are at increased risk of Vibrio infections and serious complications. Patients with end-stage renal failure who are on continuous ambulatory peritoneal dialysis (CAPD) may develop peritonitis after eating or handling raw sea fish.

Sex

Vibrio infections can occur in all persons, regardless of sex. V vulnificus infections were reported in women who engaged in sexual intercourse in brackish water of the Gulf of Mexico. In general, V vulnificus infections are more common in males (82%), according to most reports.

Age

Persons of any age who consume or are exposed to Vibrio- contaminated food or water are at risk of developing Vibrio infection, especially if they have underlying medical conditions such as advanced liver disease.

Most patients with Vibrio wound infections and septicemia are aged 50-60 years.

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Prognosis

The prognosis is excellent in immunocompetent patients who have acute Vibrio gastroenteritis.

In patients with Vibrio wound infection or septicemia, the prognosis is very grave and depends on the following:

• Underlying medical conditions such as cirrhosis or leukemia
• Pathogen (V vulnificus infection is associated with a 50% mortality rate.)
• Prompt initiation of effective antibiotic therapy
• Early fasciotomy and debridement
• Availability of intensive monitoring and medical care for serious complications
• Availability of reconstructive surgery and physical rehabilitation
• Vibrio vulnificus DNA load. Upon admission, patients who later died from V vulnificus sepsis had a significantly higher median DNA copy count of 2,300 copies/mL of blood compared with 316.5 copies/mL of blood in those who survived, as measured by real-time PCR.^[44]
• Level of the serum tumor necrosis factor-α (TNF-α) measured on admission. The median level of the serum TNF-α in the non-survivor group of patients infected with V vulnificus was 261.0 pg/mL, compared with 69.5 pg/mL in the survivor group.^[45]

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Patient Education

Educate patients with appropriate underlying medical conditions about the serious medical illness that may be associated with the consumption of raw or undercooked seafood.

Educate patients to seek medical attention promptly if fever, nausea, abdominal cramps, diarrhea, myalgia, or severe pain develops in the lower extremities.

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History

V parahaemolyticus is the leading cause of seafood-associated gastroenteritis in the United States.^[26] Most individuals with noncholera Vibrio infections report recent consumption or handling of contaminated seafood such as oysters, clams, crabs, or other shellfish.^[26] Others have a history of contact with brackish or salty waters. Persons with immunodeficiency disorders, chronic liver disease, and iron storage disorders may be particularly susceptible to severe infections and have rapid clinical deterioration. With the exception of dramatic clinical progression in wound infection and septicemia, no characteristic signs and symptoms of early-stage noncholera Vibrio infections exist.^{[9, 46]}

Table 3. Clinical Signs and Symptoms of Vibrio Infections^{[46, 9]}

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Although atypical infections with Vibrio species involving peritonitis, pneumonia, endometritis, meningitis, septic arthritis, osteomyelitis, and keratitis have been reported, in general, Vibrio causes 3 clinical symptoms: gastroenteritis, skin and soft tissue infections, and septicemia.^{[9, 46]}

Gastroenteritis

After an average incubation period of 19 hours (range, 12-52 h), patients with Vibrio gastroenteritis report abdominal pain or cramps, nausea, vomiting diarrhea, fevers and chills.^[47] Patients frequently pass several watery stools (10-15/d). The occurrence of bloody diarrhea varies. It is reported in 25% of patients with V parahaemolyticus infection but may develop in up to 75% of patients with V fluvialis infection.

Low-grade fever may be observed in patients with Vibrio gastroenteritis.

Most patients remain alert upon admission. However, elderly patients may have decreased mental status due to dehydration or sepsis. Death is rare, but would most likely be caused by concomitant Vibrio septicemia.

Skin and soft tissue infections

Patients frequently report injury associated with handling contaminated shellfish (preparation of St Peter's fish (Tilapia zillii) and preparation of crabs, lobsters, or mussels), particularly fishhooks within the fish. Injuries can also be sustained when stepping on seashells, crustaceans, or stingrays.^[48]

Initially, patients with such infections almost always report severe pain of the involved limb or body part. Numbness of the wound and the surrounding area may predominate if the patient has delayed seeking medical attention.

