GI Exam 2 Part 2

Strongyloides

The presence of characteristic rhabditiform larvae in fresh stools is diagnostic of __________ infection.

Brucellosis •B. melitensis (goats, sheep, camels); B. abortus (cattle); B. suis (pigs); B. canis (dogs) •100-200 cases annually in the US •Risk factors: Unpasteurized dairy products, hunters Brucellosis (also known as 'undulant fever,' 'Mediterranean fever,' or 'Malta fever') is a zoonotic infection transmitted to humans from infected animals (cattle, sheep, goats, camels, pigs, or other animals) by ingestion of food products (such as unpasteurized dairy products)

A hunter drinks unpasteurized goat milk and develops diarrhea and a fever that comes and goes. Dx?

Paralytic shellfish poisoning •Saxitoxins block Na+ channels •Not destroyed by heat, marinating, or freezing •Made by Alexandrium dinoflagellates •Symptoms begin in a few minutes - 4 hours after eating •Perioral tingling, ataxia, difficulty swallowing, dizziness, weakness to paralysis, respiratory failure •Improve gradually after 12 hours, resolve within a few days or Neurotoxic shellfish poisoning •Very similar to paralytic shellfish poisoning •Red tides; southeastern US, Gulf of Mexico, Caribbean •Toxins taken up by bivalve shellfish •Brevetoxins increase Na+ channel permeability •Dinoflagellate Karenia brevis •Large degree of fish/fowl kill-offs •2 clinical syndromes •Ingestion: GI distress and neurologic symptoms develop similar to PSP within 30 minutes - 3 hours. Also, Dysesthesia (hot/cold sensation reversal) •Inhalation: nasal and respiratory irritation, rhinorrhea, bronchoconstriction •Most patients recover within 3 days though coma and seizures may occur. Tx is Supportive fluids and maybe charcoal ingestion

A patient comes in having consumed food contaminated with "red tide". What pathogen? Pathogenesis? presentation?

•The life cycle of Strongyloides is broadly similar to that of hookworm, but shows some important differences: •Humans harbor only parthenogenetic females that lay eggs into the mucosa. •These eggs hatch in the intestine and the released rhabditiform larvae usually pass out in the feces •Development outside the host can follow the hookworm pattern, with the direct production of skin-penetrating filariform larvae, • OR production of a complete free-living generation including adult males and females, which then produce infective larvae.

Describe the life cycle of Strongyloides.

Taxonomy (L. monocytogenes) •Aerobic and facultatively anerobic •Beta-hemolytic, non spore forming •Short Gram + rod •Tumbling motility •Only Gram + bacterium with Lipopolysaccharide (LPS) Pathogenesis •Facultative intracellular parasite •Main virulence factor: listeriolysin O •Pore forming toxin; cholesterol dependent cytolysin •Induces TCR unresponsiveness

Describe the shape and stain of listeria? Pathogenesis?

Ascaris lumbricoides (Giant Roundworm)

Dx?

Cryptosporidium oocysts in fecal specimen

Dx?

Cyclospora cayetanensis picture recognition "I will not ask you to recognize a pathogen on the egg alone. But boards might and I will probably give you the egg in addition to other information, so it may be worth knowing" -Dr. Herrmann

Dx?

Eggs of (A) Diphyllobothrium latum and (B) Hymenolepis nana (dwarf tapeworm)

Dx?

Taenia saginata . (A) Gravid proglottid stained with India ink to show numerous side branches. (B) Egg containing six-hooked (hexacanth) larva.

Dx?

Trematode (Fluke)

Dx?

Trichinella spiralis with a muscle biopsy

Dx?

Organism Shigella Entamoeba Polymorphs and macrophages in stool Many Few Eosinophils and Charcot-Leyden crystals in stool Few or absent Often present Organisms in stool Many Few Blood and mucus in stool Yes Yes

Dysenteries of amoebic and bacillary origin can be distinguished by a number of features by.......

•Immunomodulation, •Phagocytosis of immune cells •Protease-based destruction of soluble immune mediators (as per the previous slide)

E. histolytica is able to evade the immune response by a variety of methods including:

•History is going to be very important to establish exposure > freshwater in endemic areas, so ask if people have been travelling! •Stool sample/urine sample > look for eggs •Eggs can be in tissue > rectal/bladder mucosa •Serological tests (Elisa, immunoblot) •Imaging studies may be helpful depending on presentation

How do you diagnose a trematode dz?

•Fluorescence microscopy or modified Ziehl-Neelsen staining can be used to demonstrate oocysts in thin fecal smears. •Antigen detection ELISA assays can be used •Direct immunofluorescence microscopy and PCR both have high specificity •PCR, commonly as a multiplex assay detecting Cryptosporidium , Giardia and E. histolytica, is now widely available.

How do you diagnose cryptosporidium?

•Diagnosis of Giardia infection is based on identifying cysts or trophozoites in the stool. •Formalin-ether or formalin ethyl acetate concentration is superior to direct wet film microscopy. •Immunofluorescence staining of fecal smears has high specificity. •Repeated examination is necessary in light infections. •Alternatives to microscopic methods are increasingly available, including fecal antigen detecting ELISA tests with good specificity, and PCR. • Multiplex PCR assays detecting Giardia, Cryptosporidium and E. histolytica in fecal specimens are now widely available.

How do you diagnose giardia?

•Whereas schistosomiasis is widespread in tropical and subtropical regions, other parasitic infections affecting the liver are more restricted in their distribution (e.g. clonorchiasis and alveolar hydatid disease). •In Asia, infections with the human liver fluke Clonorchis sinensis are acquired by eating fish infected with the metacercarial stage. •Juvenile flukes released in the intestine move up the bile duct and attach to the duct epithelium where they are able to live for 20 years, feeding on cells/blood and tissue fluids.

How do you get Clonorchis sinensis?

•Diphyllobothrium latum , the fish tapeworm, is widely distributed geographically •Infection is restricted to individuals eating raw or undercooked fish carrying the infective larvae. The eggs of this species have a terminal 'lid', known as an operculum and are the diagnostic stage in the stool

How do you get Diphyllobothrium latum? How do you diagnose it?

•Liver fluke, infects humans and other mammals •Common in approximately 61 countries •~ 3 million case worldwide •Humans infected by ingestion of contaminated water plants, such as water cress •Acute phase •During the acute phase, the parasite is migrating, through duodenum, peritoneal cavity, to the liver. •It burrows through the liver • Sx: fever, abdominal pain, hepatomegaly (enlarged liver), eosinophilia •Chronic phase •Biliary: cholangitis (infection of the bile ducts)

How do you get Fasciola hepatica? How does it present?

The major functions are: •generation of NADPH and five-carbon sugars •Liver has a high demand for NADPH •biosynthesis of fatty acids and cholesterol •synthesis of VLDL and bile salts

The Pentose Phosphate Pathway What is the major function of this pathway?

Campylobacter (occurs 1-3 weeks after GI symptoms)

What GI bug is associated with developing Guillain-Barre syndrome?

Of tape worms •Proglottids are the body segments containing eggs, and are periodically shed in the feces

What are Proglottids?

•In most individuals, worm infections produce chronic mild intestinal discomfort rather than severe diarrhea or other conditions. •Infections may lead to hypersensitivity responses and can also reduce responses to vaccination. •Each parasite has a number of characteristic pathological conditions linked with it that we will discuss

What are some Clinical features of pinworm infections?

E. Hystolitica - only protozoa •Some worms live there as adults and others migrate through the liver to reach other locations. •Inflammatory responses to the eggs of Schistosoma mansoni result in severe liver damage •Liver pathology in parasitic infections is most severe in S. mansoni infection. •Although the worms spend only a relatively short time in the liver before moving to the mesenteric vessels, •eggs released by the females can be swept by the bloodstream into the hepatic circulation and be filtered out in the hepatic sinusoids. •The inflammatory response to these trapped eggs is the primary cause of the complex changes that result in hepatomegaly, fibrosis and the formation of varices

What are some Parasitic infections affecting the liver?

•Symptoms - abdominal discomfort, diarrhea, vomiting, and weight loss. •Vitamin B12 deficiency and anemia may occur •Largest human tapeworm •Causes Diphyllobothriasis •Most infections are asymptomatic

What are symptoms of Diphyllobothrium latum?

Toxins S. aureus, B. cereus, C. botulinum Symptoms in 1-6 hours (pre-formed ) Trigger inflammatory cytokine release Toxin production after ingestion Vibrio, Shigella, STEC Symptoms ~24 hours after exposure Interacts with intestinal epithelium Invasion of intestinal epithelium Viruses, Salmonella, EIEC, Campylobacter Destroys endothelium Symptoms last 1 day to weeks

What are the 3 basic pathological mechanisms of food bourne illness? What pathogens fall in each category? How does this affect presentation?

Reflects 4 phases of infection •Ground itch, cutaneous larva migrans •Pulmonary symptoms (maybe) •GI symptoms •Chronic nutritional impairment •Diagnosed by finding eggs in stool •May see eosinophilia, occult blood in stool

What are the 4 phases of hookworm infection? How do you diagnose it?

