Bacterial Infectious Diarrhea & Enteric Fever

diarrhea

-passage of 3 or more loose or liquid stools per day

OR

-bowel movements more frequently than is normal for the individual

WHO epidemiology of diarrhea

-most deaths are preventable

-2.2 million lack access to safe drinking water

-3 billion people lack access to handwashing facilities/soap

-673 million practice open defecation

-5th leading cause of death in children <5 yo

-lack of sanitation worsens gender disparities

-disproportionately affects children in world’s poorest regions

bacterial enteric infections

-watery (small intestine)

-blood (dysentery- colon)

-enteric fever (systemic)

clinical approach to bacterial infectious diarrhea/enteric fever

bacterial pathogens typical transmission

microbiology of infectious diarrheas

diarrhea pathogenesis

-inoculum size

-adherence

-toxin production: enterotoxin, cytotoxin (type of enterotoxin that injures cells), neurotoxin

-tissue invasiveness

diarrhea pathogenic mechanisms

-lower the inoculum, easier to spread person-person

diarrhea pathogenic mechanisms- toxin production & invasion

host defenses

pathogenic mechanisms- neurotoxins

-Staphylococcus aureus enterotoxin: heat-stable toxin (incubation 2-4 hours), increase peristalsis by autonomic activation, resulting in intense vomiting/diarrhea

-Bacillus cereus enterotoxin: 2 enterotoxins (emetic- heat stable toxin, elaborated in starchy foods, incubation period 1-6 hours; diarrheal- incubation period 10-12 hours)

vomiting center (VC)

-located in the dorsolateral medulla adjacent to ascending reticular activating system & medullary centers controlling CV and respiratory reflexes

-afferent connections from cortex, limbic system, hypothalamus, vestibular centers, gut, and other viscera are known

-VC integrates input from central and peripheral afferents and modulates the autonomic and somatic motor response to noxious stimuli

-chemoreceptor trigger zone (CTZ) located in floor of fourth ventricle provides specific receptors for circulating toxins in the blood, CSF relays info to the VC

cholera

-clinical: variable (genetic factors- 75% asymptomatic, 20% abrupt watery diarrhea, 5% severe watery diarrhea/vomiting/dehydration), dehydration, duration 1-3 days, no tenesmus/strain or abdominal pain/fever, shed 7-14 days

-treatment: rehydration (IV or oral rehydration solution (glucose and electrolytes)), antibiotics (tetracycline, quinolone, macrolide- local resistance patterns)

-protection: stomach acid, IgA and IgG against LPS, vaccine

Vibrio cholerae

-curved gram-negative facultative bacillus with single polar flagellum

-over 200 serogroups (based on O antigen in LPS), but only O1 (El Tor is a variant) and O139 are associated with epidemic and pandemic cholera (Non-O1 or non-O139 can be pathogenic and cause small outbreaks, cholera can be epidemic or endemic)

-susceptible to stomach acid so must ingest large quantities of bacteria

Vibrio cholerae pattern and transmission

-both an endemic and epidemic pattern

-transmission through contaminated food and water, person-to-person transmission unusual

-lives in aquatic environments attached to algae or crustacean shells via surface protein

-multiplies when temperature, salinity, and nutrients are suitable

cholera pathogenesis

-consume water or fecally-contaminated food

-incubation usually 1-2 days (2 hr to 3-5 days incubation period)

-survive the acidity of the stomach

-get to the small intestine where they bind to the epithelium via pili including toxin-coregulated pillus (TCP) and aggregate to protect them from bile

-secretion of cholera toxin

cholera toxin

Yemen

-largest cholera outbreak in modern times

->1 million suspected cases

->3000 deaths reported since 2017

-due to civil war

Escherichia coli

-enterobacteriaceae

-lactose-fermenting GN rods

-pili

-flagella

-many toxins (may include shiga like toxins STX-1 and STX-2 toxins)

-found in human and GI tracts of many animals including cattle, the main reservoir for EHEC

E. coli types

ETEC (enterotoxigenic E. coli)

-840 million cases/year worldwide

-traveller’s diarrhea (30%) cases

-heat-stable (STa) or heat-labile toxin that causes hypersecretion of fluids in the small intestine

-STa: small monomeric peptide, binds to transmembrane guanylate cyclase C receptor on the intestinal epithelium, leading to an increase in cyclic guanosine monophosphate (cGMP), inc fluids out, prevents fluids in

