Minor Vibrio and Vibrio-like species associated with human disease

INTRODUCTION — Vibrios are ubiquitous environmental Gram-negative rods, with well over 100 species currently recognized. Among these species, 10 have been isolated from humans. The species responsible for the most serious diseases are Vibrio cholerae (V. cholerae O1/O139 strains causing the disease cholera and other V. cholerae strains linked with diarrhea, wound infections, and septicemia), Vibrio parahaemolyticus, and Vibrio vulnificus.

Four additional species (Vibrio mimicus, Vibrio fluvialis, Vibrio furnissii, Vibrio alginolyticus) clearly have pathogenic potential for humans but cause illness that generally is less severe. Two closely related species that were originally classified in the genus Vibrio but have undergone a change in name on the basis of recent taxonomic studies, Grimontia hollisae (formerly Vibrio hollisae) [1], and Photobacterium damselae subspecies damselae (formerly Vibrio damselae) [2], are also established human pathogens. Three species (Vibrio metschnikovii, Vibrio cincinnatiensis, and Vibrio carchariae [3-7]) have primarily been the subject of case reports, and their significance as human pathogens remains to be determined. Vibrio metoecus, within the V. cholerae-V. mimicus clade [8], and Vibrio injenensis, closely related to V. metschnikovii and V. cincinnatiensis [9], have been identified in clinical samples from patients; their role as human pathogens is uncertain.

This topic discusses the microbiology, epidemiology, clinical manifestations, diagnosis and treatment of the six minor Vibrio and Vibrio-like species that have been associated with human disease. Infections due to the major Vibrio species are discussed elsewhere. (See "Cholera: Epidemiology, clinical features, and diagnosis" and "Infections due to non-O1/O139 Vibrio cholerae" and "Vibrio parahaemolyticus infections" and "Vibrio vulnificus infection".)

EPIDEMIOLOGY COMMON TO VIBRIO SPECIES — All Vibrio species are free-living microorganisms in marine and estuarine environments. They are sensitive to temperature, with numbers of microorganisms in the environment increasing during warmer, summer months [10]. The number of Vibrio species isolated from human infections in the United States and reported to the Center for Disease Control clearly increases during the months of May to September, with 40 to 47 percent of cases occurring in July and August [11,12].

Vibrio species are associated mainly with gastroenteritis, wound infection, and occasionally bacteremia. V. mimicus, V. fluvialis, V. furnissii, and G. hollisae primarily cause gastroenteritis. V. alginolyticus and P. damselae primarily cause wound infections. The frequency and complications of these infections vary by species (table 1) [12]. In the United States, the numbers of cases reported to the Centers for Disease Control and Prevention (CDC) and identified through CDC’s FoodNet surveillance system have shown a steady increase over the past two decades [13]. Modeling studies further suggest that the risk of infection with these and other Vibrio species is impacted by ocean warming, which is likely to intensify with climate change [14].

SPECIES THAT PRIMARILY CAUSE DIARRHEA

V. mimicus — V. mimicus, identified as a separate species in 1981 [15], was initially classified as "atypical sucrose-negative V. cholerae." The species "mimics" V. cholerae in many biochemical tests, hence the name. Comparative genomic analysis suggests that V. mimicus and V. cholerae diverged from a common ancestor derived from the strain that caused the sixth cholera pandemic [16]. Despite the close genetic relationship with V. cholerae, V. mimicus do not cause epidemic cholera-like disease. Fewer than 10 percent of clinical isolates, and less than 1 percent of environmental isolates, produce cholera toxin [17]. Strains do, however, carry a variety of possible virulence factors [18,19], including genes for a type III secretion system that can be seen in V. parahaemolyticus [20]. (See "Vibrio parahaemolyticus infections", section on 'Pathogenesis'.)