•Benefits of antibiotics is unclear • Metronidazole or ceftriaxone or moxifloxacin •Anaerobic bacteria so metronidazole would be of use

What is the tx for Spirochetosis (Brachyspira pilosicoli)?

Mushroom poisoning (fatal) •Mushrooms that cause symptoms >6 hours after ingestion are more likely to have serious effects •Delayed gastroenteritis and liver toxicity •Most of these mushrooms contain amatoxin •Most fatalities due to Amanita species •Amatoxins are cyclic octapeptides •Heat stable, insoluble in water •Alpha amanitin most responsible for human toxicity •Pathogenesis •Toxin absorbed from GI tract, transported to liver through portal circulation •Inside hepatocytes, toxin binds to DNA-dependent RNA polymerase II; stops intracellular protein production, results in apoptosis •Other organs with rapid cell turnover may be affected (GI tract, renal tubules)

A patient decides to pick their own mushrooms for a pizza and presents with acute gastroenteritis 12 hours later. Dx? Pathogenesis? Other symptoms?

Mushroom poisoning (mild) •Mushrooms that only cause acute toxicity are rarely life-threatening •Symptoms that begin <6 hours after ingestion •Acute gastroenteritis (most common) •Hallucinations •Psilocybin and psilocin: stable alkaloids related to LSD •CNS excitation and depression •Caused by muscimol (depressant) and ibotenic acid (excitatory) •Cholinergic poisoning •Caused by muscarine; structurally similar to acetylcholine •Disulfuram-like reaction (acute sensitivity to alcohol) •Caused by coprine; metabolites irreversibly inhibit aldehyde dehydrogenase

A patient decides to pick their own mushrooms for a pizza and presents with acute gastroenteritis 4 hours later. Dx? Pathogenesis? Other symptoms?

Ciguatera poisoning •Caused by eating tropical reef fish contaminated w/ dinoflagellate Gambierdiscus toxicus •Grouper, snapper, amberjack, barracuda, (predators) •Ciguatoxin is lipid-soluble, heat-stable, acid-resistant neurotoxin •Opens Na channels, causes depolarization •Cooking doesn't destroy the toxin •Nausea, vomiting, diarrhea occur 1-24 hours after ingestion •Followed by hypesthesias, paresthesias, numbness, malaise, generalized weakness, temperature sensitivity, dysesthesias •GI symptoms resolve over a few days; neurologic symptoms may persist....see below Don't confuse with Neurotoxic shellfish poisoning which also presents with dysthesia but come from shellfish

A patient eats a grouper then presents with dysthesias. Dx? Pathogenesis?

Diarrheic shellfish poisoning •Outbreaks occur around the world •Associated with mussels and scallops •Several toxins; best known: okadaic acid •Lipid soluble, inhibits phosphatases •Symptoms usually occur within 2 hours of eating •N/ V/ D , chills, cramps •Resolve within 2-3 days. Tx is supportive and reassurance.

A patient eats scallops and then gets diarrhea. Pathogenesis?

Balantidium coli causes balantidiasis

A pig farmer gets diarrhea from a ciliated pathogen in the large intestine. dx?

The portal fibrosis of Schistosoma mansoni is the end result of large numbers of granulomas formed around worm eggs deposited in the liver. In the related Schistosoma haematobium infection, a similar process occurs in the wall of the bladder. (A) Egg of S. mansoni (×400). (B) Pipe-stem fibrosis in the liver as a result of coalescent calcified granulomas. (C) Cellular reaction around an egg in the liver. E, egg containing miracidium; G, giant cell; H, hepatic cell. (D) Advanced clinical schistosomiasis with massive hepatosplenomegaly and ascites due to portal obstruction.

A, B, C, D, E, G, H?

Eggs and larvae of intestinal nematodes passed in feces. (A) Egg of Ascaris (fertile). (B) Egg of Trichuris . (C) Egg of hookworm. The embryo continues to divide in the fecal sample and may be at the 16- or 32-cell stage by the time the sample is examined. (D) Larva of Strongyloides stercoralis . "I will not ask you to recognize a pathogen on the egg alone. But boards might and I will probably give you the egg in addition to other information, so it may be worth knowing" -Dr. Herrmann

A, B, C, and D?

C. hominis C. parvum

Although there are 26 species of Cryptosporidium , a very high proportion of human infection is due to ___________ , which is specific to humans, and ___________, which infects calves but is also capable of causing disease in humans.

Strongyloides •However, there is some cross-reactivity with IgG made against other nematode infections and one cannot determine whether the Strongyloides infection occurred recently or in the past

An enzyme immunoassay can be used to detect ___________ antibody and has approximately 90% sensitivity of detection.

colon Sulfapyridine and 4-ABA 5-ASA (mesalamine)

Azo-bonded 5-ASA: •Site of action is the _________. Broken down by bacteria in the intestines •Olsalazine is broken down to 5-ASA •Balsalazide is broken down to 5-ASA and 4-ABA •Sulfasalazine is broken down to sulfapyridine and 5-ASA •__________ and _________ are metabolites •____________ is active drug

•Causes trichinellosis •Undercooked meat; especially pork •Transfer via ingestion of the cyst •release of larvae in the stomach •development to adult in the GI. •Adults mate and shed larvae that burrow out through the walls of the GI, into bloodstream/lymph system. •Then move into other systems, preferentially into the muscle. • Protected there from the host immune system. •Humans are incidental host, not definitive host.

Breifly describe the life cycle of Trichinella spiralis?

•Those larvae of Ascaris penetrate the bowel wall and are carried in the blood through the liver to the lungs, •migrating up the bronchi and trachea before being swallowed and once again reaching the intestine. •The adult worms live freely in the gut lumen, feeding on intestinal contents. •In contrast, Trichuris larvae remain within the large bowel, penetrating into the epithelial cell layer, where they remain as they mature.

Briefly compare and contrast the life cycles of ascaris and trichuris.

•Largest nematode, occurs in the intestine •Egg is the infectious part of the life cycle. •Humans encounter eggs in the soil or water. •Eggs travel to the jejunum then move to the heart and lungs. •Coughed up in the trachea, swallowed down to the GI tract. •Pneumonitis, intestinal obstruction •Loeffler's syndrome (eosinophilic pneumonitis - WBC accumulation in the lung) Prevention > hygiene is most important factor

Briefly describe the life cycle of Ascaris lumbricoides ?

•Proglottids are the body segments containing eggs, and are periodically shed in the feces •Eggs ingested by an intermediate host, such as cow, pig, fish, sheep, goat. •Eggs hatch, larvae emerge and penetrate the gut, migrating from there to various tissues. •Particularly like muscle tissue. •Humans then ingest meat contaminated with encysted larvae

Briefly describe the life cycle of Taenia saginata

•Eggs passed in feces. •Ingested from the soil. •Hatch in the intestine: •Larval form moves through the body and ends in the small intestine, hatching there •Then moving to their attachment place in the large intestine.

Briefly describe the life cycle of Trichuris trichiura.

a combination of: •adhesins and lectins •damage via amoebapore-, phospholipase- and protease-induced cytolysis followed by phagocytosis. •They invade the mucosa and feed on host tissues including red blood cells, giving rise to amoebic colitis

Entamoeba histolytica-life cycle: •The cysts pass intact through the stomach when swallowed and excyst in the small intestine, each giving rise to four progeny. These adhere to the epithelial cells using.....

Budesonide Rectal Foam •Maximize colonic tissue effects and minimize systemic absorption via topical treatment of active inflammatory bowel disease in rectum and sigmoid colon •Budesonide is synthetic analog of prednisolone - high affinity for glucocorticoid receptor but rapid hepatic-first pass metabolism •Budesonide comes in controlled release formulation for delivery to distal ileum and rectal foam for colon

Excuse me....Why?

•However, infection is usually asymptomatic, apart from revulsion felt on passing the large segments. •Diagnosis involves finding these segments or the characteristic eggs in the stool

How do you diagnose Taenia saginata?

•Genotypes A and B can infect dogs, cats and cattle as well as humans, •so human infection with these genotypes can be zoonotically acquired

Genotyping has demonstrated that Giardia consists of at least seven different genotypes. Which ones amtter?

glucose-1-P

Glycogen is both formed from and degraded to ___________

•Tapeworms are not generally considered highly pathogenic, but there can be serious clinical syndromes with tapeworm infestation •Most infections are asymptomatic or minor abdominal pain •Patient may notice passing worms •Patients may have vitamin deficiencies

How do cestodes usually present?

