Acute bacterial gastroenteritis

Introduction

Acute gastroenteritis (AGE) is one of the most common bacterial infectious diseases that clinicians face in daily practice. Worldwide, bacterial enteric pathogens cause billions of infections each year with tremendous morbidity. In the United States alone it is estimated that there are nearly 200 million cases of AGE annually¹.

Epidemiology

Surveillance data provided by the National Outbreak Reporting System (NORS) https://www.cdc.gov/nors/index.html, established by the CDC in 2009, illustrates the magnitude of the problem with thousands of outbreaks, and more than one hundred thousand cases of AGE recorded in the first year of its operation². Foodborne illnesses, estimated at more than 9 million cases each year in the United States^3,4, are largely caused by bacterial pathogens (table 1). While sporadic cases of illness occur frequently with improper food handling, the nature of food processing and distribution in the United States can lead to widespread dissemination of a single bacterial pathogen to large numbers of people. More than 200,000 cases of AGE are thought to have been caused by Salmonella enteritidis distributed nationwide in ice cream prepared by a single company⁵. Multistate outbreaks of nontyphoidal Salmonella^6–13, and Shiga toxin producing E. coli (STEC)^14,15 are common and have occurred repeatedly in the United States. Fortunately, public health resources such as FoodNet can facilitate containment of these outbreaks through whole genome sequencing that link isolates from what would otherwise appear as sporadic cases of illness^16,17.

Table 1.

Epidemiology of major foodborne pathogens in the United States

pathogen(s)	cases	hospitalizations	deaths	references
Campylobacter spp.	~850,000–1.5 million	8500	80	3,143
nontyphoidal Salmonella spp	~1.4	20,000–26,000	400	3,143,160
Clostridium perfringens	~1 million	450	30	3
STEC*	~176,000–250,000	2500	20	3,15
Shigella spp.	~130,000	1500	10	3
Yersinia enterocolitica	~95,000–117,000	500–640	35	3
non-cholera Vibrio spp	~36,000–52,000	300	50	3,143
ETEC**	~18,000–80,000	12	0	3
other DEC***	~12,000	8	0	3

^*Shiga toxin producing E. coli (includes O157:H7 and other serotypes)

^**enterotoxigenic E. coli; https://www.cdc.gov/ecoli/diarrheagenic-ecoli.html

^***Diarrheagenic E. coli (Enteropathogenic, EPEC; enteraggregative E. coli, EAEC)

The incidence of bacterial gastroenteritis tends to vary considerably during the year. In contrast to noroviruses, the leading viral etiologies of AGE, bacterial enteric pathogens tend predominate during warmer weather, and are more frequently foodborne.

While the overall incidence of most infections transmitted by food has remained relatively stable, the epidemiology of these illnesses is not necessarily static. For instance, among the Salmonella enterica serotypes, Typhimurium was previously the most common but has continued to decline in incidence, perhaps due to vaccination of chickens¹⁷. It is now surpassed by serotype Enteritidis in the United States, commonly transmitted by consumption of eggs, or chicken¹⁸.

In addition, bacteria associated with AGE continue to evolve through acquisition of antimicrobial resistance traits as well as additional virulence factors. This is exemplified by the emergence of a novel STEC in Germany in association with an outbreak of more than 4000 illnesses related to sprout consumption^19,20 that resulted in 800 cases of hemolytic uremic syndrome and 50 deaths. Diarrheagenic E. coli have classically been divided into “pathovars” determined by the presence of specific virulence genes, such as Shiga toxin (stx) genes in STEC. However, the E. coli strain from the German outbreak had acquired not only Shiga toxin (stx1, stx2) genes, but also virulence genes from other pathovars of diarrheagenic E. coli in addition to extended spectrum beta lactamase resistance. A similar trend has been observed in outbreaks of Shigellosis in California in which strains gained virulence genes and enhanced resistance to fluoroquinolones²¹. Altogether, we can expect that lines separating different species and individual pathovars will continue to become less distinct as these genetically plastic organisms inevitably recombine²².