Septicemia

Symptoms usually occur within 7-14 days of contact. Patients frequently exhibit a dramatic clinical presentation of bacteremia, minus a clear focus. This may be characterized by the abrupt onset of the following:

• High fever
• Shaking chills
• Generalized myalgia
• Exquisite pain in the lower extremities (most characteristic) or, rarely, pain in the lower trunk^[49]

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Physical

The physical findings of Vibrio infections vary according to clinical presentations.

Acute gastroenteritis

Patients with acute Vibrio gastroenteritis are typically acutely ill with diarrhea, nausea, vomiting, abdominal pain, and fever (50%).

The vital signs, such as blood pressure and heart rate, vary depending on the level of dehydration.

Unless the patient has underlying disease, no physical findings are specific for acute Vibrio gastroenteritis.^[47]

Skin and soft tissue infection

After a short incubation period (3-24 h), patients with Vibrio wound infections frequently present with rapidly progressing wound swelling and severe pain.^[9]

The majority of such wounds involve the fingers, palms, or soles of the feet.

In milder cases, erythema, edema, and pain are localized to the initial wound, without signs of compartment syndrome, necrosis, gangrene, or necrotizing fasciitis.

In patients with medical conditions such as cirrhosis or malignancies, the wound infection may progress very rapidly, with formation of hemorrhagic bullae and extensive soft-tissue necrosis.

Septicemia

After a short incubation period (12-48 h) following the consumption of raw seafood or exposure of broken skin to warm seawater, patients with Vibrio septicemia frequently develop fever, shaking chills, generalized myalgia, edema, and severe pain in the lower extremities.^{[26, 49]}

Within 3-24 hours, edema of the lower extremities worsens.

Multiple hemorrhagic bullae and extensive ecchymosis distributed predominantly over the lower extremities form rapidly.

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Vibrio infections. Early bullous lesions appear over the dorsum of the foot of a patient with cirrhosis.

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Vibrio infections. In a patient with cirrhosis, skin lesion rapidly becomes necrotic.

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Vibrio infections. Bullous lesions in a patient with cirrhosis continue to progress, and the patient rapidly develops hypotension and shock despite a....

Patients frequently become hypotensive despite aggressive intravenous fluid therapy.

Patients become lethargic, obtunded, and, finally, unconscious as the disease progresses.

Oliguria may develop.

Noncardiogenic pulmonary edema may develop.

Ocular infection

This may manifest as conjunctivitis, keratitis, or endophthalmitis.

Peritonitis

This may manifest as abdominal pain and cloudy peritoneal fluid in patients receiving CAPD.

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Causes

Noncholera Vibrio infections are foodborne diseases that are largely associated with the following^{[9, 46]} :

• Consumption of raw or undercooked seafood such as oysters, clams, crabs, or mussels^[26]
• Exposure of wound to contaminated water

Acute gastroenteritis associated with noncholera Vibrio infection is frequently self-limited, although persons with certain underlying medical conditions may develop fulminant infections. These underlying medical conditions include the following^{[9, 46]} :

• Advanced liver diseases, such as cirrhosis, hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, alcoholism, hemochromatosis, and liver transplantation
• Hematologic diseases, such as acute leukemia, aplastic anemia, hemolytic anemia, and thalassemia
• Immunosuppressive therapy, including cytotoxic chemotherapy, corticosteroids, and tacrolimus
• Kidney disease involving kidney transplantation or hemodialysis
• Miscellaneous procedures and conditions, including splenectomy and diabetes mellitus

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Complications

Although reactive arthritis may occur, other complications are rare in immunocompetent patients who have noncholera Vibrio gastroenteritis.

Patients with advanced liver disease or other underlying medical conditions are prone to developing serious complications of Vibrio infections, including the following^[9] :

• Hypotension, shock
• Compartment syndrome
• Multiple organ dysfunction
• DIC
• ARDS
• Hemolysis

A delay in performing fasciotomy or debridement in a patient with a Vibrio wound infection may result in death or rapid disease progression, which may lead to amputation.^{[9, 46]}

Avoid admitting patients with noncholera Vibrio wound infection or septicemia to the regular ward. Hypotension or shock can develop very quickly.^{[9, 46]}

Frequent surgical evaluation is necessary to detect the rapid development of compartment syndrome.^{[9, 46]}