•Serology (by indirect fluorescent antibody technique [IFAT] or ELISA) is the mainstay of diagnosis for an amoebic liver abscess. •E. histolytica infection can be diagnosed in asymptomatic patients from the presence of characteristic four-nucleate cysts in the stool (see next slide) •These cysts may be infrequent in light infections, and repeated stool examination is necessary. •Care must be taken to differentiate E. histolytica from other non-pathogenic species that might be present •Trophozoites can be found in cases of dysentery (when the stools are loose and wet), •but they are fragile and deteriorate rapidly; specimens should therefore be preserved before examination. •ELISA tests are available, as is a triage panel assay that can distinguish between E. histolytica / E. dispar , Cryptosporidium parvum and Giardia intestinalis . •Differentiation of E. histolytica from E. dispar requires immunological tests or species-specific PCR.

How do you diagnose E. histolytica?

•Dx techniques - scotch tape test, put a clean piece of tape to the area and then place on a slide, microscopy •stool/ urine sample may produce eggs •Vaginal smears may show eggs •Found in examination of ano-rectal or vaginal areas •Although adult pinworm sometimes appear in the stools, the eggs are seldom seen in fecal concentrates because they are laid directly onto the perianal skin •Therefore, they can be found by pressing this area with a piece of clear adhesive tape (the 'Scotch tape' test) and examining the tape mounted sticky side down on a microscope slide.

How do you diagnose Enterobius vermicularis?

•Fasciolopsiasis caused by Fasciolopsis buski •Endemic in China, India, Malaysia, South-East Asia and Taiwan •especially in areas, where pigs are raised and fed with freshwater plants •May be asymptomatic •Symptoms can include: allergic reactions, anemia, ascites (accumulation of fluid in the peritoneal cavity), diarrhea, fever, obstruction of the bowel, abdominal pain, edema, toxemia •Diagnosis - done by identifying eggs from a stool specimen • Fasciolopsis buski and Fasciola hepatica have similar eggs

How do you get Fasciolopsis buski? How does it present? Dx?

•Related to contaminated water and thus food. Via fecal-oral. Undercooked seafood. •Onset 2 hours to 5 days •Flagellated bacterium survives the acidity of the stomach to later embed in small intestine and then drops flagella to start producing toxins. •Voluminous watery diarrhea ensues •Vomiting/ cold skin/ sunken eyes, muscle cramp sand poor skin turgor are also common •Vaccine good for 6 months at a time. Resistance developing against tetracycline/sulfa and e-mycin •< 1% fatal if quick and adequate response. > 50% mortality w/o Tx.

How do you get Vibrio cholera? How does it present?

•Isolated in 1976. related to V. cholera. Assoc. w/ brackish water and coastal areas especially Gulf of Mexico •Mobile encapsulated gram neg. curved rods with LPS •Does not alter appearance, taste, or smell of raw or undercooked shellfish •Responsible for up to 95% of seafood related infxns in the USA •Raw oysters primary culprit with major outbreaks in Apalachicola, FL and new Orleans after hurricane Katrina -Ingestion but also infects through open wounds from contaminated water -85% of septic cases are male as estrogen may offer some protection and higher rates of alcoholism. -DM/ HIV/ Asplenia/ Iron overloaded and by far those with hepatitis &/or cirrhosis are most at risk with high complication rates. Tx:.....ceftriaxone/ doxycycline/ flouroquinolones in combinations.

How do you get Vibrio vulnificus? Tx?

larvae from snail penetrate human skin •Mostly found in SE Asia, Russia, Far East •Hermaphroditic, inhabit intrahepatic biliary ducts •Infection by eating raw or poorly cooked fish

How do you get a trematode infection?

•The major risk factors for developing cryptosporidiosis are ingesting contaminated drinking or recreational water, •Transmission requires ingestion of a minimum of 10 of the resistant oocysts (4-5 µm in diameter) in fecally contaminated material •In the small intestine, the oocyst releases infective sporozoites, which invade the epithelial cells, remaining closely associated with the apical plasma membrane such that they are intracellular but extracytoplasmic. •Here they form meronts, which produce and release merozoites and these then re-invade further epithelial cells. •A second type of meront produces sexual stages known as gamonts. •Fertilization occurs, and thick-walled oocysts are released in the feces.

How do you get cryptosporidium? Describe its life cycle?

•Taenia solium ~ pork tapeworm, transmitted by ingestion of pork containing the larvae •Taenia saginata ~ beef tapeworm, transmitted by ingestion of beef containing larvae •Dyphilobotrium sp ~ fish tapeworm, ingestion of fish •Hymenolepis sp ~ dwarf tapeworm, ingestion of fecal material containing eggs •Dypillidium caninum ~ dog tapeworm, ingestion of dog fleas

How do you get each of the following: Taenia solium Taenia saginata Dyphilobotrium sp Hymenolepis sp Dypillidium caninum

•Use antibiotics judiciously (empiric to definitive therapy; appropriate use) •Use contact precautions (gloves and gowns) •Cleaning of shared medical equipment •Environmental cleaning and disinfection strategy •Note: we do not use secondary prophylaxis antibiotics because that would contribute to CDAD

How do you prevent C. diff?

•Get vaccinated against typhoid fever before travel •If get Ty21 (oral) must complete 1 week prior to travel •Four total doses on alternating days •If get ViCPS (injection) must take 2 weeks prior to travel •Will need a booster if travelling again to a region with typhoid fever if •Greater than 5 years with Ty21 (oral) •Greater than 3 years with ViCPS (IM injection) • Taking antibiotics will not prevent typhoid fever; they only help treat it.

How do you prevent Salmonella typhi?

•Improving food and drink selection •Water purification •Prophylactic medications (not routinely indicated) •Quinolones - current recommendation is levofloxacin and loperamide with first loose stool •Rifaximin or doxycycline •Other medications •Bismuth subsalicylate 2 tablets 4 times a day with meals •Probiotics - lactobacillus

How do you prevent Traveler's Diarrhea?

•Treatment is to continue eating •Aggressive rehydration with salts/sugars/ lytes...usually rice based. (ORT) •10% of body weight in first 2-4 hours •Add zinc for children especially •Improve sanitation or contaminated food and disinfect all surfaces/clothes •The study of cholera between 1849 to 1854 by John Snow in England led to significant advances in the field of epidemiology.

How do you treat Vibrio cholera?

•Large numbers of adult Ascaris can cause a physical blockage in the intestine and this may also occur as worms die following antiparasitic chemotherapy. •Intestinal worms tend to migrate out of the intestine, often up the bile duct, causing cholangitis or liver abscess. •Perforation of the intestinal wall can also occur. •Worms have occasionally been reported in unusual locations, including the orbit of the eye and the male urethra. Other: •The migration of Ascaris larvae through the lungs can cause severe respiratory distress due to pneumonitis; •ascariasis is one of the causes of Löffler's syndrome. •This stage is often associated with pronounced eosinophilia. •Worms in the intestine can cause abdominal pain, nausea and digestive disturbances. •In children with a suboptimal nutritional intake, these disturbances can contribute to clinical malnutrition. •Ascaris is highly allergenic and infections often give rise to symptoms of hypersensitivity, which may persist for many years after the infection has been cleared.

How does Ascaris present clinically?

•In heavy infections, there is a pronounced inflammatory response and proliferation and hyperplasia of the biliary epithelium. •Cholangitis, jaundice and liver enlargement are possible consequences, •but many people are asymptomatic in the early stages or experience non-specific symptoms •Chronic infection with Clonorchis sinensis or Opisthorchis viverrini is a recognized cause of intrahepatic cholangiocarcinoma •C. sinensis is classified as a group 1 biocarcinogen.

How does Clonorchis sinensis present?

•The larval stages of the dog tapeworm Echinococcus granulosus can develop in humans when the eggs are swallowed. •Larvae from the eggs move from the intestine into the portal circulation and develop into large hydatid cysts (cystic echinococcosis) in the liver • In around two-thirds of cases, lungs and occasionally other organs can be affected •Cysts can be seen on ultrasound or cross-sectional imaging as large cysts. •Apart from pressure damage to surrounding tissues, rupture of the cysts leads to secondary spread and may cause anaphylaxis.

How does Echinococcus granulosus present?

•E. multilocularis , acquired from eggs passed by wild carnivores, usually foxes, •behaves very differently: • develops in the liver not as cysts but as a mass resembling a carcinoma (alveolar echinococcosis)

How does Echinococcus multilocularis present?

•Infection is most common in children - especially daycare and child centers •Children may have increased symptoms - headache and insomnia especially •Mostly asymptomatic •or Nausea, weakness, loss of appetite, diarrhea, and abdominal pain most common

How does Hymenolepis nana present?

•Infection with species of schistosomes situated in mesenteric blood vessels: Schistosoma japonicum and S. mansoni •can also cause symptoms of intestinal disease. •As the eggs pass through the intestinal wall, they cause marked inflammatory responses, granulomatous lesions form and diarrhea may occur in the early acute phase. •Heavy chronic S. mansoni infection is associated with inflammatory polyps in the colon, •Severe involvement of the small bowel is more common with S. japonicum .

How does Schistosoma infection present?