Characteristics of major bacterial pathogens associated with acute gastroenteritis

Campylobacter

Campylobacter are Gram-negative microaerophilic, somewhat fastidious pathogens that are responsible for a large burden of disease both in the United States and abroad. More than five species of Campylobacter (C. jejuni, C. coli, C. upsaliensis, C. fetus, C. lari and others) are known to infect humans. C. jejuni infections are the major cause of disease worldwide, although microbiologic techniques have likely been optimized for jejuni²³ perhaps biasing its selection to some extent. In the U.S., a strong association with chicken consumption^24,25 is somewhat predictable given that 40 to 95% of chicken available in grocery stores is infected with C. jejuni^26,27. Campylobacter is also a major pathogen associated with diarrhea in travelers, particularly in parts of Asia where antibiotic resistance is also increasingly common^25,28–30.

Illness associated with C. jejuni is most common during summer months, and may present with diarrhea (often bloody), fever, and abdominal pain with nausea and /or vomiting (table 2). When a college student spending the summer in Arizona (e.g., the nephew of one of the authors, jmf) prepares chicken on the grill for the first time, and is later hospitalized with fever and bloody diarrhea, Campylobacter enteritis is highly likely. Although infection with any of the species which infect humans may be complicated by bacteremia, the incidence is strikingly higher in C. fetus infections, and infected individuals are more likely to be hospitalized²³.

Table 2.

Summary of common bacterial enteropathogens associated with acute gastroenteritis syndromes

pathogen(s)	exposures	clinical presentation	diagnostic tests		references
			culture	CIDT
Campylobacter spp	poultry; unpasteurized dairy products, travel abroad, puppies, reptiles, contaminated water	abdominal pain, fever, nausea, vomiting, diarrhea (often bloody), rarely bacteremia	yes	yes	25,161–164
nontyphoidal Salmonella spp	eggs, chicken, multiple foods, backyard flocks, broad range of pets including amphibians and reptiles	abdominal pain, fever, nausea, vomiting, diarrhea, bacteremia more frequent with some serotypes*	yes	yes	40,165
STEC	numerous foodborne outbreaks with multiple vehicles of transmission including beef (particularly ground), sprouts, salad greens, cookie dough; petting zoos, childcare centers	diarrhea abdominal pain vomiting >bloody diarrhea (90%)->HUS (15%)	yes	yes	49,166,167
Shigella spp.	foodborne, travel abroad, homeless, easily transmitted person>person, daycares, MSMa	1–2 day incubation period; serotype sonnei causes most disease in US. typically milder illness. watery/bloody/mucoid stool; fever, abdominal pain, nausea	yes	yes	56–58,62,168–170
Yersinia enterocolitica	pork, pork intestines (chitlins); unpasteurized milk/dairy	abdominal pain (may mimic appendicitis) diarrhea/bloody persistent diarrhea; bacteremia, particularly with iron overload states; metastatic infections	yes	yes	171,172
non-cholera Vibrio spp	raw or undercooked shellfish		yes	yes	173–175
ETECb	international travel, domestic foodborne outbreaks.	abdominal pain, watery diarrhea occasionally profuse & cholera-like, occasionally prolonged duration of illness (median up to 7days) fever, vomiting infrequent.	no	yes	53,74,78
other DECc	international travel, domestic foodborne(?); EAECd has been associated with protracted diarrhea in HIV+ patients; EPECe previously identified as a cause of infant diarrhea in U.S.	typically, watery diarrhea; borborygmi, low grade fever, nausea.	no	yes	176–178
pre-formed enterotoxin syndromes
Clostridium perfringens	beef, poultry, catered, pre-warmed foods; restaurants	diarrhea and cramps within 6–24 (median 11) hours of ingestion. fever and /or vomiting are very infrequent.	no	no**	87
Bacillus cereus	rice/fried rice; meat; restaurants	2–12 (median 5) hours, vomiting, diarrhea	no	no**	87
Staphylococcus aureus	diverse vehicles; restaurants	sudden onset nausea, vomiting, abdominal pain, diarrhea within 30 minutes to 8 hours (median 4 hours) of ingestion. self- limited.	no	no**	87,89

^*Dublin>Cholerasuis>Schwarzengrund>Heidelberg>Enteriditis~Typhimurium

^**preformed toxin detection by reference/public health laboratory

^amen who have sex with men

^bETEC enterotoxigenic E. coli;

^cDEC diarrheagenic E. coli,

^dEAEC enteroaggregative E. coli,

^eEPEC enteropathogenic E. coli

Nontyphoidal Salmonella

Worldwide, the nontyphoidal Salmonellae (NTS, Salmonella enterica serovars other than S. typhi and paratyphi) are exceedingly common causes of gastroenteritis causing in excess of 90 million cases globally³¹, and more than 1 million cases each year in the United States. The majority of transmission by these incredibly diverse pathogens is foodborne although infection of humans also occurs via animal contact with reptiles and amphibians³² or poultry³³. Unlike Typhi, NTS are not human host-restricted pathogens, perhaps accounting for their prevalence as foodborne pathogens. Within the more than 20 different NTS serovars that infect humans Typhimurium and Enteritidis are overall the dominant serovars³⁴ in most regions.