-LT1: 80% homology to cholera toxin AB5

-1-2 days incubation, 3-5 days symptoms

-watery, non-bloody diarrhea, cramping

-host cell is NOT invaded by whole bacterium

EHEC/STEC (enterohemorrhagic E. coli)

-low inoculum (<100)

-attaches to epithelial cells

-injects several proteins via type III secretion apparatus including: Tir which then appears at the epithelial cell surface and serves as a receptor for the bacteria (intimin on the bacterium binds to Tir), proteins involved in disrupting and reorganizing host cell actin

-all have lysogenic phase encoding STX-1 and/or STX-2 (binds to 28S ribosome, disrupts protein synthesis, causes cell death of both epithelial cells and capillaries → hemorrhagic colitis; may cause HUS (5-10% children <10 years): shiga-toxin enters the circulation and damages endothelial cells, binds to PMNs, and induces proinflammatory state)

hemolytic uremic syndrome (HUS)

-due to circulating STX (usually STX-2, binds to glomerular epithelial cells): hemolytic anemia with fragmented erythrocytes, acute renal injury, thrombocytopenia, CNS symptoms, HTN

-can cause capillary thrombosis and inflammation/damage colonic mucosa → hemorrhagic diarrhea

course of EHEC in children

E. coli O157 outbreaks

Shigella clinical manifestations

-12 hours after ingestion, bacterial multiplication begins in the small intestines resulting in abdominal pain, cramping, watery diarrhea, and fever

-as the colon is invaded → onset of severe lower abdomen pain, accompanied by urgency, tenesmus, and blood mucoid stools (dysentery)

-resolution of fever in a few days

-illness lasts for average of 7 days

-colonic shedding for 1-4 weeks

-antibiotics can reduce shedding

Shigellosis transmission

-contaminated: hands, food, water (sewage)

-oral-anal contact

Shigella characteristics

-small non-motile GN rod, member of Enterobacteriaceae, tribe Escherichieae (human host or non-human primates)

-very similar to E. coli, except no flagella and they are non-lactose fermenteres

-40 serotypes, 4 species: Shigella sonnei (most U.S. cases), S. flexneri (developing countries), S. dysenteriae, S. boydii (less common)

-S. dysenteriae type A1 is most virulent and potent producer of STX (shiga toxin): usually found in tropical, developing areas

Shigella pathogenesis

-low inoculum (<200 organisms, few as 10): person-to-person spread, direct fecal contamination of food, secondary cases common

-acid resistant

-invasion of intestinal epithelial cells, moving from small to large intestines, with multiplication and mucosal destruction including ulceration and abscess formation

-enterotoxin AND cytotoxin elaboration (STX)

-penetration beyond mucosa is rare

pathogenic mechanisms

-2 enterotoxins, but also a cytotoxin: shiga toxin (STX)

Shiga toxin (AB5 toxin)

-produced by S. dysenteriae 1

-not necessary for virulence

-B subunit binds to host cell glycolipid (Gb3) and facilitates transfer of A subunit

-A subunit disrupts the protein synthesis by preventing binding of aminoacyl-transfer RNA to the 60S ribosomal subunit

-results in destruction of intestinal cells and villi, decreasing intestinal absorption

-similar to STX-1 and can be associated with HUS

salmonella

-microbiology-member Enterobacteriaceae

-GN, facultative anaerobic rod

-S. enterica has numerous serovars

clinical manifestations of Nontyphoidal Salmonella

typhoid fever- clinical manifestations of S. typhi and S. paratyphi

-Rose spots- bacterial emboli to the skin

-rash of Typhoid fever

salmonella pathogenesis- tissue invasion

salmonella pathogenesis

approach to patient with acute diarrhea

-don’t usually present, but if they do…

-history:

-clinical features: onset (abrupt, gradual) and duration, stool characteristics and frequency, associated symptoms, systemic symptoms (thirst, tachycardia, orthostasis, decreased urination), lethargy, altered sensorium)

-epidemiological features: travel to developing areas, consumption of unsafe foods or water, illness in others with common food source, sick contacts, oral-anal sexual contact, recent antibiotics or hospitalization, underlying medical conditions, on laxatives?

-stool evaluations

diarrhea treatment

-rehydration most important

-antibiotics: moderately-severe invasive disease (shigella, campylobacter, salmonella), avoid antibiotics for EHEC

take home points