•Heavy intestinal infection with strongyloidiasis causes persistent and profuse diarrhea with dehydration and electrolyte imbalance. •Profound mucosal changes can also lead to a malabsorption syndrome, which is sometimes confused with tropical sprue. •People with human lymphotropic virus type 1 (HTLV-1), AIDS and cancer, or who are being treated with immunosuppressive drugs are susceptible to the development of: disseminated strongyloidiasis. •Invasion of the body by many thousands of autoinfective larvae can be fatal. •Gram-negative bacterial septicaemia or meningitis can ensue.

How does Strongyloides present clincally?

•Pathophysiology ~ often several years of incubation before Sx begin, parasite can avoid the host immune system. •Once reaches cysticerci age, immune system catches up, leads to an intense inflammatory reaction causing seizures •Over months, the lesion will resolve or appear radiographically as a small calcification •When found in the cerebral ventricles can cause obstructive hydrocephalus due to mechanical obstruction Cysticercosis •Tissue infection of Taenia solium •Caused by consuming eggs •Occurs in subcutaneous tissues such as brain, eye, heart, muscle, can occur in nervous system •Common in Latin America, parts of Africa, India, China, SE Asia Neurocysticercosis •Wide range of clinical manifestations •Can occur as a single or multiple lesion in the functional tissue in the brain •Most common parasitic disease of the nervous system and is the main cause of acquired epilepsy •Parenchymal disease •Seizures are most common •Headaches, neurological focal defects •Exraparenchymal disease: many possibilities, meningitis, stroke, obstructive hydrocephalus •Dx ~ MRI, CT, serology, histopathology •Surgical intervention

How does Taenia Solium present?

•The first symptoms of trichinellosis are gastrointestinal, •usually occurring 1-2 days after a person consumes raw or undercooked meat from a Trichinella-infected animal. •These symptoms include: Nausea, diarrhea, vomiting, abdominal pain •The classic trichinellosis symptoms often occur within 2 weeks after eating contaminated meat, and can last up to 8 weeks: •Muscle pain, fever, swelling of the face, particularly the eyes, weakness or fatigue, headache & chills, itchy skin or rash, cough, diarrhea, & constipation •Many mild cases of trichinellosis are never specifically diagnosed because they are assumed to be the flu or other common illnesses. •Furthermore, many people with Trichinella infection do not experience any symptoms at all. •May have long term issues if heart muscle is compromised •myocarditis, pulmonary problems, CNS issues (neurological deficits, confusion, delirium, ataxia, seizures...)

How does Trichinella spiralis present?

•Liver disease ~ pain, jaundice, acute bilary obstruction, infection of bile ducts, bile duct cancer •Acute pancreatitis •Asymptomatic eosinophilia

How does a treamtode infection present?

•Conjugation lowers the pKa, making them better detergents •CoA derivatives react with either glycine or taurine forming amides that are known as conjugated bile salts •Glycocholic acid and glycochenodeoxycholic acid, the bile acids are conjugated with glycine, pKa=4 •Taurine conjugates taurocholic acid and taurochenodeoxycholic acid, pKa=2

How does conjugating a bile salt change it?

•Cryptosporidial diarrhea ranges from moderate to severe. •Symptoms of infection with Cryptosporidium range from moderate diarrhea to more severe profuse diarrhea that is self-limiting in 15-40 days in immunocompetent individuals •Can become chronic in immunocompromised patients, including those with advanced HIV infection. •In individuals with CD4 + T-cell counts <100 / mm 3 , diarrhea is prolonged, may become irreversible in the absence of immune reconstitution and can be life threatening.

How does cryptosporidium present?

•Mild Giardia infections are asymptomatic; more severe infections cause diarrhea. The diarrhea may be: • acute: self-limiting, with 7-10 days being the usual course • chronic: develop into a serious condition, particularly in patients with deficient or compromised immunological defenses. •It is thought to arise from inflammatory responses triggered by the damaged epithelial cells and from interference with normal absorptive processes. •Characteristically, the stools are loose, foul smelling and often fatty.

How does giardia present?

Hookworm disease can result in iron-deficiency anemia •Migration of hookworm larvae through the skin and lungs can cause dermatitis and pneumonitis •The blood-feeding activities of the intestinal worms can lead to iron-deficiency anemia if the diet is inadequate. •Heavy infections cause a marked debility and growth retardation. Sx of hookworm infestation: •Itchiness in initial infection •Abdominal pain, diarrhea, colic, nausea, bloody stool, pyrexia Reflects 4 phases of infection •Ground itch, cutaneous larva migrans •Pulmonary symptoms (maybe) •GI symptoms •Chronic nutritional impairment

How does hookworm present clinicially?

•Acetaminophen is metabolized by Phase I and Phase II reactions •Toxic if ingested in high doses •Glucuronylated or sulfated for excretion by the kidney by Phase II reactions

How is acetaminophen excreted?

•Invasive infections: •Infection started localized in GI track à disseminated systemically to other areas/tissues of body •Patient has been hospitalized > 3 days •Evaluate for C. difficile associated diarrhea (CDAD) •Bloody diarrhea •Evaluate/test for E. coli O157:H7 and Shiga toxin •Severe Illness •Fever > 101.3 F, s/s of hypovolemia, ≥ 6 unformed stools in 24 hours, severe abdominal pain, need for hospitalization •Symptoms persisting for more than 1 week despite conservative measures •Remember, most GI infections are mild-moderate in severity and only cause mild GI symptoms (diarrhea, cramps) which is self limiting and do not require treatment with antibiotics

If any of the following factors are present during a GI infection, evaluation to treat with antimicrobials would be warranted. Antibiotic therapy, still, may or may not be used at this point based on patient presentation and severity of infection: Name these factors

•Most gastrointestinal infections are caused by members of Enterobacteriaceae: which includes many different bacteria •Includes aerobes, anaerobes, and both gram (+), and gram (-) Appropriate agents empirically that have this appropriate spectrum: •Ceftriaxone (in some instances), FQ, pipercillin/tazobactam, carbapenems, metronidazole (anaerobe)

If deemed necessary to treat a GI infection empirically (a severe infection) then we must start with at least middle spectrum to broad spectrum antimicrobials. Why? What are these agents?

Motile by pseudopodia - E. hystolytica Motile by flagella - Giardia Motile by cilia - Balantidium coli Not Motile - plasmodium

If you see a protozoa diarrhea, you can tell a lot by motility. Name an example of a pathogen: Motile by pseudopodia Motile by flagella Motile by cilia Not Motile

•Enterocytozoon bieneusi is the commonest cause, although Encephalitozoon intestinalis also occurs.

Infections with microsporidia have also become recognized as a cause of diarrhea in AIDS and other immunosuppressed patients. There are two types of microsporidia. What are they?

•Indirect bilirubin is the unconjugated form of bilirubin, bound to albumin

Is direct or indirect bilirubin bound to albumin?

•the flagellate (four pairs of flagella) binucleate trophozoite •resistant four-nucleate cyst. •Trophozoite form •The trophozoites live in the upper portion of the small intestine, adhering closely to the brush border of the epithelial cells by specialized attachment regions •They divide by binary fission and can occur in high numbers that they cover large areas of the mucosal surface. Cyst Form •Cyst formation occurs at regular intervals, each cyst being formed as one trophozoite rounds up and produces a resistant wall. •Cysts pass out in the stools and can survive for several weeks under optimum conditions. •Infection occurs when the cysts are swallowed, usually as a result of drinking contaminated water. •The minimum infective dose is very small: 10-25 cysts

Like Entamoeba , Giardia has only two life cycle stages. What are they? Describe them

•produced when the rate of glucose synthesis is limited and fatty acid oxidation is occurring rapidly •cross the blood-brain barrier •a major fuel for the nervous system (starvation) •synthesized in the mitochondrial matrix from acetyl-CoA

Liver is the only organ that produces ketone bodies. When and how are they produced? What do they do?

NAPQI glutathione\ CYP2E1

Pathways of acetaminophen detoxification •Cytochrome P450 produces the _________ (Phase I reaction) •excreted safely after conjugation with __________ (Phase II reaction) •Enzyme __________ is induced by alcohol •Consider individuals who chronically abuse alcohol: •higher percentage of acetaminophen metabolism directed toward NAPQI

First group: infection occurs by swallowing the infective eggs •Ascaris lumbricoides (large roundworm) and •Trichuris trichiura (whipworm), Second Group: infect via active skin penetration by infective larvae, •Ancylostoma duodenale and Necator americanus (hookworms) •Strongyloides stercoralis , •which infect via active skin penetration by infective larvae, • then undertake a systemic migration through the lungs to the intestine. •With the exception of Trichuris all the soil-transmitted nematodes inhabit the small bowel. •All five of the soil-transmitted species can be diagnosed by finding eggs or larvae in a fresh stool.

Soil-transmitted helminths fall into two distinct groups: What are they and what's in which?

N-acetyl cysteine •enhances the phase II reaction (Glutathione S-transferase) •reduces the levels of the toxic intermediate NAPQI

Tx for acetaminophen poisoning is __________. MOA?