Fever, abdominal pain and non-bloody diarrhea typically begin within several days of ingestion and most cases resolve spontaneously within the first week, without the need for antimicrobial therapy^35,36. Indeed, some antibiotics fail to impact the duration of symptomatic gastroenteritis while prolonging fecal carriage³⁷. Some individuals, particularly elderly³⁸ or immunosuppressed, are at higher risk for invasive infection, and some serovars (Dublin, Cholerasuis, Heidelberg) are more commonly reported from bloodstream infections in the United States. Serovars Typhimurium and Enteritidis are common causes of invasive disease in Africa^39–41, which flourishes in malnourished infants and young children^42–44.

Shiga toxin producing E. coli (STEC)

Escherichia coli that produce Shiga toxins stx1 and/or stx2 are collectively known as STEC, or previously enterohemorrhagic E. coli (EHEC). These pathogens typically require a low inoculum of bacteria to cause illness (as few as 10 colony forming units) and hence are associated with a wide range of transmission vehicles from sprouts to ground beef, as well as person-to-person spread in daycares. In the United States a particular E. coli serotype O157:H7 has predominated, however other serotypes are increasingly common and more easily identified with toxin-based culture-independent testing.

While many different routes of transmission have been reported, food vehicles often have contamination with the fecal matter of ruminant animals, particularly cattle, as the ultimate source. Cattle lack the globotriaosylceramide (GB₃) endothelial receptor for Shiga toxins⁴⁵; therefore, while their intestinal tracts become colonized with O157:H7 and other strains and cattle shed vast amounts of STEC bacteria in their stool, they do not become ill. Ground beef prepared at an industrial scale has posed a particular risk due to collective processing of meat from multiple animals into single lots. However, municipal water, and many foods, particularly foods consumed raw, e.g., leafy green vegetables^15,46 and sprouts^20,47, have repeatedly been linked to large regional or multistate outbreaks of STEC. Enteric pathogens including STEC can persist on the surface of vegetables and seeds for extended periods of time, and the pathogens can be internalized by the growing plant making them difficult to sterilize simply by washing⁴⁸.

Following ingestion of the organisms, patients typically begin to experience diarrhea within days (median 3) which begins as watery stool that becomes bloody in the majority of cases within several days. Abdominal pain and tenderness, and symptoms of pain on defecation are common while fever is not⁴⁹. While the majority of cases will resolve spontaneously, ~ 15% of patients who develop bloody diarrhea will go on the develop hemolytic uremic syndrome (HUS) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Antibiotics have been shown to accelerate release or production of Stx from lysogenic phages, and treatment antimicrobial therapy significantly increases the risk for HUS⁵⁰. Therefore, antibiotics should be avoided in initial treatment of patients with bloody diarrhea pending definitive identification of alternative pathogens such as Campylobacter, or Shigella while confirmed STEC infections should be managed supportively with volume expansion.

Shigellosis

Worldwide, Shigellae cause tremendous morbidity, and are a leading cause of diarrheal mortality in young children of low and middle income countries (LMICs), where they have also been closely associated with non-diarrheal sequelae including stunting and malnutrition^51–54. In the United States, these pathogens cause more than 100,000 cases of illness, each year.

Four main serotypes of Shigella, defined by their oligosaccharide antigens, infect humans. Shigella dysenteriae, flexneri, sonnei, and boydii have specific epidemiologic niches with flexneri being the predominant cause of disease in LMICs and sonnei the main cause of illness in the United States and other high-income regions.

