Aeromonas infections

INTRODUCTION — The genus Aeromonas consists of gram-negative rods widely distributed in freshwater, estuarine, and marine environments [1,2]. Aeromonas species grow at a range of temperatures, although they are isolated with increasing frequency during warmer months (May through October in the Northern hemisphere). Aeromonas species cause a wide spectrum of disease syndromes among warm- and cold-blooded animals, including fish, reptiles, amphibians, mammals, and humans [3,4].

MICROBIOLOGY — The genus Aeromonas has been divided into two major groups [5]:

●Motile, mesophilic species, including eight that can cause disease in humans (table 1).

●Non-motile, psychrophilic species that generally cause disease only in fish.

Aeromonas species are oxidase positive and ferment glucose. The organisms grow at a range of temperatures from 0 to 42ºC.

PATHOGENICITY AND PATHOGENESIS — The role of Aeromonas as a gastrointestinal pathogen is uncertain. Stool isolation rates among individuals with diarrhea are variable, ranging from <1 to >60 percent. In addition, Aeromonas is a common isolate from asymptomatic individuals [6,7]. There has been only one major outbreak in which Aeromonas has been implicated as the etiologic agent of disease [8]. Efforts to induce illness in volunteers with selected Aeromonas strains were unsuccessful in one trial, although selection of strains may not have been optimal [9].

Nonetheless, it is likely that certain strains of Aeromonas cause diarrheal disease [6,10-15]. One large study identified Aeromonas spp as a cause of traveler's diarrhea in 18 (2 percent) of 863 patients in Spain [13]. In the Global Enteric Multicenter Study (GEMS), which compared stool cultures among 12,110 children with diarrhea and 17,291 matched control children at seven global sites, Aeromonas was associated with diarrhea only in Pakistan and Bangladesh, where Aeromonas-positive culture rates ranged from 19 percent in the 0- to 11-month age group to 29 percent in the 24- to 59-month age group. However, Aeromonas was isolated as the sole pathogen in less than 5 percent of cases at those sites, with Shigella as the most common co-isolate [15]. In contrast, in Africa and India, rates of isolation never exceeded 1 percent. Factors responsible for these regional differences in incidence remain to be determined, and the potential role of coinfecting pathogens, such as Shigella, in disease occurrence warrants further study.

At a patient level, it is not possible to predict whether a specific Aeromonas strain is responsible for diarrheal illness. Possible virulence factors of Aeromonas species include toxins (cytotoxic and cytotonic), proteases, hemolysins, lipases, adhesins, agglutinins, pili, enterotoxins, various enzymes, and outer membrane arrays, such as an S-layer and capsule. Other factors that may contribute to virulence include VacB [16], enolase [17], and the presence of type II, III, IV, and VI secretion systems [18,19]. It is uncertain how many aeromonads contain these putative virulence factors and how these factors contribute to risk of illness.

EPIDEMIOLOGY — Mesophilic aeromonads have a global distribution [1,2] and have been isolated from a variety of aquatic environments, including [20-23]:

●Fresh water

●Estuarine (brackish) water

●Surface water, especially recreational

●Drinking water, including treated, well, and bottled

●Polluted waters

●Waste water effluent sludge [24].

Aeromonads are not generally considered marine organisms, but can be found in marine systems that interface with fresh waters and can survive at all but the most extreme salt concentrations [20]. Usually they are not part of the groundwater bacterial population, which is generally poor in nutrients.

In nutrient-rich waters, Aeromonas species can grow to large numbers and generally peak in the warmer temperatures of the summer months in temperate freshwater lakes and chlorinated drinking water [25,26]. Aeromonas species appear to tolerate polluted environments, including chemical pollution, although they are not considered to be of fecal origin [21]. The organism has also been isolated from retail produce sources and meat products [27].

Contact with any fresh or brackish water body is the most common source of human infection. The risk of infection can be reduced by caution in the setting of natural water sources (lakes, rivers, streams, ponds, bays), including minimizing the risk of traumatic wounds and avoiding oral ingestion, particularly during warmer summer months.