Indications •Induce and maintain remission in ulcerative colitis •First line therapy in mild to moderate active ulcerative colitis patients •Use enemas or suppositories in patients with ulcerative colitis or Crohn's disease confined to the rectum (proctitis) or distal colon (proctosigmoiditis) •Azo and mesalamine formulations good for patients with ulcerative colitis or Crohn's colitis that extends to proximal colon •Treatment of Crohn's disease involving the small bowel, mesalamine compounds, which release 5-ASA in colon have advantage Adverse effects •Most effects due to the Sulfapyridine moiety •Slow acetylators have more frequent and more severe adverse effects

What are the indications of 5-aminosalicylic acid (5-ASA)? SFX?

Pharmacokinetics •Depends on brand name but most formulations are delayed-release formulations of 5-ASA to ensure it reaches the distal irritated small bowel or colon •Delayed release contain either timed-release capsule or pH sensitive resin that dissolves at pH 6-7 •Can be delivered in higher concentrations either rectally as suppositories or enemas Site of action •Mesalamine pH sensitive resin compounds work in ileum and colon •Mesalamine delayed release capsules work in jejunum, ileum, and colon •Azo-bonded Mesalamine release compounds work in the colon

What are the pharmacokinetics of 5-aminosalicylic acid (5-ASA)? Site of action?

Protozoan infections of the gastrointestinal tract. (A) Entamoeba histolytica . Trophozoite found in the acute stage of the disease, which often contains ingested red blood cells. (B) Giardia intestinalis trophozoite associated with acute infection in humans. (C) Cyst of E. histolytica , with only one of the four nuclei visible. The broad chromidial bar is a semicrystalline aggregation of ribosomes (H&E stain). (D) Oval cyst of G. intestinalis showing two of the four nuclei (iron haematoxylin stain).

What are we looking at in A, B, C, and D?

raw hot dogs - listeria monocytogenes canned goods - clostridium botulinum deli meat - listeria monocytogenes

What disease do you get from: raw hot dogs canned goods deli meat

converts glycogen to glucose activated by epi and glucagon inhibited by insulin

What does glycogen phosphorylase do? What activates and inhibits it in the liver?

converts glucose to glycogen inhibited by epi and glucagon activated by insulin

What does glycogen synthase do? What activates and inhibits it in the liver?

Infliximab Adalimumab Golimumab SFX •Injection site reactions •Infusion reactions •Neutropenia •Infections •Demyelinating disease •Heart failure (HF) •Cutaneous reactions, including psoriasis •Malignancy •Induction of autoimmunity Black Box Warning on all Anti-TNF-α: -SERIOUS INFECTIONS AND MALIGNANCY --SERIOUS INFECTIONS (tb) Patients treated with XXXXXX are at increased risk for developing serious infections that may lead to hospitalization or death -rare type of T-cell lymphoma,

What drugs are Anti TNF-α? SFx?

Acute schistosomiasis (Katayama fever) •May be asymptomatic or light itching (Swimmers itch) •Intestinal and Dermatitis versions of schistosomiasis seen (based on movement of fluke) •Patients with acute schistosomiasis (Katayama fever): -Present usually 4-8 weeks after contact with infested water -Occurs 2-8 weeks after exposure to S japonicum or S mansoni -Katayama fever is common in heavily infested areas where there is S japonicum -Fever, lethargy, malaise, and myalgia are the most common symptoms of Katayama syndrome -Less common symptoms include cough, headache, anorexia, and rash (urticarial or papular) -Right upper quadrant pain and bloody diarrhea may also occur. •Chronic schistosomiasis leads to inflammation in lungs, brain, spleen, & liver.

What is Katayama fever? How does it present?

•Loeffler's syndrome (eosinophilic pneumonitis - WBC accumulation in the lung) Ascaris lumbricoides (Giant Roundworm)

What is Löffler's syndrome? What is it associated with this block?

•Composed of glucosyl units linked by α-1,4-glycosidic bonds, with α-1,6-branches occurring roughly every 8 to 10 glucosyl units

What is glycogen composed of?

•Cases of secondary peritonitis involve bowel perforation, ruptured appendix, or ruptured diverticula Upper tract sources (e.g. perforated ulcer): •Gram-positive Lower tact sources (e.g. distal small bowel or colon): •Anaerobic (e.g. Bacteroides fragilis) •Gram-negative aerobes (e.g. E. coli, Klebsiella, Proteus, Enterobacter)

What is the Infecting Organism for Secondary Peritonitis?

Mechanism of action •Recombinant fully human monoclonal antibody to TNF-α. Complexes with soluble TNF-α receptors. Results in down-regulation of macrophage and T-cell function Indications •Crohn's Disease: Inducing and maintaining clinical remission in moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy or infliximab. •Ulcerative Colitis: Inducing and sustaining clinical remission in moderately to severely active ulcerative colitis who have had an inadequate response to immunosuppressants such as corticosteroids, azathioprine or 6-MP. Pharmacokinetics •Clearance decreased by 40% and formation of human anti-monoclonal antibody decreased with concurrent MTX use.

What is the MOA of Adalimumab? Indications? Pharmacokinetics?

Mechanism of action •Purine anti-metabolites that have immunosuppressive properties •They undergo a series of biotransformations that produce inactive metabolites Indication •Induction and maintenance of remission of ulcerative colitis and Crohn's disease •After 3-6 mths, 50-60% of patients achieve remission, 80% maintain remission •Allow dose reduction or elimination of steroids in majority of patients that require long-term glucocorticoid therapy to control active disease Adverse effects •N, V, hepatic toxicity, bone marrow suppression leading to leukopenia, macrocytosis, anemia, and thrombocytopenia •Embryo-fetal toxicity: cause fetal harm. Advise women of potential risk to a fetus Drug Interactions •Severe leukopenia predisposes patient to opportunistic factors

What is the MOA of Azathioprine/6-mercaptopurine (6-MP)? Indication? SFX?

Indication •Severe cases of IBD that are refractory to other therapies Mechanism of action •A fat-soluble cyclic polypeptide antibiotic that blocks T-cell activation. •Inhibition the synthesis of interleukins (e.g. IL-2) by activated T cells. Drug interactions •Metabolized through CYP 450 so many drug interactions Adverse effects •Renal toxicity/Hypertension/Hyperkalemia •Increased risk of opportunistic infections (viral, bacterial, fungal) and cancer Black box warning: May be administered with other immunosuppressive agents but the increased susceptibility to infection and the possible development of lymphoma and other neoplasms may result from the increase in the degree of immunosuppression.

What is the MOA of Cyclosporine? Indication? SFX?

•Macrolide antibacterial drug •Mechanism of action •bactericidal agent inhibiting RNA synthesis by RNA polymerases - resulting in inhibition of protein synthesis (macrolide antibiotics) •Bactericidal towards Clostridium difficile •Indications •treatment of Clostridium difficile associated diarrhea •Minimal systemic absorption so minimal side effects •It was second line for CDAD but new guidelines in December 2018 has now moved it to first line •Guidelines recommend fidaxomicin as a treatment option for the initial episode of CDI (non-severe [supportive clinical data: WBC ≤15,000 cells/mm3 and serum creatinine <1.5 mg/dL] and severe [supportive clinical data: WBC >15,000 cells/mm3 and serum creatinine ≥1.5 mg/dL), first recurrence (if vancomycin given for the initial episode), and second or subsequent recurrence

What is the MOA of Fidaxomicin? indication?

Mechanism of action •Inhibit production of inflammatory cytokines (TNF- α and IL-1) and chemokines (IL-8) •Reduce expression of inflammatory cell adhesion molecules •Inhibit gene transcription of nitric oxide synthase, phospholipase A2, cyclooxygenase-2 Indications •Treatment of patients with moderate to severe active inflammatory bowel disease •Treatment of inflammatory bowel disease involving the rectum or sigmoid colon •Prefer rectal administration because less absorption •Treatment of mild to moderate Crohn's disease involving the ileum and proximal colon •Maintaining disease remission •Use in combination with aminosalycilates or immunosuppressive agents •Prednisone (oral) and methylprednisolone (IV) are the most commonly used glucocorticoids •Intermediate half-life allows once-a-day dosing orally •Hydrocortisone enemas, foams, or suppositories

What is the MOA of Glucocorticoids? IBD indication?

Mechanism of action •Golimumab is a human monoclonal antibody that binds to both the soluble and transmembrane bioactive forms of human TNFα Indication •Moderate to severe Ulcerative colitis (UC) with an inadequate response or intolerant to prior treatment or requiring continuous steroid therapy inducing and maintaining clinical response, improving endoscopic appearance of the mucosa during induction, inducing clinical remission, achieving and sustaining clinical remission in induction responders Pharmacokinetics •Concomitant use with MTX ↑ Golimumab levels and ↓ autoantibodies

What is the MOA of Golimumab? Indications? Pharmacokinetics?