Like STEC, these organisms are easily transmissible, requiring few organisms to cause infection⁵⁵. Unlike nontyphoidal Salmonella, STEC, Campylobacter and Yersinia, humans are the only known natural host for Shigella. Person-to-person transmission, with high rates of secondary spread can occur in daycares and other settings^56,57. Outbreaks have also emanated from restaurants, where food may be inadequately prepared or served by infected food handlers⁵⁸. Shigella infections along with those caused by STEC, and NTS are over represented in lower socioeconomic communities^59–61. Notably, drug-resistant Shigella flexneri, as well as S. sonnei transmitted internationally and domestically among men who have sex with men (MSM)^62–66 have emerged repeatedly in outbreaks in recent years. Clinicians caring for MSM, as well as travelers should be alert to treatment-resistant Shigellosis.

After an incubation period of 1–4 days infected individuals may manifest fever, anorexia, vomiting and watery diarrhea that may resolve without further progression in many healthy hosts. Alternatively, a proportion of cases, particularly with S. dysenteriae infection, will then progress to dysentery symptoms of abdominal pain and tenesmus accompanied by frequent small volume stools containing blood and mucus.

Diarrheagenic E. coli

In addition to Shiga toxin producing E. coli, several other types of Escherichia coli can cause acute gastrointestinal illness. These include the enteropathogenic (EPEC), enteroinvasive (EIEC), enteroaggregative (EAEC), and enterotoxigenic (ETEC) pathovars, which are defined by specific genes that differentiate these pathovars from one another and from commensal E. coli. Until recently, these pathogens were not easily distinguished in clinical microbiology labs, and only reached recognition during the course of fairly large outbreaks that prompted the involvement of state health departments and/or the CDC. All of these pathogens are more common in low-middle income countries where they contribute to the large burden of diarrheal morbidity that is concentrated among young children. Although each of these organisms can be isolated on occasion from travelers returning with diarrhea, ETEC is by far the predominant pathogen perennially associated with diarrhea in travelers⁶⁷.

Interestingly, while classically thought of as a pathogen in LMICs and travelers, foodborne outbreaks of ETEC have occurred repeatedly in the U.S.^68–80 and have been linked to vehicles as diverse as sushi⁷⁵ and potato salad⁷⁰. While the actual incidence of ETEC infections in the United States is not certain, recent studies conducted by the Minnesota Department of Health (MDOH) suggest that ETEC is not only the most common etiology of diarrhea in travelers, but perhaps a relatively common etiology of domestically acquired AGE^74,81. Only ~40% of the documented cases of ETEC in the MDOH study were from international travelers, raising the possibility that many domestic cases have gone unrecognized.

Fortunately, the majority of these infections are self-limited and do not require anything beyond replacement fluids in the form of oral rehydration. Occasionally however, ETEC can be severe and cholera-like, requiring hospitalization and intravenous hydration⁸². Indeed, the initial recognition of the ETEC pathovar came from patients presenting with severe, cholera-like illness in whom V. cholerae could not be identified^83–86.

Pre-formed enterotoxin syndromes

Three bacterial pathogens associated with acute gastroenteritis, Staphylococcus aureus, Bacillus cereus, and Clostridium perfringens (table 2) have in common rapid onset of illness due to toxins elaborated in inappropriately prepared or preserved foods prior to ingestion⁸⁷. Each of the enterotoxins produced by these pathogens induce diarrhea, while vomiting is a predominant manifestation of S. aureus and B. cereus intoxications but not that related to C. perfringens. The food vehicles involved are often quite diverse. In the case of staphylococcal food poisoning they simply need to support production of any of the more than 20 different enterotoxins produced by S. aureus strains^88,89. The incubation time from ingestion of the contaminated food to onset of symptoms is short (typically within hours). Fortunately, these are self-limited ailments that resolve with supportive treatment within 24–48 hours.

Predisposing factors

Medications that counter fundamental host defenses against invading enteric pathogens can put patients at increased risk. Proton pump⁹⁰ inhibitors may increase the risk for symptomatic infection⁹¹ with a number of enteric pathogens including nontyphoidal Salmonella, and Campylobacter^92,93 by reducing gastric acidity an essential first line of host defense. Similarly, prior antibiotic use has been shown to promote infection by both of these pathogens presumably by removing the colonization resistance of competing normal flora, or by fostering the selection of resistant organisms^24,94.