Epidemiology — Consumption of seafood is the main risk factor for V. mimicus gastrointestinal infection. The microorganism has been isolated from shrimp and other shellfish in fish markets in Malaysia and Mexico [19,21,22] and from mussels in Italy [23]. In the US, occurrence of V. mimicus diarrhea has been associated with eating raw oysters and other shellfish, including crayfish [24,25]. In a large Thai outbreak, "fish soup" was implicated as the vehicle of transmission [26], and infection has been linked to consumption of raw turtle eggs in Costa Rica [27]. In a pattern analogous to that seen with non-O1/non-O139 V. cholerae, the organism is likely to be introduced into communities through seafood, with further transmission in the developing world related to fecal contamination of food and water sources. Wound and ear infections occur to a lesser extent and are generally seen in the setting of exposure to estuarine waters [24], which serve as a reservoir for the microorganism.

Clinical manifestations — Gastroenteritis, with typical symptoms of diarrhea, nausea, vomiting, and abdominal cramps, is the primary clinical manifestation of V. mimicus infection. While diarrhea is generally mild, occasional cases can be severe, requiring hospitalization for intravenous rehydration. Wound and ear infections occur rarely, as does bacteremia.

In an initial case series (which was probably biased toward more severe cases), median duration of illness was six days, with 44 percent of patients having fever, and 16 percent having bloody diarrhea [24]. Approximately 57 percent of V. mimicus clinical isolates in the US reported to CDC in 2014 (the most recent year for which data are available) were from hospitalized patients (table 1). In the Thai outbreak involving over 400 persons, symptoms were milder, with 91 percent reporting diarrhea, 66 percent abdominal pain, and 27 percent vomiting [26]. Symptoms resolved in two-thirds of these patients within 36 hours, with less than a third seeking medical attention.

V. fluvialis — V. fluvialis was identified as a separate species in 1981, with the name derived from the Latin for "river," reflecting its early isolation from river and estuarine waters [28]. Strains do not appear to produce cholera toxin. They have been shown to have cytopathic/cytotoxic effects on HeLa cells [29], and to cause fluid accumulation in rabbit ileal loops and diarrhea and death in infant mice [30,31]. V. fluvialis has been associated with high rates of bloody diarrhea, raising the possibility that it is invasive in the intestinal tract, despite reports that isolates are negative for invasiveness in laboratory testing [32]. A variety of potential virulence factors have been identified in genetic studies [33].

Epidemiology — V. fluvialis is widely distributed in the estuarine and marine environment and has been isolated from shellfish and fish, including fish in Turkey [34], shrimp and other shellfish in fish markets in Malaysia [21], and mussels in Italy [23]. It is also recognized as an important pathogen for some marine species, with "V. fluvialis-like" strains identified as the cause of "limp lobster" syndrome [35] and isolates cultured from the blood of ill manatees [36].

In humans, V. fluvialis has been linked with large outbreaks in Bangladesh and India, including outbreaks of diarrheal disease after the major cyclone Aila [32,37], as well as with endemic diarrheal illness [38]. In the United States, it is a relatively common Vibrio species isolated from patients, with 71 cases reported to the CDC in 2014 (table 1) [12].

In reports from Bangladesh and India, cases have been concentrated in children and persons aged 55 and older [29,37]. Similar age-related incidence patterns were not observed in studies in Indonesia [39]. Median age among cases in the United States in 2014 was 60 years [12]. In a pattern analogous to that seen with non-O1/non-O139 V. cholerae, the organism is likely to be introduced into human populations through seafood or water contact, with further transmission in the developing world related to fecal contamination of food and water sources.

Clinical manifestations — Gastroenteritis is the primary clinical manifestation of V. fluvialis infection. Infections at other sites, including wounds and ears, also occur, with rare reports of bacteremia and death [40]. Among 100 persons with "moderate to severe" illness following cyclone Aila in whom V. fluvialis was implicated as the etiologic agent, symptoms included watery diarrhea (86 percent of patients), bloody diarrhea (62 percent), abdominal pain (57 percent), vomiting (41 percent), and fever (21 percent) [37]. In an earlier outbreak in Bangladesh (1976-77), 75 percent of patients were found to have blood cells and leukocytes in their stools on microscopic examination [32]. The duration of diarrhea with antibiotic therapy ranged from 16 to 80 hours.