Mechanism of action •Recombinant human monoclonal antibody to TNF-α •Chimeric (25% mouse, 75% human) IgG1 monoclonal antibody •Binds with high affinity to the soluble and tm forms of TNF-α •Complexes with soluble TNF- α and prevents interaction with p55 and p75 surface receptors •results in down-regulation of macrophage and T-cell function •Intravenous infusion in 250 ml 0.9% sodium chloride at 125 ml/hr Indications •Ulcerative Colitis: reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy. •Crohn's Disease: reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active disease. Pharmacokinetics •Elicits human antichimeric antibodies in up to 62% of patients •Concurrent therapy with methotrexate decreases prevalence of human antichimeric antibodies

What is the MOA of Infliximab? Indications? Pharmacokinetics?

•Antimetabolite of folate with beneficial effects in many chronic inflammatory disease such as Crohn's disease and rheumatoid arthritis Mechanism of Action •Inhibition of dihydrofolate reductase (enzyme important in production of thymidines and purines) •High doses inhibit cellular proliferation •May interfere with the inflammatory actions of interleukin-1 •May stimulate increased risk of adenosine (endogenous anti-inflammatory autocoid) •May stimulate apoptosis and death of activated T lymphocytes Indications •Low doses are used to Induce and maintain remission in patients with Crohn's disease Contraindications •Can cause fetal death or teratogenic effects when given during pregnancy (Category X) •Contraindicated in patients with hepatic and renal impairment Adverse Effects •Nausea and mouth and mucosal ulcers (inhibit proliferation of rapidly dividing cells), leukopenia, anemia, GI ulcerations, alopecia •Decrease incidence of GI side effects and LFT by giving leucovorin (folinic acid) 24 hours after each weekly dose

What is the MOA of Methotrexate? Indication? SFX?

Mechanism of action •Natalizumab is a humanized monoclonal antibody against the cell adhesion molecule α4-integrin. Inhibits the adhesion of leukocytes to their receptors. Indications •For inducing and maintaining clinical response and remission in adult patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional CD therapies and inhibitors of TNF-α. •Important Limitations: Should not be used in combination with immunosuppressants or inhibitors of TNF-α. Contraindications •Patients who have or have had PML Warnings and precautions •Fatal herpes infections and liver failure requiring transplant have occurred. Adverse reactions •Headache, upper respiratory tract infections, nausea, and fatigue BLACK BOX WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY: Natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability

What is the MOA of Natalizumab? Indications? CI/SFX?

•non-aminoglycoside semi-synthetic, nonsystemic antibiotic derived from rifamycin] •Mechanism of action •binds to the beta-subunit of bacterial DNA-dependent RNA polymerase resulting in inhibition of bacterial RNA synthesis •Stays in the gut; doesn't leave GI tract (like oral vancomycin) •Indications •Hepatic encephalopathy •Traveler's diarrhea caused by E. coli (not if blood in stool or complicated by fever) •IBS-D •Adverse effects - stays in GI, not a lot of peripheral adverse effects •C. difficile-associated colitis

What is the MOA of Rifaximin? indication?

Mechanism of Action •Targeted synthetic small molecule janus kinase enzyme (JAK) inhibitor •JAK activate transcription regulators that modulate gene expression •Influences transcription of several genes that are crucial for the differentiation, proliferation, and function of NK cells, T and B lymphocytes Indication •For the treatment of adult patients with moderately to severely active ulcerative colitis (approved May 2018). •Limitations of Use: Use of Tofacitinib in combination with biological therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. •Also treatment of Rheumatoid Arthritis Adverse Effects •nasopharyngitis, elevated cholesterol levels, headache, upper respiratory tract infection, increased blood creatine phosphokinase, rash, diarrhea, and herpes zoster •Reduce dose in pts taking CYP or with renal or hepatic impairment

What is the MOA of Tofacitinib? Indications? CI/SFX?

Mechanism of action •Recombinant human monoclonal antibody against IL-12 and IL-23 prevents inflammatory and immune responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation. Indication •Ustekinumab is approved to treat Crohn's disease (September 2016) Warnings and precautions •Tuberculosis (TB): Evaluate patients for TB prior to initiating treatment •Infections: Serious infections, Malignancies Adverse reactions •injection site erythema, vulvovaginal candidiasis/mycotic infection, bronchitis, pruritus, urinary tract infection, and sinusitis

What is the MOA of Ustekinumab? Indications? CI/SFX?

•Note that we are talking about ORAL VANCOMYCIN HERE •CDAD is the only time we are using oral vancomycin due to minimal absorption of the oral formulation (we use IV if we want to treat systemic infections) •Mechanism of action •inhibiting proper cell wall synthesis in gram-positive bacteria •Indications •Treatment of C-difficile associated diarrhea •Oral vancomycin is first line treatment for initial presentation of CDAD •Fidaxomicin is first line for recurrence (also is an option for initial presentation) •Treatment of enterocolitis caused by Staphylococcus aureus (including methicillin-resistant strains •for oral use only because it is not systemically absorbed, it stays in the GI tract where the infection is located •CDAD dosing: oral vancomycin 125mg four times a day

What is the MOA of Vancomycin Orally? Indication?

Mechanism of action •Vedolizumab is a humanized monoclonal antibody that binds to integrin α4β7 a lymphocyte Peyer's patch adhesion molecule. •Blocking the α4β7 integrin results in gut-selective anti-inflammatory activity. Indications •Adult patients with moderately to severely active UC/Crohn's who have had an inadequate response with, lost response to, or were intolerant to a tumor necrosis factor (TNF) blocker (approved May 2014) •Warnings and precautions •Hypersensitivity Reactions (including anaphylaxis) •Infections •Progressive Multifocal Leukoencephalopathy

What is the MOA of Vedolizumab? Indications? CI/SFX?

•Supportive therapy •Fluid replacement •If age >3, can use antimotility agents in combination with rehydration •Adults can receive antiemetics •Antibiotics are not beneficial (viral infection!!)

What is the Treatment of viral gastroenteritis?

•Primary therapy --> (TMP/SMX or ciprofloxacin or levofloxacin) PLUS metronidazole (for bacteroides)

What is the abx tx for a drained perirectal abscess outpatient?

Hepatic Bile Bladder Bile - denser, moe acidic Total Solids 2.5% 10% Inorganic Salts 0.85% 0.85% Bile acids/salts 1.2% 6% Cholesterol 0.06% 0.4% Lecithin 0.04% 0.3% Bile pigments 0.2% 1.5% pH 7.4 5.0 - 6.0

What is the difference in composition of liver bile and gallbladder bile?

•Bile salts that lack a hydroxyl group at position 7 are secondary bile salts •deconjugated and dehydroxylated by bacteria •less soluble and less readily resorbed from the intestinal lumen

What is the difference primary and secondary bile salts?

•>95% of the bile salts are recycled by the liver and secreted into the bile •Secondary bile salts re-conjugated but not re-hydroxylated •<5% of the bile salts are excreted into the feces •However, serves as a major route for cholesterol removal from the body

What is the fate of primary bile salts after secretion?

Indication •For the treatment of mild to moderate ulcerative colitis, and as adjunctive therapy in severe ulcerative colitis •For the prolongation of the remission period between acute attacks of UC MOA •Sulfapyridine likely causes suppression of T-cell response, inhibition of B-cell proliferation •Mesalamine inhibits release of inflammatory cytokines produced by monocytes or macrophages (IL-1, IL-6, IL-12 and TNF-α)

What is the indication of Sulfasalazine? MOA?

•Gram-positive, aerobic/facultatively anaerobic, motile, spore-forming rod •Catalase positive, beta hemolytic (complete RBC lysis on the blood or chocolate agar media) Presentation: •2 types of toxin-mediated illness •Diarrheal syndrome vs emetic syndrome •Both cause disease within 24 hours of ingestion •Virulence factors Diarrheal toxins - heat labile •Syndrome caused by ingesting vegetative cells Emetic toxin (cereulide) - heat stable •Fried rice syndrome

What is the pathogenesis of B. cereus food poisoning? Presentation?

•S. aureus produces many different enterotoxins •Up to 50% of strains produce enterotoxin •Food (especially processed meats) is contaminated by human carriers •Pathogenesis •Acts as a superantigen (binds to MHC resulting in T-cell stimulation) •Heats kills the SA but not the toxin produced •Severe vomiting within 3-6 hours •Usually recover within 24 hours •Not typically diarrhea

What is the pathogenesis of S. aureus food poisoning?

•All transferases are Phase II reactions •Many different groups can be transferred (glycine, sulfate, glutathione, etc.) •Increases solubility in water •Easier to excrete material into bile

What is the purpose of a phase 2 reaction in the liver?

•Olsalazine is broken down to 5-ASA •Balsalazide is broken down to 5-ASA and 4-ABA •Sulfasalazine is broken down to sulfapyridine and 5-ASA •Sulfapyridine and 4-ABA are metabolites •5-ASA (mesalamine) is active drug Olsalazine (Two 5-ASA molecules azo bonded together) •10% of patients may have stimulation of secretory diarrhea Balsalazide •Renal tubular Safer than sulfasalazine •damage, interstitial nephritis

What is the relation of Olsalazine and Balsalazide and Sulfasalazine to Azo-bonded 5-ASA?