Our understanding of human host genetic predisposition to enteric pathogens is still evolving. S. typhimurium has been studied extensively in molecular pathogenesis and susceptibility studies in mice, yet parallel confirmation of the importance of individual genes in humans is generally absent⁹⁵. Nevertheless, relapsing Salmonella typhimurium infection reported in a patient with a mutation in the NF-kB signaling pathway, critical to both innate and adaptive immune responses to pathogens, highlights the potential importance of host genetics to susceptibility⁹⁶. The outcome of enteric infections can also be determined by host factors that permit more efficient colonization by enteric pathogens. For instance, recent studies of enterotoxigenic E. coli demonstrate that a common ETEC extracellular adhesin preferentially binds to A blood group glycans on enterocytes to promote host engagement and toxin delivery⁹⁷. In addition, human volunteers challenged with ETEC were more likely to develop severe illness if they were blood group A, recapitulating earlier studies in Bangladesh⁹⁸ that demonstrated that A+ young children were predisposed to develop symptomatic illness following ETEC infection compared to those in B or O blood groups.

Complications and sequelae of acute bacterial enteritis

It is important to recognize that although most cases of bacterial gastroenteritis will resolve spontaneously, they are occasionally followed by important sequelae. (table 3). Acute infections caused by invasive enteric pathogens, particularly non-typhoidal Salmonella (NTS), can be complicated by early dissemination of the pathogen to distant extraintestinal sites. Bacteremia with metastatic foci of infection, including aortitis, and bone and joint infections are well-described⁹⁹. Remarkably, ingestion of vehicles not regulated by the FDA, such as rattlesnake capsules, has on occasion resulted in serious extraintestinal NTS infections, particularly in immunosuppressed patients^100,101 seeking remedies outside of traditional medicine

Table 3.

Complications and sequelae of gastroenteritis

condition	associated pathogens	^risk/predispositions	references
bacteremia; extraintestinal infections	non-typhoidal Salmonella>Campylobacter, Yersinia	elderly, immunosuppressed infants, young children, mutations in TLR genes, immunocompromised adults in LMICsa	95
intestinal perforation, toxic megacolon	Shigella dysenteriae, infrequently complicates infection with other Shigella serotypes and other etiologies of colitis	typically, S. dysenteriae infections	51,179
nonsuppurative complications
reactive arthritis	Campylobacter, Salmonella, Shigella, Yersinia,	adult females, severe illness ±HLA-B27, ?PPIb, ?antibiotic administration, SNPc in IFNGd, duration of diarrhea	108,180–184 106,107
Guillain-Barré syndrome	Campylobacter jejuni	males ~1.5 × females. molecular mimicry of lipopolysaccharides of some strains and host gangliosides. SNPs in some host genes may contribute.	185
erythema nodosum	Yersinia, Shigella, Salmonella		90,186,187
sequelae of enteric infections in low-middle income countries
tropical sprue	?toxin-producing E. coli/Enterobacteriaciae	expatriates with extended exposure (e.g., Peace Corp volunteers) and residents of LMICs	114–116,119,124,125
environmental enteric dysfunction	ETECe and DECf pathovars, Shigella, Campylobacter	young children in LMICs	133,134,137,139

^aLMIC low-middle income country

^bPPI proton pump inhibitor

^cSNP single nucleotide polymorphism

^dINFG interferon gamma gene

^eETEC enterotoxigenic E. coli,

^fDEC diarrheagenic E. coli

Campylobacter bacteremia infrequently complicates AGE^102,103, typically in the setting of underlying chronic illness. Likewise, Yersinia enterocolitica is an infrequent cause of bacteremia and extraintestinal infection, and tends to occur in the setting of underlying iron-overload states including hemochromatosis^104–106.

Importantly, there is a very large burden of invasive NTS (iNTS) in LMICs, particularly in Africa, where large populations of young, often malnourished infants and children, as well as immunocompromised adults are at substantial risk¹⁰⁷. However, while iNTS infections far exceed cases of bacteremia complicating AGE in developed countries, iNTS dissemination tends to be more typhoid-like in presentation without clear antecedent gastroenteritis.

Nonsuppurative sequelae that evolve after resolution of the acute infection include reactive arthritis (including a subset of patients with the triad of arthritis, urethritis and conjunctivitis), and erythema nodosum. These have been linked to varying degrees to Campylobacter, Salmonella, Shigella and Yersinia infections. Curiously the incidence of reactive arthritis following AGE has ranged from 2/100,000 overall to remarkably high rates of 19% following a well-documented foodborne outbreak of Salmonella enteritidis¹⁰⁸ gastroenteritis, perhaps suggesting that some pathogens are more likely to be involved in molecular mimicry of the host.