Underlying host factors may also influence the likelihood of infection [12]. In the Global Enteric Multicenter Study (GEMS) study, breastfeeding was associated with a lower likelihood of Aeromonas infection, but only in patients 24 months of age or younger [15]. In a study from Bangladesh, detection of Aeromonas in diarrheal samples was associated with severe acute malnutrition (odds ratio = 25.7) [28]. Hematologic malignancies and cirrhosis are associated with increased risk for infection [29-31].

ASSOCIATED DISEASES — Diarrheal disease is the most common manifestation of Aeromonas infection. The organism has also been associated with a variety of extraintestinal presentations [4,6,10,32-34].

Diarrhea — Aeromonas spp are associated with a range of diarrheal presentations including:

●Acute, secretory diarrhea, often accompanied by vomiting

●Acute, dysenteric diarrhea with blood and mucus

●Chronic diarrhea, lasting more than 10 days

●Choleric diarrhea with "rice-water" stools

●Traveler's diarrhea (probably the most commonly recognized presentation in the United States)

There have been two reports of Aeromonas hydrophila enterocolitis associated with the hemolytic uremic syndrome (HUS) [35-37]. (See "Diagnosis of immune TTP".)

Wound infections — Aeromonas can cause mild to severe wound infections. Infection typically occurs on the extremities following traumatic aquatic injury. Such wound infections affect men three times more commonly than women. The most typical presentation is cellulitis [38]; myonecrosis (with and without gas production), rhabdomyolysis, and lesions mimicking ecthyma gangrenosum have also been reported [39-42]. The potential severity of these infection is reflected in a case series from Taiwan, in which 11 of 31 patients with necrotizing fasciitis due to A. hydrophila or Aeromonas veronii biovar sobria died, despite early fasciotomy and treatment with a third-generation cephalosporin [43].

A. hydrophila, A. veronii biovar sobria, Aeromonas schubertii and Aeromonas caviae are the species most commonly isolated from wound infections [4,6,44,45]. Aeromonas was a common wound isolate among tsunami victims in southeast Asia in 2004, and elevated numbers of Aeromonas spp were recorded in floodwater samples in New Orleans following Hurricane Katrina in 2005 [46,47].

Serious wound infections and sepsis have also been reported following the medicinal use of leeches [48-50]. Aeromonads reside in the gut of the leech Hirudo medicinalis, where they assist in the enzymatic digestion of the blood ingested by the leech [48,49,51,52]. Patients undergoing leech therapy often receive systemic chemoprophylaxis with ciprofloxacin to prevent such infection. Emerging reports of ciprofloxacin-resistant strains of Aeromonas isolated from leeches may limit the utility of this practice [50,53-55].

Bacteremia — Sepsis with Aeromonas species is strongly associated with infection with A. veronii biovar sobria. These patients present with the classic signs and symptoms of gram-negative sepsis and may have gastrointestinal symptoms, including abdominal pain, nausea, vomiting, and diarrhea [4,56].

Sepsis tends to occur in older patients with hematologic malignancy [29], serious hepatobiliary disease, other immunocompromising conditions, or traumatic injuries. One case report described recurrent Aeromonas bacteremia over two years in an elderly man who had repeated exposure through contaminated well water [57]. Pediatric case reports of sepsis due to A. hydrophila have been reported, including one case of a patient with diarrhea and pneumonia and one case of acute renal failure [58,59]. Cases have also been rarely reported among pregnant women; in 2011, three cases of bacteremia with Aeromonas spp were identified in pregnant women at the Thailand-Myanmar Border [60].

It is not always possible to identify the source of the organism in cases of sepsis; in such cases, it is reasonable to surmise that it was acquired from the gastrointestinal tract.

Miscellaneous extraintestinal sites — Aeromonas spp have been implicated in cases of ocular infections, osteomyelitis, meningitis, respiratory infections following "near drowning," pelvic abscesses, otitis, cystitis, endocarditis, peritonitis, cholecystitis, and joint infections [4,6,44,61-63].