Grapefruit juice is potent inhibitor of CYP3A4-mediated drug metabolism if statin is regularly taken with grapefruit juice, its level in the blood may increase as much as 15-fold

What is the significance of grapefruit juice in liver function?

The Pentose Phosphate Pathway substrate = Glucose-6-phosphate -->Ribulose-5-phsophate -->Xylulose-5-phosphate Product = fructose-6-phsophate + Glyceraldehyde-3-phosphate

What is the substrate and product of the pathway that produces most NADPH for use in the body?

•Most patients --> supportive therapy only •More systemic disease in an immunocompromised host •Primary therapy --> gentamicin •Alternative therapy --> ampicillin or imipenem

What is the tx for Campylobacter fetus?

•Most patients --> no treatment (supportive) •Patients with severe disease or risk for severe disease (immunocompromised) --> treat with azithromycin or erythromycin •Ciprofloxacin was used but resistance has developed

What is the tx for Campylobacter jejuni?

Gallbladder disorders: Cholecystitis, cholangitis, biliary sepsis, common duct obstruction Treatment •Primary treatment •Piperacillin/tazobactam or ampicillin/sulbactam •If life threatening --> imipenem, meropenem, or doripenem (carbapenem) •Alternative treatment •(3rd generation cephalosporin and metronidazole) ,(aztreonam and metronidazole), (Ciprofloxacin and metronidazole), or moxifloxacin •In severely ill patients, antibiotics complement adequate biliary drainage •15-30% require decompression by surgical, percutaneous, or ERCP-placed stent •Discontinue antibiotics after surgery completed

What is the tx for Cholecystitis? What other conditions are treated the same way?

•Primary treatment --> ciprofloxacin or norfloxacin •Alternative therapy --> ceftriaxone

What is the tx for Cirrhosis?

•20% of infections resolve with discontinuing the offending antibiotic •Avoid anti-motility agents •Hydrate the patient and Isolate the patient (decrease risk of spread) •New Guidelines Update (Dec, 2018) •Treat with a 10 day course of •First line treatment for initial presentation: fidaxomicin or oral vancomycin •Vancomycin is not orally absorbed (no systemic ADRs) •Second line treatment for initial presentation: metronidazole (used to be first line) •Moved to second line due to too broad spectrum (increased risk of recurrence of C. diff) and increased risk of neurotoxicity •For recurrence: fidaxomicin is preferred and oral vancomycin is second line after fidaxomicin •Fecal Transplantation for the Treatment of Clostridium difficile Infection

What is the tx for Clostridium difficle?

•NO treatment with antibiotics •Worsens condition •NO treatment with anti-motility agents •Supportive therapy only

What is the tx for E. coli O157:H7?

Primary Choices •PPI + Clarithromycin + Amoxicillin •PPI + Clarithromycin + Metronidazole (PCN allergic patients) Quadruple therapy •PPI BID + metronidazole + tetracycline + bismuth subsalicylate

What is the tx for H. pylori?

•Health care-associated pathogen acquired from environmental source (hospital-acquired infection) •Usually associated with antibiotic use Treatment •Stop offending antibiotic •Multi-drug resistant organism •If deemed severe enough to treat - •Think big-broad spectrum antibiotic

What is the tx for Klebsiella oxytoca?

•Most GI infections caused by Listeria require no antibiotics •Manage with fluid and electrolyte replacement •Antibiotics only for patients who •Have a serious illness (such as severe diarrhea, high fever, bloodstream infection, or condition requiring hospitalization). •Are considered at high risk for serious disease or complications (such as infants, adults over 65 years old, pregnant females, and people with weakened immune systems). •Usually ampicillin or TMP/SMX •Remember, ampicillin is usually the DOC for Listeria !!! •Board check: ampicillin is DOC for pts > 50 yo with listeria monocytogenes meningitis

What is the tx for Listeria?

•Examples: focal periappendiceal peritonitis, peridiverticular abscess, endomyometritis) •Primary therapy --> Piperacillin/tazobactam or ertapenem or moxifloxacin (more broad spectrum antibiotics in this case)

What is the tx for Mild diverticulitis inpatient?

•Primary therapy --> (TMP/SMX or ciprofloxacin or levofloxacin) PLUS metronidazole (for bacteroides)

What is the tx for Mild diverticulitis outpatient?

Primary therapy --> piperacillin/tazobactam or ceftriaxone or ertapenem •Note the spectrum of the above agents: they have a broad-spectrum because the infection may be due to a number of different organisms •If resistant to E. coli/ ESBL Klebsiella species (one of the following) Fluoroquinolones •Ciprofloxacin •Levofloxacin •Moxifloxacin Carbapenems •Imipenem + cilastatin •Meropenem •Ertapenem (no PSA coverage) •Doripenem Secondary prohpylaxis: Trimethoprim-sulfamethoxazole OR Ciprofloxacin •Note: tmp/smx and ciprofloxacin are used very frequently as secondary prophylaxis agents •SBP has a high rate of recurrence (up to 70% of patients within 1 year). For such at-risk patients(after their first episode of SBP) antibiotic prophylaxis can reduce this rate to <20%. Currently recommended drug regimens for adults with normal renal function include: •Decreases peritonitis or spontaneous bacteremia from 27% to 3%

What is the tx for Primary (Spontaneous) Bacterial Peritonitis?

•If acquired in Asia •Ceftriaxone or azithromycin or chloramphenicol •If not acquired in Asia •Ciprofloxacin or levofloxacin

What is the tx for Salmonella typhi?

•Most require no antibiotics •Manage with fluid and electrolyte replacement •Antibiotics only for patients who •Have a serious illness (such as severe diarrhea, high fever, bloodstream infection, or condition requiring hospitalization). •Are considered at high risk for serious disease or complications (such as infants, adults over 65 years old, pregnant females, and people with weakened immune systems). •Primary therapy --> ciprofloxacin or levofloxacin •Alternative therapy --> azithromycin

What is the tx for Salmonella?

•Surgery is indicated to eliminate the source of contamination and prevent recurrence •Empiric treatment with broad spectrum drugs that cover both gram-negatives aerobes and gram-negative anaerobes •Primary treatment for mild to moderate disease •Piperacillin/tazobactam •Alternatives: therapy for mild to moderate disease •Metronidazole + cefepime •(ciprofloxacin or levofloxacin) + metronidazole •Ertapenem (note: you do not need to add metronidazole to ertapenem bc erta covers anaerobes also) •Moxifloxacin •Primary therapy for severe life-threatening disease (ICU patient) •Imipenem, Meropenem or Doripenem (Carbapenems) •Metronidazole + ampicillin + aminoglycoside •Metronidazole + ampicillin + (Ciprofloxacin or levofloxacin)

What is the tx for Secondary Peritonitis?

•Aztreonam and metronidazole •Alternative - [ciprofloxacin or levofloxacin] and metronidazole

What is the tx for Severe diverticulitis inpatient in a patient with a penicillin allergy of anaphylaxis?

•Inpatient treatment - severe, life-threatening disease (ICU unit) •Imipenem or meripenem or doripenem (carbapenems only) •Note: do not need metronidazole in this regimen because carbapenems cover for anaerobes also - definition of broad spectrum)

What is the tx for Severe diverticulitis inpatient?

•Most patients require supportive therapy •Avoid anti-motility agents (may allow Shigella to remain in GI system longer) •Bismuth subsalicylate may be helpful •Shigella is often resistant to antibiotics •Primary therapy --> ciprofloxacin •Alternative therapy --> azithromycin

What is the tx for Shigella?

•Most common causative agent isolated in countries surveyed has been enterotoxigenic Escherichia coli (ETEC) •Self-limiting illness lasting 1-5 days Treatment •Fluid replacement •Antibiotics - if needed •Quinolones (ciprofloxacin, levofloxacin, or ofloxacin) •Azithromycin (preferred for pediatric patients and pregnant patients) •Rifaximin (newer agent - see end of presentation for notes on rifaximin) •Antimotility agents (for non-pregnant adults with no fever or blood in stool) •It's ok to use antimotility agents in Traveler's Diarrhea •Loperamide

What is the tx for Traveler's Diarrhea?

•Initial Treatment •Doxycycline and hydroxychloroquine X 1 year (very long duration) •After 1 year --> doxycycline for life!

What is the tx for Tropheryma whipplei?

•Most patients require supportive therapy •Antibiotic options --> [doxycycline or tetracycline] or azithromycin

What is the tx for Vibrio cholereae?

•Most patients require supportive therapy •Severe or prolonged cases --> Ciprofloxacin

What is the tx for Vibrio parahaemolyticus?

•Can cause serious diarrhea, wound infections, and septicemia •Treat right away •Primary therapy --> [ceftriaxone or ceftazidime] and [doxycycline or minocycline] •Note that V. vulnificus is more severe than the others - must treat

What is the tx for Vibrio vulnificus?