V. furnissii — V. furnissii, initially identified as biovar II for V. fluvialis, was designated as a separate species in 1983 [10]. A complete genome sequence has been reported for an environmental strain. It lacked the gene for cholera toxin, other cholera toxin-related toxins, and genes encoding a type III secretion system [41].

The organism can be isolated from the environment, and has been isolated from mussels in Brazil [42]. It has been retrospectively identified as the cause of at least one outbreak (gastroenteritis on an airplane flight from Tokyo to Seattle [43]), has been linked with gastroenteritis in Peru [44] and Indonesia [39], and has been reported as the cause of bacteremia in a patient with diabetes in Virginia [45] and a malnourished patient in Japan [46]. However, its role as a pathogen remains somewhat controversial, particularly as in the Peru study, in which it was isolated more frequently from persons who were asymptomatic than from persons with diarrhea.

Grimontia hollisae — G. hollisae, initially known as V. hollisae, was designated as a separate species in 1982. G. hollisae is known to have a type III secretion system and produce a thermostable direct hemolysin [47], which has been linked with hepatotoxicity in studies in mice [48].

G. hollisae has been isolated from the environment in Australia [49] and from mussels in Italy [50], but reports are limited; it is unclear whether this reflects a decreased environmental presence compared with Vibrio species or technical problems in environmental isolation. It has been associated primarily with sporadic cases of gastroenteritis, and there is a suggestion that illness is associated with consumption of seafood [51,52]. Cases appear to be more common in North America, although isolation from patients with diarrhea has been reported from Indonesia [39], and a case of bacteremia has been reported from Europe [51]. Of five patients with bacteremia reported in the literature [53], three had a history of underlying liver disease, similar to the pattern seen with non-O1/non-O139 V. cholerae and V. vulnificus.

SPECIES THAT PRIMARILY CAUSE WOUND INFECTION

V. alginolyticus — V. alginolyticus is widely distributed in the environment [54,55], has been isolated from fish and shellfish [56], and is recognized as a major pathogen for fish and crustaceans. It is the most common cause of Vibrio-associated wound infections in the United States (table 1) [57]. It has also been associated with otitis, particularly in children. Wound infections and otitis are almost all associated with exposure to marine or estuarine waters [57]. In immunocompromised patients and patients with underlying liver disease, there are rare reports of severe wound infections, including necrotizing fasciitis [58].Rare cases of bacteremia are reported, almost always associated with wound infections, and generally in immunocompromised or burn patients [59,60]. In contrast to other Vibrio species, it is only rarely isolated from stool (ie, in 5 percent of cases reported to CDC between 1988 and 2012 [57]), and questions have been raised about its ability to cause gastrointestinal disease in humans.

In a study in Western Australia, V. alginolyticus was isolated from 20 of 36 samples (56 percent) taken from infected superficial wounds contaminated with seawater [61]. Most infections cleared within one or two days without the use of antibiotics. The general lack of severity associated with V. alginolyticus infections is further reflected in the fact that only 12 deaths occurred among the 1331 infections reported to the CDC in the United States from 1988 to 2012 [57]. Of these, two were due to drowning and six were in patients noted to have underlying cardiac problems. In a 10-year study from Florida, no deaths were reported among 131 infections [10].

V. alginolyticus is known to produce extracellular proteases and collagenases, which may contribute to its virulence [62]. It has also been found to have a type III secretion system that has been linked with the ability of the microorganism to cause rapid apoptosis, cell rounding, and osmotic lysis of fish cells [63]. Other studies have highlighted the importance of genes associated with motility and adhesion [64].

Photobacterium damselae — P. damselae has gone through several name changes: originally designated as V. damsela (based on its pathogenicity for damsel fish [65]), it has been known as Listonella damsela, and is currently designated as P. damselae subspecies damselae. It is pathogenic for fish and other marine organisms, including cetaceans [66]; strains have been associated with unusual mortality events in striped dolphins [67]. While the number of reported human cases in the United States is relatively low (table 1), P. damselae is a recognized cause of wound infections after exposure to marine or estuarine waters [52]. Bacteremia has been reported in association with wound infections, and there are reports of isolation from patients with necrotizing fasciitis [68,69].