DIAGNOSIS — Laboratories using traditional microbiological procedures are generally not able to isolate Aeromonads by using standard protocols for isolation of stool pathogens. For cases in which Aeromonas is suspected clinically, the laboratory should be advised so that specialized techniques can be employed, as needed. The microorganism is readily identified in routine wound or blood cultures. Automated genetic identification systems can identify most true Aeromonas isolates to the level of A. hydrophila group or A. hydrophila/A. caviae. However, these identifications are often incomplete or erroneous due to insufficient discriminatory markers to detect interspecies differences [64-66]. A study evaluating the ability of six commercial systems to identify clinical Aeromonas isolates noted that accuracy of these systems was limited by outdated databases and taxonomy, weak algorithms, and the need for impractical tests [67]. Certain algorithms, however, performed well, such as the Aerokey II [68], which correctly identified 95.5 percent of 87 isolates to the species level. This dichotomous algorithm can differentiate the emerging virulent species known as A. dhakensis, which has been linked with severe infection, including septicemia [69].

Hemolysis is variable on blood agar media; most species display beta hemolysis. Although aeromonads grow on nearly all enteric media, they often are overlooked on MacConkey agar because A. caviae is lactose-positive just like Escherichia coli. Ampicillin-containing medium should not be used to suppress normal enteric flora, since a substantial portion of A. caviae isolates and all Aeromonas trota isolates are sensitive to ampicillin and therefore will not grow on such a medium [70,71]. This is especially important in light of reports implicating A. trota in pancreatic abscess and septic shock with cirrhosis, and A. caviae in cystitis [72-74].

Aeromonas spp are oxidase-positive, polar flagellated, glucose-fermenting, facultatively anaerobic, gram-negative rods that are resistant to the vibriostatic agent O/129 and unable to grow in 6.5 percent NaCl. The presumptive identification of an isolate involves the initial separation from other oxidase-positive genera such as Vibrio and Plesiomonas to avoid misidentification. This can be accomplished with simple tests such as O/129 susceptibility, tolerance to various NaCl broth concentrations, and the ability to ferment inositol [71].

Antimicrobial resistance markers and susceptibility studies should be determined by either the standard agar dilution method or by Kirby-Bauerdisk diffusion method using the 2010 CLSI Standard M45-A2 for Aeromonas species [75]. Some automated MIC systems, such as BioMerieux Vitek, Inc. may not be reliable for detection of beta-lactam resistance [76].

THERAPY

Antimicrobial susceptibility — Clinical studies have demonstrated differences in antimicrobial susceptibility among species, highlighting the importance of both species identification and susceptibility testing for all isolates, particularly in the setting of serious infection. With the caveat that there may be substantial differences in regional resistance patterns, most Aeromonas strains are resistant to penicillin, ampicillin, carbenicillin, and ticarcillin; most are susceptible to trimethoprim-sulfamethoxazole (TMP-SMX), fluoroquinolones, second- and third-generation cephalosporins, aminoglycosides, chloramphenicol, and tetracyclines [6,61,77-82]. As noted below, there have been increasing reports of resistance to carbapenems [83,84]. There have also been several reports of infection with fluoroquinolone-resistant A. hydrophila strains following leech therapy [50,53-55].

Most Aeromonas species produce an inducible chromosomal beta-lactamase, which may not be detected by rapid commercial susceptibility systems [76]. Aeromonads produce beta-lactamases from three different classes: a class C cephalosporinase, a class D penicillinase, and a class B metallo-beta-lactamase (MBL) of the "CphA" type [7]. Two other MBLs (VIM and IMP) in strains of A. hydrophila and A. caviae have also been detected, encoded on an integron and a plasmid, respectively [85,86]. There have now been several reports of the emergence of multiple Aeromonas spp. displaying CphA-mediated carbapenem resistance in Australia and Singapore; the predominant species found was A. dhakensis, previously known to be the cause of more serious human infections [83,84]. (See "Carbapenem-resistant E. coli, K. pneumoniae, and other Enterobacterales (CRE)", section on 'Classifications and geographic distribution'.)

Regional resistance patterns include the following:

●In Bangladesh, Aeromonas spp have the highest reported level of multidrug resistance (MDR) among enteric pathogens, at 82 percent [87]. This includes resistance to fluroquinolones (73 percent of isolates), macrolides (99.8 percent), tetracycline (72 percent), and TMP-SMX (85percent).