•Most patients require only supportive therapy •Severe or complicated enterocolitis --> ciprofloxacin or tmp/smx •Severe septicemia or severe disease --> ceftriaxone + gentamicin

What is the tx for Yersinia enterocolitica enterocolitis?

•Primary treatment --> metronidazole + ([ceftriaxone or cefoxitin]or [IV anti-pseudomonal penicillins] or [ciprofloxacin or levofloxacin]) •IV anti-pseudomonal penicillins are ampicillin/sulbactam, piperacillin/tazobactam, or ticarcillin/clavulanate

What is the tx for a Hepatic abscess?

•Most common organisms are urease-producing gut bacteria •Treatment is rifaximin

What is the tx for a Hepatic encephalopathy?

•Primary treatment --> ciprofloxacin or norfloxacin •Alternative therapy --> ceftriaxone

What is the tx for variceal bleeding?

Ancylostoma duodenale and N. americanus •Adult female hookworm lay thin-shelled eggs that hatch in the feces shortly after leaving the host •The larvae of these hookworm feed on bacteria until infective, and then migrate away from the fecal mass. •Infection takes place when larvae come into contact with unprotected skin (or additionally, in the case of Ancylostoma, are swallowed). •They penetrate the skin, migrate via the bloodstream to the lungs, ascend the trachea and are swallowed. •Adult worms attach by their enlarged mouths to the intestinal mucosa, ingest a plug of tissue, rupture capillaries and suck blood.

What species make up hookworms? Describe their life cycle.

filiform larvae penetrate skin

What stage of Ancylostoma duodenale infects humans?

•The trophozoite stages of the amoebae live in the large intestine on the mucosal surface. •Reproduction of these stages is by simple binary fission, and there is periodic formation of resistant encysted forms, which pass out of the body. •These cysts can survive in the external environment (for up to 30 days in water) and act as the infective stages. •Infection occurs when food or drink is contaminated either by infected food handlers or as a result of inadequate sanitation. •Transmission can also take place as a result of anal sexual activity. •The cysts pass intact through the stomach when swallowed and excyst in the small intestine, each giving rise to four progeny.

What stage of Entamoeba infects humans? How is it passed?

send them home and manage symptoms May need tests in patients with systemic illness, prolonged symptoms, or serious comorbid conditions........(if bloody, temp>101.3 F, > 1 week, severe pain, recent abx/hospital, >70 yoa., IBD, pregnant Test for O&P selectively

When a patient presents with a suspected foodbourne illness, what is the proper next step.

•Glycolysis and glycogen synthesis are inhibited •Gluconeogenesis and glycogenolysis are activated

When blood glucose levels drop, what does the liver do?

•Hymenolepis nana, the dwarf tapeworm, occurs primarily in children, •Infection occurring directly by swallowing eggs •This worm has the ability to initiate autoinfection within the host's intestine, so that a large number of worms can build up •Leads to diarrhea and some abdominal discomfort •Infection is most common in children - especially daycare and child centers •Children may have increased symptoms - headache and insomnia especially •Low sanitary/hygiene areas •Ingesting fecally contaminated foods or water, by touching your mouth with contaminated fingers, or by ingesting contaminated soil •Infection through eggs

Who gets Hymenolepis nana? How?

Botulism •Bacterial spores are Concentrated in anerobic conditions of soil and water and improperly canned foods that have inadequate salt/acid content. Also can be found in honey. •Toxins are produced that can inhibit acetylcholine causing paralysis •Toxin is destroyed by heating rather than the bacterium. •Infant Botulism (floppy baby syndrome) occurs when bacterium introduced to an immature gut (low levels bile salts) then toxin produced. Typically < 6 mos. •Wound Botulism on the rise due to IV drug abuse and "skin popping " w/ black-tar heroin •Fatal in 5-10% cases w/ Tx. 50% if untreated •12-72 hour onset typically •Weakness/ fatigue/ speech and swallow issues/ diplopia/ drooping eyelids/ resp. failure •Cranial nerves and voluntary muscles then autonomics •Classic is Bulbar palsy, DESCENDING paralysis, lack of fever and a clear sensorium. •Tx:.........anti-toxin which promotes passive immunity and does NOT reverse current symptoms.....Antibiotics for wounds w/ surgical debridement.......Ventilator up to 2-8 weeks •Do not introduce Honey to infants less than 1 yoa.

Why can't babies eat honey? Pathogenesis? Symptoms?

•Enterobius - threadworm (also known as pinworm) •dwarf tapeworm

Worm Parasites produce eggs or larvae that require a period of development outside the host before they become infective •Two major exceptions are:

5-aminosalicylic acid (5-ASA) Mechanism of action •Blockade of prostaglandin synthesis by inhibition of cyclooxygenase (primary) •Anti-inflammatory therapy by inhibiting the production of inflammatory mediators from both cyclooxygenase & lipoxygenase pathways •Inhibit cellular functions of natural killer cells, mucosal lymphocytes, and macrophages •Scavenge reactive oxygen metabolites •Only work topically in areas of diseased GI mucosa (not systemically)

_____________ are first-line drugs to induce and maintain remission in mild to moderate forms of active ulcerative colitis & Crohn's disease. MOA?

Giardia intestinalis

______________ is the most commonly diagnosed intestinal parasite in the USA, having been detected in both drinking and recreational water.

Strongyloides •Identification of the species of hookworm also requires charcoal culture of the stool to allow the eggs to hatch and the larvae to mature into the infective third stage. Ascaris , hookworms and Strongyloides

•All five of the soil-transmitted species can be diagnosed by finding eggs or larvae in a fresh stool. •Although these stages may be detected in direct fecal smears, concentration techniques are more sensitive and a charcoal culture of feces is added if ___________ is suspected. •Acute infections with ___________ are often accompanied by a marked blood eosinophilia (although this is not diagnostic, it is a strong indicator of helminth infection)

cholesterol 7α-hydroxycholesterol •Chenodeoxycholic acid •Cholic acid

•Bile acids are synthesized in the liver from ___________ •First step is rate-limiting produces ___________ •Two different sets of compounds are produced in subsequent steps _________ and _________.

heme albumin glucuronate bilirubin monoglucuronide and diglucuronide

•Bilirubin is a degradation product of ___________ •transported to the liver bound to ___________ •Function of _____________ in the excretion of bilirubin is to add negative charges and increase their solubility •Glucuronate residues are transferred from UDP-glucuronate to two carboxyl groups on bilirubin, sequentially forming ____________ •conjugated forms of bilirubin •Increases active transport into the bile for excretion

oxidize substrates CYP3A4 hydroxyl groups oxygen and NADPH

•CYP450 activity is a Phase I reaction •Major role of the cytochrome P450 enzymes is to ____________. •___________ isoform accounts for 30% to 40% of CYP450 enzymes •Mono-oxygenase activity to produce ____________ •Uses _________ and ____________.

the lesion formed in the liver consists of necrotic liver tissue rather than pus. •True liver abscesses - walled-off lesions containing organisms and dead or dying polymorphs (pus) - are frequently polymicrobial, containing a mixed flora of aerobic and anaerobic bacteria •E. histolytica liver abscess (necrotic liver tissue) can become secondarily infected with bacteria.

•E. histolytica can move from the gastrointestinal tract and cause disease in other sites, including the liver •However, the term amoebic liver abscess is not strictly accurate because......

•In fact, rather than a single species behaving differently, the explanation is that two species are involved: •E. histolytica is invasive •E. dispar is non-pathogenic and non-invasive.

•For many years, it was considered that infections with E. histolytica could be asymptomatic or pathogenic, with dysentery a key symptom when the amoebae invaded the mucosa. This isn't true. The explanation is that......

citrulline ammonium ion BCAAs (valine, leucine, and isoleucine - essential amino acids) heme, purines, and pyrimidines

•Key points concerning hepatic amino acid metabolism are: •contains all the pathways for catabolism of all amino acids •contains the urea cycle •the gut uses dietary aspartate, glutamate, and glutamine as carriers for the nitrogen from gut metabolism of these amino acids is passed to the liver as __________ or __________ via the portal vein •______________ can be used as a fuel by most cell types, including the gut and skeletal muscle •uses the carbon skeletons and nitrogens of nonessential amino acids for the synthesis of nitrogen-containing compounds such as _____________.

•Phase I reactions - introduce/expose hydroxyl groups or other reactive sites that can be used for conjugation reactions (i.e. oxidation by CYP450) •Phase II reactions- Conjugation reactions add a negatively charged group such as glucuronide, sulfate, acetate or glycine to the molecule

•Liver is the principal site in the body for the degradation of xenobiotics. This reaction is in 2 phases. What are they?

taurine or glycine deconjugated dehydroxylated

•Primary bile salts form conjugates with ____________ in the liver •After secretion into the intestine, they may be _____________ and ___________ by the bacterial flora, forming secondary bile salts