Infections due to non-O1/O139 Vibrio cholerae

INTRODUCTION — Vibrio cholerae is a highly diverse species, with a worldwide distribution in estuarine environments. Only a small subset of V. cholerae strains carry the requisite genes to cause the disease cholera. In an effort to identify cholera-causing strains, investigators studying the "cholera bacillus" (V. cholerae) in the early 1900s divided strains into two groups: those that agglutinated with serum from cholera patients (designated as being in O group 1, or V. cholerae O1), and those that did not [1]. This latter strain group (most of which consisted of environmental isolates) has been designated, variously, as "non-cholera Vibrios", "non-agglutinating V. cholerae" (also referred to as "NAGs"), or "non-O1 V. cholerae".

Subsequent serologic studies have resulted in the identification of over 200 different O groups within the species V. cholerae. While it is now recognized that serotype does not correlate directly with the ability to cause the disease cholera, use of these serologic designations continues to be useful with almost all cholera-causing strains falling into O group 1 or the recently recognized O group 139 [2]. However, cholera toxin-producing strains of V. cholerae in other serogroups have also been implicated as the cause of outbreaks of cholera-like illness (O141 and O75 in the United States; O5, O6, O10, O12, O14, and O37 strains from other parts of the world) [3-9]. In phylogenetic studies, all cholera-associated strains tend to cluster closely together, consistent with the concept that there is an "epidemic genotype" that includes multiple genes necessary for epidemic disease [10-12].

In general, strains outside of these serogroups (commonly referred to as "non-O1/non-O139 V. cholerae") are non-pathogenic or asymptomatic colonizers in humans, or cause mild, sporadic illness (such a gastroenteritis, wound or ear infections) in otherwise healthy hosts. However, in persons who are immunocompromised or who have underlying liver disease, non-O1/non-O139 V. cholerae strains are capable of causing severe wound infections or sepsis, with high associated mortality rates.

PATHOGENESIS — Non-O1/non-O139 V. cholerae strains tend to be highly diverse genetically, and there is not a single route by which they cause human disease. Occurrence of illness is dependent on the particular combination of possible virulence genes carried by the infecting strain, combined with the health status of the host.

Gastroenteritis — A small number of non-O1/non-O139 V. cholerae strains carry the genes for and produce cholera toxin (CT), the toxin responsible for the dehydrating diarrhea characteristically seen in epidemic cholera [3,13,14]. These strains have been associated with gastroenteritis (which, at times, may be severe) but do not appear capable of causing epidemic cholera. In phylogenetic studies, they do not cluster with V. cholerae strains responsible for epidemic disease and generally lack multiple genes/gene complexes that have been associated with "typical" cholera.

Another group of non-O1/non-O139 V. cholerae strains produce a heat-stable enterotoxin (designated NAG-ST), which closely resembles the heat-stable enterotoxin of enterotoxigenic Escherichia coli [15]. These strains, designated "enterotoxigenic V. cholerae," can cause diarrheal disease in humans, based on observations from volunteer studies as well as epidemiologic studies of outbreaks and sporadic cases [16-18].

Genetic studies have identified a type III secretion system in some strains, which may also contribute to virulence [19]. The type III secretion system has been associated with pathogenicity in other diarrheal pathogens (eg, Shigella spp, Salmonella spp, enteropathogenic E. coli, and other Vibrio species) [20-22]. In a 2023 Australian study, some strains were also noted to express type 6 secretion system genes [23].

The role of other virulence factors in causing disease is less clear [24,25]. Various extracellular products (eg, cytolysins, hemolysins, a putative exotoxin, and two different RTX toxins) have been identified, but their role in pathogenesis remains to be determined [19,26-28]. In human studies, three non-O1/non-O139 V. cholerae strains have been fed to volunteers [23]. One strain, which produced NAG-ST, caused illness; the other two strains did not, although they did colonize the volunteers, consistent with the idea that many isolations of non-O1/non-O139 V. cholerae from stool represent identification of non-pathogenic, colonizing strains that may have been acquired incidentally from the environment.

Septicemia — Virtually all non-O1/non-O139 V. cholerae strains isolated from the blood are heavily encapsulated [29], suggesting that the degree of capsule expression is a key element in determining whether sepsis will occur. This polysaccharide capsule provides protection against serum bactericidal activity and phagocytosis [30]. Multiple capsular types have been identified, although data are insufficient to link specific polysaccharides with virulence. The association of virulence with encapsulation is similar to that reported for Vibrio vulnificus, with encapsulated non-O1/non-O139 V. cholerae capable of producing a V. vulnificus-like clinical syndrome in immunocompromised patients.

EPIDEMIOLOGY — V. cholerae are ubiquitous in the marine environment. While generally found in estuarine areas, V. cholerae can grow in fresh water and have been isolated from fresh-water lakes. Vibrios have also been isolated from freshwater insect egg masses (including non-biting midges) as well as from a variety of birds, wild animals, and domestic animals (including dogs, cows, goats, chickens, ducks, seagulls, horse, lambs, and bison) [31,32].