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Approach Considerations

Patients at risk for vibriosis should be considered for Vibrio infection if presenting with watery diarrhea after eating raw seafood, particularly oysters, or if they have wounds exposed to coastal waters, especially those with heightened susceptibility to Vibrio.^{[10, 26]}  Noncholera vibrios occasionally are referred to as nonagglutinable Vibrios, because they do not agglutinate when exposed to serum from cholera patients.^[46]

Treat suspected Vibrio wound infections Immediately without waiting for confirmatory tests. Diagnosis involves identifying Vibrio in stool, wound, or blood samples, via culture-independent testing or bacterial isolation through culture. For Vibrio wound infections, obtaining cultures from the affected area is crucial, with V vulnificus isolates requiring referral to a public health laboratory. Blood cultures are advised if the patient demonstrates febrile episodes, hemorrhagic bullae, or signs of sepsis. The patient's history of exposure to raw seafood or coastal waters should be elicited to inform treatment decisions.^{[9, 10, 26]}

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Laboratory Studies

It is important to remember that initial laboratory findings may be unremarkable, but they may yield clues to underlying medical conditions such as chronic liver disease, chronic hemolytic anemia, hemochromatosis, diabetes, renal insufficiency, or adrenal insufficiency.

CBC count with differential and platelet count

Findings on blood count are initially nondiagnostic in patients with Vibrio infection.

In patients with underlying medical conditions, such as cirrhosis, the presence of thrombocytopenia and/or schistocytes is an early indicator of disseminated intravascular coagulation (DIC).

Serum chemistries (comprehensive metabolic panel)

Serum electrolytes, BUN, and creatinine levels may become abnormal in patients with dehydration, hypotension, and severe sepsis.

Monitoring serum electrolytes is essential in the treatment of severe gastroenteritis.

Stool examination for occult blood and fecal leukocytes

The presence of either fecal occult blood or fecal leukocytes is a reliable marker for invasive infectious diarrhea.

Stool examination for ova and parasites and stool cultures for Salmonella, Shigella, Campylobacter, Yersinia, and Vibrio species

Stool examination for parasites and stool culture are indicated in patients who present with diarrhea and who have a history of recent travel and/or consumption of contaminated food or water.

Perform these tests in patients with gastroenteritis, especially upon suspicion of foodborne illness.

The physician may alert the public health department if a specific pathogen is identified in a group of people.

Prothrombin time and activated partial thromboplastin time

Prothrombin time (PT) and activated partial thromboplastin time (aPTT) may be prolonged in patients with DIC.

Coagulation tests are indicated in patients who require extensive surgical debridement.

Gram stain and culture

Organisms may be recovered from blood (patients with sepsis), bullae or wounds (skins and soft tissue infections), and stool (gastroenteritis).

Gram stain may reveal gram-negative rods, or studies may be used to isolate a specific pathogen for antibiotic sensitivity testing.

Organisms may be recovered or demonstrated in other body fluids and/or exudates such as peritoneal fluid or ocular exudates.

Blood cultures

Blood cultures are indicated in patients with sepsis, severe skin and soft tissue infections, or unstable vital signs (eg, hypotension, multiple organ dysfunction).

Patients with advanced liver disease, malignancies, or hemochromatosis may develop bacteremia and serious complications more often than those without these medical conditions.

Blood cultures are frequently positive in patients with V vulnificus infections.

Arterial blood gas

Arterial blood gas (ABG) is indicated in patients with severe sepsis, septic shock, multiple organ dysfunction, DIC, or acute respiratory distress syndrome (ARDS).

ABG may show severe metabolic acidosis due to tissue hypoperfusion and/or hypoxia.

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Imaging Studies

Chest radiography in patients with Vibrio infections may show fluffy bilateral pulmonary infiltrates compatible with ARDS. Radiographic examination of the injured anatomic parts, such as fingers, hand, foot, or trunk may reveal foreign objects, such as fragments of fishhooks or seashells. The presence of gas feathering in the soft tissue may help to identify other potential diagnoses, such as gas gangrene.

CT scanning of the injured body parts may be indicated if the patient develops signs and symptoms of compartment syndrome or necrotizing fasciitis.

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Other Tests

Other tests may be unnecessary upon admission but may help identify the underlying medical conditions that predispose the patient to serious Vibrio infection and/or complications.