P. damselae subspecies damsela has a variety of potential virulence factors, including toxins with hemolytic and cytolytic activities [66], and shows striking virulence in mouse models [70]. Increases in water temperature (as seen with climate change) have been found to up-regulate multiple physiological and virulence-related functions [71].

DIAGNOSIS — The diagnosis of these Vibrio species is established by isolation of the organism from the relevant clinical specimen, generally stool or wound specimens, as well as blood. They can grow on standard media used for wound and blood cultures. Isolation of Vibrio species from stool generally requires a selective media to suppress growth of other organisms, such as thiosulfate, citrate, bile salts, and sucrose (TCBS). The laboratory should be alerted regarding cases of diarrhea in which illness due to Vibrio species is suspected so that the appropriate media can be used.

While species can be readily identified using molecular methods in a research setting, clinically available commercial molecular diagnostic systems will generally not identify these bacteria to a species level, necessitating reliance on traditional microbiologic approaches, including the use of standard biochemical tests.

Certain species have particular diagnostic characteristics:

●V. mimicus and P. damselae appear as green colonies on TCBS agar. V. cholerae, V. alginolyticus, V. fluvialis, and V. furnissii are yellow.

●V. fluvialis shows marked biochemical similarity to Aeromonas species. When the British Public Health Laboratories reviewed all of their old anaerogenic, lysine-decarboxylase-negative Aeromonas strains, they found that one-third were actually V. fluvialis [28]. Microbiologic identification schemes in current use in the United States will sometimes mistakenly identify V. fluvialis as Aeromonas [31]. Where V. fluvialis is suspected, isolates should be screened for salt requirements (V. fluvialis grows in 6 to 7 percent sodium chloride, while Aeromonas generally does not) to help differentiate the two species.

●G. hollisae does not grow on TCBS agar, in contrast to Vibrio species. Isolation is possible on blood agar or marine agar but tends to be difficult, particularly from stool [52].

TREATMENT

Diarrheal disease — Volume repletion is the most important element of therapy in patients with diarrheal disease and is best done through the oral route with solutions that contain water, salt, and sugar. (See "Approach to the adult with acute diarrhea in resource-abundant settings", section on 'Fluid repletion'.)

Although diarrhea associated with these Vibrio species is often mild and self-limited, antimicrobial therapy is reasonable in moderate to severe cases, particularly in V. fluvialis infections, given its association with blood and leukocytes in the stool. Evidence to guide antimicrobial selection when treatment is indicated is extremely limited, and antimicrobial resistance is a growing problem with substantial geographic variability. We suggest azithromycin (1 g single oral dose) as initial therapy if susceptibility testing results are not yet available. However, resistance is emerging [72]. Alternatives include doxycycline (300 mg single oral dose) or ciprofloxacin (1 g single oral dose). Susceptibility testing should be performed to confirm susceptibility to the chosen agent.

No controlled trials of therapy of these Vibrio species have been performed, and there are limited observational data. In the Thai outbreak of V. mimicus, patients were treated with norfloxacin [26]; no outcome data were reported. Successful therapy with ciprofloxacin has been reported in one case of severe diarrhea and sepsis with G. hollisae infection [53]. Particular concerns regarding antimicrobial resistance have been noted for V. fluvialis, with the resistance patterns varying widely by geographic area. In one report from India, 24 percent of V. fluvialis isolates from patients with acute diarrhea harbored an NDM-1 resistance plasmid (conferring resistance to carbapenems); all of these were resistant to ciprofloxacin but susceptible to doxycycline [73]. In contrast, in a study from Nigeria, almost all strains were resistant to tetracyclines, but 100 percent were susceptible to ciprofloxacin [74]. In both of these studies, strains retained susceptibility to azithromycin; however, there has been a report of azithromycin resistance in a V. furnissii isolated in China [72].

Even though strains may show in vitro susceptibility to ampicillin, studies with V. cholerae suggest that ampicillin has decreased efficacy in Vibrios; its use is not recommended. (See "Cholera: Epidemiology, clinical features, and diagnosis".)