V. cholerae are sensitive to temperature. In temperate climates when water temperatures exceed 20ºC (generally in the summer) Vibrios can be isolated easily from water, suspended particulate matter, plankton, algae, sediment, fish, and shellfish. During the winter months, non-O1/non-O139 V. cholerae decline markedly in number in the aquatic environment and are found primarily in sediments. This seasonal variability is reflected in the increase in incidence of non-O1/non-O139 V. cholerae and other Vibrio infections seen in temperate areas during summer months. This effect has been exacerbated by global warming, leading to rises in sea surface temperature and the occurrence of localized heat waves. One example was the large cluster of non-O1/non-O139 V. cholerae cases in Sweden and Finland in 2014, which was associated with a record heat wave and in which cases occurred within 100 miles of the Arctic Circle [33]. A similar heatwave-associated increase in infections was noted in Germany in 2018 and 2019 [34].

In resource-rich settings, cases of gastroenteritis due to these organisms can almost always be linked to consumption of seafood, particularly raw or undercooked shellfish [35]. In resource-limited settings, the pattern is often less clear, due in part to the increased risk of fecal contamination of food and water sources and/or cross-contamination of foods by seafood.

Wound infections occur in conjunction with environmental exposure to water containing the organism. Septicemia may occur secondary to a wound infection or as a result of ingestion of the organism in shellfish or seafood ("primary septicemia"). Septicemia occurs almost exclusively in persons who have underlying liver disease (cirrhosis, chronic hepatitis), often with a history of alcohol abuse; hemochromatosis; chronic diseases such as diabetes or renal failure; or who are immunosuppressed [36-39].

Non-O1/non-O139 V. cholerae have been isolated from 2 to 3 percent of patients with diarrheal illness in tropical areas (including travelers); isolation rates are higher in coastal areas [32,40,41]. In 2014, the United States Centers for Disease Control and Prevention (CDC) through the Cholera and Other Vibrio Illness Surveillance System (COVIS) reported isolation of non-O1/non-O139, non-toxigenic V. cholerae from a total of 80 patients in the United States [42]. Forty-six percent of these patients were hospitalized, and 5 percent died. While national reporting systems are biased toward reporting more severe illness, these reports underscore the microorganism's potential for causing serious and potentially fatal illness.

CLINICAL MANIFESTATIONS

Gastroenteritis — Patients with gastroenteritis due to non-O1/non-O139 V. cholerae may have diarrhea, abdominal pain, fever, nausea, and vomiting. In one study of 14 United States sporadic cases reported to the United States Centers for Disease Control and Prevention (CDC), all patients had diarrhea (25 percent had bloody diarrhea), 71 percent had fever, and 21 percent reported nausea and vomiting; the median duration of illness was 6.4 days [43]. Cases identified through outbreak investigations have been associated with less severe disease, with a reported incubation period of 12 to 24 hours and median duration of illness ranging from 12 to 24 hours [32].

Wound infections and infections at other sites — Non-O1/non-O139 V. cholerae wound infections generally occur following exposure of wounds to seawater or brackish water; there have also been cases associated with non-saline water, including reports of necrotizing fasciitis caused by non-O1/non-O139 strains linked to Austrian bathing sites [44]. Less commonly, strains have been implicated as a cause of otitis and pneumonia following near-drowning episodes [36,45].

Sepsis — Patients with an appropriate exposure history (consumption of raw shellfish, wound infection associated with exposure to estuarine water) and underlying chronic illness or immunosuppression may present with hypotension and other signs consistent with sepsis. Patients with sepsis often require prolonged hospitalization in intensive care units, with long-term complications resulting from multiorgan system failure. Mortality rates for patients with sepsis may range up to 40 to 60 percent [36,37].

DIAGNOSIS — V. cholerae can be identified through many of the non-culture-dependent diagnostic systems that are being used with increasing frequency in hospital and commercial diagnostic laboratories. In laboratories still using traditional culture methods, V. cholerae grows on standard media used for wound and blood cultures. As is true for V. cholerae strains associated with cholera, isolation of the microorganism from stool generally requires a selective media to suppress growth of other organisms, such as thiosulfate, citrate, bile salts, and sucrose (TCBS), on which V. cholerae appears as a typical yellow colony. The laboratory should be alerted regarding cases of diarrhea in which illness due to V. cholerae is suspected so that the appropriate media can be used. Species identification is based on standard biochemical tests.

All V. cholerae identified require further characterization to determine, (a) if they carry the gene for cholera toxin, and (b) if they are in serogroups O1 or O139. If the isolate has been cultured, such testing can generally be done in state health department laboratories or at the CDC. Strains that carry the gene for cholera toxin, but are not in O groups 1 or 139, will require further genetic/serologic assessment to see if they might represent a cholera strain outside of the "standard" cholera serotypes [7].