Serology for HBV and HCV and serum iron studies are used to identify the etiology of advanced liver disease.

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Procedures

Aspiration of skin bullae or a wound can be performed for Gram stain and culture in patients with skin and soft tissue infections.

Placement of central venous catheter for intravenous rehydration may be indicated in patients with profound hypovolemia or shock.

Early wound debridement is indicated in patients with Vibrio wound infection or septicemia. A delay of wound debridement may lead to amputation. Debridement must be performed urgently if the patient develops compartment syndrome.

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Histologic Findings

Findings on histologic examination of the skin and/or soft tissue in patients with noncholera Vibrio wound infection frequently demonstrate gram-negative bacilli, acute inflammatory reaction with extensive tissue necrosis, and fat infarction. In patients with rapidly progressing illness, examination of biopsy specimens of the skin may demonstrate an absence of cellular response.

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Medical Care

Medical care depends on the clinical presentation and the presence of underlying medical conditions.

Because Vibrio gastroenteritis is self-limited in most patients, no specific medical therapy is required. Patients who cannot tolerate oral fluid replacement may require intravenous fluid therapy. Although most Vibrio species are sensitive to antibiotics such as doxycycline or quinolones, antibiotic therapy does not shorten the course of the illness or the duration of pathogen excretion. However, if the patient is ill and has a high fever or an underlying medical condition, oral antibiotic therapy with doxycycline or quinolone can be initiated.

Patients with noncholera Vibrio wound infection or septicemia are much more ill and frequently have other medical conditions. Medical therapy consists of the following:

• Prompt initiation of effective antibiotic therapy
• Intensive medical therapy with aggressive fluid replacement and vasopressors for hypotension and septic shock to correct acid-base and electrolytes abnormalities that may be associated with severe sepsis

Antimicrobial resistance

Up to 90% of seafood consumed in the United States is imported, of which 50% is wild-caught. The United States imports seafood mainly from China, Thailand, Canada, Indonesia, Vietnam, and Ecuador. The top imports include shrimp, freshwater fish, tuna, salmon, groundfish, crab, and squid.^[50]

V vulnificus and V parahaemolyticus have shown resistance to multiple antibiotics owing to overuse and misuse of prophylactic antibiotics in aquaculture. In contrast with the extensive investigation of antibiotic resistance in Vibrio cholera and Salmonella species, few studies of this type in noncholera Vibrio species have been conducted in the United States.^{[51, 52]} A study on antimicrobial susceptibilities of 168 V parahaemolyticus isolates and 151 V vulnificus isolates from Louisiana Gulf and retail raw oysters was conducted in 2005 and revealed ampicillin resistance in 57% of V parahaemolyticus strains and intermediate ampicillin resistance in 24% of V parahaemolyticus strains.^[53]

Another study on 296 V parahaemolyticus isolates and 94 V vulnificus isolates from oysters (during an oyster relay study), published in 2018 and identified more than three quarters of the V vulnificus and about a third of the V parahaemolyticus isolates resistant to at least one antimicrobial. Furthermore, 48% of V vulnificus and 8% of V parahaemolyticus isolates showed resistance to more than one antimicrobial. For V. vulnificus isolates, resistances to cephalothin were 67%, tetracycline 29%, amoxicillin-clavulanic acid and ampicillin 26%, doxycycline 21%, ceftriaxone and ceftazidime 12%, and cefotaxime 7%.^[54]

The antimicrobial resistance pattern of V parahaemolyticus is an important factor to consider for successful treatment. However, such data in Vietnam are limited. A study was conducted in 2010 to investigate the antimicrobial susceptibilities of 130 isolated samples of V parahaemolyticus from various sources (acute diarrheal patients, food, environment). Overall, most strains were susceptible to the majority of antimicrobials tested, including tetracycline (90%), chloramphenicol (97%), ciprofloxacin (100%), sulfamethoxazole/trimethoprim (Bactrim), and doxycycline (93%). About a third (34%) of tested strains were resistant to ampicillin.^[55]

A recent study has found Extended Spectrum Beta-Lactamase (ESBL) activity in more than a quarter of V. parahaemolyticus isolated from shrimps purchased from 40 different markets in Ho Chi Minh City, Vietnam.^[56]

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Surgical Care

Early fasciotomy within 24 hours after development of clinical symptoms can be life saving in patients with necrotizing fasciitis.