Shigella infections, particularly those caused by Shigella dysenteriae can infrequently be complicated by toxic megacolon, rectal prolapse and intestinal obstruction or perforation. On occasion, Shigella dysenteriae and sonnei^109,110 have been linked to development of HUS, although not with the frequency of STEC¹¹¹. Likewise, although HUS has been reported following antibiotic treatment of Shigella dysenteriae with antibiotics¹¹², the risk appears to be quite low relative to STEC infections¹¹³.

Guillain-Barré syndrome (GBS), closely linked to antecedent Campylobacter jejuni gastroenteritis, tends become manifest ~3 weeks after the infection. Infection with C. jejuni is thought to elicit production of antibodies against lipopolysaccharide glycans that cross react with host gangliosides present in peripheral nerves. As fewer than 1/1000 individuals develop GBS following C. jejuni enteritis, investigators have sought host factors that may be required for effective molecular mimicry between LOS and gangliosides.

Sequelae in low-middle income countries

Additional potential sequelae of these infections are seen almost exclusively in LMICs. These include tropical sprue in adults and environmental enteric dysfunction (EED) in young children. Both conditions share features of altered nutrient absorption and alteration of the small intestinal architecture.

Tropical sprue is most clearly manifest in expatriates^114–116 living for extended periods of time in areas highly endemic for diarrheal diseases (e.g. Peace Corp volunteers)¹¹⁷, who typically present with weight loss, periodic diarrhea, steatorrhea, and vitamin deficiencies^{114,115,118–123}. Tropical sprue remains the most common etiology of malabsorption in some areas of Asia^119,124,125. Studies in the 1970s revealed the presence of toxin-producing Enterobacteriaciae, including E. coli in small intestinal aspirates of tropical sprue patients^126–130 however Koch’s postulates clearly linking individual pathogens to these illnesses have yet to be established. Fortunately, antibiotic therapy combined with folate administration has been shown to ameliorate tropical sprue^131,132.

EED or “environmental enteropathy”^133,134 is a complex condition of young children in LMICs characterized by growth faltering, and nutrient malabsorption^135–137. EED has also been epidemiologically linked to prior exposures to enteric pathogens including ETEC^138,139, other diarrheagenic E. coli, Shigellae and Campylobacter¹⁴⁰. Similar to tropical sprue the precise role of these pathogens in the molecular pathogenesis of EED is still not well defined. Unlike tropical sprue, EED has not been shown to be reversed by administration of antibiotics and folate supplementation.

Advances in diagnostic testing and the impact of molecular culture-independent methods

Previously, the majority of cases of AGE and foodborne illness never received a pathogen-specific diagnosis, in part due to limitations of culture-dependent methodologies¹. The recent and expanding deployment of syndromic culture-independent molecular diagnostic tests (CIDTs) for acute gastroenteritis to clinical microbiology laboratories has already had an appreciable impact on the approach to these illnesses¹⁴¹. While the FDA-cleared platforms currently in use vary in the breadth of pathogens that can be detected, they generally share high degrees of sensitivity and specificity and offer some advantages over traditional culture dependent methodologies including:

1. The detection of pathogens such as the diarrheagenic E. coli (other than STEC), for which there were no reliable culture-based methods. Overall, diagnosis of ETEC and other diarrheagenic pathovars of E. coli (DEC), enteropathogenic (EPEC), enteroaggregative (EAEC), and more fastidious pathogens like Campylobacter spp are among pathogens most likely to benefit from CIDTs.

2. CIDTs permit more rapid diagnosis, typically within hours relative to culture-dependent methods which may take days.

3. The sensitivity relative to culture-based methods is typically superior. Nevertheless, many cases of AGE will not receive an etiologic diagnosis even with the improved detection relative to conventional tests.

4. CIDTs may foster more frequent targeted therapy (by excluding viruses) over conventional testing.

5. Conversely, CIDTs may also prevent inappropriate empiric antibiotic administration¹⁴¹ (e.g., in cases of STEC which can be exacerbated by antibiotic administration⁵⁰).

Unfortunately, CIDTs in their current state, when used without cultures, also have significant limitations¹⁴² including inability to provide antimicrobial sensitivity data, and impairment of outbreak investigations due to lack of isolates for molecular typing and characterization¹⁴³. Therefore, positive CIDTs should be complemented by cultures to generate antibiotic sensitivity data and to preserve the isolate when appropriate.