●In Spain, resistance to nalidixic acid has been reported; a surveillance study of 43 strains reported that 26 percent of A. caviae, 20 percent of A. hydrophila, and 88 percent of A. veronii biotype sobria were resistant to nalidixic acid. Although still susceptible to ciprofloxacin, these strains had a mutation in the A subunit of DNA gyrase and could easily develop a second mutation resulting in resistance to ciprofloxacin [79].

●In China, colistin resistance (mcr-3) has been described [88].

Clinical approach — Most cases of Aeromonas-associated diarrhea are self-limited and can be managed with supportive therapy, including oral and intravenous rehydration. Based on anecdotal data, antibiotics may be of value in patients with severe diarrhea and/or a history of immunosuppression [78]. Aggressive antimicrobial therapy is essential in serious wound infections and/or sepsis [31,43,79].

Given emerging patterns of antimicrobial resistance, antimicrobial susceptibility testing of isolates is essential to guide antibiotic selection. Pending species identification and susceptibility testing, initial empiric therapy of suspected Aeromonas spp infections with a fluoroquinolone, third-generation cephalosporin, and/or TMP-SMX would provide reasonable antimicrobial coverage. For infections acquired in areas with high levels of resistance, such as Bangladesh, therapy with a third-generation cephalosporin and/or an aminoglycoside should be considered. Once susceptibility testing results are available, the antibiotic regimen can be tailored appropriately to a single agent.

Guidelines from the Infectious Diseases Society of America suggest a combination of doxycycline plus either ciprofloxacin or ceftriaxone for treatment of necrotizing skin infections caused by Aeromonas spp [89]. However, there are no data that indicate this combination therapy offers a benefit over monotherapy. 

Nevertheless, certain agents should be avoided; therapy with ampicillin or first-generation cephalosporins is not appropriate. All species of clinical aeromonads are resistant to ampicillin except for A. trota and sometimes A. caviae. A. veronii biovar sobria (formerly Aeromonas sobria) is uniformly resistant to first-generation cephalosporins, but in vitro testing suggests that it is susceptible to third- and fourth-generation cephalosporins. (See 'Antimicrobial susceptibility' above.)

There are no clinical trial data to guide the duration of therapy; therefore, treatment should be guided by clinical response. Reasonable courses of therapy include three days of therapy for treatment of diarrhea, 7 to 10 days of therapy for treatment of wound infections, and two weeks of therapy for treatment of bacteremia. The course of therapy may need to be adjusted depending on patient characteristics, including immunosuppression or other underlying conditions.

SUMMARY AND RECOMMENDATIONS

●The genus Aeromonas consists of gram-negative rods widely distributed in freshwater, estuarine, and marine environments. Aeromonas species have been isolated with increasing frequency during warmer months. The organisms cause a wide spectrum of disease syndromes among warm and cold-blooded animals. (See 'Microbiology' above.)

●Diarrheal disease is the most common manifestation of Aeromonas infection. The organism has also been associated with a variety of extraintestinal presentations, including wound infections and bacteremia. Necrotizing fasciitis has been reported with species such as A. hydrophila, A. veronii biovar sobria, Aeromonas schubertii, and Aeromonas caviae. Aeromonas dhakensis is also associated with severe infections.

●Aeromonads are not routinely identified in traditional microbiology laboratories as part of the normal protocol for isolating stool pathogens. Most molecular testing systems can identify Aeromonas, but suboptimally identify an isolate to the species level. (See 'Diagnosis' above.)

●Clinical studies have demonstrated differences in antimicrobial susceptibility among species and among geographic locations, highlighting the importance of both species identification and susceptibility testing for all isolates, particularly in the setting of serious infection. (See 'Antimicrobial susceptibility' above.)

●Pending species identification and susceptibility testing, we suggest initial empiric therapy of suspected Aeromonas infections (severe diarrhea, wound infections, bacteremia) with a fluoroquinolone, third-generation cephalosporin, and/or TMP-SMX (Grade 2C). For areas with known high levels of resistance (such as Bangladesh), a third-generation cephalosporin and/or an aminoglycoside are alternatives. (See 'Clinical approach' above.)