Early debridement of the infected wound has an important role in successful therapy and is especially indicated to avoid amputation of fingers, toes, or limbs.

Expeditious and serial surgical evaluation and intervention are required because patients may deteriorate rapidly, especially those with necrotizing fasciitis or compartment syndrome.

Reconstructive surgery, such as skin graft, is indicated in the recovery phase.

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Consultations

A team effort is required to ensure successful therapy in patients with noncholera Vibrio wound infection or septicemia.

Do not wait for consultation with an infectious disease specialist or laboratory confirmation of V. vulnificus infection to initiate treatment.{73}

Urgent consultation with an infectious diseases specialist for diagnosis and possible investigation of foodborne illness

Urgent consultation with a general surgeon or orthopedist for debridement

Consultation with a critical care specialist to manage possible developments such as severe sepsis, septic shock, and multiple organ dysfunction (eg, ARDS, renal failure)

Consultation with a gastroenterologist since many patients with Vibrio infections have advanced liver disease and may develop serious complications such as gastrointestinal bleeding

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Diet

Patients with Vibrio gastroenteritis are permitted oral intake as tolerated.

Patients with Vibrio wound infection and septicemia are frequently too ill to tolerate oral intake during the acute phase.

Some patients with advanced liver disease develop hepatic encephalopathy and may require oral or parenteral hepatic nutrition.

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Prevention

Avoid eating raw or undercooked seafood. Contaminated seafood cannot be distinguished by smell or taste. This is especially important for individuals with conditions that predispose to invasive Vibrio infections.^{[26, 57]}

• Fry, bake, steam, or boil oysters, clams, and mussels 4-9 minutes or until plump.
• Boil shrimp or crab until shells turn pink and the meat is cooked in the middle.
• Fish is cooked until the thickest part is opaque.

Avoid exposure to seawater in summer months or along the coastal regions in the southeastern United States.

Promptly seek medical attention if fever, nausea, abdominal cramps, diarrhea, myalgia, or severe pain in the lower extremities develops.

Studies of V vulnificus bacteriophage SSP002 have demonstrated its protective efficacy in infected mouse models and its potential use as a biocontrol agent against V vulnificus in the food industry.^[58]

High hydrostatic pressure (HPP), a nonthermal process, has been shown to be effective in inactivating V vulnificus and V parahaemolyticus in oysters without changes in original nutrient, flavor, or appearance. However, because of the high cost of HPP, this process may not be affordable by most oyster producers.^[59]

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Long-Term Monitoring

Noncholera Vibrio gastroenteritis is self-limited and does not require further outpatient care.

Patients who survive devastating halophilic Vibrio infections may sustain finger, toe, or limb amputation and massive destruction of skin and soft tissue. These patients require extensive reconstructive surgery and physical rehabilitation.

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Further Inpatient Care

Daily or repeated surgical debridement may be necessary.

Continue intensive medical care for fluid, electrolytes, and acid-base abnormalities.

Blood transfusion or infusion of platelet or clotting factors is necessary for the treatment of DIC.

Perform hemodialysis for renal failure, if indicated.

Medically monitor and treat other underlying medical conditions such as advanced liver disease, diabetes mellitus, or leukemia.

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Transfer

Patients with serious noncholera Vibrio infections may require transfer to a facility where intensive monitoring and surgical expertise is available.

In contrast to the treatment of gas gangrene, hyperbaric oxygen therapy (HBO) has not been studied or proven effective in the treatment of serious halophilic Vibrio infections. Therefore, transfer to an HBO facility is not recommended.