Therapy

Treatment of acute gastroenteritis has been reviewed extensively in recently published guidelines^142,144,145. Therefore, here we summarize salient developments that may impact patient care since these were released. It is important to recognize that most cases of AGE, both viral and bacterial, resolve without specific antimicrobial therapy.

Alarmingly, however many of the bacterial pathogens associated with AGE have become increasingly resistant to antibiotics^146,147. Campylobacter, nontyphoidal Salmonella, and Shigella have all been cited recently by the CDC as posing serious threats as multidrug resistant pathogens¹⁴⁸. The rapid exchange of genetic information between Gram-negative pathogens and their surroundings will continue to confound a strictly empirical approach to antibiotic treatment of AGE, and necessitate confirmatory sensitivity testing to modify therapy. Antibiotic resistance in Shigella has been particularly alarming, and has now emerged in many communities¹⁴⁹. Heavy use of antibiotics is likely to exacerbate this problem as plasmids encoding extensive drug resistance appear to be easily transferred from commensal E. coli to Shigella¹⁵⁰. Both use of antibiotics and traveler’s diarrhea have been independently associated with colonization by ESBL-producing Enterobactericiae¹⁵¹.

Antibiotic administration can clearly be life-saving in patients with moderate-severe illness, particularly in the setting of extraintestinal infection. However, it has become increasing appreciated that antibiotics may exert negative effects on the microbiota^152,153 leading to consequences to human health that persist well beyond the acute infection^154,155. In addition, fluoroquinolones, widely used for treatment of AGE in the past, have been linked to substantial side effects that should limit their use to more severe infections¹⁵⁶. Collectively, these developments argue for judicious use of antibiotics to treat what are most often self-limited infections.

Discussion

Foodborne illness and acute gastroenteritis caused by bacterial pathogens is very likely to present a continued challenge for clinicians. Although much of the foodborne illness caused by live bacteria could be mitigated by more extensive food irradiation¹⁵⁷, this strategy has been slow to be adopted in the United States despite the repeated recommendations of multiple public health agencies^158,159. While networked public health laboratories can now extinguish outbreaks by investigating the relatedness of isolated pathogens by whole genome sequencing, it is likely that bacterial gastroenteritis will pose a continued threat for the foreseeable future. Moreover, these pathogens will inexorably evolve through acquisition of virulence traits and resistance determinants posing additional challenges. Only interruption of food contamination at the source is likely to decrease the perennial onslaught of acute bacterial gastroenteritis.

Key Points.

• Bacterial gastroenteritis syndromes are exceedingly common globally and in the United States where most infections are foodborne, and food distribution networks can lead to widespread outbreaks.

• Nationwide reporting and strain characterization efforts are in place to mitigate these outbreaks.

• Pathogens continue to evolve through genetic exchange of virulence traits and antibiotic resistance genes.

• Culture-independent molecular based diagnostic testing provides some advantages over traditional microbiologic approaches. However, cultures remain important to provide antibiotic sensitivity data and to archive bacteria for outbreak investigations by public health authorities.

• Most bacterial infections associated with acute gastroenteritis resolve spontaneously with supportive treatment, and antibiotic use may promote resistance and alteration of the microbiota providing strong impetus for judicious antibiotic use.

Synopsis.

Acute bacterial gastroenteritis is among the most common infections worldwide with millions of infections annually in the United States. Much of the illness is foodborne, occurring both in the form of sporadic cases and large multistate outbreaks. Pathogen evolution through genetic exchange of virulence traits and antibiotic resistance determinants, poses challenges for empiric therapy. Culture-independent diagnostic tests in clinical laboratories afford rapid diagnosis and expanded identification of pathogens. However, cultures remain important to generate sensitivity data and strain archiving for outbreak investigations. Fortunately, most infections are self-limited, permitting judicious selection of antibiotic use in more severe forms of illness.

Clinical care points.

• AGE is predominantly caused by bacterial pathogens during warmer months while Noroviruses predominate in winter

• CIDTs can accelerate diagnosis and tailor treatment options in most instances. However, in their current state, complementary cultures are recommended to obtain susceptibility data and to provide isolates for analysis in the event of an outbreak.

• Most acute gastroenteritis can be managed supportively. Antimicrobial resistance profiles continue to evolve rapidly and many pathogens including some Shigella strains are now extensively multidrug resistant, limiting effective empiric treatment options.