Isolation of V. cholerae from a patient in the United States (or other resource-rich country) who lacks a history of travel to a cholera-endemic area will almost certainly represent a non-O1/non-O139 strain of environmental origin. While these strains can cause serious disease in susceptible hosts, they do not represent the public health threat posed by toxigenic O1/O139 V. cholerae.

TREATMENT — Volume repletion is the most important element of therapy in patients with non-O1/non-O139 V. cholerae gastroenteritis. In most cases, diarrhea is mild and self-limited. Antimicrobial therapy is reasonable in more severe cases, since antibiotic therapy is known to decrease the duration of diarrhea and the excretion of infectious organisms among patients with cholera. (See "Cholera: Epidemiology, clinical features, and diagnosis".)

There are no controlled trials of therapy for gastroenteritis due to non-O1/non-O139 V. cholerae strains. Based on clinical trials in cholera and in vitro susceptibility data, doxycycline is a reasonable antibiotic choice; alternatives include macrolides and fluoroquinolones. There are increasing reports of non-O1/non-O139 strains having resistance to tetracyclines and fluoroquinolones, so susceptibility testing should be done on all isolates to confirm that the antibiotic selection was appropriate. The duration of therapy depends on the antibiotic chosen, as outlined separately for cholera.

Wound infections require debridement and antimicrobial therapy. Mild wound infections in patients who do not have significant underlying diseases generally respond well to local wound care and oral antibiotics (such as a tetracycline or a macrolide). Duration of therapy is dictated by clinical response; most patients respond to five to seven days of antibiotics. Patients with severe wound infections require aggressive debridement and treatment with antimicrobial agents, as described below for patients with sepsis.

In the absence of controlled trials for sepsis due to non-O1/non-O139 V. cholerae, it is reasonable to follow the approach used for management of sepsis due to Vibrio vulnificus, which causes a similar clinical syndrome. Given the reported mortality rate with non-O1/non-O139 sepsis of up to 40 to 60 percent, patients with a presumptive diagnosis of septicemia should be started immediately on empiric 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 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. This approach is in keeping with the approach for treatment of V. vulnificus infection. (See "Vibrio vulnificus infection", section on 'Treatment'.)

PREVENTION — The risk of infection from non-O1/non-O139 V. cholerae (as well as other Vibrio species) can be reduced by avoiding the consumption of raw or undercooked shellfish, particularly during warm summer months. This is particularly important for individuals who are immunosuppressed or have serious underlying liver disease. Such individuals should also avoid exposure of wounds to estuarine waters; the increasing sea surface temperatures associated with global warming have expanded the northern range of where such infections might be expected.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute diarrhea in adults".)

SUMMARY AND RECOMMENDATIONS

●Vibrio cholerae is a highly diverse species, of which only a small subset of strains (generally those that produce cholera toxin and are in serogroups O1 and O139) cause the disease cholera. Other V. cholerae (loosely grouped as "non-O1/non-O139 V. cholerae") tend to be acquired from environmental sources and are either are either non-pathogenic or cause mild illness in humans. However, strains can cause severe and potentially fatal infections in immunocompromised patients or patients with underlying liver disease. (See 'Epidemiology' above.)

●Non-O1/non-O139 V. cholerae have been associated with gastroenteritis, wound infections and septicemia. Gastroenteritis is frequently linked to seafood ingestion, particularly raw or undercooked shellfish; it may also occur as a result of fecal contamination of food and water sources. Wound infections occur in conjunction with environmental exposure to water containing the organism. Septicemia occurs almost exclusively in persons who have underlying liver disease or are immunosuppressed, resulting from consumption of the microorganism in seafood or as a complication of a wound infection. (See 'Clinical manifestations' above.)

●As is true for all V. cholerae, non-O1/non-O139 strains grow on standard media used for wound and blood cultures. Isolation from stool generally requires a selective media such as thiosulfate, citrate, bile salts, and sucrose (TCBS). The organism can also be identified through many of the non-culture-dependent diagnostic systems. (See 'Diagnosis' above.)

●For mild diarrhea in otherwise healthy persons, symptomatic treatment, including oral or intravenous rehydration, as necessary, may be sufficient. In more severe cases of diarrhea, antibiotics may reduce the duration of illness. For patients with severe diarrhea, we suggest empiric therapy with doxycycline pending susceptibility testing results (Grade 2C). (See 'Treatment' above.)

●Treatment of wound infections requires debridement and antimicrobial therapy. For patients with mild wound infections in the absence of risk factors for serious infection, we suggest empiric treatment with a tetracycline or macrolide (Grade 2C). (See 'Treatment' above.)

●For patients with sepsis and for patients with wound infections in the setting of risk factors for sepsis (immunosuppression or underlying liver disease), we suggest treatment using combination therapy with a third-generation cephalosporin plus either a tetracycline or a fluoroquinolone (Grade 2C). (See 'Treatment' above.)

●Susceptibility testing of all isolates should be performed, with antibiotic regimen adjustment as appropriate. (See 'Treatment' above.)