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Medication Summary

In adults with noncholera Vibrio infections other than gastroenteritis, the combination of a third-generation cephalosporin (eg, ceftazidime, cefotaxime, ceftriaxone) and tetracycline or one of its analogues (eg, doxycycline) or a single-agent regimen with a fluoroquinolone (eg, levofloxacin, ciprofloxacin) is the therapy of choice.^{[60, 61]}

Among children with serious noncholera Vibrio infections in whom tetracycline and fluoroquinolone are contraindicated, trimethoprim-sulfamethoxazole plus an aminoglycoside (eg, gentamicin) is recommended.^[60]

Analyzing the efficacy of 3 antibiotic regimens (group 1, a third-generation cephalosporin; group 2, a third-generation cephalosporin plus minocycline; group 3, a fluoroquinolone with or without minocycline) in terms of patient outcomes in the treatment of 89 cases of V vulnificus necrotizing fasciitis, authors reported that a fluoroquinolone or the combination of a third-generation cephalosporin plus minocycline are antibiotics of choice in lowering mortality rates (61% in group 1 vs 14% in group 2; 61% in group 1 vs 14% in group 3).^[6]

Another alternative regimen with documented synergism in an in vivo study on mice is cefotaxime and minocycline.^[62]

In a retrospective chart review of 93 patients hospitalized with serious Vibrio infections, the combination of a third-generation cephalosporin and tetracycline or its analogue was an independent factor for lower mortality (odds ratio, 0.037).^[43]

A recent study done in Republic of Korea on 218 subjects with V. vulnificus septicemia showed the 30-day survival rate of the third-generation cephalosporin (TGC) plus doxycycline group was not statistically different from that of the TGC plus ciprofloxacin group (38% vs.54%). There was no significant difference in survival rate between the TGC monotherapy and TGC plus doxycycline groups.^[63]

Tigecycline, a novel glycylcycline, has a potent in vitro antimicrobial effect against Vibrio species. The efficacy of tigecycline in combination with cefpirome has been highlighted as "salvage" therapy in a child with V. vulnificus necrotizing fasciitis who was not clinically responding to ceftazidime and minocycline.^[64] The survival rate in mice treated with the combination of tigecycline and ciprofloxacin was significantly higher than those treated with the combination of cefotaxime and minocycline (71% vs 42%).^[65]

Other newer antibiotics such as daptomycin and linezolid that were approved for the treatment of serious skin and soft-tissue infections have not been studied in serious Vibrio infections. Therefore, the authors do not recommend the use of these antibiotics in the treatment of serious Vibrio infections.

Adjuvant therapy: Recombinant human activated protein C (drotrecogin alfa activated) has been used as an adjuvant therapy in patients with severe sepsis who scored 25 or more on the Acute Physiology and Chronic Health Evaluation (APACHE II). A few patients with V vulnificus sepsis who were successfully treated with antibiotics, surgical debridement, and recombinant human activated protein C were reported. In view of serious bleeding associated with the continuous infusion of recombinant human activated protein C and the potential requirement for repeated surgical debridement in patients with V vulnificus sepsis, routine use of this adjuvant therapy is not recommended.^[66]

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Doxycycline (Bio-Tab, Doryx, Vibramycin, Doxy)

• Dosing, Interactions, etc.

Clinical Context:  Inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.

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Piperacillin and tazobactam (Zosyn)

• Dosing, Interactions, etc.

Clinical Context:  Antipseudomonal penicillin plus beta-lactamase inhibitor. Inhibits biosynthesis of cell wall mucopeptide and is effective during stage of active multiplication.

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Ticarcillin and clavulanate (Timentin)

• Dosing, Interactions, etc.

Clinical Context:  Inhibits biosynthesis of cell wall mucopeptide and is effective during stage of active growth. Antipseudomonal penicillin plus beta-lactamase inhibitor provides coverage against most gram-positive, gram-negative, and anaerobic bacteria.

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Ciprofloxacin (Cipro, Ciloxan)

• Dosing, Interactions, etc.

Clinical Context:  Fluoroquinolone with activity against pseudomonads, streptococci, MRSA, Staphylococcus epidermidis, and most gram-negative organisms but no activity against anaerobes. Inhibits bacterial DNA synthesis and, consequently, growth.

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Cefotaxime (Claforan)

Clinical Context:  For septicemia and treatment of gynecologic infections caused by susceptible organisms. Arrests bacterial cell wall synthesis, which in turn inhibits bacterial growth. Third-generation cephalosporin with gram-negative spectrum. Lower efficacy against gram-positive organisms.

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Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. Antibiotic combinations are usually recommended for serious gram-negative bacillary infections. This approach ensures coverage for a broad range of organisms and polymicrobial infections. In addition, resistance from bacterial subpopulations is prevented, and additive or synergistic effects are provided. Once organisms and sensitivities are known, the use of antibiotic monotherapy is recommended.

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