Wound infection — There are few data on treatment of wound infections due to these Vibrio species. Treatment suggestions are based upon clinical experience. Serious wound infections generally require debridement and antimicrobial therapy. Mild wound infections generally respond well to local wound care and oral antibiotics. In the case of V. alginolyticus infections of superficial wounds, antibiotics may not be necessary, as reflected by the report from Australia in which most cases resolved spontaneously [61]. Based upon antibiotic susceptibility patterns and clinical response of other Vibrio species, we suggest doxycycline, a fluoroquinolone, or azithromycin for severe wound infections and infections in immunocompromised hosts. Susceptibility testing should be done to confirm sensitivity to these agents. We typically use oral doxycycline 100 mg twice daily, ciprofloxacin 500 mg twice daily, or azithromycin 500 mg on day 1 followed by 250 mg once daily. Duration of therapy is dictated by clinical response; most patients respond to five to seven days of antibiotics.

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

●Epidemiology – Vibrio species are naturally occurring marine and estuarine microorganisms that are found worldwide. They are sensitive to temperature, and infections peak during warmer, summer months. (See 'Epidemiology common to Vibrio species' above.)

●Species that primarily cause diarrhea (see 'Species that primarily cause diarrhea' above)

•Vibrio mimicus primarily causes gastroenteritis and 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. (See 'V. mimicus' above.)

•Vibrio fluvialis primarily causes gastroenteritis and has been associated with large outbreaks in Bangladesh and India. Bloody diarrhea and fecal leukocytes are common in V. fluvialis infection. It is very similar biochemically to Aeromonas, with which it may be confused in the laboratory. (See 'V. fluvialis' above and 'Diagnosis' above.)

•Vibrio furnissii has been associated with gastroenteritis, although its role as a pathogen remains controversial. (See 'V. furnissii' above.)

•Grimontia hollisae primarily causes gastroenteritis, although cases of bacteremia are reported. Infection has been linked to seafood ingestion. (See 'Grimontia hollisae' above.)

●Species that primarily cause wound infection (see 'Species that primarily cause wound infection' above)

•Vibrio alginolyticus is the most common cause of Vibrio-associated wound infections in the US; most infections are mild.

•Photobacterium damselae is a rarer cause of wound infection.

Infections with both are linked with exposure to marine or estuarine waters.

●Diagnosis (see 'Diagnosis' above)

•The diagnosis of these Vibrio species is established by identification of microorganism in relevant clinical specimens, generally stool or wound cultures. Vibrio species can grow on standard media for wound and blood cultures. For patients with gastroenteritis, the laboratory should be alerted of the suspicion for Vibrio, as isolation from stool requires a selective media to suppress growth of other organisms. In contrast to Vibrio species, G. hollisae does not grow on TCBS, the standard selective media used in isolation of Vibrios from stool; it does grow on blood agar.

•Molecular diagnostic systems generally do not identify strains below the genus level, requiring use of traditional culturing methods, which requires submission to a state or other reference laboratory.

●Management

•Diarrheal disease – Volume repletion is the most important element of therapy in patients with diarrheal disease due to these Vibrio species. For those with moderate to severe infection, particularly with V. fluvialis, we also suggest antibiotic treatment (Grade 2C). When antibiotic therapy is indicated, we suggest azithromycin (Grade 2C). Doxycycline and ciprofloxacin are alternatives. Given emerging patterns of resistance that are being seen at an international level, susceptibility testing should be performed to confirm susceptibility to the chosen agent. (See 'Diarrheal disease' above.)

•Wound infection – Wound infections require local wound care and possibly debridement. For patients with mild superficial wounds due to V. alginolyticus, we suggest initial observation without antibiotics (Grade 2C). Antibiotics should be given to those with moderate to severe infections or an underlying immunosuppressive condition. For such patients, we suggest using doxycycline, a fluoroquinolone, or azithromycin (Grade 2C). This choice is based upon antibiotic susceptibility patterns and clinical response of other Vibrio species. (See 'Wound infection' above.)